Female Reproduction (Lec 13 & 14)

progesterone --> 17 alpha-OH-progesterone via what enzyme?

17 alpha hydroxylase

pregnenolone ---> progesterone via what enzyme?

3 beta-HSD

Near mid cycle (the time of ovulation) mucus from the cervix becomes more hydrated to aid sperm migration. At this time mucus drying on a glass slide will form the 'fern' patterns seen here. At other times in the cycle, or during pregnancy, the mucus dries in a beaded, non- ferning pattern because of the presence of progesterone. therefore, if there is a ferning pattern during pregnancy, is this good or bad?

BAD

17 alpha-OH-progesterone --> androstenedione & testosterone via what enzyme?

C17, 20-lyase

protein: SHBG what binds to it? binding affinity low or high? binding capacity low or high?

DHT, testosterone, estradiol high low

_____ stimulates follicle maturation; estrogen synthesis parallels folliculogenesis

FSH

GnRH acts on ant pituitary to release ___ & ___

LH & FSH

Estrogen and FSH upregulate ___/____ receptor sites in preparation for ovulation. After ovulation, the luteinized ovary maintains these receptors that allow activation in case there is an implantation.

LH/HCG

Hypothalamus & pituitary are closely connected anatomically via a a) ______ circulation & b) _____ axons & synapses. This anatomic arrangement allows rapid, undiluted delivery of neurohormone (GnRH), which has a half-life of only a few minutes, to its target organ.

a) portal b) nerve

Progesterone Is an Agonist or Antagonist? at Progesterone Receptors (PR)

agonist note: they occupy--> dimerize--> transport to nucleus--> gene transcription

LH released by what? fxn?

ant pituitary stimulates steroid hormone secretion by ovaries; stimulates ovulation

Increasing _____ levels 1-2 days prior to and at ovulation also cause the cervical mucous (vaginal secretions) to become clear and profuse and the os to dilate. These two actions may facilitate the transport of semen (containing sperm) from the vagina, through the uterus, and into the fallopian tube.

estrogen

The follicular phase of the menstrual cycle selects & prepares a follicle for ovulation. There are changes in ovarian steroid (_____) secretion that coincide with follicle maturation. The rise in this hormone levels is required to create an environment in the oviduct and cervix compatible with fertilization of the egg

estrogen

LH & FHS stimulate ______ & ______

estrogen & progesterone

_______: Loss of Viable Egg Follicle Reserve = Loss of Ovarian Estrogen & Progesterone Biosynthesis

menopause

menstrual cycles are automatically reactivated every 28-30 days by a ______ ______ (hypothalamic arcuate nucleus) serving as a pulse generator that fires @ regular intervals

neuronal 'clock'

______ controls pulsatile GnRH release rate & LH surge

neutransmission

chol ---> pregnenolone via what enzyme?

p450 SCC

Release of hormones from hypothalamus & anterior pituitary is constant or pulsatile?

pulsatile

Ovarian steroid hormones exert + or -? feedback over pituitary hormone release for most of the follicular & luteal phases of the menstrual cycle

-

Estrogen (E2) input exerts a predominant + or -? action on Kiss1 expression at the ARC, which contributes to negative-feedback control of GnRH/LH. Rising E2 levels in the follicular phase stimulate Kiss1 gene expression in the AVPV that contributes to the surge of LH (positive feedback). In addition to its transcriptional effects, E2 seems to elicit a state of enhanced responsiveness to kisspeptin at GnRH neurons, during the periovulatory period. The AVPV population is involved in positive feedback regulation by estradiol and the control of the surge-mode of gonadotropin secretion.

- or inh

what 2 things happen in the luteal phase?

-CL -endometrium secretory state

estrogen is needed for other things in the body like what? -brain? -breast? -liver? -bone?

