Physiology Exam 2

Prevalence of Cryptorchidism: -Bull- -Dog- -Cat- -Horse- -human-

-Bull- 0.17%, increased risk in Polled Herefords and Shorthorns -Dog- 0.8-15%, higher in purebreds and some particular breeds-especially toys -Cat- 1.3% recently reported in study of feral cats (trap-neuter program) -Horse- 2-8% -human- 4-5% at birth dropping to 2% by 6-12 months

X-inactivation: Each X chromosome contains over __________ genes, compared to between 33 and 45 total genes on the Y chromosome. Genes that do exist on the Y include several that are vital for spermatogenesis, a couple that may be associated with height and tooth size, and some involved in cardiac traits for blood pressure regulation and cholesterol metabolism. Most of the remaining DNA has unkindly but perhaps accurately been described as genetic _________.

1,000; junk

examples of sexually dimorphic areas in the brain

1. Anteroventral nucleus of the preoptic area (AVPv-POA) - involved in generation of the LH surge that causes ovulation - larger in females than males 2. Spinal Nucleus of the Bulbocavernosus (SNB) - the SNB is the motor nucleus for the bulbocavernosus muscles - vital for penile erection - both the muscles and the SNB are present and equal in size in male and female neonates - degenerate during female development 3. Sexually dimorphic nucleus of the preoptic area (SDN-POA) - 5-6X larger in male

Lactational Anestrus in Dairy Cows Nutrient Use - Priority Ranking

1. Basal Metabolism 2. Activity 3. Growth 4. Energy Reserves 5. Pregnancy 6. Lactation 7. Additional Reserves 8. Estrous Cycles 9. Excess Reserves

modern high-producing cow consequence of selection for production: new priority ranking

1. Basal Metabolism 2. Activity 3. Growth 4. Pregnancy 5. Lactation 7. Energy Reserves 8. Additional Reserves 9. Estrous Cycles 10. Excess Reserves *more food = more milk (not increased body reserves)

2. Lyse the CL - Prostaglandins: e.g. Cattle • 25 mg lutalyse or 500μg estrumate • 2 doses ____ days apart. (Mature lactating dairy cows often works better at 14-15 days apart) • Expect in estrus in ~ ____ days. • Inseminated at observation of estrus • or inseminate twice at ______ and ______ hours after 2nd treatment • or inseminate once at ______ hours after 2nd treatment. • Heifers generally inseminated ~ 12 hours earlier

11; 3; 72 and 96; 80

- calf weaned- average days to first ovulation of the mom is _____ days - calf present with unrestricted udder access- average days to first ovulation of the mom is ________ days

14; 34.7

Short cycles (short-lived corpora lutea): - In primates and most polyestrous (repeated sequential cycles in the absence of pregnancy)* farm animals the CL of a normal cycle functions for between _____ and _______ weeks, and cycle length is from about 2½ - 4 weeks. - If there is no functional pregnancy in the uterus, the CL is actively ________________ in these species (see luteolysis section) to permit another opportunity for estrus and mating. Here the "natural lifespan" of the CL is shortened. ` *Polyestrus- may occur continuously through the year (cow, sow, human), or the sequence may eventually be interrupted by a seasonal anestrus in seasonally breeding animals (sheep, horse) --> continuous (non-seasonal) and seasonal breeders respectively.

2 and 2½; destroyed

The secondary follicle: - As granulosa cells continue to divide more layers are added. - When the follicle has ____-____ layers of granulosa cells in rodents and ____-____ in ruminants, a signal causes migration of another cell type to the outside of the follicle. - On reaching the basement membrane surrounding the granulosa, these cells orient parallel to each other to form a _______________ cell layer around the follicle that is precursor to both __________ interna and externa and the follicle enters the early secondary stage. - With further mitosis to about four granulosa layers in rodents, the fibrous cell layer is invaded by one or two ________________ which form a network of capillaries adjacent to the basement membrane. Coincident with this, the fibrous cells acquire LH receptors and begin the differentiation to theca interna and externa. - Development up to the secondary follicle stage can occur in the absence of ______________________ in all species. After that the story varies. In rodents, connection to the systemic vasculature signals the onset of gonadotropin dependence, and progress to the antral stage cannot occur in their absence. The situation in larger animals is a little different.

2-3; 4-6; fibroblast; theca; arterioles; gonadotropins

Process of Freemartinism: -vessel anastomosis at ______-______ days of gestation. - bull calf starts to develop testicles at around 40 days - male is producing AMH from about day ______ - female gonads are inhibited by AMH after day 50, mullerian ducts start to regress but not completely - From 60-80 days female gonadal regression and loss of germ cells continues. A ____________ _________________ may form around the gonad. - From 90-100 days ovarian stunting in the freemartin is complete. May get development of ____________ cells and development of seminiferous tubules in ovarian medulla/rete region with MIS production now from the female, but the damage is already done by circulating MIS from the male co-twin. Some ___________ cell formation may occur after 3 months. These sex-reversed gonads produce testosterone instead of estrogen, initially due to inhibition of the ___________________ enzyme by AMH.

28-30; 50; tunica albuginea; Sertoli; Leydig; aromatase

Suckling anestrus: • If you compare non-nutritionally stressed beef cows suckling a calf, to average not-terribly-nutritionally-stressed dairy cows; ______-______% of the dairy cows will ovulate the dominant follicle of the first wave, but it takes beef cows till wave ____ on average to have that first ovulation (3.2 ± 0.2). So cows that are only suckled, while having far lower milk production than milked cows, have a ______________ lactational anestrus due to the suckling stimulus. • If you just look at suckled animals in good body condition then the system likely works almost solely via the stimulus of suckling acting at the hypothalamus to reduce ___________ secretion (and thus gonadotropin secretion). The effectiveness depends on the total daily duration of suckling (frequency of suckling x duration of each episode). The longer that high intensity suckling is maintained, the longer _______________ persists. In fact the suckling stimulus, up to a point, doesn't even have to be suckling, just the presence of a calf that the cow ______________ to is sufficient, even if suckling is prevented (although inguinal contact helps). If the frequency of suckling is reduced to 2x daily, like milking, then the duration of suckling anestrus is reduced but is still greater than that seen in the milked cow.

30-80; 3; longer; GnRH; anestrus; bonded

Sex Differences in Time of Puberty: • While ewe lambs are capable of puberty at about _______ weeks, ram lambs start the process at ______ weeks. This is due to sexually imprinted (brain sex) differences in the controls over ___________ secretion. Giving female fetuses testosterone in late gestation allows them to go through puberty at 10 weeks also. The testosterone removes the strict requirement for ____________________ alterations and thus puberty can occur earlier. The males of many seasonally reproducing species are less seasonal than their female counterparts, and often enter the breeding season earlier, perhaps due to the time lag required for sperm production. • In other species (e.g. humans) females may enter puberty before males.

30; 10; GnRH; photoperiod

3. Induction of ovulation examples: • Horse - 2500-3000 units HCG when in estrus with >_____ mm follicle - ovulation 36-48 hours - Commercial "natural"GnRH preparations (or the gonadorelins) do not reliably cause ovulation in the mare. Their half-life is probably too short. _________________ acetate (sucromate®) or similar long-acting analogs are needed. Deslorelin is a GnRH analog with ~50 times the potency of the natural hormone. • Cat - To take a queen out of heat can give 100-250 units HCG on day ____ or ____ of estrus - ovulation - Similar effect using GnRH 5-25μg per cat. - Some people like to do this if the queen presents for ______________ while in heat → you spay a few days later when they have ovulated and are out of heat.

35; Deslorelin; 1 or 2; spaying

Puberty: - Puberty is the period during which reproductive competence is attained. It culminates in the production of functionally competent gametes in sufficient numbers for fertility, and in normal reproductive behavior. - For convenience, puberty is often referred to as occurring at a specific time, such as production of _______ x ________ sperm in bulls, menarche in girls, and first ________________ in females of other species. - However, the physiological changes culminating in these milestones start well before they are achieved, and sexual __________________ continues long after "puberty" (by these definitions) in both sexes. Sperm number, % motile and % with normal morphology increase in males. In females, fertility increases for some time after the first ovulation, at least partly due to functional differentiation of the uterus under the influence of ovarian _____________ hormones. So in reality the process is gradual, in humans taking 4-5 years.

50 x 106; ovulation; maturation; steroid

Dogs: Persistent Mullerian Duct Syndrome (PMDS): - A form of male pseudohermaphroditism. These dogs are 78 XY, have bilateral testes but ~ ______% of affected dogs are bi- or unilateral cryptorchids. Otherwise they are normal males externally. Internally, in addition to male structures they have full Mullerian structures - _________________, _____________, ____________, and _____________ _____________. The cranial uterine horns are attached to the testes (thus probably mechanical cryptorchids - see general PMDS section). - PMDS is inherited most commonly in Miniature ___________________ in the U.S. (Basset hounds in Europe) where it is transmitted as an autosomal recessive trait and is due to peripheral resistance (i.e. receptor defect) - homozygous affected dogs have normal levels of bioactive AMH. - Since they are phenotypically normal (except cryptorchidism) externally they may not be diagnosed till castrated or they present when older for signs associated with _________________ or _____________ cell tumor.

50; oviducts, uterus, cervix and cranial vagina; Schnauzers; pyometra; Sertoli

- Few germ cells at beginning of migration, (variously reported at ~ ____-______ in the mouse), but multiply during migration so that 2,600-5,700 enter the genital ridge 4 days later. - Further vigorous division occurs within the gonad. A similar expansion is seen in human embryos where for the female embryo there are only a few hundred migrating cells at 3-5 weeks but 600,000 by the eighth week and 7 million by the fifth month of gestation. This is followed by a wave of atresia (degeneration) - During the multiplication phase in the gonad (future ovary) some oogonia will already have entered the first meiotic division leading to the formation of _____________ _______________. Soon after birth and the wave of atresia, all remaining germ cells in the ovary will be primary oocytes arrested in the first meiotic prophase.

8-70; primary oocytes

Cattle Freemartinism: - This is the best known syndrome causing derangement of sexual development in the cow. It affects female calves in twin pregnancies where the co-twin is a male. Over ______% of female calves from such pregnancies are affected. The disorder requires _______________ ____________________ of chorioallantoic vessels between the 2 placentas. - Affected females have a rudimentary ovary, with no or few germ cells, and may even have some testicle-like tissue. The ovary may have a tunica albuginea, similar to the covering of a normal testicle. The ________________ _________ is variably regressed, generally the oviducts are more regressed, there is a rudimentary uterus. From the urogenital sinus there is a small vulva and a short blind-ending vagina (ie the Mullerian duct and urogenital sinus derivatives have not joined together). Masculinization of external genitalia is usually ___________, rarely is the clitoris enlarged. There may be testosterone dependent growth of some Wolffian duct derivatives, such as seminal vesicles and epididymides.

90; vascular anastomosis; Mullerian duct; slight;

Follicle Atresia: - Over _____% of the follicles present in the ovaries at the time of birth will undergo atresia. - Follicles at all stages of formation are vulnerable, with greatest losses actually occurring before _________, involving both oogonia and oocytes. - Atresia is an ________________ process, i.e. programmed cell death. The fate of an individual follicle depends on the balance of factors promoting development, growth and differentiation vs. those promoting apoptosis. - Atresia appears to 1st affect the ________________ cells and without their support the oocyte dies. - _______, ______, and __________________ factors appear to control atresia by inducing or suppressing the apoptotic pathway. FSH is especially protective for ___________ follicles.

99%; birth; apoptotic; granulosa; FSH, LH and intraovarian; antral

Effects of stress on generation of the LH surge: • ___________ stress can prevent the occurrence of the pre-ovulatory LH surge. _________ severe stressors can delay its occurrence and decrease its amplitude. • Effects represent a combination of reduced GnRH secretion from the hypothalamus and reduced LH secretion in response to GnRH.

Acute; Less

• To be able to initiate puberty an individual needs to achieve species-specific targets for growth or metabolism. The body detects achievement of the growth/somatic targets (or reduction in ________) by peripheral signals. When these signals indicate the appropriate metabolic state has been achieved ("metabolic gate"), then puberty can proceed. The postulated peripheral signals are the same ones we've seen previously that mediate the nutritional effects on reproductive function: glucose, insulin, _________-____, and ___________ among others. • leptin→kisspeptin system is involved, but it probably doesn't have primacy • Remember that these signals of somatic development are only "_________________" of puberty, they do not directly cause it. Puberty itself will be initiated by a genetic program (developmental clock) sometime after they are reached. In certain continuous breeders (humans, cows, pigs) the appropriate degree of somatic development is the only permissive signal you need to achieve in order to be able to initiate puberty. In other species there are other signals or cues involved, and actual size and age at puberty will depend on the interplay of these factors. They can largely be divided into _______________ and ____________.

BMR (basal metabolic rate); IGF-1 and leptin; permissive; seasonal and social

1. Mimic the CL by administering progesterone or progestogens: e.g. Cattle • ___________-B - controlled internal drug release (T-shaped) 1.38 grams progesterone- intravaginal • Insert CIDR and leave in for ____ days (longer than this may give reduced conception rates) • Give prostaglandin injection on day ____ • Estrus expected 1-3 days after removal • Breed _____ hours after 1st detect estrus • Similar devices at appropriate doses and sizes are available for sheep and goats

CIDR; 7; 6; 12

2. Early Follicular Phase - Depending on species this will include proestrus and the early part of estrus. - In this stage there is no _______ and thus no progesterone - The only feedback is from ________________ and ______________ being produced from the growing follicle(s); Estrogen levels are increasing - Hypothalamus: In the absence of progesterone there is the potential for an increased frequency of GnRH pulses, and to some extent this occurs. However, the increasing but still moderate (below threshold) _______________ levels feed-back negatively on the GnRH pulse generator to prevent surge release of GnRH - Anterior Pituitary: Increasing frequency of GnRH release permits increased frequency of ______ pulses (helps drive follicular estrogen production); However, estrogen also feeds back negatively on the pituitary gonadotropes to reduce LH and FSH secretion in response to this GnRH = "_______________ __________", again preventing the LH surge - Inhibin (and estrogen) also from granulosa cells of the developing follicle(s) feeds back directly on gonadotropes to specifically reduce ________ secretion, this is especially true as we move from early to mid and late follicular phase.

CL; estradiol and inhibin; estrogen; LH; pituitary clamp; FSH

Follicular and Luteal Phases: - Usually used in reference to the human menstrual cycle, but also occasionally for estrous cycles. The follicular phase is the time when follicles are growing and there is no _______ present on the ovaries (in most estrous cycles this would include proestrus and estrus). The luteal phase is the time when there is an active (______________________ secreting) CL present on one of the ovaries.

CL; progesterone

Hypothalamic Effects of Stress: • Effects of stress on pulsatile GnRH secretion: - Stressful situations cause release of _________ and ________ in the hypothalamus. - CRH predominates in response to "weak stressors" - AVP is secreted along with CRH in response to more intense stressors • These actions occur within the hypothalamus. • While receptors for CRH and AVP have been demonstrated on GnRH cell bodies, many of the inhibitory effects appear to be mediated by the activation of inhibitory interneurones which use _______________ and ____________ to either directly affect the activation of GnRH neurons, or to suppress activity of the kisspeptin system.

CRH (corticotropin releasing hormone) and AVP (arginine vasopressin); opioids and GABA

5α-Reductase defects: - Also part of the testicular feminization syndrome. Have T but can't make ________. - Normal androgen receptor --> T can function normally - Patients are XY, have bilateral testes and normally virilized Wolffian structures but these terminate at a _________ ___________, the external genitalia is female. Often have male brain sex. - Testes may be descended to labia majora - Increases in T after puberty can result in __________________ and desire to change assigned sex to male.

DHT; blind vagina; virilization (development of male physical characteristics (such as muscle bulk, body hair) in a female)

3. Estrus - The LH surge - ______________ is very high; Inhibin can also be high - Hypothalamus: Exposure to high levels of estradiol (in the absence of progesterone) for a certain time (~______ hours - depends on species) switches the effect of feedback from negative to positive. The increasing estrogen has now crossed a threshold level to become positive (and/or activate the __________ "surge center" if one exists); Positive estradiol feedback gives a great increase in GnRH secretion - Anterior Pituitary: Further elevation in levels of estradiol first removes the ________________ that it previously exerted on the pituitary gonadotrope response to GnRH (i.e. removes the "pituitary clamp"). Subsequently, the elevated estrogen appears to facilitate the GnRH self-priming mechanism that increases the amount of LH release in response to each unit of GnRH. (i.e. the high estrogen first removes the inhibitory effect and then actually increases the _________________ of the pituitary gland to GnRH)

Estradiol; 36; GnRH; inhibition; sensitivity

General hypothalamo-pituitary-ovarian physiology of the pregnant and early post-partum cow: - During the first two-thirds of pregnancy things function pretty much as they do in diestrus: in response to periodic elevations of _________ waves of follicles emerge and regress at about ____-_____ day intervals and since progesterone is high the dominant follicles can't go through final maturation and ovulate. - In late pregnancy not only are progesterone levels high, but _______________ rises also (from the feto-placental unit). This functions to suppress FSH so follicle waves no longer emerge and the ovary (apart from the CL of pregnancy) is quiescent. - At birth, with luteolysis and passage of the fetus and placenta, both progesterone and estrogen levels fall, removing inhibitory feedback and FSH release occurs. This first FSH rise occurs within ____-____ days and thereafter the usual pattern of FSH release at 7-10 day intervals is re-established. Successive waves of follicular growth follow, the initial one capable of giving rise to a dominant follicle by 7-10 days post-partum. So post-partum anestrus is NOT due to lack of follicular waves, it is due to defects in the attainment of follicular ___________________ and final maturation of dominant follicles (at least in cows).

FSH; 7-10; estrogen; 3-5; dominance

5. Increasing Ovulation Rate • Superovulation - Higher total doses of ________ are given over several days to induce a superovulatory response. FSH is most commonly used (various preparations). The schedule is generally started in mid-______________ (and/or the animal has a progesterone-releasing device inserted) and injections are given daily or twice daily on a constant or decreasing dose schedule. A dose of _____________________ is given on the 3rd day of a 4 day treatment schedule in cattle (and progesterone device removed) to permit estrus. Due to the increased number of follicles, and thus higher estrogen, these animals experience their LH surge and ovulate more rapidly than those having a single follicle and thus are _____________________ earlier. • Apart from their use for superovulation - FSH and _________ or an eCG/hCG combination product (____________) at low doses are given to sheep and goats at the time of ________________ removal during regular AI programs in order to increase synchrony and mildly increase ovulation rate. - eCG (equine chorionic gonadotropin) is the newer name for PMSG (pregnant mare serum gonadotropin) a hormone found in ________________ mares, that in other species has long-lasting mixed FSH/LH activity.

FSH; diestrus; prostaglandin; inseminated; eCG (PMSG); PG600; progestin; pregnant

- The upshot of this decreased estradiol production by growing follicles is less feedback inhibition of ________ secretion. With less inhibitory feedback the FSH levels are higher and more follicles are supported through the selection process. - So while the ovary is the primary target of increased nutrition, the feedback loops involving the hypothalamo-pituitary-ovarian axis are critical to the result of increased number of ____________________.

FSH; ovulations

______________: the ability to produce young _________________: fruitfulness, ability to produce many young

Fertility; Fecundity

The fate of germ cells to continue mitosis (testis) or enter meiosis (ovary) is determined by exposure to either __________ which prevents entry into meiosis, or _____________ acid (RA, a vitamin A derivative) which promotes it.

Fgf9; retinoic

Ultimate Factors in seasonality: - An ultimate factor is the reason that something develops or occurs. __________ ____________________ has been termed the main "ultimate factor" in seasonal reproduction - it is the reason behind its development. Ultimate factors act on an evolutionary timescale → animals giving birth in spring are selected for (basically those with a predisposition to give birth in the spring were more successful and came to dominate the population while those giving birth at other times were less successful and died out, so the trait gradually became fixed). - Other potential ultimate factors would be expected milder environmental temperatures in certain seasons (offspring survival), food ___________________ (where several species in an area consume the same food resource - nice if your maximum requirement doesn't coincide with that of a competing species if the food supply is fairly constant) and _______________ pressure.

Food availability; competition; predator

The basic requirements for female cycles are: 1. The hypothalamus - which drives the whole thing • It does this by secreting ___________ 2. The anterior pituitary gland - transduces the coded GnRH signal from the hypothalamus and sends it to the ovary. • It does this using the gonadotropin hormones: _________ and ______ o In some species it also uses prolactin (Prl) in partial fulfillment of this role 3. The ovaries - containing follicles and the corpus luteum (CL). • Follicles respond to gonadotropin signals by growing and maturing the oocyte, releasing it at ovulation and secreting ______________ to give behavioral and physiologic traits necessary for mating. • The corpus luteum forms from the remnant of the ovulated follicle. It secretes _____________________ to prepare the uterus for pregnancy. 4. The endometrium (uterine epithelial lining) - detects the presence or absence of pregnancy. Causes return to estrus in cycles that don't result in pregnancy. • It does this by secreting _______________________ ________ (PGF2α)* (*at least in our model species, which has "short" cycles)

GnRH (gonadotropin-releasing hormone); FSH (follicle stimulating hormone) and LH (luteinizing hormone); estrogen; progesterone; prostaglandin F2α

Examples of Stress Effects on Different Stages of Reproduction: 1. Stress effects on breeding - Cows and ewes have reductions in ____________ and _______ following transport stress. - Captive wild animals that have high _____________ and low sex steroid levels are not reproductively successful until this situation normalizes. - A change in an individual's social status within the group can be important. In some situations only the dominant or alpha pair will breed. - Couples emotionally stressed about infertility have lower success in assisted reproductive programs. Women IVF patients with higher blood pressure and heart rate in response to a stress test had fewer _________________ _______________ and transferable embryos than those with low stress scores. 2. Stress and Gestation - In pregnant women, exposure to psychosocial stressors at 28-30 weeks of gestation ________________ the pregnancy and lowers birth weights. 3. Crowding - Social stress of crowding can decrease reproductive cycles in females (e.g. the Lee-Boot effect in rodents).