-brain: vasomotor & temp reg -breast: breast duct dev & adipose tissue -liver: dec in lipogenesis & gluconeogesis; inc in insulin sensitivity -bone: maintains bone density

The menstrual cycle requires coordination along the hypothalamic-pituitary-ovarian axis. The components include what 4 things? Gonadotrophe cells in the anterior pituitary , responsive to GnRH, release gonadotropins, follicle-stimulating hormone (FSH) & luteinizing hormone (LH), which then stimulate folliculogenesis & steroid & peptide hormones secretion from ovaries. Hypothalamic & pituitary activities are strictly controlled by ovarian hormone feedback loops. The GnRH pulse generator is also modulated by inputs from other neural centers.

-hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator -the pituitary gonadotrophes - the ovaries -the uterus

progesterone does what 4 things during luteal phase?

-stimulates secretion of viscous mucus (high viscosity) cervical fluid -induces epithelia diff -dec cilia contractility & inc secretory activity -dec contractility of myometrium, stimulates secretory activity, stroma becomes edematous, spiral arteries coil

estrogen does what 4 things during the follicular phase?

-water secretion/low viscosity of cervical fluid -epithelia prolif in vagina -inc growth of endometrium & contractility of myometrium, spiral a. elongate -inc cilia formation & contractility note: all these make the uterus a more viable environment for the sperm to fertilize the egg

the 2 cell: 2 gonadotrophin model of folliculogenesis what are the 2 cells & 2 gonadotrophins?

2 cells= granulosa & theca cells 2 gonadotrophins= FSH & LH

_____ Shapes The Female Genital Tract To Facilitate Egg Fertilization The increased _______ (same as first blank) milieu in the late follicular phase modifies the genital tract. The glandular endometrium proliferates, characteristics of cervical mucus change (increased secretion, decreased viscosity, and increase in pH), and cornification of the vaginal epithelium occurs.

Estrogen

____ stimulates the development of follicles from the primordial pool. *It is essential for the eventual 'selection ' of one dominant follicle* . Maturation and development of dominant follicle into theca and granulosa cells coincides with its ability to synthesize progressively increasing amounts of estrogens, which initially restrain FSH levels (feedback inhibition during the follicular phase) , but eventually stimulate the release of LH and FSH at mid-cycle.

FSH

The first day of menstruation occurs when levels of estrogen & progesterone are low. In response to these low levels, the hypothalamus secretes *gonadotrophin releasing hormone (GnRH)* which triggers the *anterior pituitary gland* to release two hormones: ____ & ____

FSH & LH

Following menstruation, estrogen and progesterone levels are low, triggering the hypothalamus to once again release _____, starting the entire cycle again

GnRH

Ovulation.... At mid-cycle, day 14, the anterior pituitary releases a 'surge' of LH & FSH. A distinctive feature of the mid-cycle is a change in the rate and amplitude of ____ release from the hypothalamus. This increase in the GnRH pulsatile release rate is initiated by rising levels of estradiol & progesterone exerting a stimulatory effect on both the anterior pituitary and nerve circuits in the hypothalamus.

GnRH

arcuate nucleus releases ____ periodically into the hypothalamic-pituitary portal vasculature

GnRH

______ neurons modulate GnRH secretion.

Kisspeptin (Kiss1)

Progesterone secretion is negligible during the follicular phase; however, there is a small but significant rise in this hormone at the time of initiation of the ___ surge. It appears that this increase in progesterone is required for a full LH surge. For instance, administration of a progesterone antagonist at mid-cycle in humans delays or abolishes the LH surge. In small amounts, progesterone can facilitate LH release.

LH

When estrogen levels are highest they provoke an ___ 'surge' . The ovarian follicle "ruptures" and releases one egg which is "swept" into the fallopian tube by *ciliae* that line the *fimbriae* (the fringe-like end of the fallopian tube that is closest to the ovary). This process is called ovulation.

LH

____ surge stimulates ovulation; corpus luteum progesterone synthesis readies & maintains endometrium for a fertilized egg

LH

Fertility is initiated at puberty by pulsatile secretion of GnRH from a small number of neurons in the hypothalamus (____). GnRH is released into the portal blood system. The GnRH acts on the anterior pituitary to stimulate the release of LH & FSH. These gonadotrophic hormones act on the ovaries to stimulate sexual maturation in females. GnRH neurons are a critical component of the reproductive axis, kisspeptin (Kp) peptides have been identified recently as vital upstream regulators that integrate central and peripheral signals with GnRH release, thereby playing a pivotal role in the control of reproduction.