GnRH and LH; cortisol; fertilized oocytes; shortens;

How Seasonal Histogenesis Seems to Work in the Ewe to alter GnRH Pulse Frequency: - The seasonal hypothalamic changes/plasticity that control variation of GnRH pulse frequency are an area where of research is ongoing and knowledge is in its early stages. The following is based on information from the ewe, a short-day breeder, and is the best understood system but it remains a model with a number of holes. - In the ewe two mechanisms appear to be at work to inhibit the frequency of GnRH pulses in the non-breeding season: 1. By far the dominant system is a massively increased sensitivity of the __________ ____________ _________________ to inhibitory gonadal steroid (estrogen) feedback. This system becomes extremely sensitive so that even tiny amounts of estrogen are sufficient to keep GnRH pulses in check 2. Secondly, there appears to be a steroid ______________________ mechanism at work because a less severe restriction of GnRH pulse frequency is seen seasonally in ovariectomized animals. - The relative importance of these may vary in other species and by the sex of the animal.

GnRH pulse generator; independent

3. Induction of ovulation Critical points: - Have to have a mature follicle that can respond - You can either supply ___________ or an analog and rely on the animal's own LH release or - Supply LH or an analog directly; usually this means _________ which has long-lasting LH activity

GnRH; HCG (human chorionic gonadotropin)

Short Term Energy Restriction: - Short term severe under nutrition in previously well fed female monogastric animals causes an almost immediate decrease in __________ pulse frequency and ______ levels. In ruminants the same effect takes several ________ to achieve because fermentation continues in the rumen. These changes are rapidly reversed when normal nutrition is restored.

GnRH; LH; days

Leptin: • Leptin sits with a foot in both metabolic fuels and critical body fat hypotheses. • Within the reproductive system the peptide appears to function as a permissive signal for pulsatile secretory activity of ___________ neurons. In good conditions and thus adequate leptin levels: - Leptin inhibits ________ neurons that are in turn inhibitory both directly and indirectly on GnRH neurons. - Inhibition of other hypothalamic GnRH inhibitory pathways by leptin, including ___________ and _________ are also probably involved (both opioidergic and GABAergic neurons inhibit GnRH neurons). (Different POMC products may have opposite effects: β-endorphin inhibits GnRH whereas MSH derivatives appear to be stimulatory) - More recently leptin has been shown to stimulate (possibly indirectly via other neurones) the ____________ __________________ system which directly stimulates GnRH pulses. Leptin appears to be the major permissive controller of these neurons (i.e. leptin level has to be above a certain threshold in order for them to function optimally). Thus low leptin levels decrease KNDy neuron activity, kiss secretion, and thus GnRH. • When fat stores decline or the animal is fasted, circulating leptin levels drop and the GnRH pulse generator is suppressed.

GnRH; NPY; POMC (proopiomelanocortin) and GABA; KNDy kisspeptin

Puberty represents a re-activation of the hypothalamo-pituitary-gonadal axis. • If we split the early life of an animal into neonatal, juvenile, pubertal and mature periods then: - ___________ neurones in the late fetal and neonatal periods are capable of and do secrete GnRH. - In the juvenile period GnRH secretion _________________ and is maintained at very low levels, but at this stage: 1. If you specifically stimulate GnRH neurones they can secrete GnRH. 2. If supplied with GnRH: the pituitary of juvenile animals responds with secretion of LH and FSH (i.e. the pituitary is functional in juveniles). 3. If stimulated appropriately with FSH and LH: the ovaries will respond with full ________________ development and ________________ (i.e. the gonads are capable of function). • So during the juvenile state, the hypothalamo-pituitary-gonadal axis is held in check by suppression of GnRH secretion from the hypothalamus. Puberty isn't so much an initial activation of the system as a _____________________.

GnRH; decreases; follicular; ovulation; reactivation

Mechanisms for Control of GnRH Neuron Activity • The critical change for puberty is in the hypothalamus: an increase in the frequency of ___________ pulses. During the juvenile period the developmental clock/permissive signal combination appears to use both decreased stimulatory inputs on GnRH neurons and increased inhibitory inputs, which are then reversed during puberty. • When these alterations do not involve gonadal steroid feedback (at least in the juvenile and early pubertal stages) they are represented by the "___________ __________" hypothesis. • When inputs involved in suppression and reactivation of GnRH neurons include re-setting of sensitivity to gonadal steroid feedback, the explanation is termed the "___________________" hypothesis.

GnRH; direct drive; gonadostat

Breeding Season vs. Non-Breeding Season = ↑Frequency vs. ↓ Frequency GnRH pulses: - The mechanisms of seasonal/photoperiod control of reproduction are still being worked out. The critical final event is alteration in the frequency of __________ secretion from the pulse generator; higher frequency in the breeding season, low frequency in the non-breeding season. - In the breeding season high frequency GnRH secretion gives _____________________ release and active ovaries. In the non-breeding season low frequency GnRH pulsatility causes little synthesis or secretion of gonadotropins and the ovaries will be inactive (remember we are talking chronic lack of GnRH pulsatility now, not just acute like we saw during the cycles, thus ________ will be fairly low too).

GnRH; gonadotropin; FSH

Feedback Control of GnRH secretion - Progesterone acts at the hypothalamus and exerts an inhibitory control of ____________ secretion. Its action is largely to decrease GnRH pulse frequency. - Estrogen can exert both negative and positive feedback depending on its level in the blood and the length of exposure. In general terms: low to moderate levels of estrogen (below threshold) are _________________, while those above threshold are __________________.

GnRH; inhibitory; stimulatory

6. Combinations - As we've already seen, rather than being used in isolation, the above hormones (and others) are most often combined in management of the cycle and while these are the common ones, they are but a few of those available. - The "ovsynch" program in cattle uses __________ (to ovulate any large follicles and allow emergence of a new follicular wave) followed in 7 days by ____________________ (to lyse resultant CLs and thus induce estrus) and then another ___________ shot to cause ovulation (she's bred to conceive on this). - Other programs also incorporate CIDRs and common protocols for bovine embryo transfer have CIDRs, prostaglandin, FSH and maybe GnRH over an 8-10 day period.

GnRH; prostaglandin; GnRH

_______________ follicles: - These are large mature tertiary follicles - the type you might palpate in a cow or mare.

Graafian

Seasonal Influences on Age at Puberty: Photoperiod: • Those species that are seasonal breeders can only attain puberty within the breeding season. Lambs are born in spring and the breeding season for sheep is fall/winter. Ewe lambs can achieve puberty at ~ 30 weeks (7.5 months) of age. • Whether puberty is achieved in the first available breeding season after birth will depend on the interaction of: 1. _____________ Rate 2. Their _________ of birth in the previous spring • Their time of birth will decide how much time they have to achieve the necessary target growth before the end of the subsequent fall breeding season. Their growth rate will determine how long it takes them to achieve the target. Fast growing ewes will achieve puberty in their first season, slow growing ones won't. Intermediate growth rate ewes may if born very early in the previous spring, but won't if born later. They may well reach the metabolic target in the following spring or summer but will not go through puberty due to inhibitory ____________________ at this time. They will have to wait until the following fall.

Growth; time; photoperiod

The brain areas that will become sexually dimorphic start out as monomorphic in early development and differences can subsequently arise through 3 broad mechanisms: 1. _______________ exposure o Here we are referring to the gonadal steroids testosterone and estrogen 2. Genetic (____________________) constitution of the cell o The direct effect of the cell being XX or XY 3. _________________ Effects o Particularly here are changes associated with differential methylation of DNA/acetylation of histones (i.e. imprinting of genes similar to what happens in X-inactivation but related to individual genes rather than an entire chromosome - and can affect autosomally located genes)

Hormone; chromosomal; Epigenetic

Follicular Dominance: - The mechanism by which one follicle becomes dominant is incompletely understood, but the process appears to be under the control of intraovarian factors, especially the _______ system. - Within the follicle the actions of FSH are amplified by ________________ and ________-____. - It is currently thought that within the cohort, one follicle becomes more biochemically advanced than its peers (achieves biochemical dominance) - It has been hypothesised that increasing development of this system as the follicle matures enables the dominant follicle to become ___________________ of the systemic (hormonal) environment it is creating - Increased estradiol and inhibin production by this advanced follicle, combined with that from others in the cohort, reduces systemic ________ levels, impeding the development of less advanced cohort members. The higher intrafollicular levels of _______________ and free _______-____ in the selected follicle means it can survive on the reduced FSH support and thus becomes dominant. In some regards these follicles can eventually use LH in place of FSH.

IGF (insulin-like growth factor); estrogen and IGF-1; independent; FSH; estrogen and free IGF-1

Inguinoscrotal descent: Bottom line: - _____________ dominates the transabdominal stage and _________________ dominate the inguinoscrotal stage of testicular descent.

INSL3; androgens

Problems involved with cryptorchidism: 1. __________________ 2. ___________ formation - Sertoli cell tumor in dogs- seminoma in human 3. Heritability - generally considered not to be a simple genetic trait but one that has a large genetic component. In most species has been thought to be autosomal ________________ (or perhaps dominant with incomplete penetrance) - recommendation not to use affected animals for breeding.

Infertility; Tumor; recessive

Seasonal Anestrus Mechanism 1: Altered sensitivity to steroid feedback - the Ewe: 1. There are fewer ___________ neurons in the ARC and those present have fewer projections to GnRH neurons (seasonal plasticity - so there is numerically less drive input on GnRH neurons) 2. A subset of dopaminergic (DA) neurons (A15 dopaminergic neurons) become active and • inhibit ___________ secretion from axon terminals in the median eminence • possibly inhibit ___________ neurons (in the ARC) These dopaminergic neurons don't have estrogen receptors but: 3. Stimulatory inputs onto the dopaminergic neurons from ______________________ neurons are increased • These glutaminergic neurons have estrogen receptors and are stimulated by estrogen to which they are exquisitely sensitive • During anestrus the number of these glutaminergic neurons _________________ as does the number of contacts (synapses) they make with DA neurons (i.e. seasonal plasticity). 4. Inhibitory inputs onto the dopaminergic neurons by GABA neurons are inhibited by ________________ • there are no fewer GABA neurons during anestrus but their activity is inhibited by estrogen at this time (seasonal plasticity in receptors or post-receptor mechanisms has increased their sensitivity to this inhibitory estrogen feedback?) ` - So the GnRH stimulatory kisspeptin system is down-regulated in the non-breeding season while the GnRH inhibitory _________________ system is up-regulated at the same time by alterations in the balance of estrogen sensitive glutaminergic and GABAergic inputs to it.

KNDy; GnRH; KNDy; glutaminergic; increases; estrogen; dopamine

In the Breeding Season: • There are large numbers of ___________ neurons present and functioning to generate GnRH pulses. • They have normal sensitivity to feedback inhibition by ________________ and ______________________ so we get the typical estrous cycle function. • The inhibitory dopaminergic (DA) neuron system is NOT functioning because o It is inhibited by a functioning ____________________ system o The highly _______________-sensitive glutaminergic neuron system that stimulates the dopaminergic neurons (is/is not?) functioning (there are few of these neurons at this time and those present are poorly connected to the dopaminergic ones)

KNDy; estrogen and progesterone; GABAergic; estrogen; is NOT

NOTE: -the steroids progesterone and estrogen don't directly act on the GnRH neurons but act on the ___________ neurons which then act on GnRH -_____________________ acts on dynorphin to increase the time between pulses -______________ when it's below threshold, down-regulates the stimulatory NKB/NK3 system -for late follicular stage, estrogen is stimulatory on the kisspeptin neurons (the neurons do not contain NKB/Dynorphin at this time)

KNDy; progesterone; estrogen

General hypothalamo-pituitary-ovarian physiology of the pregnant and early post-partum cow: - The fate of the dominant follicles in these early waves is largely tied to the frequency of ______ pulses (which we know depend on the frequency of GnRH pulses). If the LH pulse frequency can get to approximately ___/________, then the large follicle can go through final maturation, synthesize and secrete enough estrogen to induce an LH surge and go on and ovulate. This could happen for the dominant follicle of the first wave, but in a suckled beef cow or a high producing dairy cow it usually doesn't and this follicle becomes atretic and another wave emerges. This process continues until sufficient LH pulse frequency can be re-established.

LH; 1/hour

If Stress inhibits the HPG Axis, How can Transport Stress be used to Hasten Puberty? • Many neurons involved in the transduction of stress effects within the hypothalamus (those involved directly or indirectly in inhibition or activation of GnRH neurons) are steroid responsive. • Ewes in seasonal anestrus, that are highly sensitive to feedback inhibition by estradiol, respond to transport stress with an increase in ______ (and presumably GnRH) pulsatility. This is the reverse of the response they experience when in the breeding season. The thinking is that ________ released by stress overcomes the highly sensitive inhibitory action of estradiol feedback during anestrus, rather than directly causing ___________ release. A similar highly sensitive feedback mechanism to estrogen is in operation prior to puberty.

LH; CRH; GnRH

Control of Gonadotropin Secretion: GnRH: - The main factor controlling release of the gonadotropins is GnRH → stimulatory - Secretory episodes of ______ can only follow a GnRH pulse and release is pulsatile with little release between pulses. - ________ release, while stimulated by GnRH, is less closely under its control, and significant release can occur (at least in the short term) without a GnRH pulse. - ___________ frequency GnRH pulses tend to favor LH release, and _______ frequency GnRH pulses favor FSH.

LH; FSH; Higher; low

Overall Effect of Estrus: - The increased GnRH and increased pituitary sensitivity to it results in surge release of ______ - Whether there is an FSH surge as well as an LH surge (and their relative timing) depends on _____________. But most species have both - so it's really a "gonadotropin" surge. - Note: The decline of the LH surge (i.e. why it stops) is not due to slowing GnRH secretion in most species (in these the GnRH surge continues for longer than the LH surge) but rather to loss of __________________ ______________________ sensitivity to GnRH

LH; species; pituitary gonadotrope

Luteotropins: • The CL(s) requires hormonal support for its function. Hormones that do this are termed luteotropins. • There are many luteotropins and they vary in importance between species. They probably do not act in isolation but form a "luteotropic complex". The hormone that is luteotropic in a species may also change over the estrous cycle or pregnancy. - _______ is luteotropic in all species examined and is responsible for at least the early changes of luteinization. As such it has been termed the "_______________ luteotropin". - ______________ (also from the anterior pituitary) is an important luteotropin in carnivores, mice, rats and hamsters. It may also be important in other species. - ______________ is a vital luteotropin in the rabbit, but in some other species may have the opposite action (be luteolytic). - While ____________ is the luteolytic hormone in all mammals examined, other prostaglandins may have luteotropic functions. Prostacyclin (PGI2) in cattle and PGE2 in women are 2 examples.

LH; universal; Prolactin; Estradiol; PGF2α

Androgens: - Produced from cholesterol in the ___________ cells of the testicle - Testosterone (T) is the major androgen produced - _______________________________ (DHT) is formed from testosterone by the 5α-reductase enzyme*, mostly in peripheral (target) tissues (*This enzyme has 2 known _______________, type II is present in the external genitalia)

Leydig; Dihydrotestosterone; isoforms

With all these costs why does sexual reproduction persist? Two of the main theories have been:

Muller's Ratchet; The Red Queen

MIS excesses in females: - Systemic exposure of female fetuses to MIS during early embryogenesis causes regression or agenesis of ______________ structures and later potentially an "endocrine sex reversal" of the ovaries (because MIS inhibits aromatase). Immature ovaries exposed to MIS have reduced aromatase activity and hence produce more ______________________ (it builds up because they can't convert it to estrogen).

Mullerian; testosterone

Overriding the Inhibition of Stress: • Most of the time stress inhibits reproduction because it makes more sense to breed when that stressor is gone. However, in some instances it makes sense to override or ignore the stressful aspects of the current environment and breed anyway, changing the trade-off of survival as an individual with the chance to pass on your genes • Theoretically this occurs in at least 5 situations: 1. ________ individuals that have little chance of future reproductive success. 2. _______________ breeders, especially those with very short breeding seasons. 3. Species where both partners provide _______________ care (loss of one parent is less important). 4. ____________________ species where there is only one breeding period followed by death. 5. Dominant animals in social groups where only the dominant pair breed and dominance is __________________. • At which level(s) in the interaction of the HPA and HPG axes these species exhibit resistance is largely unknown.

Old; Seasonal; parental; Semelparous; temporary

menstruation: -basalis and functionalis layers - endometrial ______________ causes myometrial contraction and decreased oxygen - the decreased oxygen leads to lysosomal and plasma leakage and blood cell extravasation; which all leads to endometrial _________________ - the myometrial contraction and endometrial sloughing leads to expulsion of the ___________________ layer; which results in menses

PGF2a; sloughing; functionalis

Counter-Current Exchange (local transfer) vs Systemic Route of PGF2α Action: - In some short-cycling species, _____________ in the systemic circulation is rapidly and almost completely (99%) metabolized on a single passage through the lungs and thus is unable to cause luteolysis. To circumvent this they have developed a means of local transfer to ensure sufficient PGF2α secreted into the uterine veins reaches the CL to ensure luteolysis. - These species have a specialized anatomy of the ovarian artery which is _______________ and closely applied to the uterine vein. - _____________________ from the uterine endometrium passes up the uterine vein and a portion of it is transferred across vessel walls into the ovarian artery, from where it can directly access the CL. Prostaglandins are extremely _______________ so they can readily accomplish this cross-vessel diffusion. - This strict system applies to the __________ and ____________ _______. In horses and rabbits there is no such system and the PGF2α is transferred via the systemic circulation, a much less active metabolism in the lungs permitting this route to be effective. - While cows are generally considered to be in the counter-current exchange group, there is some evidence that they and pigs may use a combination of both this local transfer mechanism and the systemic circulation route.

PGF2α; tortuous; Prostaglandin; lipophilic; sheep and guinea pig

How they think PIS works: - In normal XX (female) animals (XX PIS+/+ or XX PIS+/-) PIS is a promotor region which up-regulates transcription of nearby genes PISRT1, FOXL2 and PFOXic. _____________ (PIS-regulated transcript 1) inhibits SOX9 (which is critical for testis formation) and thus prevents formation of a testicle. FOXL2 and PFOXic are pro-______________ genes. So there are anti-testis and pro-ovarian genes close together and none get up-regulated appropriately; recent work suggests lowered FOXL2 is the most important factor in this syndrome - In an affected XX animal, with deletions of PIS on both copies of chromosome ___ (XX PIS-/-), while these pro-ovarian and anti-testis genes are still present (they are outside the region of the deletion) they do not get up-regulated because their _______________ is missing. - Being homozygous for the polled gene also impacts bucks. Homozygous polled bucks (XY PIS-/-) tend to become sterile due to blockage of the epididymal duct in the caput epididymis, resulting from poor differentiation of the duct. This leads in turn to palpable sperm __________________ formation.

PISRT1; ovarian; 1; promoter; granuloma

Goats: - ____________/______________ Syndrome (PIS) occurs in European dairy breeds (Saanen, Toggenburg and Alpine) and appears to be the most common form of intersex in domestic animals. The affected animals are _______ _______________ females being XX genetically but have ovotestes or testes. Phenotypically they are mostly ______________ at birth but on attaining puberty they become larger than normal females, the head becomes masculine, erect hair develops on the neck, the clitoris enlarges and may be visible externally. They have small teats, develop buck odor and become aggressive with male type libido. The polled condition is autosomal _______________ (P) and is linked (ie located close to) the intersex region (_________________) on goat chromosome 1. The affected animals are _______ negative but have a deletion of 11.7-kb DNA from chromosome 1 (currently referred to as PIS-/- because as it is recessive they have a deletion on both copies of chromosome 1 to be affected).

Polled/Intersex; sex reversed; female; dominant; recessive; Sry

1. Mimic the CL by administering progesterone or progestogens: • _____________________: a compound with progesterone-like activity; • The aim here is to administer exogenous progesterone for a period to keep them out of heat and then once you stop treatment they will come into heat at a predictable time. • Critical Points: - If the animals are cycling (and they usually are when these are used) then they may have their own _________. You need to administer the progestogen for sufficient duration to _____________ these so that when you stop giving the progestogen they will come into heat at a reliable time (if you don't outlast their endogenous CL it will still be there and stop them coming into heat predictably). - BUT if you do this (long progesterone therapy) the ______________ at the induced cycle may be reduced. - To avoid this, the progestogen is often given for shorter duration and combined with _____________________ injection to lyse the endogenous CL (usually given on about the last day of progestogen treatment). - Since treating with progesterone is just like them having a CL they will have waves of _______________ growth while on treatment - i.e. progestogen treatment alone stops entry into heat and ovulation but does NOT control follicle growth.

Progestogen; CLs; outlive; fertility; prostaglandin; follicular

The Indifferent (Bipotential) Gonads During embryonic development 3 sets of kidneys develop sequentially: 1. __________________, which degenerates, but its duct persists as the mesonephric duct 2. _____________________, contains tubules induced to form by the residual mesonephric duct, with which they communicate. Also degenerates except for some of the caudal tubules and the mesonephric duct 3. ___________________, develops into kidney and ureter

Pronephros; Mesonephros; Metanephros

1. Mimic the CL by administering progesterone or progestogens: e.g. Horses • _________________ (altrenogest): - Progestagen given orally or on feed once a day. ___________ inactivated so stored in dark opaque containers prior to use. - Widely used in breeding management and to keep performance mares from showing estrus. ___________ mg/kg (1 cc per 100 lb) - Old protocol was give for 15 days then withdraw (to outlast CL). - Now usually give for ____-_____ days with a PGF2α injection on last day of treatment. Most mares show estrus 2-5 days later.

Regumate; Light; 0.044; 8-12

-It is now considered that the testis-determining trigger factor in eutherian mammals is the product of the gene _________ (Sex-determining Region Y chromosome) -By convention: SRY = human gene, sry = gene in other species, SRY = encoded protein -If you have this gene (and it is expressed) you are kicked down the pathway to developing testes; if you don't then the ovarian genetic cascade ensues.

SRY

Anti-Mullerian hormone (AMH; aka Mullerian inhibiting substance MIS): - Glycoprotein produced by ____________ cells in male - Related to TGF-β, inhibin, activin - Causes regression of the Mullerian ducts in ___________ fetuses

Sertoli; male

Seasonal Breeding Rhythms: • Rhythms are an integral part of life and numerous examples are found in both plants and animals. They are classified on their periodicity: - _______________ rhythms are those that occur at intervals of less than a day (ex. heartbeat, respiration) - ________________ rhythms are those that occur around a day in length (ex. body temperature, adrenal activity, sleep/wake cycles) - ______________ rhythms are those that occur at periods of longer than a day, and this category includes those with an annual occurrence, the circannual rhythms (ex. estrous cycles, migration, pelage changes, hibernation and seasonal reproduction)

Ultradian; Circadian; Intradian

-There are many means of reproducing. Having 2 separate male and female sexes (gonochorism or bisexuality) is just one. -____________________ reproduction- is used by bacteria, many plants and some invertebrate animals. It includes such strategies as budding (yeasts), fission (bacteria) and fragmentation. -___________________________- is reproduction using eggs, but without sex - i.e. the eggs are never fertilized* by a male. -Both these systems allow you to pass on your genes to the next generation intact (effectively achieving "genetic immortality"). Every member of the population can "give birth" so a population can rapidly populate a new environment, and no members of the population are consuming resources without reproducing - so they are efficient systems. In the short term, parthenogenesis in groups such as insects can be shown to be very advantageous. However parthenogenesis generally appears to be __________-lived on an evolutionary time scale, species exhibiting it tend to be in the minority in their family or genus. _________________ are the only group where parthenogenesis has never been successful - Why? In mammals the genome is parentally _________________ during oogenesis and spermatogenesis, both maternal and paternal chromosome sets are needed for normal development of the offspring.

Vegetative; Parthenogenesis; short; Mammals; imprinted

Androgens: - Both testosterone (T) and dihydrotestosterone (DHT) bind the same androgen receptor (AR) to have their effects, but influence different sites during development: - T-AR: signals differentiation of the ______________ duct in the male embryo (Also later regulates hypothalamo-pituitary axis for LH secretion and has a vital role in spermatogenesis) - DHT-AR: signals development of ______________ ________________ and _______________ in male embryo; causes elongation and ventral closure of the penile anlagen to move the urethral orifice from the perineum to the tip of the penis (Also involved in pubertal changes eg hair pattern, male pattern baldness and maturation of external genitalia during/following puberty) - Different effects of the two hormones bound to the same receptor may be due to binding _____________ (DHT has ~ 10x higher affinity for AR than T does) or an effect on receptor _______________ (DHT-AR activates some genes more easily than T-AR)

Wolffian; external genitalia; prostate; affinity; function

Sexual Differentiation of the reproductive tracts: - To achieve either male or female gonads the starting point was a single indifferent structure, which then differentiated as either male (testicle) or female (ovary). The strategy for developing the male and female duct systems is the opposite. All embryos start with the rudiments of both male and female systems, one of which will regress while the other develops under the influence of the now sexually differentiated gonads. - In the early, sexually undifferentiated embryo, the rudimentary male ducts (_______________ or mesonephric ducts) appear first, as the excretory ducts of the ______________________. - The rudimentary female ducts (________________ or paramesonephric ducts) only develop after the early indifferent gonad is visible. They develop adjacent to the Wolffian ducts, starting near the gonad and developing _______________, apparently using the Wolffian/mesonephric ducts as a guide (hence paramesonephric).

Wolffian; mesonephros; Mullerian; caudally

Androgen Receptor Defects: - Androgen receptor is the product of an ____-linked gene in humans - Complete deficiency (no AR) leads to testicular feminization/complete androgen insensitivity (_______________ ________________ ___________________ _________________: CAIS) - Affected individuals are XY, have testicles but phenotypically are taller than average females with male (larger) tooth size - No T-AR --> ________________ duct regression (do have T but it can't work) - No DHT-AR --> ______________ _______________ _______________ (do have DHT but it can't work) - Normal MIS --> Mullerian duct regression (have MIS and MIS receptor so it does work) - Testes located ________________, occasionally labial - Some mutations of the receptor cause only partial inactivation --> partial masculinization = variable phenotype (_____________ _________________ ___________________ ________________: PAIS ~ 10% of androgen insensitivity cases are partial)

X; complete androgen insensitivity syndrome; Wolffian; female external genitalia; inguinally; partial androgen insensitivity syndrome

Genetic Sex -Mammals utilize the dominant ____, single pair method of chromosomal sex determination. -It has been argued that development of _________________ (live birth) and a _______________ meant that mammals could no longer use the _______________________ cues or altered ________________ levels used by "lower animals" for sex determination. Instead they had to co-opt/modify other genes to be the pathway trigger, though they could still preserve the function of those genes that were further down the cascade

Y; viviparity; placenta; environmental; estrogen

Patterns of antral follicle development during the estrous cycle continued: - The development of these dominant anovulatory follicles of the luteal phase has been divided into three stages: 1. An ___________ _______________ phase, where the dominant follicle progressively increases in diameter 2. A ___________ phase, extending from cessation of diameter increase to commencement of progressive reduction of diameter 3. A ________________ phase, extending from the end of the static phase until the follicle is no longer detectable. - During the growth and early static phases the "dominant" follicle is both morphologically (i.e. ____________) and functionally (able to suppress other follicles) dominant, but late in the static phase, while still morphologically dominant, it loses functional dominance permitting emergence of the next wave.

active growing; static; regressing; largest

The Red Queen -Sex is a big advantage for ________________ to a new environment or to environmental change since it makes our offspring variable and some of them likely to succeed/be well adapted to the new conditions. But once the population is optimally adapted sex should go away because it may dissociate the advantageous genes that have been acquired and thus the population becomes less well adapted to the now fixed environment (though it is useful to avoid Muller's ratchet). So if sex is persisting there should be some ever-changing part of the environment that a population is forced to constantly adapt to - what is it? Our biological enemies, such as _______________ and _______________, are constantly evolving to overcome our defenses. There are lots of them and they reproduce a lot faster than we do, so genetic mutations that give them an advantage can become prevalent very quickly. Our defense against this is to be as genetically variable as possible so that some of us are resistant to the mechanisms our enemies evolve (→ constant "_________________________ pressure").

adapting; bacteria and parasites; coevolutionary

Steps 3 and 4: The melatonin signal acts on the Pituitary Pars Tuberalis to cause directed TSH release: - This mechanism involves a 3rd "part" of the pituitary, the pars tuberalis which is a layer of cells that wrap around the neural stalk but are part of the ___________________________. The pars tuberalis contains cells that produce _________; i.e. in this regard they are like the thyrotrophs of the anterior pituitary gland. In other regards they are not. - Regular thyrotrophs respond to hypothalamic thyroid releasing hormone (TRH) by producing TSH, and are subject to inhibitory feedback by T3 so that circulating levels of thyroid hormone are controlled. - However, these pars tuberalis thyrotrophs do not have TRH receptors or T3 receptors, so unlike anterior pituitary thyrotrophs they don't respond to stimulatory input by hypothalamic TRH and are not inhibited by T3. - What these cells do have are ________________ receptors. The cells respond to short daily melatonin signals by secreting _______ (i.e. they secrete on long-days). This TSH is transported in a retrograde manner to the hypothalamus, particularly to cells around the 3rd ventricle

adenohypophysis (anterior pituitary); TSH (thyroid-stimulating hormone); melatonin (MT1); TSH

Control mechanisms for the migration of the primordial germ cells are still being explored but involve alterations in cell ________________ molecules, and a path defined by combinations of _________________ and ________________ signals (which probably change in different areas of the migration pathway).

adhesion; attractant and repulsive

Insulin: - Insulin levels fluctuate throughout the day in response to glucose, but its overall concentration is also directly proportional to amount of _____________ tissue in the body. While in culture insulin can increase GnRH secretion directly, in vivo its greatest contribution may be indirect, by inhibiting ________ neurons

adipose; NPY

How are Males Chosen? • There will obviously be some differences here based on the mating system of the species. However in general terms males _______________ for mates. • Advertisements can be long or short-range and most are ___________ or _______________ in nature but may also be ____________________. They include mostly secondary sex characteristics like ornamentation and song quality in birds. Advertising signals are used not only for intersexual mate choice but also in intrasexual competitions between males (intrasexual selection). • Advertisements need to be costly to ______________ (ornamental feathers) or ______________ (harem/territory defense) - this keeps the signal "honest". If a great advertisement could be produced by low quality males then there would be no point the female using it as a selection criteria because it doesn't honestly reflect the quality of the male - the best males need to have the best advertisements. Costly advertisements are a direct reflection of the quality (genetic, disease resistance) of the male. To circumvent cheating by males, females will often assess multiple cues (advertisements) in making their decision.

advertise; visual or auditory; pheromonal; produce; maintain

Induced ovulation continued: - The mating causes increased GnRH release from the hypothalamus which then triggers LH release. This is an example of a neuroendocrine reflex - the _____________ arc is neural and the ______________ arc is endocrine. - The female needs to be ______________ dominated (i.e. be in estrus) for a surge LH release to occur in response to mating - In the absence of mating there is no LH surge and thus no ovulation; the large follicles lose dominance and become atretic. The female leaves estrus to a short anestrus (a.k.a. ________________ or postestrus) lasting 1-2 weeks while a new wave of follicles develops. When these are sufficiently mature she will move into the next proestrus and then estrus. - The division of species between spontaneous and induced ovulators is not always strict. _________________ __________ ovulation is where copulation hastens ovulation in a species generally considered spontaneous, while occasional spontaneous ovulations occur in species that are generally induced ovulators - An ________________-________________ factor (OIF) has also been demonstrated in the seminal plasma of camelids (old and new world) which can induce an LH surge even if given by intramuscular injection. It is a much larger molecule than GnRH but acts in a similar manner on the pituitary.

afferent; efferent; estrogen; interestrus; Facultative reflex; ovulation-inducing

• How the GnRH pulses are held in check during the juvenile period and then re-activated again during puberty is still an area of active research and the controls seem to have different degrees of importance between sexes and potentially species. • At the core level there appears to be some kind of "developmental clock" that times the genetic program for puberty and sets a lower ________ _________ on its occurrence. • This clock then receives input from various permissive signals that may delay puberty if they are _____________, but if not limiting (or even if they are in excess) they cannot advance puberty earlier than the genetically preset lowest age (you can approach this minimum age but not pass it). • The relative importance of these permissive signals again varies with species and sex, but they include _____________ balance, __________________ (seasonal breeders) and __________ cues. • The identity of the developmental clock and the integrating mechanism between it and the permissive signals is still unknown.

age limit; limiting; energy; photoperiod; social

Other ways to subdivide estrus cycles 1. Monoestrous vs Polyestrous • Cycle once then enter _______________ vs. a series of consecutive cycles if non-pregnant 2. Continuous (non-seasonal) vs Seasonal • Will cycle at any time of the year vs. strict breeding season (anestrus outside this) 3. Spontaneous ovulators vs Induced ovulators • Ovulation occurs irrespective of mating vs. mating required to cause ovulation 4. Short vs Long cycles • Length of each cycle is largely determined by the lifespan of the ______________ ______________

anestrus; corpus luteum

Next step in differentiation of the Ovary: - The germ cells enter meiosis fairly synchronously in a wave from ________________ to ________________, becoming oocytes and these germ cells within clusters now move apart. These developing oocytes now induce the supporting cells to continue differentiation as pre-granulosa cells rather than Sertoli cells through the action of the transcription factor _________ (factor in germ line a). -The oocyte surrounded by its pre-granulosa cells is now a _________________ follicle. The time when these follicles form depends on the species specific time when the oocytes reach the _______________ stage of first meiotic prophase. This may occur during fetal life or post-natally, but in most species ovarian follicles form after birth. So follicle formation (and thus normal ovarian structure) is dependent on the presence of germ cells (and as we'll see later the follicles are required for ovarian ________________________ - so no germ cells means no ovarian hormones).

anterior to posterior; Figα; primordial; diplotene; steroidogenesis

The antral or tertiary follicle: • Pools of follicular fluid begin to appear between the granulosa cells; These pools coalesce to form the ____________ of the small tertiary follicle. • There are slight species differences in moving into this stage: - For rodents it appears that initial formation of the antrum (transition from secondary to tertiary) requires the actions of both _________ and _________________ (i.e. is FSH-dependent). - In larger animals (e.g. ruminants and us) the transition is FSH independent (directed by Gdf9 et. al.) but FSH-_________________ (i.e. you can influence/accelerate it with FSH but it doesn't need FSH). • However, continued growth of follicles through the antral stage (going from small antral to large antral) is FSH-_________________ for all species. - Because the follicles are now gonadotropin dependent, inadequate FSH support leads to _____________.

antrum; FSH and oestrogen; responsive; dependent; atresia

Follicles The Graafian (mature) follicle consists of: • an ____________ which is the fluid filled area in the middle • surrounding this is a layer of _________________ cells • outside this is a ________________ _________________ (membrane propria) • outside this again are the ___________ ____________ cells • the oocyte is contained in a ball of granulosa cells, the ________________ __________________. This ball floats in the follicular fluid of the antrum tethered by a stalk of granulosa cells to the granulosa layer of the follicle wall.

antrum; granulosa; basement membrane; theca interna; cumulus oophorus

Now that the early follicle is formed, the supporting cells (granulosa cells) maintain the structure and prevent formation of male gonadal features. In the absence of this supporting action the oocytes undergo _________________, without oocytes the follicle structure degenerates and again a ___________ gonad forms (so you can get a streak gonad either by never having germ cells in the ovary or by losing them early in development).

apoptosis; streak

Metabolic Fuels Hypothesis • What site(s) detect the information about metabolic fuel oxidation? - The best candidate at present is the _________ ________________ (AP) located in the hindbrain. Inhibiting glucose oxidation in this area had been shown to inhibit the reproductive axis. There is also some evidence for direct glucose sensing by GnRH neurons. • Signaling the Hypothalamo-Pituitary Axis How does this information from the hindbrain influence GnRH neurones? GnRH neurons appear to be inhibited by neuronal transmission from the hindbrain in at least 2 ways: - Neuronal projections from the hindbrain inhibit GnRH neurons directly using ________ and ________________________ (CA: norepinephrine and epinephrine) as the neurotransmitters. (NPY may act indirectly by suppressing KNDy neurons) - NPY and CA neurons from the hindbrain also activate ________ neurons which then inhibit GnRH neurons

area postrema; NPY (neuropeptide Y); catecholamines; CRH (corticotropin releasing hormone)

- After formation of the ovary and female reproductive tract, AMH is also produced in small quantities by granulosa cells of ovarian follicles. Insufficient for systemic effects, it appears to have local roles (autocrine and paracrine) in inhibiting ovarian steroidogenesis (inhibition of ________________) and inhibition of oocyte maturation

aromatase

Which Hormone is actually doing the work? - The testes secrete testosterone so the action has to be due to testosterone... right? Not necessarily: - Depending on species (and perhaps region of the brain and/or neuron type) the action of testosterone on the brain may be exerted directly via androgen receptors or the testosterone may only be effective after it is __________________ locally (in the brain) to ________________ which then acts on estrogen receptors (alpha or beta - usually alpha). In rodents the vast majority of testosterone actions to masculinize the brain appear to depend on its local conversion to estrogen and there is only a very minor role for direct action of testosterone acting through androgen receptors in setting organizational brain patterns. In human/primates evidence indicates that direct actions of testosterone acting via _________________ receptors are much more important. Most other species haven't been looked at.

aromatized; estrogen; androgen

Turner's Syndrom (XO): - most common chromosome anomaly in humans - Tend to have streak gonads. The ovaries are normal in the early gestation fetus but have an accelerated rate of ____________, the XO germ cells are lost at an increased rate as they enter meiosis. By the time of birth there are few _______________ left in the ovaries. Why? Two X chromosomes are functional in female germ cells during oogenesis, and this seems normally to be a requirement for successful completion of the process. The ovaries of XO individuals degenerate to "streaks" of _____________ connective tissue, unable to generate follicles or perform steroid synthesis, hence there are few _____________________ ________ characteristics. Most of these individuals have a juvenile reproductive tract and 97% have primary amenorrhea. - In 80% of human XO individuals the X chromosome that is present is _______________ in origin (Xm), thus the cause of most cases has been considered paternal, a result of defective ___________ (devoid of a sex chromosome due to errors in meiosis or mitosis during spermatogenesis. More recent reanalysis suggests many arise during mitosis in the early embryo and that most or all Truner's syndrome individuals that survive to birth are actually (cryptic) ______________. - Turner's syndrome is recognized most frequently in ____________. Affected mares tend to be short, have longer ears and very small ovaries with a small uterus.

atresia; oocytes; fibrous; secondary sex; maternal; sperm; mosaics; horses

experiment with female mice that were only transgenic for the SRY gene led to development as males; all the downstream genes in the sex determination cascade must be _________________ or ____-____________ if the SRY gene can make a fetus male on its own

autosomal or X-linked

Cats: - The tortoiseshell cat is an example of X chromosome inactivation. Their coat is a patchwork of orange and black or tabby. Black and tabby genes are ________________ while orange (O) is located on the ____ chromosome. The O is dominant over the autosomal genes, so skin cells with an XO will produce orange fur irrespective of what is on the autosome. Those without the O gene (X-) will produce black or tabby. Given normal (XY) males only have 1 X chromosome, they can be orange (XOY) or black or tabby (X-Y) , but not a combination. Female cats could receive an XO from one parent and an X- from the other. Random X-___________________ of cells early in development will result in clones of daughter cells where O is active in some but not in others, resulting in the patchwork coat. Since you need an XX chromosome constitution to be a tortoiseshell, males with this coat pattern are rare, but they do occur. Some are XXY and sterile, however most are chimeras with 2 cell populations XX/XY or XY/XY and some of these are fertile.

autosomal; X; inactivation

Dogs: XX sex reversal: - Chromosomally female (78,XX) but most have ________________ _____________ (usually cryptorchid), epididymes, vas deferens and prostate. These are male externally but have some abnormalities of the genitalia (hypospadias, other penile malformations). Internally they also have a small _____________ but no oviducts. Another part of this syndrome is XX true _______________________. These usually have bilateral ovotestes and female genitalia that is variably masculinized; i.e. masculinization in this syndrome is related to amount of testicular tissue. - Seen most commonly in some families of _____________ _______________ in the USA where it is transmitted as an autosomal recessive trait, but cases reported in at least 18 breeds. All K9 cases so far have been Sry ______________ and the gene or genes involved have not been identified.

bilateral testes; uterus; hermaphrodites; Cocker Spaniels; negative

Effects of freemartinism on the male co-twin: - There is also passage of cells across the placental anastomoses, germ cells and blood cell precursors are known to migrate. Resultant calves, both male and female are __________-cell chimeras. These bull calves generally mature to have poorer fertility than normal males, with poor quality semen and low fertility (in bovine AI this is called a ________ ________-____________ rate - i.e. lots of females are returning to be re-bred on subsequent heat cycles because they are not getting pregnant). - Freemartinism is also reported at low incidence in __________, __________, and _________. The incidence in sheep appears to be increasing with increasing use of high fecundity breeds, risk for the syndrome is greater with litter sizes of 4 or more. It is not reported in marmosets or humans despite extensive vascular anastomoses between twin placentas.

blood; low non-return; sheep, goats and pigs

• The stimulatory effects of improved energy balance on ovarian function (increased ovulation rate) are seen before there are changes in the __________ ___________ of thin animals but also continue when body weight is increasing and remain after it stabilizes at a higher body condition. The nutritional effects have thus been divided into: - ___________ effect - seen before body weight change is detectable - ______________ effect - seen while body weight is increasing - ___________ effect - seen when body weight is maintained at high level • Changes are mediated in the ovary by metabolic hormones and fuels that we have mentioned previously: - glucose - insulin system - leptin system - IGF system

body weight; Acute; Dynamic; Static

Suckling Anestrus Continued: • It is important that the female is ______________ to the suckling calf (or appropriate other species) • At least in some species, the inhibitory effect of suckling on hypothalamic GnRH secretion seems to involve increases in the __________. Suckling of a bonded offspring causes release of maternal EOPs in the hypothalamus and these suppress GnRH neurons. So-far unproven but likely pathway for this inhibition is by the opioids binding to the dynorphin/kappa opioid receptors on KNDy neurons. You can treat these species (like the cow) with _______________, an opioid antagonist, and decrease the duration of suckling anestrus (not practical for on-farm use). o In other species, such as humans, naloxone appears to have little effect, and other neurotransmitters such as ________________ are involved in GnRH suppression. • Increased sensitivity to negative feedback inhibition by ________________ also plays a role. This may also in part be that these early follicles are less steroidogenically active and thus estrogen levels stay low to moderate (inhibitory) never getting to the high levels needed to exceed the threshold required to trigger an LH surge. • Beef cows calving in poor body condition and/or losing significant condition following calving also have components of the "____________ anestrus" physiology. Instead of ovulating the dominant follicle from wave 3 (3.2 on average) at about 30 days post-partum, these cows don't ovulate till follicle wave 10.6 ± 1.2, at 70-100 days after calving.

bonded; EOP's (endogenous opioid peptides); naloxone; serotonin; estrogen; milked

Non-Reproductive organ sexual dimorphisms: - All organs and tissues likely exhibit sexual dimorphism; to date the most widely studied organ in this regard is the __________. Behavioral differences between the sexes, particularly in social and reproductive settings, triggered extensive studies of brain structure and function; and while most until recently have focused on regions associated with reproduction and reproductive behaviors, it is likely that the differences involve every brain cell to some extent. Some of these are highly phylogenetically conserved from insects to mammals. They vary from gross anatomical differences, through ultrastructure, biochemistry and molecular mechanisms. Among other things the ________ of specific areas of the brain may vary by sex, as may clusters of neurones (nuclei), the projections and connections between different areas, concentrations and distributions of enzymes, neurotransmitters and their receptors, and the receptors for steroid hormones.

brain; size

Transabdominal Testicular descent: - However, the most important change for transabdominal descent involves the gubernaculum. In the male the gubernaculum thickens ("swelling reaction"), forming the gubernacular _________ as the cranial suspensory ligament regresses, this anchors the testicle to the internal inguinal region. So rather than the testicle being pulled across the abdominal cavity from up near the kidney, it is actually anchored to the inguinal region by the gubernaculum while the abdomen of the embryo elongates (and everything else moves cranially). - The hormone responsible for this gubernacular growth is ___________-_________ ____________ ____ (INSL3) which is secreted by Leydig cells of the fetal testis. INSL3 binds to its receptor ____________ (G protein-coupled receptor affecting testicular descent; a.k.a. LGR8 - now renamed RFXP2 = relaxin/insulin-like peptide family receptor 2). It appears that the effect of INSL3 can be augmented by AMH and testosterone but that these are of relatively minor importance.

bulb; insulin-like factor 3; GREAT

Post-Partum Cow: • In late pregnancy feed intake declines and cows enter negative energy balance (NEB). • Post-partum, NEB worsens as feed intake further declines and energy requirement for lactation starts to increase. The cow cannot meet her requirements from feed intake and begins to _________________ body tissue. • __________ (worst) of NEB is usually 1-2 weeks post-partum (but this is variable). • GnRH secretion is _______________ until the cow is past nadir of NEB and then it increases. • 1st ovulation generally occurs ____-____ weeks after the nadir of NEB is passed

catabolize; Nadir; inhibited; 2-3

Mechanism of lactational anestrus • How lactational anestrus works is going to depend on what species you examine and under what conditions. Outside of the laboratory rodents, the phenomenon is most closely studied in ____________ (with its ramifications for the profitability of beef and dairy operations) and in _____________ (where the Population Council of the WHO is interested in employing it for contraception). • The syndrome can probably be further subdivided into _____________ anestrus (offspring removes milk - most common) and ____________ anestrus (dairy animal where the offspring is weaned and farmer removes milk) as the physiology of cycle suppression appears to be different in these 2 cases. - In the suckled animal suppression of cyclicity relies on the daily frequency of suckling episodes by a ______________ offspring. - In the milked animal suppression of cyclicity is related to _____________ balance. (Note that a suckled female who is in poor body condition will have components of both)

cattle; women; suckling; milked; bonded; energy

Cell Life vs Death: - Sexual dimorphism in the size of different brain nuclei (groups of cells) involved in reproductive function in the hypothalamus is the result of selective __________ ____________. The nuclei start the same size in males and females and then depending on the region in question, steroid exposure either rescues/preserves the neurons in ___________ (the female ones aren't rescued and die off giving males a bigger nucleus in these areas) or it actively results in neuron ___________________ (the female ones aren't destroyed so in these areas males have a smaller nucleus). - The steroids don't just affect those cells that have receptors for them, which represent only a fraction of brain cells and are located in specific areas. The steroid may also secondarily affect cells lying in close proximity to these primary targets and also cells with which they have a connection.

cell death; males; destruction

Protein: - Extremely low protein diets will cause _________________ of estrous cycles in monogastrics, however most effects of protein deficiency are further down the reproductive axis. Specific ___________ _________ deficiencies are important in monogastrics, causing increased embryonic, fetal and neonatal losses. - In ruminants, excess protein and non-protein nitrogen result in increased urea and ammonia levels. These do not (yet) appear to have an adverse effect on cyclicity. However, in ovarian follicles they cause decreased oocyte quality with consequent reductions in ____________________ rates and blastocyst formation. Increased circulating urea levels also result in decreased uterine _______ which in some studies caused increased embryonic death. (These last results are somewhat controversial.)

cessation; amino acid; fertilization; pH

steroid biochemistry: - Go from __________________, to _____________________ system, to _________________ system, and then to _________________

cholesterol; progesterone; androgen; estrogen

- Disorders of Sexual Development (DSD): Any congenital condition in which the development of _____________________, ________________, or ____________________ sex is atypical. - Older term: Intersex: shows one or more anatomical features of both sexes

chromosomal, gonadal or anatomical

Types/levels of Sex - genetic - sex specific _____________________ pattern - gonadal - ovary vs testis - germ cell - egg vs sperm - hormonal - estrogen vs testosterone (and MIS/AMH + INSL3) - __________________ - internal and external genitalia, secondary sex characteristics - _____________- (e.g. brain, liver, muscle) - behavioral - legal (how sex or gender is defined under the law)

chromosomal; phenotypic; somatic

- The primordial germ cells of females also undergo X inactivation, probably during migration to the urogenital ridge. However both X chromosomes are required to be active for normal meiotic _____________________ _____________ during oogenesis, and the inactivated X of _______________ is reactivated as the germ cells enter meiosis (~12.5 dpc in the mouse). These oocyte X chromosomes remain active until they in turn are involved in formation of a new embryo in the next generation, when lineages of their daughter cells are inactivated as above.

chromosome pairing; oogonia

Photorefractory and Photoinducible: - Animals kept under stimulatory photoperiods eventually stop responding to them, they have essentially reached the end of that phase of the endogenous __________________ rhythm and are said to be _________________________. The length of time it takes to become photorefractory varies with the species in question, being very short in some birds with restricted breeding seasons. These birds end their breeding season by becoming refractory to the long-day stimulus that kicked things off, they may even become refractory while daylength is still increasing. - Animals that become photorefractory may need a period of exposure to ________-__________________ photoperiods before they again become responsive to stimulatory ones (change from being photorefractory to again being _______________________). This can be a very important concept for artificial manipulation of breeding cycles. - Exposure to non-stimulatory photoperiods also appears to be able to hasten the end of the breeding season (to some extent), before the animal would normally cease activity by becoming photorefractory (reaching the end of its endogenous circannual rhythm) - so there is a degree of plasticity in the system.

circannual; photorefractory; non-stimulatory; photoinducible

Inguinoscrotal descent: - In most species we deal with the inguinal canal now ____________ (or rather tightens) preventing migration of other abdominal contents or ascension of the testes. This is also under the influence of androgens, acting through the ________/___________ system. In species such as rodents, the inguinal canal/processus vaginalis maintains a fairly open communication with the peritoneal cavity, and herniation of abdominal viscera is prevented by a ________ ________ attached to the epididymis, which on being drawn into this area as the testicle and epididymis descend, effectively plugs the canal.

closes; GFN/CGRP; fat pad

2. Lyse the CL - Prostaglandins: e.g. Horses • 5-10mg lutalyse or 250-500μg estrumate • Warn owners mare will get _____________ and sweat profusely for ~ 1 hour if using these doses. (Can use ___/____th these doses if give on 2 consecutive days and don't get the side effects) • If have responsive CL, see in heat ____-____ days, (with the ~ 6 day estrus in mares ovulation is usually 9-11 days after the prostaglandin treatment but actual day depends on size of follicle present when give injection - large they may come in and ovulate fast).

colicky; 1/10; 3-5

Why Develop Seasonal Reproduction? - Generally, seasonality is more pronounced the farther a species lives from the equator. Even within a genus or species those members living on the equator may breed _____________________, while those at higher latitudes will exhibit strict seasonality. While we will largely refer to temperate areas, many tropical environments change through the year. In the tropics temperatures only vary in a narrow range, however rainfall and thus food availability can be extremely variable, but often predictable seasonally. - ______________ usually exhibit stricter seasonality in their reproductive capacities than ____________. Males of most species can breed year round, though perhaps with some decline in libido and sperm output in the off season. Examples of this are sheep and horses. In a few species, like temperate __________, males are strictly seasonal and the testes atrophy in the non-breeding season.

continuously; Females; males; deer

Other Nutritional Influences: - Specific vitamin and mineral deficiencies are also more likely to cause embryonic and neonatal losses than to affect female cyclicity. However, ______________ and ______________ deficiencies are reported to cause irregular or suppressed estrous cyclicity.

copper and iodine

At the end of their migration, primordial germ cells become concentrated in the ______________ region of future females and preferentially in the ______________ of genetic males. Migration probably ceases in part because the cells have now reached the highest concentration of attractant.

cortical; medulla

Long Days, Short Days. What is What? - In some cases there is a "_____________ ____________________" or set threshold of light exposure that must be exceeded each day to achieve the desired effect. For example once daylength increases beyond 12.5 hours it is considered a long-day and you might "kick off" reproductive function in spring breeder (like a hamster). - However, in most species, rather than there being a "critical photoperiod" the "photoperiod _____________" is more important. For example: if an animal had been on 8 hours of light: 16 hours of dark (8L:16D) for the past couple of months, exposure to 12L:12D would be interpreted as a switch to _________ days. Alternately, if that same animal had been on 16L:8D, then a change to 12L:12D would be interpreted as a switch to __________ days.

critical photoperiod; history; long; short

The primary follicle: - With the start of development the surrounding precursor granulosa cells become _______________ and then commence mitosis, and formation of the __________ _______________ (z.p.) begins. This change is prolonged and is directed initially by the oocyte and then a cross-talk between oocyte and granulosa cells using secretion of _______________ factors and ___________ cell-cell contact. Specialized junctions (e.g. ________ _______________) appear between the oocyte and granulosa cells. - The appearance of the zona pellucida (z.p.) coincides with the initiation of oocyte growth. The oocyte and its single layer of differentiated (cuboidal) granulosa cells are now termed a primary follicle. - Receptors for ________ on the granulosa cells first appear at the primary follicle stage but the follicle is still independent of FSH action.

cuboidal; zona pellucida; paracrine; direct; FSH

Horses: - Turner's syndrome (63,XO) mares with gonadal dysgenesis are the most common - present for failure to __________ or won't stand for the stallion. (Some suggestion they also have smaller stature and reduced athletic performance). These have the _____________ gonads you would expect. Some reports of cyclicity and pregnancies but these are likely to have been mosaics (XX/XO). - Kleinfelter's syndrome also reported → infertile stallion that may or may not be cryptorchid. - Both XX and XY sex-reversal have been reported in recent well documented cases. So far all XX sex reversed horses have been ________-_______________ (i.e. downstream issue). All reported cases of XY sex-reversal have been _______-________________ (i.e. lack of sry was the issue). - Most cases of "sex reversal" in the older literature were probably complete or partial androgen insensitivity cases and this may be the second most common syndrome in the horse. Though as a species difference, most affected animals have fairly strong __________ behavior following puberty (probably via circulating testosterone acting directly on the brain after it is converted to estrogen, which does seem able to support good libido in stallions). - More recently genetic mutations/copy number variations associated with defects in androgen synthesis in XY individuals have been reported (present as female externally with small testes internally).

cycle; streak; sry-negative; sry-negative; male;

Breeding Season vs. Non-Breeding Season = ↑Frequency vs. ↓ Frequency GnRH pulses: - The currently proposed theory on how the activity of the pulse generator is altered over the year is "_______________ _____________________" or the "histogenesis hypothesis". - Basically this proposes that cells/tissues (in our case the hypothalamus) have an approximately annual cycle of synchronized _____________________: growth, remodeling, degeneration and replacement (think of it as like the haircoat). _________ cells in the tissue divide to increase numbers, migrate to appropriate sites and differentiate to give mature functioning cells; then cell aging, degeneration and death complete the cycle. - Changes in the __________ ______________________ of the stem cells are considered vital for generation of these circannual rhythms. In a temperate, strictly seasonal species, this synchronized process will be entrained to photoperiod changes and for our purposes will result in activation or quiescence of the reproductive axis at different times of the year. Since the central control point for reproduction lies with altering output of the GnRH pulse generator in the hypothalamus, these changes are seen in the brain and reflect a functional plasticity of the neural tissues in this area.

cyclical histogenesis; regeneration; Stem; local environment

Androgen Based Disorders: - Genetic defects that ________________ androgen action in genetic males or _______________ it in genetic females are the most frequently diagnosed causes of disorders in sexual differentiation in humans. Reduced androgen action in genetic males results in the "testicular _____________________" syndromes (affected individuals have testes but a female phenotype)

decrease; increase; feminization

Delayed Puberty in female rodents: • Puberty is delayed in young females housed at high ____________ with other females (age and cycling status of other females not critical). The urinary pheromones causing the delay depend on an intact ______________ ____________ - i.e. the stress of crowding causes their production and they function to delay puberty in young females.

density; adrenal gland

Manipulating an Estrus Cycle to Improve reproductive efficiency: - In many livestock species this (combined with management convenience) is the driving force. In cattle using artificial insemination, the requirement may be to improve heat ________________ efficiency, or program the animals well enough that heat detection is not required at all and timed _____________________ can be performed. It may be desirable from this standpoint to synchronize the cycles of many animals to make the most efficient use of time and labor, or looking at the future, to reduce the period over which calves are born and to have a uniform group of offspring for future sale. Similar scenarios exist for ___________, ___________, __________, and ___________ breeding.

detection; insemination; goats, sheep, pigs and horse

Organizational vs Activational Dimorphisms: - What we've talked about above are largely organizational differences, these are regarded as ________________________ and ____________________. In some cases you see their effects early on (e.g "rough and tumble play" in males vs females), prior to hormonal exposure at puberty. In other cases you need the activational effect of post-pubertal hormones to observe the full structural/physiological/behavioral manifestation. - Activational changes are regarded as _________________ or transient (in response to hormone exposure in later life). But organizational dimorphisms may be required for full manifestations of an activational change: if you give a heifer testosterone and she'll mount cows but will not have the full bull mating behaviors because she doesn't have the underlying organizational changes.

developmental and permanent; reversible

Anti-Mullerian hormone: - Causes regression of the Mullerian ducts in male fetuses - Mostly thought to act locally by _______________ rather than as a classically secreted hormone (though enough is secreted systemically to have some effect - see Freemartins in the Disorders of Sexual Development section later). - Regression of the Mullerian duct in males occurs earlier than does regression of the Wolffian duct in females - Mullerian ducts of developing embryos are only sensitive to MIS for a limited period shortly after _______________ _________ differentiation. Exposure before or after this period is ineffective. - Regression of the Mullerian ducts progresses from cranially to caudally

diffusion; gonadal sex

Meiosis in Females is Arrested Twice: - In females the first meiotic division continues up to the _______________ stage of _______________ where it is arrested at about the time of birth in most animals. - Reinitiation of this first meiosis occurs at some time after ______________. This is a result of the preovulatory LH surge. This action of LH is limited to large ______________ follicles which have survived the selection process in that cycle (i.e. these are the ovulatory follicles for this cycle), because only in these do the granulosa cells have sufficient LH receptors. - The oocyte completes this meiosis and the first polar body - The oocyte immediately enters the 2nd meiotic division and is again arrested. - This second block occurs at the __________________ stage of the second meiosis. - It is in this state that oocytes are ovulated in most species. - Completion of this second meiotic division occurs when the oocyte is reactivated by a penetrating ___________ at the time of fertilization. - Because of these two blocks, and especially the first one, meiosis in females can take years. In women for example, all oocytes have entered the first stage of arrest by birth. If we assume puberty doesn't occur till 12 and menopause is not complete till 50 then meiosis for the oocyte could take anywhere from 12 to 50 years to be completed.

diplotene; prophase; puberty; Graafian; metaphase; sperm

- In females, lack of INSL3 means the gubernaculum never enlarges, remaining a long thin band of tissue. Thus during early embryonic development the female gonad is relatively tightly bound to the ____________ _________ wall while that of the male is relatively tightly bound to the _______________ region. - The final position of the ovary varies with species, remaining closely associated with the dorsal body wall in rodents, dogs and cats; intermediate in the _________; and fairly loosely associated in the _________.

dorsal body; inguinal; mare; cow

Differentiation of the female reproductive tract: Rabbits have a ___________ uterus with totally separate uterine horns and 2 cervixes. Pigs have a ________________ uterus with long horns, little body but a single cervix, ruminants have a ______________ uterus with a larger uterine body. Primates have a _____________ uterus, where the oviducts enter directly into the uterine body. *Note that females, just like males, have ________________ receptors and the 5α-reductase enzyme present in their tissues and as such could be masculinized IF exposed to androgens. They are normally not because they do not have the surge of testosterone production seen in male fetuses.

duplex; bicornuate; bipartite; simplex; androgen

The Bruce Effect • Seen in several rodent species and best described in the mouse, occurrence in other species less certain. When an __________ ________________ female (prior to implantation = before day 4 in mouse) is exposed to a different __________, her pregnancy will fail and she returns to estrus. The significance for the new male is that he gets to put his genes into the population more quickly. • Explanation 1 (usual/traditional explanation): Basis is a __________________ in male urine, detected by the female which causes an increase in _________________ release from the hypothalamus resulting in suppression of ________________ secretion from the anterior pituitary. Since prolactin is a required luteotropin at this stage in mice the CL regresses and pregnancy fails.

early pregnant; male; pheromone; dopamine; prolactin

Origin, migration, multiplication and fate of the Primordial Germ Cells: - The origin of the primordial germ cells (PGCs) is thought to be the primitive _________________ cells of the inner cell mass (a.k.a. the epiblast), under the influence of __________ ___________________ protein (BMP). - PGCs move from their origin to the base of the _______________ and after a period here they are passively incorporated into the endoderm that will form the hindgut. - As this structure expands and elongates the PGCs use it as a conveyor belt to arrive adjacent the gonadal ridges. - Distribution of PGCs along the hindgut in the posterior part of the embryo, coupled with the long narrow shape of the adjacent early gonad, facilitates transfer of the germ cells, which migrate through the dorsal hindgut mesentery and into the ______________ _______________.

ectodermal; bone morphogenic; allantois; genital ridges

Manipulating an Estrus Cycle to Improve management convenience/efficiency: - This is usually tied to improving reproductive or operational _________________. It can be used to concentrate and make predictable the farm labor requirements. If your clients also have town jobs, the time they have available for animal husbandry tasks is further reduced making efficiency paramount.

efficiency

Inguinoscrotal descent: - Sometime after it completes inguinoscrotal migration (timing depending on species), the bulky gubernaculum regresses, allowing the __________________ and _______________ to enter the scrotum. The testicle may enter the inguinal canal and scrotum by a combination of traction from the regressing gubernaculum and being pushed by the increasing intraabdominal pressure that results from the enlargement of other organs.

epididymis and testicle

Differentiation of the male reproductive tract: - The efferent ducts that connect the rete testes to the ________________ arise from residual mesonephric tubules. During development from the Wolffian duct the epididymis becomes extremely __________________, in preparation for its task of sperm maturation and storage following puberty. - More distal parts of the duct becomes the ________ ________________ and small outpouchings form the _______________ _______________. - From the region of the urogenital sinus: the urogenital folds elongate and fuse to form the penile __________, genital swellings fuse to form the ______________, and the genital tubercle develops into the ___________ __________. - Positive effects of reproductive tract male sex differentiation (vas deferens, epididymis, seminal vesicles, penis) are ________________ dependent. - Negative aspects of male differentiation (regression of Mullerian duct) are controlled by __________

epidiymis; convoluted; vas deferens; seminal vesicles; shaft; scrotum; glans penis; androgen; AMH (aka MIS)

The primordial follicle: - Soon after its entry into meiosis the oocyte becomes surrounded by a single layer of flattened ________________ cells, precursors to the ________________ cells, in a structure termed the primordial follicle. These structures are ______________ or non-growing. - Primordial follicles re-commence growth under all physiological conditions and the initiation of development is a _________________ process (i.e. there are always some follicles leaving the resting primordial pool and re-commencing development). The reason for initiation of development in the primordial follicle is unknown, a local balance of inhibitory and stimulatory _____________ factors is involved, but the process is independent of ____________________ stimulation.

epithelial; granulosa; inactive; continuous; growth; gonadotropin

Kleinfelter's Syndrome (XXY): - Defect arises approximately _____________ from mother (XX oocyte) and father (XY sperm) due to errors in ______________. Germ cells are generally present in lower numbers during infancy and the losses accelerate dramatically with onset of puberty accompanied by degeneration of the ____________________ tubules. These boys tend to be tall but have delayed puberty, low testosterone production, sparse pubic and body hair and a relatively small penis. Following puberty affected males are generally ____________. The testes are small, atrophied, have no or few germ cells and the majority of seminiferous tubules are atrophied. As with females, one of the 2 X chromosomes in these individuals is visible as a heterochromatic ________ _________. Loss of germ cells is currently thought most likely to be due to excessive action (double-dosage) of ____-linked genes that escape X-inactivation.

equally; meiosis; seminiferous; sterile; Barr body; X

1. The Luteal Phase (late metestrus and diestrus) - Progesterone is high (primarily responsible for preparing the uterus for pregnancy); Some _______________ and ____________ are being produced by the developing cohorts of small follicles - the follicular waves - Hypothalamus: High progesterone from the CL feeds back on the hypothalamus to decrease the frequency of __________ pulses; Small amounts of estrogen from developing follicles synergize with progesterone to decrease GnRH secretion - Anterior Pituitary: Low frequency GnRH pulses "favor" ________ secretion over LH secretion (this gives some follicular development); Low levels of _______________ from developing waves of follicles suppress release of FSH and LH in response to GnRH (so estradiol has inhibitory action at pituitary as well as hypothalamus) - Inhibin from these developing follicles also functions to inhibit FSH secretion

estradiol and inhibin; GnRH; FSH; estradiol

4. Immediately Post-ovulation (early metestrus): - With ovulation of the large follicle we have lost _______________ and ____________ - The CL (currently a corpus hemorrhagicum, CH) is not yet producing much _______________________; i.e. we are in an ovarian hormone vacuum - Hypothalamus: Levels of GnRH eventually become depleted after the surge and while ______________ exist there is no huge increase in release despite the absence of negative steroid feedback - Anterior Pituitary: LH secretion is often briefly _________________ following the surge. It usually returns in less than a day but levels are reduced, perhaps due to a combination of down-regulation of the GnRH _______________ mechanism, reduced GnRH, and depleted LH stores. (The exact mechanism probably varies between species). - In the absence of inhibition from ovarian estradiol and inhibin there is often a surge release of _________ in the days following ovulation.

estradiol and inhibin; progesterone; pulses; abolished; receptor; FSH

Feedback Control of GnRH secretion: 1. During the progesterone dominated luteal phase of the cycle ______________ levels are low to moderate and thus it acts synergistically with progesterone to decrease the secretion of GnRH. - Note that in animals without progesterone, low to moderate levels of estrogen alone also inhibit GnRH. When acting in an inhibitory fashion, estrogen tends to inhibit GnRH pulse _________________. 2. In the early follicular phase estrogen is ________________ but still below threshold, so it is acting alone to reduce GnRH secretion (there is no progesterone at this stage). - Essentially at this stage it is preventing a large release of GnRH that would trigger a premature LH surge. 3. In the late follicular phase, the higher estrogen level switches from being inhibitory to being stimulatory (once it exceeds a threshold level and exposure time). At this time estrogen causes increased GnRH release - the GnRH surge- which may be just a huge continuous release or due to summation of an increase in amplitude of each GnRH pulse (note that because there is no progesterone during proestrus and early estrus the GnRH pulse frequency has already been increasing).

estrogen; amplitude; increasing

Hormonal Sex: - The main ovarian product in this regard is _______________. In eutherian mammals (the placental mammals) estrogens have been considered to play no role in development of the ovary or female phenotype during fetal life (precluded because both sexes are exposed to _________________ produced estrogens during embryonic and fetal life). - Estrogen is vital for the changes seen during and after ______________. These include not only the physiology of ovarian cycles and secondary sex changes but also in maintenance of the ovary where it prevents loss of follicles and transformation toward male (testicular) structures.

estrogen; maternally; puberty

Follicular Steroidogenesis: - The granulosa cells are the site of ________________ synthesis but they need the help of the theca cells to accomplish the task. While competent to produce everything down the steroidogenic cascade as far as ____________________, granulosa cells cannot convert progesterone to androgens. On the other hand the theca cells can't __________________ androgens to estrogens. To get around this the follicles use the two-cell two-gonadotropin model in order to synthesize estrogens. - _______ stimulates the synthesis of androgens in the theca interna; The androgens (mainly androstenedione) diffuse across the basement membrane into the granulosa cells. In the granulosa these androgens are aromatized to form estradiol under the influence of _________

estrogen; progesterone; aromatize; LH; FSH

Manipulating an Estrus Cycle to manage undesirable behavior: - In pet, show or performance animals sometimes the goal is merely to remove the ___________ behavior altogether rather than synchronize it. These owners may desire drugs rather than surgery if they wish to breed the animal in future.

estrus

Luteolysis in Species with Short Cycles: - In species with short cycles there has to be a mechanism whereby if the animal is not pregnant she is returned to ____________ so another attempt at fertility can be made. - Since the CL inhibits the hypothalamo-pituitary axis by its secretion of progesterone, in order for a new cycle to commence the influence of the CL must be removed. - In these species the natural lifespan of the CL is not so short as the ~____ weeks of activity we see from it. Rather the CL of these species is actively killed off in the absence of pregnancy to allow the next cycle to occur. This process is termed luteolysis.

estrus; 2

• Low estrogen levels as a result of continued low LH (mech 1) plus 2 and 3 above means: - there is reduced expression of ___________ (increased silent estrus and reduced length and intensity of estrus expression) and - LH surge is not induced, the follicle is anovulatory, becomes ___________ and a new follicle wave emerges (though these follicles may also become cystic) • Eventually with improved energy balance: - central inhibition of GnRH pulses is lifted permitting increased ______ pulses - increased insulin stimulates receptors for growth hormone on the ________ and the somatotropic axis is restored - Dominant follicles can now fully mature and secrete sufficient estrogen to give an LH surge and ovulation. • When it occurs, the first ovulation is still likely to be accompanied by a silent _________ and potentially a short-lived ______. Mechanism for reduced intensity of estrus is partly explained above - by reduced estrogen levels but may also involve: - lack of recent ______________________ priming of behavioral centers for cows with prolonged anestrus (see sheep seasonality.) - Effect of reduced _______-____ levels (IGF-1 signaling in the brain is necessary for normal estrogen priming of estrus behavior)

estrus; atretic; LH; liver; heat; CL; progesterone; IGF-1

Estrous vs Menstrual - The vast majority of animals do not menstruate, and in these species the most obvious manifestation of ovarian cyclicity is ___________ (a.k.a. "heat"); the time when she will accept mating. - estrus is a __________________ phenomenon - Menstrual cycles are largely restricted to humans and old-world (Asian and African) primates. Only women do not also have an estrus (behavioral) cycle as well. The other primates can be classified as having both estrus and menstrual cycles, depending on how you want to observe them.

estrus; behavioral

The Whitten Effect: • Involves induction of ___________ when a novel male is introduced into a group of non-cycling females. Females housed in groups often have ___________________ cycles. The introduction of the male overcomes this suppression and the induced cycles are _______________________ in a majority of the females.

estrus; suppressed; synchronized

Patterns of antral follicle development during the estrous cycle: - There is a concept that is being applied to more and more species as they are examined (especially polyestrous species), that growth of antral follicles occurs in waves during the cycle. In this scheme: 1. A cohort of small antral follicles is recruited and grows rapidly (____________________ ____________ phase). 2. _______________ is applied and some follicles undergo atresia while others continue development 3. The ________________ follicle(s) arise. - If a dominant follicle develops at a time when it can trigger an ______ surge (by its estradiol production exceeding the threshold and there is no progesterone in the system), it will ovulate. - However, if the follicle becomes dominant when there is still an active ______, high circulating progesterone levels means it cannot trigger an LH surge. This dominant follicle will enter atresia and lose its functional dominance (stop producing _______________ and ____________). Loss of its suppressive activity allows an increase in FSH secretion and another cohort of small antral follicles is recruited and commences exponential growth ⇨ the process repeats. - Different species may have 1, 2, 3 or more waves of follicles occurring in an estrous cycle until one of them gives rise to a dominant follicle that can induce ________________ - The number of waves per cycle will depend on the time taken for follicles to grow to ________________ (or dominant) size, and the length of the ___________ phase of the cycle.

exponential growth; Selection; dominant; LH; CL; estrogen and inhibin; ovulation; ovulatory; luteal

Inguinoscrotal descent: - While the gubernaculum thickens it also grows out through the internal inguinal ring and canal and moves through the ______________ inguinal ring and into the future _______________. It also hollows out to allow an out-pouching of peritoneum (processus vaginalis) to go with it, which will eventually form the _______________ ___________. The _________________ muscle forms from the outer rim of the gubernaculum. - There is good evidence that the inguinoscrotal movement of the gubernaculum is controlled by androgens and these now appear to act via the _____________________ nerve (GFN). The spinal nucleus of the GFN is sexually dimorphic in rodents, containing more cells in males than females and transection of the GFN inhibits migration of the gubernaculum into the scrotum. It appears that under the influence of androgens, the GFN releases the neurotransmitter ________________ gene-related peptide (CGRP), binding sites for which have been demonstrated on the gubernaculum during the phase of its outgrowth. CGRP causes growth of the tip of the gubernaculum and directs its migration through the inguinal canal and into the scrotum. Androgen exposure also appears to have a role in priming the gubernacular tip to respond to CGRP

external; scrotum; vaginal tunic; cremaster; genitofemoral; calcitonin

Signaling Metabolic Status and altering Hypothalamic GnRH Secretion: Leptin - Leptin is a peptide hormone secreted from white adipose tissue. Circulating levels are directly correlated with _______ ___________, though other short term factors may acutely influence plasma concentrations independent of overall adiposity. Acutely, fasting ______________ leptin within 24 hours in ruminants whereas increased food intake is associated with _________ leptin levels, and these high levels precede any weight gain by the animal. Thus leptin functions as a marker of both long-term nutrition ("fatness") and relatively short-term __________________ changes.

fat stores; reduces; high; metabolic

Long Term Malnourishment: - On the other hand, for individuals that are chronically undernourished (and therefore thin), starting them on a normal ration will not always quickly restore circulating gonadotropin levels or reproductive activity. This has led to the concept that there is a certain degree of "_____________" that is necessary for normal reproduction and has been the basis of body condition scoring in cattle (also horses and sheep) herd health programs. This concept is known as the "____________ _________ _______ hypothesis" and it is still fairly widely accepted. - Using this hypothesis and based on epidemiologic evidence it has been estimated that _____-_____% body fat is required for male spermatogenesis and females require ~______% body fat for optimal cyclicity.

fatness; critical body fat; 12-14; 22

Ovulation: - In all mammals studied, the gonadotropin surge is the event that starts the cascade for ovulation. - This surge may occur spontaneously (spontaneous ovulators) due to ________________ mechanisms in the hypothalamo-pituitary-ovarian axis or may be induced by the stimuli of mating (induced or reflex ovulators). - The interval from the LH surge to actual ovulation varies with species, ranging from 10 hours in the ___________ to ______ hours in women and mares. - The follicle does not rupture under the influence of intrafollicular fluid pressure per se. Rather, the current hypothesis (and evidence) is that ovulation is the result of an inflammatory cascade that weakens the _______________ ________. - The egg and surrounding _____________ ________________ are usually expelled within ____ minutes of follicular rupture, signaling the completion of the process.

feedback; rabbit; 36; follicular wall; cumulus oophorus; 2

Long Term Malnourishment: - However, when individuals are kept well below these levels of body fat for long periods they may resume ___________ ______________ without any improvement in body condition. There appears to be a degree of adaptation available, or put another way, the "degree of fatness" and the reproductive control axis can be separated from each other. This dissociation can also be shown experimentally and has lead to the more recent concept that, while fatness and the reproductive axis are associated, the association is not a _____________ ___________ one. - There may also be species variation in the relative importance for thin animals of replacing minimal body fat levels vs. getting some acute increases in available calories; and this may depend on reproductive strategies and life history of the species. - The theory that looks at more acute changes in caloric availability as controlling GnRH secretion is borrowed from the control of eating behavior and is called the "_________________ ___________ hypothesis".

fertile cyclicity; directly causal; metabolic fuels

Mammalian sex determination/differentiation has been regarded as a 3 step process: 1. Genetic (chromosomal) sex is determined at the time of _____________________, the X containing oocyte is fertilized by either an X- or Y-bearing sperm 2. Sex determination occurs when the bipotential or indifferent ___________ is put on the male or female pathway. The action of a Y chromosome _________ in male embryos kick-starts a cascade that results in testis formation. In female embryos the absence of this gene allows dominance of the ovarian pathway. 3. Sexual differentiation of male and female ___________________ result from the specific ________________ secretions of the now determined testis or ovary

fertilization; gonad; gene; phenotype; hormone

Overall Effect of the Early Follicular Phase: - You have increasing pulse frequency of GnRH from the hypothalamus, increasing pulse frequency of LH and enough FSH from the pituitary to permit continued _____________ ____________ (particularly of dominant follicles) and increasing estrogen concentrations BUT an LH surge is prevented by negative _______________ actions on both the hypothalamus and pituitary (the estrogen has not yet reached the threshold level needed to switch from negative to positive feedback).

follicle growth; estrogen

Overall Effect of the Luteal Phase on FSH: FSH release ➔ _____________ growth ➔ increased estradiol and inhibin ➔ decreased ________ ➔ follicle regression ➔ decreased ________________ and _____________ ➔ FSH release ➔ follicle growth ➔ etc.

follicle; FSH; estradiol and inhibin

Overall effect of immediate post-ovulation phase: - This FSH release may function to recruit a new cohort of ______________ to the growing pool for the new cycle (i.e. it kicks off a "wave" of follicle growth).

follicles

Stages of the estrous cycle (Not all species will experience all phases): 1. Proestrus - Stage of _______________ growth prior to estrus (estrogen increasing) 2. Estrus - Time when female will accept mating by the male (estrogen _________) 3. Metestrus - Period immediately following _________________. (______________________ increasing) - The stage of the developing corpus luteum (CL). - Immediately post ovulation the vacated follicular cavity fills with blood and is termed a corpus _______________________ (CH). Over the next few days (metestrus) this develops into the CL. 4. Diestrus - The stage of ____________ _____________ dominance of the cycle. (progesterone high) - Uterus is prepared for and receptive to establishment of pregnancy. - Window of opportunity for the embryo to establish itself. 5. Anestrus Time of reproductive quiescence. Not pregnant, no follicles, no CL. o Juvenile anestrus o Seasonal anestrus o Lactational anestrus o Nutritional anestrus o Pathological anestrus o Senile anestrus o Behavioral anestrus* 6. Interestrus - Term sometimes used for ________________ ovulators - If they go from proestrus into estrus and then aren't mated they go out of heat for a while until the next wave of follicles grows and puts them back in _________________. Instead of using anestrus for the short period of inactivity it is termed interestrus

follicular; high; ovulation; progesterone; hemorrhagicum; corpus luteum; induced; proestrus

If 2 sexes are so good why not 3, 4 or more? -These systems are seen in some higher ___________ and lower ___________________ and can give multiple mating types (can mate with every sexual type but your own). These systems have not become more widely spread and it is thought that they are unstable and tend to revert to 2- or 1-sex systems.

fungi; eukaryotes

• In most species the overall (population) sex ratio is approximately equal (male:female). However, the parental investment of the two sexes is generally unequal: - Females usually have a far greater physical input into reproduction in terms of raising the next generation. They do the gestation, lactation and most (or all) of the offspring care. Females also produce relatively few _______________ (eggs or oocytes) and require relatively few ______________ to ensure that these are fertilized. While females are engaged in much of their reproductive activity they are unavailable for mating (put another way: mating is a small component of their total reproductive effort). - Males generally produce lots of ______________ (sperm) and have little or no involvement in supporting gestation, lactation and offspring rearing. Thus mating is a large part of their reproductive effort and they are capable of fertilizing more than a single female's eggs.

gametes; matings; gametes

Meiosis in the Female: - Meiosis is a specialized form of cell division practiced by the germ cells. It involves a single round of DNA replication followed by 2 consecutive rounds of cell division. These 2 consecutive divisions are meiotic divisions. - The progeny cells (_______________) end up with half the chromosome complement of the parent cell. During the 1st division genetic material is _________________ as DNA is exchanged between the original maternal and paternal chromosomes. Thus the gametes produced are genetically mixed and will combine with other genetically mixed gametes from the sexual partner to form the next generation. As such, meiosis is fundamental to the advantages of sexual reproduction. - Meiosis in females has 2 unique features: The cell divisions are _____________, and the process is arrested ___________.

gametes; reshuffled; unequal; twice

Seasonal Influences on Age at Puberty: Food Supply: • Seasonal variations in nutrition influence growth rate and thus the achievement of the metabolic _________. This may not matter so much if you are long-lived like a human, that now achieves puberty at 12 instead of 16 like 180 years ago - either way you still have lots of reproductive opportunities. • However, it can be vital for short-lived species. Deer mice live ~ ______ weeks, with earliest puberty at ~ 5 weeks. If they are born late in the season when food is scarce, their only chance for reproduction is to try and overwinter to achieve success in spring. Many members of short-lived species with strict photoperiodic controls may never achieve puberty before they die, because they grow too slowly if food is limiting.

gate; 18;

X-inactivation: - Since there is little genetic information on the Y chromosome but considerable amounts on the X, there is a genetic inequality between the sexes in mammals. - X-inactivation is the process that equalizes these quantitative genetic differences in mammals. This process silences or inactivates most of the ___________ on one of the X chromosomes in XX individuals (in individuals with more than 2 X chromosomes, all but one are inactivated). The inactivated X forms the _________ body visible in some cell preparations. - During embryonic development, the presence of 2 active X chromosomes is actually incompatible with normal progression beyond the __________________ stage

genes; Barr; blastocyst

Brain Sex and other somatic sexual dimorphisms: It isn't all Hormones: - The hormonal mechanism controlling somatic sexual dimorphisms in mammals has primacy, but it is not the only story. Several sexual dimorphisms appear to be the result of direct _____________ influences or epigenetics independent of hormone exposure. - Genetic (chromosomal) constitution of the cell o The direct effect of the cell being XX or XY; The genes are uniquely expressed in one sex (e.g. non-pseudoautosomal region Y chromosome genes occur only in male mammals); they are expressed at higher level in one sex due to _____________ effects (X-linked genes that escape X-inactivation in female mammals) - Epigenetic Effects o Particularly here are changes associated with differential ___________________ of DNA/acetylation of histones; they are imprinted (e.g. different expression of Xp vs Xm copy); sex-specific regions of heterochromatin that exert epigenetic effects on other parts of the genome?

genetic; dosage; methylation

Why do females Choose? When assessing potential mates in a pool, a female is interested in a number of things: 1. Get the best _______________ for her offspring • offspring survival - ______________ resistance - Ability to cope with environment • offspring breeding success - "__________ _________" - if a male has characteristics that are particularly attractive he will potentially pass these on to his sons and they will also be attractive and have lots of mating success. So by breeding with an attractive male the female increases the chances that her genes will be passed on. 2. Best resources for raising offspring 3. Ideally she would like to avoid exposing herself to _____________ during the mating process. 4. _______________ assistance with offspring care

genetics; Disease; Sexy sons; disease; Paternal

XX sex-reversed males = XX Testicular DSD: - Have testes and are phenotypically male though sterile. Sterile because XX __________ cells seem unable to survive in the testes. - Fairly common in humans - 1/20,000 male babies - Causes: Translocation of ________ to X or an autosome. (80% of human cases are SRY positive) _______________ of a downstream gene that activates the testis cascade in the absence of sry

germ; SRY; Mutation

Differentiation of the Ovary: - The stage of the undifferentiated gonad is prolonged in females compared to males (because males have SRY to give them a head start) - In the female embryo, cords of mesonephric tissue colonize the central part of the indifferent gonad, pushing the _________ cells to the periphery (cortex). Germ cells remaining in the central region eventually degenerate. The cells in the cortex multiply and differentiate and establish cortical dominance, with clusters (or "nests") of germ cells (______________ at this point). Somatic cell lineages, including the supporting cells (pre-granulosa cells) which are thought to be from the ____________________, proliferate and express female pre-granulosa pathway marker genes (_____________ and __________) and not male ones . Up to this point, even if there are no germ cells, the somatic cells of the ovary develop normally on the female pathway.

germ; oogonia; mesonephros; FOXL2 and Wnt4

Under conditions of acutely increased nutrition: _______________, ____________, and ___________ are all increased, and according to the model, intrafollicular levels of IGF binding proteins are also increased (remember from the follicular dominance section that these render IGF _______________). In states of maintained high nutrition, with high fat stores, leptin is increased. • Glucose and insulin increased to high levels = increased glucose uptake into follicles; This (paradoxically) suppresses _______________ secretion from follicles • Leptin increased; This suppresses ________________ secretion from follicles • Intrafollicular IGFBP increased = less free IGF; This suppresses estradiol secretion from follicles

glucose, insulin and leptin; inactive; estradiol; estradiol;

The Zona Pellucida: - This is a ___________________ coat, produced by the oocyte from the primary follicle stage onward. It surrounds the oocyte but allows cellular connections from the _______________ _________________ cells to be maintained - Important role in fertilization

glycoprotein; cumulus granulosa

Sex-Reversal - XX males and XY females: - In these syndromes both ______________ and _____________________ sex agree but are at odds with _____________________ sex. Since gonadal sex is at odds with chromosomal sex these are known as Disorders of Gonadal Sex in the new classification system. - In both XX and XY sex-reversal, true hermaphrodites may also occur.

gonadal and phenotypic; chromosomal

Induced ovulation: - This could more accurately be described as induced ____________________ surge. - Diverse species are induced ovulators, including: ferret, mink, rabbit, domestic cat, racoons, beavers, voles and new- and old-world camelids. - The LH surge of induced ovulators is caused by a _________________________ reflex that is activated by mating - The sensory receptors or fields are not restricted to the genital area (vagina, cervix, sperm deposition), but also include body surface _____________ receptors, __________________, ____________, and ______________ stimuli. - To successfully induce an LH surge, mating usually must activate several of these. - A single mating occurrence will often be insufficient to ensure an LH surge (i.e. she may need multiple matings/interactions with a male to ensure ovulation)

gonadotropin; neuroendocrine; tactile; olfactory, visual and auditory

The Direct Drive Hypothesis: • In this scenario puberty is simply the result of an increased drive for GnRH secretion, a function of brain centers. It is steroid independent: i.e. there is no role for the _____________ in the early stages- the same sequence occurs in intact and gonadectomized animals (until you start getting the mature cycle-control feedback mechanisms laid down). This system fits well with the events of puberty in __________ ________________. Different cell types in the hypothalamus provide inhibitory or stimulatory inputs to the GnRH neurones. During the juvenile period the inhibitory neuron influence predominates and at puberty this is reset in favor of the stimulatory inputs. This input can be direct or indirect, and at least some of the indirect is mediated by inhibition of _________________ (KNDy) neurons in the juvenile state. • Inhibitory influences: ___________ (main one) and NPY (male primates) • Stimulatory Influences: _________________ (main one), Norepinephrine?, NPY? (Female primates), Astroglial cells • The jury is still out on whether the initial event is a decline in inhibition or an increase in stimulation.

gonads; male primates; kisspeptin; GABA; Glutamate

Control of Gonadotropin Secretion: Inhibin: - Inhibin is a product of the ______________ cells of ovarian follicles - It acts at the pituitary to specifically decrease ________ secretion (mainly during ____________)

granulosa; FSH; estrus

Actions of the Gonadotropins: FSH: • _________________ cell differentiation (granulosa cells are a major component of ovarian follicles) • positively influences ovarian steroidogenesis by increasing levels of rate-limiting enzymes especially ________________ (therefore increases estrogen production) • stimulates ____________ production (so it's directly involved in its own inhibition) • Acts with estrogen to increase FSH _______________ • Stimulates formation of receptors for ______ and ________________

granulosa; aromatase; inhibin; receptors; LH and prolactin

Dietary Fat: - Feeding some fat to ruminants also results in increased propionate production, with similar effects to ionophore feeding. It increases __________________ proliferation, increases medium sized follicle population and improves _________________ performance independent of any effect on energy balance. There may also be increases in ________________ and ____________ steroidogenesis. - The ratios of n-6:n-3 polyunsaturated fatty acids (PUFAs) in the diet may have numerous effects on reproduction though some of the research is still unclear - There is evidence that the use of high dietary concentrations of the n-____ series found in fish meal and fish oils, can reduce the formation of prostaglandin by the uterine endometrium and perhaps decrease the sensitivity of the CL to prostaglandins that are released. This may result in longer _____________ cycle (diestrus) and increased embryo survival. - So it has been suggested to feed n-3 PUFAs around the time of breeding. Relatively high n-3 levels may also reduce the risk of pre-term labor by reducing levels of circulating inflammatory __________________. - By contrast n-6 PUFAs promote ______________ production and it has been suggested to feed them in the immediate post-partum period to promote uterine involution and clearance of bacterial contamination.

granulosa; breeding; follicular and luteal; 3; estrous; cytokines; PGF2α

What's the physiology for the Whitten Effect? (the following is the current model) o The follicles present in late anestrus at the time of male introduction are of lower quality, particularly in regard to their ________________ cell function o After the male is introduced they respond to increased gonadotropins (ex. FSH) by secreting enough _______________ to induce the LH surge and ovulate but they result in a lower quality CL o Reduced function of the large luteal cells (from granulosa cells) means that ______________________ secretion from these CLs is lower by day 4 post-ovulation than that of normal CLs o The wave of follicle growth occurring at this time increases systemic estrogen levels o Reduced progesterone and increased estrogen increases the E:P ratio which results in premature onset of the luteolytic mechanism (by day ____-____) and the CL is destroyed.

granulosa; estrogen; progesterone; 5-6

Milked anestrus: • In the dairy cow that is milked rather than suckled, and in mothers of other species that are in lower body condition, a nutritional or metabolic anestrus comes into play. • Increase in ____________ hormone following calving drives nutrient partitioning to support lactation (i.e. cows will prioritize certain systems for energy allocation and estrous cycles and maintaining body stores rank lower on their list of priorities than does lactation). High milk production per se is not the problem, you can largely divorce the effects of high milk production from poor cyclicity (and fertility) if you can maintain the cow in reasonable energy balance. It is the inability of ___________ to keep pace with increased demand. • Multiple factors influence the time it actually takes a dairy cow to have her first ovulation after calving including parity, calving difficulties, developing a metabolic disease, heat stress, lameness, metritis and endometritis; but by far the most important is ____________ _______________, particularly the severity of body condition score (BCS) loss.

growth; intake; energy balance

Timing of testicular descent: Ram and bull - ________ way through gestation Boar - last quarter of gestation Stallion - just before birth to 1st 2 weeks postnatally Tom - usually by birth, should be easily palpable at first vaccination (6-8 weeks) Dog - ______-______ days of age but may not be fully in scrotum till 6-8 weeks (6 months limit) human - __________ to birth

half; 10-14; prior

Cell Division During Female Meiosis is Unequal: - The end result expected from these 2 meiotic divisions would be 4 daughter cells each having half the chromosomal content of the parent. - During spermatogenesis in males this is exactly what happens. - However, in females each original 2N oogonia entering meiosis gives rise to only one ____________ _____________ at the conclusion of the two meiotic divisions. - This is because cytokinesis (the cell division or formation of daughter cells part) in females is uneven. Nearly all the cytoplasm goes to one of the cells at each division. The smaller remnant cells are called ___________ _____________. - The first polar body, arising from the first meiotic division, is 1N 2C. - The second polar body, from the second meiotic division, is 1N 1C. - This unequal cell division is required in order to preserve oocyte cytoplasmic content/products needed for development of the early embryo (e.g. _______________________, _______________________).

haploid oocyte; polar bodies; microtubules, mitochondria

Effects of Stress on Reproduction: - Stress can be defined as any state in which ____________________ is lost (or potentially lost) - Whereas a ______________ would be a stimulus (real or perceived) which may threaten homeostasis. As such, stressors provide the animals with information on adverse environmental conditions. - We saw previously that reproduction represents a significant energetic crunch, but one which is fairly predictable in terms of timing (such as late pregnancy and lactation). It makes sense for an animal, in the face of an adverse environment (stress) to temporarily avoid committing to the future increased metabolic load that reproduction requires. The effect of stress on reproduction does vary by species, sex, and in females by their hormonal status (stage of cycle). - ______________ stress is almost universally inhibitory to reproduction whereas the effect of ___________ stress is more variable (negative, zero or even positive).

homeostasis; stressor; Chronic; acute

Along with the autosomes mammals have a pair of sex chromosomes: -In females these are XX; females are the chromosomally ____________________ sex - both sex chromosomes look alike and the homogametic sex - all female gametes (oocytes) have an X chromosome -In males they are XY; males are the chromosomally _____________________ sex - one X and one Y chromosome and the heterogametic sex - sperm may contain either an X or a Y chromosome

homologous; heterologous

Hormonal Sex: - Differentiation of the bipotential gonad as a testicle, or later as an ovary, determines its major __________________ products. These are important in determining further sexual differentiation of the individual. It does not matter what the chromosomal makeup of the individual is, functional testes will secrete ______________________, _________-_________________ hormone [AMH a.k.a. Mullerian inhibiting substance (MIS)] and Insulin-like factor____. These are important for subsequent differentiation as a male during fetal life, and for developing the male secondary sex characteristics seen following puberty. Their presence drives genetic cascades to give male __________________ and in their absence genetic pathways to female phenotype are followed. In support of this, castration of a male fetus (prior to testis determination) results in development of a phenotypically female animal.

hormonal; testosterone, anti-Mullerian; 3; phenotype

Hormone Exposure is largely responsible for setting "Brain Sex" in Mammals: - For brain sexual dimorphisms in mammals, particularly for those associated with reproductive function and behaviors, the most important influence is ________________ exposure; i.e. "brain sex" is largely set by steroid exposure. This exposure happens in the "_________________ ______________ period" (late fetal to early neonatal depending on species), occurs in males, and is due to the second surge of testosterone production from the testes. - the first testosterone surge was involved in setting phenotypic sex, whereas it is the second one that sets __________ sex (and many other somatic sex differences).

hormone; perinatal sensitive; brain

General model of luteolysis: - The sustained high levels of progesterone throughout the luteal phase finally cause down-regulation of the progesterone receptor in both the ________________________ and _______________ ________________________. - This means that progesterone has less influence at the tissue level and small amounts of _______________ from developing follicles can have more influence. - The results of this effective increase in the ratio of Estrogen/Progesterone are that: 1. Receptors for _______________ are up regulated in the uterine endometrium 2. The activity of the central oxytocin pulse generator (involving the hypothalamus and posterior pituitary) is _________________. - This increased oxytocin release and the increase in its receptors on the uterine endometrium cause ______________ release. - The PGF2α acts on the corpus luteum to cause luteolysis.

hypothalamus and uterine endometrium; estrogen; oxytocin; increased; PGF2α

Effects of Nutrition on the Estrous Cycle: - Under nutrition primarily affects the _______________________, reducing GnRH secretion, which is then reflected in function of the pituitary and ovaries. - Increased nutrition has the ___________ as the primary target with the H-P axis secondarily affected by altered feedback.

hypothalamus; ovary

Which X to inactivate? - In females one X chromosome is maternally derived (Xm), and one is paternal (Xp), as indeed are all the autosomes. They are said to be parentally ________________ (in normal XY males all X chromosomes are maternally derived and all Y's are paternal). - The current general model for X-inactivation is as follows: Xp (paternal X) is inactivated in _______ cells during the early cleavage divisions of the embryo. At the early _________________ stage the Xp is then re-activated in cells of the inner cell mass (ICM) [so both Xp and Xm are briefly active in cells that will form the embryo proper, while Xp remains inactive in cells that will form the _______________ (the now differentiated trophoblast and primitive endoderm)]. The cells of the inner cell mass then undergo random X-inactivation (either Xm or Xp).

imprinted; all; blastocyst; placenta

During X-inactivation: 1. The X chromosomes are counted and all but one is/are __________________ 2. The inactivation spreads from its site of initiation to silence the majority of the genes on the affected X chromosome. o Parts of the affected chromosome escape inactivation, this appears especially true of the region carrying homologous genes (present on both X and Y = the _________________________ region, PAR) that is involved in chromosome pairing during cell division. Currently it is thought that around ____% of genes on the inactivated X actually escape inactivation (are transcribed). 3. The inactivation is stabilized so that the inactive X is clonally ___________________ through successive cell divisions o i.e. all daughter/granddaughter/etc cells resulting from mitotic division of this first cell that gets X-inactivated in embryonic development will have the same X chromosome inactivated. So you wind up with different cell ________________ in the embryo, some having one X inactivated and some having the other.

inactivated; pseudoautosomal; 5; transmitted; lineages

Use of Pheromones in Mate Choice: • Similar to visual cues, olfactory cues influence mate selection. Both sexes may use pheromones in mate choice as a mechanism for avoidance of ___________________. The scent of an individual is specific and represents the genetic constitution of the major histocompatability complex. It has been shown that within a species individuals will choose a mate with a different chemical signal in preference to one who is similar. This confers several potential advantages: 1. Inbreeding avoidance and the associated loss of ____________ that accompanies it. 2. MHC _______________________. If your mate is different in the MHC then by combining yours with theirs you give genetic variation to your offspring - they are likely to have resistance to a greater range of _________________ and __________________ • Olfactory cues can also be used to determine the ___________ of potential mates. In several species females have shown the ability to differentiate diseased and healthy males based on scent alone, and they chose the healthy one. • Note that female responsiveness to male pheromones varies across the estrous cycle. Recently shown in mice that ______________________ blocks female responsiveness to male urinary proteins (MUPs). She still detects them on the olfactory epithelium but progesterone blocks the signal transduction mechanism. The effect is specific: progesterone exposure has no effect on her response to predator chemosignals (kairomones).

inbreeding; fitness; heterozygosity; parasites and pathogens; health; progesterone

Stages and Speed of Follicular Growth: 1. Preantral growth phase: - Covers the time from entry of the primordial follicle into the growing pool until it is a large secondary follicle, i.e. the period of preantral growth. (FSH _____________________) - This is a ________ phase of growth (several months). 2. Tonic growth phase: This phase takes the secondary follicle to a small antral (or tertiary) follicle. (FSH ________________ in larger species) - Takes 2 months in women 3. Exponential growth phase: - A sub-population of follicles (a cohort) are recruited from those at the end of the tonic growth phase (2-5 mm in women) and enter the exponential growth phase that will result in a large, ________________ (perhaps ovulatory) follicle. (FSH _________________ till near end)

independent; slow; responsive; dominant; dependent

The Lifespan of the Corpus Luteum Determines Cycle Length: - Eutherian mammals (have placenta) can be categorized based on how long the corpus luteum functions for in the non-fertile/non-mated estrous cycle. - The shortest would be the ______________ ovulators where no ovulation occurs in the absence of mating and there is no luteal phase at all. - If we leave these out then the rest (spontaneous ovulators) have been categorized as having either ultra-short, short or long cycles.

induced

Cryptorchidism: - Cryptorchidism is the failure of one (unilateral) or both (bilateral) testicles to descend into the scrotum at the normal time. Since testicular descent is a complex process the condition could have multiple etiologies. That said many of the cases seem to be _______________ rather than ___________________ retained and a case can be made for a defect in the androgen pathway for inguinoscrotal descent (production/receptor/post-receptor), perhaps with a role for the GFN. It is often suspected in human medicine to be due to a defect in _______________ _______________ secretion. Lack of androgen action could also theoretically result in retention of the cranial suspensory ligament which would prevent transabdominal descent, in practice this doesn't seem to happen - so long as the ____________ system is active the testes will get through the transabdominal stage even in the complete absence of androgen action. Other causes could be __________________ (eg abdominal wall defect so no increase in abdominal pressure) and ___________________ (eg GFN/CGRP anomalies). Aberrant migration of the gubernaculum, with insertion in the scrotal neck or side rather than base, has also been reported.

inguinally; abdominally; prenatal androgen; INSL3; mechanical; neurological

How does the GnRH Pulse Generator Work?: - The main direct stimulator of GnRH neurons is a peptide called ________________. GnRH neurons have receptors for kisspeptin and respond to it by releasing GnRH. - In the pulse generator region, the neurons containing kisspeptin also contain two other transmitters: ________________ ____ and _________________. These neurons are thus known as KNDy neurons and are the basis of _______________ activity. These KNDy neurons are spontaneously active and are interconnected by their dendrites and axons. In one cell the membrane reaches electrical threshold and triggers an action potential which causes release of _________ from its dendrites and axons. This NKB acts on its receptors (NK3) on this cell and the interconnected cells, causing multiple cells to fire (depolarize) which then recruit more and more cells so the whole interconnected population fires approximately synchronously releasing not only NKB but also kisspeptin and dynorphin. The kisspeptin acts on its receptors (GPR54) on GnRH axon terminals in the _____________ _________________ to cause release of GnRH into the hypophyseal-portal system. Dynorphin release is slower and it's action (via kappa opioid receptors; KOR) to activate cell membrane channels that will _________________ the cell membrane is delayed; but once it acts the KNDy cell is inhibited for a more prolonged period before it can fire again. - The result for the ARC KNDy cell population is a brief period of high, synchronous activity where kisspeptin is released, followed by a longer inhibited period when it isn't and this is reflected in the intermittent pulses of GnRH.

kisspeptin; neurokinin B (NKB) and dynorphin; pulsatile; NKB; median eminence; repolarize

Ultimate Factors in seasonality: - One limitation on development of seasonality or how strictly it is adhered to is the _______________ of individuals in the species concerned. If your lifespan is only a few months you may well die out if you only breed in a short season. - Thus animals with short lifespans tend to be more _______________________. They may have a "normal" breeding season, but if conditions become favorable outside of this, many of them are capable of breeding (lots of rodents fit in here and these often live in a favorable "microclimate"). - Another factor that will influence the development of seasonal breeding is the ________________ strategy of the species or population. If you have a special diet then you tend to be more restricted as to its availability and thus are more likely to show seasonality. If you are willing to eat anything then your breeding season can be longer, and may be year round.

lifespan; opportunistic; foraging

Steps 1 and 2: Measuring Daylength and SCN Control of Daily Melatonin Secretion: • However under natural conditions the activity of these SCN clock genes is entrained to the _________-________ cycle. The result for the pineal gland is that the SCN stimulates it to secrete melatonin in hours of darkness, starting at dusk. - In mammals the SCN gets its light vs dark information using photoreceptors in the __________. - Nerves from the retina project via the retinohypothalamic tract to the ________________________ nucleus (SCN). • Once the entrained SCN oscillator has been triggered at dusk, left to its own devices it would like to stimulate the pineal to secrete melatonin till it oscillates off (i.e. reaches the end of its endogenous circadian cycle - the _____ hours in sheep above). However, once the animal has been in darkness for a threshold amount of time (often ____-____ hours), light exposure of sufficient intensity and duration will bypass the SCN and cause the cessation of melatonin secretion. In a natural state this means at dawn but can be created artificially by turning on the lights at night after the required duration of dark exposure has been passed.

light-dark; retina; suprachiasmatic; 16; 8-9

Insulin-like Growth Factor 1 (IGF-1): - While some is produced locally in astrocytes, the great majority IGF-1 seen by the hypothalamus comes from circulating levels produced by the _________ in response to _____________ ________________ stimulation. IGF-1 can directly enhance secretion by __________ neurons and also appears to be able to act indirectly by increasing kiss secretion from KNDy neurons. Under conditions of restricted feeding IGF-1 levels _______________ and consequently so do these stimulatory inputs.

liver; growth hormone; GnRH; decrease

Flushing: - This is an old technique of increasing ovulation rate in sheep (and other species) that are in ________ body condition. It works by using the acute phase of the mechanism above. The females are put on a high plane of nutrition (>NRC recommendations) 2-3 weeks prior to breeding. However flushing only works in _________________________ ewes and only brings them up to the reproductive level of _________________ conditioned animals. It is a short-term tool that allows them to achieve but not to exceed their genetic potential.

low; undernourished; normally

Gonadal Descent: - Testicular descent occurs only in ________________, where it is present in the vast majority of species. In these the testes require the lower temperature present in the scrotum (____-____ °C below core body temperature) for successful spermatogenesis. Species that have internal testes as a normal state are known as ____________________ (from the latin condere meaning "to hide") and in mammals this includes elephants, armadillos, chinchillas and the cetaceans. The control mechanisms behind testicular descent are slowly being worked out and the current biphasic model is presented below.

mammals; 2-5; testicondids

Social Influences on Reproduction: - The biological aim of an individual is to ensure that their genetics are passed on to the next generation. Ideally, you also ensure that this next generation is given every opportunity to succeed both in terms of survival and in mating, so that your genes are passed on for generations to come. The best way to maximize the chance of this happening is to breed with the best available __________: hopefully the characteristics that made them successful will be passed on (you want to include their genetic superiority in your offspring). To this end there is competition for mating opportunities, which involves selection both within the members of a sex and between the sexes. This process is termed sexual ________________ (______________________ and _____________________ respectively).

mate; selection; intrasexual and intersexual

The Stressful effects of Reproduction • Males and females are often stressed differently by reproduction. Especially in polygynous species where males compete to mate but then have no role in care of the offspring. • For males ____________ is a stressful business. They need to grow and maintain the secondary sex characteristics that will let them attract females and intimidate or fight rivals. They may have to defend a territory or mates against rivals and perform courtship displays. All of these things are taxing, stressful and take resources from homeostatic areas like the ______________ system. • The stress of _____________ in reindeer increases glucocorticoids, which decreases immune function, making the animals prone to high parasite burdens. • An extreme example is the _____________ ___________________, a small marsupial. Males of this species are involved in a frenzy of fighting other males and prolonged mating bouts with females. The result is increased glucocorticoids, involution of lymphoid tissues, reduced immune function, parasitism and death in their first year. • In females the stresses arise during pregnancy and lactation. It is usually hypothesized that reduced ______________________ function in pregnancy is required to avoid rejection of the fetus. However, it may be that the energetic demands of pregnancy cause nutrient repartitioning that results in the reduced immunologic competence. A reduction in ________________ resistance and increased shedding of parasite eggs is a well-recognized phenomenon after birth and during early lactation.

mating; immune; rutting (sound they make); brown antechinus; immunologic; parasite

A further proliferation then occurs in other, non-Sertoli cell lines and these cells are recruited to the male pathway by the Sertoli cells using cell-cell interactions: • The germ cells are drawn into the _______________ and then groups of them are surrounded by Sertoli cell clusters which will develop into the testis cords (which become prominent by 12.5 dpc in mice; _____ days in sheep). The cords will become the future ______________________ ________________ after a central lumen develops and a basement membrane forms. • Leydig cells are induced to differentiate by fetal Sertoli cells and are partitioned to the __________________ (outside the cords). • In males, ___________ cells migrate into the genital ridge from the mesonephros and surround the cords, perhaps participating with Sertoli cells in cord development. The myoid cells also separate the Sertoli and Leydig cells.

medulla; 31; seminiferous tubules; interstitium; myoid

Why Develop Seasonal Reproduction? - Reproduction represents a huge energetic crunch, especially for females. In mammals, not only does the mother carry the young and nourish them during gestation, but also provides for rapid post-natal growth by lactating. - While doing this she has to attend to her own energy needs for _________________ maintenance, thermoregulation, locomotion (with greater foraging time required for her now increased needs); and perhaps her own growth, fat deposition and further reproductive efforts (cyclicity). - ________________ usually represents the time of greatest food need for the female; this is especially true for smaller mammals such as rodents, where caloric requirement may triple. - Seasonal breeding develops to move maximal energy requirement to the time of maximal food availability and in a temperate environment this generally means spring. This is a time of increasing food abundance and moderating environmental conditions. It also provides time for offspring to be ______________ and still put on sufficient body stores to survive the lean times ahead in winter. So seasonal breeding maximizes offspring survival and thus parental reproductive success.

metabolic; Lactation; weaned

Long cycles (long-lived corpora lutea): - This pattern is seen in some ____________________* species. - In this case a fully functional CL forms after ovulation irrespective of ____________ and its lifespan is not shortened by prostaglandin-mediated destruction. The CL of the non-pregnant cycle lives out its natural lifespan, slowly declining in function as degenerative changes accumulate. - This is the pattern in _________ where in both pregnancy and non-pregnancy the CL lasts for around 60 days (often it actually lasts a bit longer in non-pregnancy than pregnancy). ` * Monoestrous species have just 1 cycle after which they become ______________ for a period. Examples besides the domestic dog, which tends to be non-seasonal, are the wolf and roe deer which are seasonal. (Non-seasonally monoestrus vs seasonally monoestrus)

monoestrous; mating; dogs; anestrus

Step 6: It's (Seasonal) Histogenesis Time: • Local T3 levels are hugely important for tissue ________________________. For example they are involved in controlling the transformation of tadpoles to frogs and regrowth of severed limbs in other amphibians (speed and success of which intriguingly depends on photoperiod!). • As we saw earlier, for our short-day breeding ewe example this long-day increase in T3 causes remodeling that increases _______________ of the GnRH pulse generator and stops cyclicity by: - decreasing the number of __________ neurons and increasing their sensitivity to estrogen inhibition - increasing the number of estrogen sensitive glutaminergic neurons that stimulate the inhibitory ________________ system (which inhibits GnRH release) - Increases sensitivity of __________________ neurons inhibitory estrogen feedback so they no longer inhibit activity of the dopamine neurons

morphogenesis; inhibition; KNDy; dopamine; GABAergic

Ultra-short cycles (________-__________________ corpora lutea): - These occur in the ___________ and _______. In the absence of mating they ovulate but a fully functional CL doesn't form and the length of the estrous cycle is only 4-5 days. In this case the CL doesn't fully differentiate and only minimal progesterone is secreted. - If a sterile mating (i.e. vasectomized male) occurs then a functional CL does form in response to the luteotropic action of an initial mating-induced _______________ secretion. This CL lasts 12-14 days under continued support from diurnal prolactin secretion from the pituitary.

mouse and rat; non-functional; prolactin

The antral or tertiary follicle continued: • The granulosa layer of antral follicles is both structurally and functionally heterogeneous with at least 3 populations of cells present: - The ___________ granulosa cells near the follicular basement membrane are the most ___________ steroidogenically. - ____________ granulosa cells line the antral cavity. - ______________ cells surround the oocyte and have little or no aromatase activity. • These different sub-populations of granulosa cells have different but cooperative functions. • Despite the differences, extensive communications via gap junctions and ______________ messengers ensure integrated responses within the granulosa compartment and between it and the oocyte. • Late in development, large preovulatory follicles acquire ______ receptors on the granulosa cells, but only on those of the __________ layer. This is vital for their final maturation and ability to respond to the LH surge.

mural; active; Antral; Cumulus; chemical; LH; mural

- In the developing ovary there is no ___________ precursor invasion as seen in the testicle, and the supporting follicular (granulosa cells) are eventually in direct contact with the steroid secreting __________ cells (well, they do have a basement membrane between them, but no other cell type). - Thus, while __________ cells are not required for the formation of the testes and its cords, they are an absolute requirement for formation of the normal ovary with _______________ structure.

myoid; theca; germ; follicular

Muller's Ratchet -Most genetic mutations are deleterious and these will accumulate over time in species that reproduce asexually - these populations ratchet forward with gradually decreasing _____________ ______________. This is also known as the "mutational meltdown of the clones". Sexual reproduction helps avoid this problem through the process of genetic mixing and repair that occurs during meiosis when sperm and eggs are produced.

natural fitness

Pigs - Rarely is there evidence of vascular anastomosis in the developing placentas of early pig fetuses. When abutment of membranes does occur at the tips they generally become ______________. Thus freemartinism is rare, obviously a good thing given the large number of mixed sex piglets in each litter. - Other forms of intersex are however not unusual in genetically _____________ pigs. These generally involve the presence of ovotestes or testes. The higher levels of intersex are associated with inbreeding and the use of particular boars.

necrotic; female

The Gonadostat Hypothesis: • In this model the secretion of GnRH during the juvenile period is kept in check by ______________ feedback inhibition from _______________ steroids (hence "gonadostat"). In these species, ovariectomy of juveniles causes GnRH pulse frequency to increase to that (or near that) seen in pubertal animals. • The passage through puberty is controlled by changing sensitivity of the ______________________ to gonadal steroid feedback. During the juvenile period, sensitivity to inhibitory steroid feedback (estrogen in females) is very _________. During puberty this sensitivity decreases (resetting of the gonadostat), GnRH secretion increases and acts on the pituitary to give increases in FSH and LH which then allow full follicular development of the ovaries. • The gonadostat hypothesis fits fairly well for some species, such as ___________ and _____________, especially females - less research has been done on males of these species. • In many species it is postulated that both systems (direct drive and gonadostat) have a role and there may be a difference between the sexes. Thus in male primates direct drive appears operational while in females a combination of direct drive and gonadostat theories are required to explain the observations.

negative; gonadal; hypothalamus; high; sheep and cattle

Germ-cell Sex Determination: Mitosis vs. Meiosis - Primordial germ cells sometimes migrate to extragonadal sites, usually the adrenals or kidneys. Irrespective of the sex of the embryo, all germ cells at these non-gonadal sites differentiate as _____________ (ie both XX and XY primordial germ cells) and enter meiosis at the same stage as oocytes would in the ovary. These ____________ cells later degenerate, probably due to the absence of surrounding _________________ (follicle) cells; a similar fate awaits those in the ovary that fail to become surrounded by supporting cells to form a follicle. Thus all germ cells are potentially "female" irrespective of their genetic sex, unless they migrate to a developing testis and are enclosed in the ____________________ cords. - The reverse occurs in seminiferous cords of the testes. Here both XX and XY germ cells will enter mitotic arrest and develop as T-__________________________.

oocytes; ectopic; supporting; seminiferous; spermatogonia

- Thus, whether the primordial germ cells differentiate into oocytes or spermatogonia depends on the gonadal environment in which they find themselves, not on their genetic makeup. - However, their genetic sex does significantly impact their fate/success during subsequent ___________________ or _____________________________: - The presence of only one X chromosome in oogonia causes a reduction in oocyte survival during meiosis. XO (_______________ syndrome) and XY (sex-reversed) females have decreased number of oocytes in the post-natal ovary. In mice this leads to a reduced reproductive lifespan. Perhaps due to the increased time from birth to puberty compared to mice (months or years vs weeks), and thus increased time for losses to occur, women and most of our domestic species females of XO and XY constitution are almost invariably ____________. - Conversely, the presence of XX chromosomes in germ cells of the testicle results in male infertility, the germ cells fail to progress beyond ____________________________ and degenerate when mitosis resumes after birth. Presumably this is due to lack of Y chromosome genes controlling spermatogenesis and possibly excess dosage of an ____-___________ gene.

oogenesis or spermatogenesis; Turner's; sterile; prospermatogonia; X-linked

- _______________: female germ cell dividing by mitosis (numbers increasing); when finished this stage they become: - _____________: female germ cell that has entered meiosis (dividing to become haploid, no increase in cell numbers)

oogonia; oocyte

Behavioral Sex: - Still other behaviors observed post-puberty require no apparent ________________________ changes - they can be induced in animals exposed to steroids for the first time as adults. - Trying to find which brain dimorphism results in which behavior can be difficult and the work that has been done is largely confined to laboratory animals and some birds. - e.g. copulatory behavior - SDN of POA rats, voles male > female - Another problem is that behavior can vary depending on how it is ________________: "Crying infant response" in male and female rhesus monkeys- When tested separately both male and female monkeys respond, When tested together only female responds

organizational; observed

Steps 1 and 2: Measuring Daylength and SCN Control of Daily Melatonin Secretion: • Within neurons of the SCN there are a series of _______________ "clock" genes responsible for circadian rhythms (the SCN is the body's main circadian pacemaker). These genes alter the electrical activity of the SCN and thus the activity of the tissues it innervates. • The suprachiasmatic nucleus directs fibers to the ______________ ______________ ganglion (SCG). • The superior cervical ganglion is the sole innervation of the ____________ ___________ which secretes melatonin (and the pineal gland only secretes melatonin when it is told to by the SCN) o Because of this if you keep an animal under constant darkness, the pineal gland will not secrete melatonin for the whole time, eventually the circadian pacemaker in the SCN will shut it off (because of oscillating activity innate to the SCN).

oscillating; superior cervical; pineal gland

Increasing Energy to Increase Reproduction: - While effects of negative energy balance were mediated at the level of the hypothalamus, improving nutrition beyond normal does not seem to stimulate the H-P axis to further increase GnRH secretion. Rather, the positive influence of elevated nutrition is mediated at the ____________/____________ level with some secondary input from the H-P axis. It results in an increase in the number of mature ______________ that develop per cycle and thus the number of ovulations and eventually in increased __________ size. - The energy requirements to mature follicles are probably infinitesimal when compared to body requirements so it isn't that you need the extra energy in order to grow the extra follicles. Rather, the metabolic systems signal the ovary that environmental conditions are exceptionally good for reproduction right now and the ovary responds.

ovarian/follicle; follicles; litter

In lower animals the indifferent gonad has 2 distinct regions: the cortex and the medulla. The cortex differentiates into the ___________ and the medulla into the _____________. A similar, if less defined, arrangement occurs in mammals.

ovary; testicle

True Hermaphrodite: - True hermaphrodites have both ovarian and testicular tissue. There may be one ovary and one testicle, the presence of an ________________, or any combination. These are rare in mammals. - They can occur in 2 situations: 1. When the timing of expression of the male pathway is shifted _________ or that of the female pathway is shifted _____________ so that they overlap. 2. When male and female __________________ cells are simultaneously present in the developing gonad. If under ~______% of the supporting cells are XY (future Sertoli cells) then these start to differentiate as Sertoli cells but are too scattered to form testis cords. In the absence of testis cords the germ cells can enter meiosis, becoming ______________, which then recruit all the supporting cells (including those that already started to become Sertoli cells) to form follicles, and an ovary results. - The resultant sexual phenotype may be male, female or hermaphrodite, depending on the ratio of Y containing ___________________ cells to other types in the gonad.

ovotestis; later; earlier; supporting; 30; oocytes; supporting

Formation of the corpus luteum (CL): - The corpus luteum forms from the remnants of the _________________ _____________. Species with multiple ovulations form multiple corpora lutea. - The process of CL formation is termed luteinization. It begins following the LH surge but prior to ovulation, when follicles begin to secrete less _______________ and more ______________________ - The initial stages of luteinization in all species are due to the LH surge. - Following ovulation the collapsed follicle reorganizes. _________________ and ___________ cells respectively form the large (>20μm) and small (<20μm) luteal cells (sometimes called granulosa lutein and theca lutein cells respectively). The presence of both small and large luteal cells has been found in most but not all species examined; the __________ is one of the exceptions, while both follicular granulosa and theca cells give rise to luteal cells there is no appreciable difference between them in this species. - Large luteal cells are responsible for most of the baseline _____________________ secretion but do not respond to LH by increasing progesterone secretion. Small luteal cells do respond to LH with increased progesterone secretion. - The function of the CL is secretion of progesterone to prepare the uterus for the ensuing pregnancy. It also prevents _____________ receptivity. Further ovulations are prevented by the action of progesterone to suppress gonadotropin surge release from the hypothalamo-pituitary axis. - _________________ growth may still occur

ovulated follicle; estrogen; progesterone; Granulosa and theca; bitch; progesterone; sexual; Follicular

Follicle Selection: - Recruitment results in a cohort or pool of similar sized, rapidly growing antral follicles. - While they grow in size, the number of follicles in the cohort is reduced to the species specific _________________ __________ in a process termed selection (in cows, mares and women this will result in 1-2 ovulatory follicles, in sows it may result in 20). - The process involves both the emergence of the follicle(s) destined to ovulate (________________ follicle of the ovulatory wave) and _____________ of the others.

ovulatory quota; dominant; atresia

Luteolysis in ruminants: - In ruminants not only does the above counter-current exchange system apply, but they have an additional source of ______________, the CL itself. - In these species release of oxytocin from the pituitary is backed up by release from the ___________, setting up a positive feedback loop where release of _____________ from the uterine endometrium causes oxytocin release from the CL, causes more uterine PGF2α release, and so on (also known as a feed-______________ loop), this drives the CL to destruction.

oxytocin; ovary; PGF2α; forward

Pseudohermaphrodite - These are an abnormality of __________________ sex. The chromosomal and gonadal sex are the same but the phenotype of the internal and/or external genitalia show some features of the opposite sex. - They are classified as male or female on the basis of their ______________ sex. - male pseudohermaphrodite: Has XY ______________________ and _____________ but female characteristics of internal or external genitalia; in the female is it opposite

phenotypic; gonadal; chromosomes and testes

Social Factors in Attainment of Puberty • These cues are mostly _____________________, and perhaps tactile. A pheromone in the urine of male mice accelarates puberty onset in young females. The pheromone is produced in response to androgens and is strongest in urine from dominant males (they have more testosterone). • Boar steroidal pheromones _______________________ and ______________________ will hasten puberty in gilts. Similar effects have been seen in goats, sheep and cattle. Collectively this hastening of puberty on exposure to males is termed the _____________________ Effect.

pheromonal; androstenone and androstenol; Vandenberg

Coolidge Effect • Noted first in male rodents where it is thought to be _____________________ mediated. Males mated to _________________ or refusal with one female will recover ____________ when exposed to another female. Also seen in other species where it may not be entirely pheromonal (e.g. visual) and is also described in females on exposure to new males.

pheromonally; exhaustion; libido

- This has practical implications for the stud manager wanting to breed mares in February when they are normally anestrus. Light exposure must begin in December to be effective by the desired time of mating. Alteration of _____________________ is also applied to other livestock to alter reproduction: chickens are given increased hours of light to stimulate egg production, sheep are occasionally housed in "light-tight" buildings so that the hours of darkness can be increased for out of season breeding in intensive lamb raising enterprises. - There are also sex differences within a species and breed for these responses. Thus in rams the H-P-G axis fires up ____-______ months _____________ than it does in ewes. This earlier onset in rams is important because spermatogenesis takes ~45 days, whereas ewes can ovulate within 7-28 days of commencing their transition

photoperiod; 1-1.5; earlier

Proximate factors in seasonality: - These are the cues animals actually use to time their seasonality. By far the most important in species we deal with is ____________________ (duration of light in a 24 hour period). - Photoperiod is good because it changes reliably with the seasons, it is a signal with little "noise" (whereas temperature tends to fluctuate more on a daily basis). - When referring to photoperiod, the interval of light exposure is called "___________________", while the time of darkness is called "____________________".

photoperiod; photophase; scotophase

Pheromones: - These are substances secreted by one individual that give specific ____________________ reactions in other individuals of the same species. - It used to be thought that all these signals were detected by the _____________________ organ and processed through this "__________________ olfactory system" (AOS). It is now known that many pheromonal signals are interpreted by the __________ olfactory system (MOS) and that the systems cooperate to influence behavior and physiology. The MOS is particularly useful at interpreting _____________ signals because the vomeronasal organ has to actually contact the pheromone source (e.g. urine).

physiologic; vomeronasal; accessory; main; distant

Control of Gonadotropin Secretion: Progesterone: - Progesterone appears to have little or no direct _______________ action and thus reduced gonadotropin (especially LH) secretion in diestrus is secondary to its action on hypothalamic GnRH secretion.

pituitary

Extrahypothalamic Sites of HPA-HPG Axis Interaction: - There are also reports of CRH acting directly on the ________________ and ____________, and for hypothalamic, pituitary and gonadal actions of ACTH and cortisol. At present the studies are confusing and our most consistent information is that stress primarily inhibits reproduction via CRH (and AVP) acting within the hypothalamus.

pituitary and gonad

Control of Gonadotropin Secretion: Estrogen: - Most of the actions of estrogen feedback on LH and FSH secretion are mediated via its actions on hypothalamic GnRH secretion, but it can also act directly at the ______________, in either an inhibitory (most of the cycle) or stimulatory (to generate the LH surge) manner. - When acting in an inhibitory manner, particularly during diestrus, estrogen seems to especially reduce _________ secretion (LH is already more suppressed at this time by the lower GnRH levels since it is more GnRH dependent). - During proestrus/early estrus estrogen acting in an inhibitory manner at the pituitary gland is known as the "pituitary __________", reducing the sensitivity of pituitary gonadotropes to GnRH. So at this brief time of the cycle in most species it acts both to decrease GnRH secretion from the hypothalamus and the pituitary response to it. - Once the threshold level of estrogen is exceeded (later estrus), it first acts to remove inhibition of pituitary sensitivity (lifting of the pituitary clamp) and then to have the reverse action: actually increasing the _______________ of the pituitary gonadotropes to GnRH. The sudden increase in GnRH secretion by the hypothalamus combined with this higher pituitary sensitivity = surge release of ______.

pituitary; FSH; clamp; sensitivity; LH

4. Suppression of Hypothalamo-pituitary axis - with a non-progestagen 1. GnRH super agonists • Critical Points: Work by down regulating ________________ responses to GnRH, but first give a surge of gonadotropin output and ovarian stimulation before the shut-down occurs. - Now occasionally being used as medium-term contraceptives in _________, _________ and wild carnivores. - Bitches: 6 mg deslorelin implant causes anestrus for _____-_____ months. But initial surge response causes proestrus and estrus (fertile). This can be prevented by using 2mg/kg of ________________ ______________ for 14 days at time of implant. - With the risks associated with megestrol acetate (pyometra), some clinicians are using __________________ instead (similar feedback inhibitory effect on GnRH as progesterone - see mibolerone below). 2. GnRH antagonists - Replacing the GnRH super agonists in women since they do not cause an initial burst of pituitary (and thus ovarian) activity prior to inhibition. - Act by competing with GnRH for ________________ at the pituitary (i.e. they "block" the receptors) - Still prohibitively ________________ for veterinary use. 3. Mibolerone drops (Cheque, Upjohn - now off market but can compound) - Bitches: _______________ steroid, 41x more anabolic and 16x more androgenic than methyltestosterone; Put on feed, supplies feedback inhibition of hypothalamus. Some anabolic activity - popular among the field-trial set.

pituitary; dogs, cats; 12-20; megestrol acetate; androgens; receptors; expensive; Anabolic

Seasonal Breeders: The Predictor Option: - Animals that are seasonal reproducers are said to have taken the "_________________ ______________" - they are planners and use a reliable predictor (change in photoperiod) of a future seasonal change (to abundant food/good conditions) as a timing device for maximal reproductive competence. Even though this often means conditions may not be optimal when they are undergoing their period of ______________/________________, they will be (or are likely to be) by the time gestation is completed. - When considering when to start triggering reproductive competence (return to fertile cycles) in the year, the species needs to take into account not only their gestation length but also how long it will take them to transition from ________________ to fully functional ______________. The length of this transition varies by species and sex, but it may take weeks to months to restore full functionality to the hypothalamo-pituitary-gonadal axis. - So the equation is essentially: Start up H-P-G axis = Spring - (gestation length + transition period)

predictor option; fertility/breeding; anestrus; cyclicity

ANESTRUS: • Anestrus is the absence of estrus or, more broadly, the absence of cyclicity. Whenever an animal presents for this complaint one of your first steps, before doing anything invasive, should be to ensure she is not ________________. Anestrus is typically divided into several categories • Juvenile Anestrus - Prior to ______________ the animal is acyclic, though there will be follicular development these follicles will not fully mature. • Nutritional Anestrus - In periods of nutritional stress and poor body condition, cyclicity ____________. • Seasonal Anestrus - Seasonal breeders will be anestrus in the non-breeding season (or pregnant depending on whether mated and their gestation length). • lactational anestrus

pregnant; puberty; ceases;

Menstruation vs. Pseudomenstruation in other Species: - Blood coming from the vagina is a natural part of the estrous cycle in some species. But it is usually not menses as we know it in women (and old-world primates) with destruction and sloughing of the endometrium at the end of the luteal phase. - Female Dog: Vaginal bleeding is a normal part of ________________ in the bitch. Generally the discharge clears to a straw color as they enter estrus, but this is far from a hard and fast rule, with some continuing to bleed. High estrogen levels in proestrus cause rapid development of the uterine ___________________. Blood cells are lost into the uterine lumen at this time by __________________ and following rupture of small capillaries. This blood can seep through the relaxing cervix ⇨ discharged from vagina. - Cow: Bleeding may be evident at the vulva in ________________. This occurs in the majority of animals, approaching 100% in heifers, down to around 50% in mature cows - incidence depends on observation! Source is the ________________ capillaries (parts of the uterine lining), which hemorrhage following the rapid decline in estrogen after ovulation. - Bats: Real ____________________ is seen in the phyllostomid family of bats. This family includes the short-tailed fruit bat and vampire bat. This menses is associated with decline in ___________ function and involves sloughing of the endometrium. - Elephant Shrew: Real menstruation

proestrus; endometrium; diapedesis; metestrus; caruncular; menstruation; luteal

Basic Approaches to Manipulate an Estrus Cycle: 1. Mimic the CL by administering progesterone or _______________________. 2. Lyse the CL by administering a luteolytic drug - usually _____________. 3. Induce ________________ of a mature follicle by causing an LH surge or administering one. 4. Prevent _______________ by suppressing the hypothalamo pituitary axis (drug other than progesterone) 5. Increase ovulation rate by administering ________ or FSH-like compounds 6. Various combinations of the above

progestagens; PGF2α; ovulation; cyclicity; FSH

Corpus luteum: - The LH surge induces luteinization of the granulosa cells of the follicle, so in most species they start to secrete some ____________________ prior to ovulation. After ovulation the granulosa and theca cells further differentiate to form the mature corpus luteum. Progesterone secretion from this structure usually consists of a baseline intrinsic level upon which is superimposed an LH responsive component.

progesterone

Sodium Ionophores (e.g. monensin): - Alters rumen microflora and results in shift away from acetate and butyrate and toward ___________________ as the product of fermentation. This is gluconeogenic, which in turn increases insulin. Has been shown to increase pituitary sensitivity to ___________ and improve reproductive performance, especially under less than ideal nutrition.

propionate; GnRH

Lee-Boot Effect: • Another one from mice. Mature females housed in crowded groups have extended estrous cycles by entering a period of _________________________/extended _______________. An estrogen dependent pheromone in the ____________ (likely of dominant females) is received by the _____________________ organ of other females where it increases prolactin levels, which are _____________________ in mice - extending the diestrus phase of the cycle and keeping them out of heat.

pseudopregnancy; diestrus; urine; vomeronasal; luteotrophic

Behavioral Sex: - Males and females show many sexually dimorphic behaviors that either occur or are imprinted prior to the large differences in sex-specific steroid secretion that occur during and following ________________. - These behaviors are largely thought to be set during sexual _____________________ of the __________ in the late fetal or neonatal period (organizational changes). Thus in female rats behavior can be masculinized by a single androgen injection in the first few days of life. - While set early in life, the behavior may not be evident until after the occurrence of puberty and its high circulating steroid levels (activational change). In studied species, mate preference appears to be developmentally programmed to some extent by exposure to androgen in the ________________ sensitive period but is not activated until re-exposure to androgens at puberty (males). - Still other behaviors observed post-puberty require no apparent ________________________ changes - they can be induced in animals exposed to steroids for the first time as adults.

puberty; differentiation; brain; perinatal; organizational

A similar multiplication phase occurs in the developing testes. However, in males meiosis does not commence until ______________. Rather, the germ cells of the male fetus enter mitotic arrest as ___________________________ when the female germ cells are entering meiosis (13-15 dpc in mice), and these prospermatogonia resume mitotic proliferation post-natally.

puberty; prospermatogonia

- For its function it is vital that GnRH secretion is ______________. If you give constant infusions of GnRH you down-regulate the system and secretion of LH and FSH (FSH to a lesser degree) cease. - However, in vivo, GnRH neurons don't secrete much GnRH autonomously (without being told to) and don't organize themselves to do so synchronously (to give a GnRH pulse release). There is another layer of control: In rodents, but less certainly in other species, the hypothalamus has separate "pulse" and "surge" centers controlling GnRH release. The pulse (or tonic) center (____________ _____________) is responsible for the discrete episodic secretions described above and is under inhibitory control by gonadal steroids - this is the GnRH release system for most of the cycle. The surge center (_______________________ nucleus of the ________________ area) is only involved during generation of the preovulatory GnRH surge that causes the LH surge which results in ovulation. It has a threshold level of _______________ for response - once the threshold is passed it is stimulated to release GnRH.

pulsatile; arcuate nucleus (ARC); anteroventral nucleus of the preoptic area - AVPV; estrogen

1. Mimic the CL by administering progesterone or progestogens: e.g. Bitches • Induction of _________________ is always a risk with progestogen so now used infrequently. • _________________ _______________ (Ovaban) no longer on US market - available compounded on script • Given orally in: ________________ to stop entering heat - 2.2 mg/kg daily for ____ days. Confine to avoid males. May fail if start too early (she comes back in when you stop) or start too late (she'll have a fertile cycle during treatment). - Suppression in 3-8 days, delay next cycle ____-____ months. anestrus to delay next heat - 0.55 mg/kg daily for a month, start 2 weeks before next expected proestrus. - Delays next proestrus for 4-6 months after end treatment.

pyometra; Megestrol acetate; proestrus; 8; 4-6

Metabolic Fuels Hypothesis • This hypothesis hinges on the body's ability to detect changes in metabolic fuels that are available for oxidation. There are 2 parts to this: - The fuel (calories in some form) has to be present in the body in sufficient ________________ - It has to be available for ________________ in tissues • What are the fuels being detected? - Based on experimental evidence the most important of these is _______________. - Note that the glucose not only has to be circulating to be available but also has to be able to get into the tissues where it is oxidized. States where there is a deficit in glucose oxidation are termed ______________________. - Fatty acids available for oxidation are also potentially important (lack = lipoprivation) but evidence for an effect on the reproductive axis is lacking at present.

quantity; oxidation; glucose; glucoprivation

The Whitten Effect: • In sheep and goat breeding this phenomenon is known as the ________ or _________ effect. It is used hasten the entry of late anestrus ewes and does into the breeding season. Introduction of a novel ram to ewes on the verge of cycling often results in the majority of ewes starting synchronized cycles ___________________. _____________________ present in the neck fleece and secretions of the orbital (head) glands of the ram and buck are responsible for the effect. These are produced under the influence of ________. Females use both the MOS and AOS to detect the signals which are relayed through the __________________ to KNDy neurons in the arcuate nucleus. This increases firing rate of these neurons and thus the frequency of GnRH release. • Females (ewes and does) with well-developed follicles will experience an LH surge in _______ hours and ovulate by day ____ after male introduction (1st ovulation). Some of them might go on to have regular cycles after this but in many you get the following sequence: - The corpus luteum of this first cycle undergoes early luteolysis and she has a second ovulation ____-____ days after the males were introduced. On this second cycle the CL functions for a normal length of time and she has regular cycles hereafter.

ram or buck; immediately; Pheromones; DHT (dihydrotestostrone); amygdala; 24; 3; 6-9

While sheep are short-day breeders, their annual cycle is really controlled by long days? - If you keep sheep under constant short photoperiods they will become ________________ and stop cycling but they won't start cycling again - at least not in something resembling a breeding season (no cycles or odd cycles). If you give them long-term constant release melatonin implants the same thing happens. - However, if you keep them under constant long photoperiods they show ____________ ______________ breeding seasons (with a periodicity of about 10 months). These are short-day breeders so what the heck is happening? -Exposure to long days actively __________________ the reproductive axis (spring/summer under ambient conditions) but it can only do this for a maximum of about 7 months after which the ewes become refractory to the inhibition and resume breeding. So you need exposure to long days to initiate ________________ of the reproductive axis to which the animals then become ________________ to enter the next breeding season; i.e. they need long days to re-set the system. While there doesn't seem to be a critical short-day photoperiod to stimulate entry to the season, it appears that these long days required for re-set have a minimal required daily photoperiod (light exposure) of 12.5-13 hours and they need exposure to these long days for a minimum of ______ days. - Once they've had exposure to at least 35 long days then if you expose them to short days you can hasten entry into the breeding season BUT short days are not necessary for them to have a breeding season (they will become refractory to long days eventually and have one) whereas long day exposure is necessary to program the next season (having constant short days means they stop cycling when they hit the end of their endogenous __________________ cycle and won't re-start because they need long days to re-set it i.e. YES: the photoperiodic system of this short-day breeder is really under control of long days). You can exploit the system by exposing them alternately to 3 month periods of long and then short days (and repeat) and get 2 breeding seasons a year.

refractory; robust regular; suppresses; inhibition; refractory; 35; circannual

• As a result, males and females tend to have different priorities: - Female reproductive success is limited by access to _________________ to develop eggs and raise offspring - Male reproductive success is limited by access to ______________ __________ • If a male wants to breed then he needs to have some characteristic, physical or behavioral, that allows him to out-compete his rivals and convince the females he is worth mating with.

resources; female eggs

2. Lyse the CL - Prostaglandins Critical Points: • Work by lysing the CL so for this to work: - The animals HAVE to be cycling (if they are anestrus there is no point) - The CL has to be at a _________________ stage of development (in most species this means ____ days post-ovulation but for sows and bitches it is longer) • Prostaglandin F2α and its analogs - _______________ (Upjohn) - Dinoprost - ________________ (Bayer) - Cloprostenol • Can use 1 dose (i.e. treat all herd/flock on 1 occasion) but only a percentage (usually ~ ______%) of animals respond because they need to have a CL at a susceptible stage of development. Thus ____ injections are often given, the second timed so that animals not responding to the first will respond to the second and those that did respond to the first will also have a suitable CL to respond again.

responsive; 5; Lutalyse; Estrumate; 60; 2

Circannual Rhythms: - While many species will have an annual rhythm of reproduction, not all species have them entrained to the seasons. For example a domestic bitch has a "circannual" rhythm (or at least an intradian one) of reproduction but it is not tightly controlled by ________________ ______________________ changes, whereas in a wolf it is. - The innate nature of circannual rhythms is shown when animals displaying strict seasonal patterns are kept artificially under constant daylengths. For example, if you keep mares under constant long days (say 16L:8D) which are normally considered stimulatory to reproductive activity, they will eventually become ________________ anyway. Under these constant photoperiod conditions the endogenous circannual oscillation often has a period of about _____ months (instead of a year), and this applies to diverse species and body system changes, including reproduction. - Domestication of a species commonly decreases ______________________ controls over time, or at least extends the breeding season compared to the wild counterpart.

seasonal photoperiod; anestrus; 10; photoperiod

The Whitten Effect Continued: - In ewes (sheep) the first ovulation and often the second one is __________ (no signs of estrus), whereas in does (goats) about ______% show estrous on the first male-induced ovulation and all show by the second. Why? Ewes need ______________________ priming (prior exposure) to show the full signs of estrus, does do not. For ewes the short-lived lower-level exposure to progesterone from the first CL is also often not enough to prime them for the second cycle, so they have 2 silent heats (one at about day 2-3 and the next at day 6-9) following ram introduction.

silent; 60; progesterone

Differentiation of the Testicle -Currently, the earliest noted change during sex determination is a doubling in the _________ of the gonads in XY embryos compared to its XX counterpart. This is initially due to a massive proliferation of pre-Sertoli cells that is directed by Sry. This proliferation is required for formation of the testicle and potentially to inhibit the female pathway (ovarian development). A threshold number (~ >_______%) of cells in the gonad must be Sry-expressing pre-Sertoli cells or a testicle cannot form and an ovary will result. -Expression of Sry in these pre-Sertoli cells is short-lived. The protein product of Sry working together with that of ______-____ results in up-regulation of Sox9 which then needs to be continually expressed - The up-regulation and continued expression of Sox9 is the critical step to cause differentiation of the supporting cells into Sertoli cells. - The fact that only 30% of supporting cells (future Sertoli cells) need to express Sry implies that _______________ signals from these cells can recruit other supporting cells (Sry negative or prior to Sry expression) to the Sertoli cell pathway.

size; 30; SF-1; paracrine

Gonadotropin Releasing Hormone (GnRH) - GnRH, like other hypothalamic releasing and inhibiting hormones is produced in very __________ quantities and precisely timed ___________. By secreting in bursts the signal can be coded for different effects: __________________ and __________________ can be altered independently. The fidelity of this signal to the anterior pituitary is maintained by using the hypothalamo-hypophyseal portal system permitting the hormones to be transported a very short distance in a small volume blood system.

small; bursts; amplitude and frequency;

Opportunistic Breeders: - Seasonal breeders are not the only ones that don't breed continuously. The opportunists are a group of generally _________, short-lived animals (and some birds) that alter their reproductive activity based on food availability. If given sufficient food these animals will breed year round. - To take advantage of this strategy they also have short ________________ periods - you don't want the food to run out before you need it for lactation and newly weaned offspring. - It is another strategy for coping with a harsh environment but this time one that changes unpredictably. It is a strategy you might see in a desert dweller. - Some of these animals even respond to the promise of food. In a desert good rains will result in the growth, flowering and seeding of plants (another opportunistic group of desert reproducers). The local animals breed with the ________, so after a short gestation or egg incubation period they can make use of the flush of growth.

small; gestation; rain

Permissive Signals Altering the Time of Puberty: Somatic Growth and Composition (Nutrition): • Timing of puberty represents an interaction of genetic and environmental factors. The earliest possible puberty for an individual is genetically limited, how close the animal goes to achieving this lower limit is probably related to when it achieves a set level of _____________ development. Thus the initiation of puberty is generally more closely tied to body ____________ than to chronologic age. • Essentially, if you haven't reached these markers you are not ready to reproduce (certainly not ready for a successful pregnancy) so making the developmental clock wait until the permissive signals are achieved is a __________________ mechanism. • Restricting dietary intake retards growth and delays the time of puberty.

somatic; growth; protective

Actions of the Gonadotropins: LH: • main controller of follicular _________________________ • maintains steroidogenic enzymes but also acts to increase substrate availability for steroidogenesis • adequate pulsatile secretion of LH is necessary to drive conversion of __________________ (the steroidogenesis substrate) to androgens (which can then be converted to estrogen) - The LH surge also: • sets in motion the ovulation cascade • induces granulosa cell ____________________ (developing of CL) • causes resumption of oocyte ______________

steroidogenesis; cholesterol; luteinization; meiosis

Ghrelin: - Ghrelin is a peptide hormone secreted by the ______________ in an endocrine manner. Secretion increases with _____________ and has a transient surge in anticipation of food (surge controlled by the same cholinergic system that causes anticipatory increases in salivation and gastric acid secretion). Essentially in some ways ghrelin is the opposite of leptin and circulating levels are inversely related to body condition - it is a signal of energy insufficiency. Recent evidence suggests it ___________________ the kisspeptin system and thus GnRH.

stomach; fasting; suppresses

XY Sex-reversed females = XY Gonadal Dysgenesis: - Female phenotype and ovaries but chromosomally XY. In humans and most of our species the ovaries degenerate to ___________ gonads hence termed XY gonadal __________________ rather than XY Ovarian DSD in new terminology. - The precise genetic cause is currently unknown in 75% of human cases. - Deletion of ________ from the Y chromosome or a mutation causing its inactivation is the most obvious cause - Doesn't have to be SRY, inactivating mutations of various genes in testis determining cascade could give similar phenotype.

streak; dysgenesis; Sry

Manipulating an Estrus Cycle: Assisted/advanced reproductive techniques - To increase offspring from a female using ______________________ and ______________ ______________; or using other techniques in an effort to obtain offspring from a valuable ______________ animal. In both cases manipulation of the cycle is necessary.

superovulation and embryo transfer; infertile

-The fate of the bipotential gonads as testicles or ovaries is decided by the fate of the _________________ cells (Sertoli vs granulosa) and this battle is waged by 2 competing genetic cascades. Among many others: on the male side is __________ and _______________ growth factor-9 (Fgf9), on the female side is the _______-____, ____-______________, the ____-_____________ pathway, and ___________. The function of Sry appears to be to tip the balance in favor of the male pathway by kick-starting (up-regulating) __________ before the female cascade can get going. -There is accumulating evidence that this battle between male and female pathways in the supporting cells is not just embryonic but continues post-natally and throughout life.

supporting; Sox9; fibroblast; Wnt-4, R-spondin1 (RSPO1), the β-catenin pathway, and FOXL2; Sox9

In the final gonads (what we are aiming for eventually) there are 4 cell lines: - 3 somatic cell lineages: · ________________ cells (Sertoli in male, follicular granulosa cells in female) · _____________-producing cells (Leydig in male, theca in female) · ____________________ cells (peritubular myoid cells and vasculature of testis, connective tissue and vasculature of ovary) - 1 germ cell lineage: (________________________ in male, _______________ in female)

supporting; steroid; mesenchymal; spermatogonia; oogonia

Transabdominal Testicular descent: - In the embryo the gonad on the urogenital ridge is anchored to the body wall by cranial and caudal ___________________ ligaments (derivatives of the genital fold). The caudal suspensory ligament is called the ______________________ or genito-inguinal ligament, and connects the gonad to the future inguinal region. - During embryonic development the cranial suspensory ligament regresses in the male but not the female. Regression in the male is generally considered to be mediated by _____________________ (though this is not universally accepted).

suspensory; gubernaculum; testosterone

Step 5: Thyroid hormone activation locally within the Hypothalamus: • In the hypothalamus the TSH binds to receptors on _________________ and ________________ cells (i.e. not neurons) that surround the base of the 3rd ventricle (and there is some thought that the TSH is actually carried to them in the CSF that fills this structure). • TSH binding to these cells alters the activity of the __________________ enzymes that control conversion of inactive thyroid hormone (T4) to active thyroid hormone (T3) and catabolism of active hormone to inactive hormone. - type ____ deiodinase (DIO2) converts inactive T4 to active T3 at the cell surface - type ____ deiodinase (DIO3) catabolizes T4 to rT3 and T3 to T2, both end-products being inactive • Of the limited number of species examined, ________ stimulus (long days) causes up-regulation in __________. Less frequently there is down-regulation of DIO3. In either case, exposure to _________ days increases the level of active T3, which is now available to affect surrounding cells.

tanacytes and astroglial; deiodinase; II; III; TSH; DIO2; long

Genetic Influences on Age at Puberty: • Some of these differences will be mediated by alterations in the genetic developmental clock. Others will be due to alterations in the time taken to achieve certain permissive cue goals, particularly somatic development/body composition. • Cattle - Bos ____________ breeds achieve puberty earlier than Bos _____________. - Smaller British beef breeds (Angus) will generally achieve puberty before larger European breeds (Charolais). - ______________________ decreases age at puberty. - Selection for _________ yield decreases age at puberty. - Selection of bulls for large scrotal circumference results in earlier puberty in their daughters. • Goats - European breeds 6-8 months, Pygmy goats as early as 3 months. • Sheep - Prolific breeds (Finnsheep) earlier. • Dogs - Generally, the _____________ the breed the earlier it will cycle. - Small breeds 6-10 months. - Large/giant breeds 18 months-2 years. - Lots of individual variation within breed (laboratory beagles - 1st proestrus 6-13 months) • Cats - 80% mature weight, 6-9 months (5-12) - Conventional wisdom?: _________________ later than garden variety; Persians late

taurus; indicus; Crossbreeding; milk; smaller; Purebreds

-Absence of a Y chromosome: XX, XO and XXX individuals are all female. -A single Y chromosome is sufficient to send development along the male pathway, thus: XY, XXY, XXYY, XXXY and XXXXY individuals all undergo ________________ differentiation.

testicular

- The newly differentiated Sertoli cells rapidly aggregate to form the ___________ __________ (the male-specific "second proliferation of the sex cords"). - These testis cords, and a hormonally functional ______________ will differentiate irrespective of whether germ cells are present (but of course if no germ cells are present the animal will be sterile since he will produce no sperm).

testis cords; testicle

The 3 stages of testosterone secretion: In most mammals examined there are 3 sexually dimorphic (found only in males) peaks of _____________________ during development. Their precise timing depends on species. 1. During early/mid ________________ to masculinize the fetal genitalia (~day 45-50 in calves, week 10-20 in humans) 2. ______________ - sets non-reproductive tract somatic organ sexual dimorphisms • fetal period of ruminants • at birth in pigs • post-natal in humans from 6 months through first few years of life 3. From ______________ - gives secondary sex characteristics, supports spermatogenesis - Females have no exposure to gonadal hormones at the time of peaks 1&2, but obviously do cyclically from the commencement of puberty (estrogen and progesterone sequentially).

testosterone; gestation; Perinatal; puberty

Overview of the Steps in Photoperiod Control of Reproduction: - The cyclical histogenesis described above that alters cell numbers and inputs on the kisspeptin/GnRH pulse generator is in turn controlled by seasonal variations in tissue levels of active _____________ hormone; so it is really the final step in a cascade. How this works and gets entrained to photoperiod follows: 1. Ambient daylength is perceived by the retina and used to entrain an endogenous circadian clock in the _________ 2. The SCN (via nerve relays) controls melatonin production by the pineal gland, ensuring melatonin secretion only occurs at _________ (thus length of daily melatonin secretion is inversely proportional to hours of light). 3. Melatonin circulates and the duration of melatonin elevation controls the activity of target cells (have melatonin receptors) • Long melatonin signal = short day • Short melatonin signal = long day 4. Special ___________________ located in the pars tuberalis of the pituitary have melatonin receptors and respond to short melatonin signals (= long days) by secreting ________ 5. This TSH activates cells in the hypothalamus - tanacytes around third ventricle - to increase levels of _________ (and/or decrease levels of DIO3) causing inactive thyroid hormone (_____ from the circulation) to be converted to active thyroid hormone (_____) locally in the hypothalamus. 6. T3 is one of the main controllers of tissue histogenesis. It currently appears that: • In long-day breeders the histogenesis results in increases in cell types and alterations in connections that increase and stimulate __________ neurons so there is increased kisspeptin and thus increased GnRH pulse frequency. These animals are stimulated to start cycling. • In short day breeders the histogenesis results in increases in cell types and connections that ____________ KNDy neurons and thus keep GnRH pulse frequency low. These short day breeders start cycling when they become __________________ to this input.

thyroid; SCN (SupraChiasmatic Nucleus); night; thyrotropes; TSH (thyroid stimulating hormone); DIO2; T4; T3; KNDy; inhibit; refractory

All mammals, and the vast majority of all animals, use sexual reproduction. At first glance this is puzzling, because the system is fairly inefficient: • Only about half the members of the population (the females) can actually give birth and similarly in the next generation half their offspring are males which also can't give birth, so the population grows more slowly than one producing asexually. This halving of potential population growth per generation is known as the "________-________ _________ of sex" • The males are required only for _____________________ but consume resources year-round, decreasing the number of reproducing females that can be supported by an ecosystem. • The next generation contains only half of each parents genes (i.e. the parents don't achieve total genetic ___________________). • There are increased costs associated with finding a mate, courtship and mating. These include increased risks of _________________ and increased _____________ requirements.

two-fold cost; fertilization; immortality; predation; energy

Dogs: - Many disorders of sexual development have been described in dogs, mostly affecting males. - Hypospadias: In this condition there is a partial failure of fusion of the _________________ ___________. Thus the urethra does not open at the end of the glans penis but further back, anywhere from the penile shaft to the perineal region. It is a (mild) form of male pseudohermaphroditism. Could be due to inadequate ____________________ production, inadequate activity of ______-_________________ locally (to convert T to DHT), an ________________ receptor problem, or defects in down-stream genes involved in epithelial-mesenchymal interactions. Maternal overexposure to estrogens or endocrine disruptors reported as a cause in humans.

urogenital folds; testosterone; 5α-reductase; androgen

The gonads develop from the __________________ __________, a strip of mesenchyme adjacent the ventromedial surface of the mesonephric kidney. In both sexes this mesenchyme is invaded by ______________ mesothelial (epithelial) cells which along with cells from degenerating mesonephric tubules, form the ______________ __________ of the indifferent gonad (the "first proliferation of the sex cords"). The transcription factors are thus acting on ______________ cells --> you don't need germ cells to form the indifferent gonad.

urogenital ridge; coelomic; cellular cords; somatic

Luteolysis in Primates: - In primates, unlike all other species examined, there is apparently no role for the _____________ ______________________ in prostaglandin production that causes luteolysis. - Endometrial prostaglandin does have a role in these species in causing shedding of the endometrium at ____________. - The theory (and evidence) here is that central oxytocin release acts on __________ oxytocin receptors which gives local formation of _____________ (within the CL). - Like ruminants they also have oxytocin production in the CL so a positive feedback loop is then established within the ___________ between oxytocin and prostaglandin, resulting in luteolysis.

uterine endometrium; menses; luteal; PGF2α; ovary

Persistent Mullerian Duct Syndrome in males: - A heterogenous disorder resulting in male pseudohermaphroditism. Affected individuals are relatively normal males that may have cryptorchidism but also have a _____________ and _______________. This can be the result of either deficiency of ________ or end-organ unresponsiveness. The disease in humans has been described with both aetiologies - some have no MIS, others normal MIS levels and presumably a receptor defect. Most human cases are also autosomal ________________, so only homozygous males are affected, heterozygous males and homozygous females are phenotypically normal. - Cryptorchidism in patients with PMDS may have different mechanisms for failure of testicular descent than those previously discussed. In these patients the testis is tightly linked to the retained oviducts and the observed phenotype depends on how mobile these are. In most cases they are fairly mobile and the testes descend, dragging the oviducts and a portion of the uterus along into the inguinal canal. This is often _______________, 1 testis enters its inguinal canal first dragging everything with it, the opposite testis attached to its associated oviduct is pulled towards the midline and cannot descend into its inguinal canal. - Less frequently the round ligament restrains the uterus and oviducts, and thus the testes, leading to bilateral cryptorchidism.

uterus and oviducts; MIS (or AMH); recessive; unilateral

Gut Fill? - Neural sensory inputs from the gastrointestinal tract via the __________ provide information on gut fill to control food intake. It is postulated that these may also have a minor role in controlling the __________ pulse generator, but evidence suggests that it is the caloric content (absorbed) of the meal, rather than gut fill/distension that mediates the reproductive effects

vagus; GnRH

1. Cows in poor body condition and those with lowest ________________ ____________ (actually generally the fattest cows) are in the greatest negative energy balance, lose the most BCS and take the longest time to return to cyclicity due to decreased GnRH pulsatility. The control mechanisms within the hypothalamus are largely those we saw in the section on nutrition (induced ____________ resistance due to lactational drive means glucose is not available as a fuel in the "metabolic fuels hypothesis"). These cows may also have increased sensitivity to estrogen feedback. 2. Cows with low feed intake and/or catabolizing large amounts of body tissue have high circulating non-esterified ___________ __________ but low levels of ___________________, _______________, and _____________. Low insulin prevents formation of growth hormone receptors on the liver so even though growth hormone is high, levels of ________-____ stay low (the growth hormone axis is uncoupled). - Along with reduced LH, combined low levels of cholesterol, glucose, insulin and IGF-1 result in decreased _________________ cell estrogen production in the dominant follicle and it doesn't fully mature 3. Increased feed intake in high producing cows (even those that are in not-too-bad energy balance) increases _____________ blood flow and thus clearance of estradiol (and eventually progesterone), so there is lower circulating level of estrogen.

voluntary intake; insulin; fatty acids; cholesterol, glucose and insulin; IGF-1; granulosa; hepatic;

Mosaic - These are also composed of 2 (or more) cell lines but they arise from a single _____________. Early in embryonic development a ____________________ may be lost from one cell and all the cells in the lineage resulting from it. The chromosome may be added to another line of cells. They arise from disorders of mitosis during cell division (mitotic _______-___________________) where the paired chromosomes do not separate normally. Most likely to be seen in the sex chromosomes because all autosomal monosomies (1 copy) and most autosomal trisomies (3 copies) are ___________ during embryonic development, resulting in death of the cell lines involved or the entire embryo. - Examples of mosaics could be XY/XO, XX/XO XY/XXY. These could also be chimeras so further genetic studies (eg chromosomal banding) would need to be done to ascertain whether or not only one zygote was involved. - Note that NOT all of these chimeras and mosaics will present as __________________, it depends on their chromosomal constitution and proportion of gonadal cells involved

zygote; chromosome; non-disjunction; lethal; intersexes

Chimera - This is an animal composed of a mixture of genetically different cells which originate from different ______________. Usually thought to occur by amalgamation of (usually 2) different early _______________ which then continue development as a single individual, can also be due to double fertilization of an oocyte containing 2 nuclei (1 nucleus + 2nd polar body?). A readily detectable chimera would have _______/________ combinations of cells. They could also be XX/XX or XY/XY but these are a bit more difficult to detect and usually would not result in an abnormal sexual differentiation. XX/XY chimeras may develop as fertile males or females depending on the balance of XX and XY somatic cells in the early gonad. ___________ generally outnumber ______________ by 3 to 1. True hermaphrodites also occur but are less common.

zygotes; embryos; XX/XY; Males; females