POA

Develop in female fetus within a) ___ to ___ weeks of development. Consists of a primary oocyte surrounded by granulosa cells. They go through mitotic divisions until there are about 7,000,000 at 7 months of fetal development. The cells arrest in prophase of Meiosis I before the fetus' birth. Only b) _____ oocytes will be ovulated in a woman's lifetime. The rest undergo atresia which is programmed cell death of the follicles.

a) 8-10 b) 450

A dominant follicle contains more a) ___ in follicular fluid. FSH induces the aromatase activity that metabolizes androgen substrate to estradiol (E2 ). Thus E2 and androstenedione (A4) accumulate in very high concentrations in the follicular fluid of the b) dominant or non-dominant? follicle.

a) FSH b) dominant

Folliculogenesis & follicle maturation depend on progressive increases in: • a) _____ released by the anterior pituitary • b) _____ generated by ovary(follicle) LH release in relatively constant ...

a) FSH b) estradiol

The follicular phase of the ovarian cycle ... Between day 1-13 one egg follicle is selected from a primordial pool for dominance and maturation into a Graafian follicle, destined to ovulate. a) _____, a pituitary peptide hormone, stimulates folliculogenesis (follicle selection & maturation). b) _____, an ovarian steroid hormone produced by maturing follicles (from androgens), rises steadily during the follicular phase in parallel w/ folliculogenesis. Enzymes expressed in thecal & granulosa cells of a maturing follicle coordinate the biosynthesis of estradiol, which stimulates endometrial proliferation.

a) FSH b) estradiol

Ovulation depends on: • Expression of a) ____ receptors in the follicle • b) ____ & ____ 'surge' from anterior pituitary • After ovulation the corpus luteum produces c) _____ & _____.

a) LH b) LH & FSH c) prog & estradiol

Theca cells express a) ___ receptors. this stimulates expression of enzyme activity required for b) ______ synthesis

a) LH b) androgen

38% of Estradiol/estrone circulate bound to a) _____; 60% bound to b) ____. Only 1-2% is 'free' hormone

a) SHBG b) albumin (b/c everything binds to albumin)

In females, high levels of estrogens & progesterone *stimulate* kisspeptin neurons of the a) _____ to induce the pre-ovulatory surge of GnRH/LH, whereas they exert an *inhibitory* action on Kiss1 gene expression expression in the b) _____.This population seems to regulate tonic-mode of gonadotropin secretion and mediation of negative feedback of sex steroids.

a) anteroventral periventricular nucleus (AVPV) b) arcuate nucleus (ARC)

If the egg is not fertilized the corpus luteum turns into the a) ______ ______ & ovarian steroid hormone secretion ceases. Withdrawal of progesterone & estradiol terminates the support of the endometrium, and b) _______ occurs. The menstrual cycle lasts 25 to 30 days in most women. Although the follicular phase lasts 13 days in the typical 28-day cycle, in reality its length is variable. In contrast, the life span of the corpus luteum is remarkably constant, and the luteal phase lasts 13 to 15 days.

a) corpus albicans b) menstruation

negative feedback reg: -a) _____ acts on pituitary to dec FSH & LH -b) _____ acts on hypothalamus to dec GnRH

a) estrogen b) progesterone

After ovulation the luteal phase shapes the environment in the endometrium to favor implantation and embryonic development if the egg is fertilized. Theca interna and granulosa cells of the follicle differentiate into large and small luteal cells of the corpus luteum. The large luteal cells as well as interstitial cells make a) ______. this is synthesized from pregnenolone by action of b) ____(enzyme?).

a) progesterone rmr: dominant stimulus is LH b) 3β-HSD. (need this enzyme for progesterone!!)

Granulosa cells surrounding an oocyte express FSH receptors during follicle development. Differentiated theca interstitial cells exist in a matrix of loose connective tissue & blood vessels. In a graafian follicle, *LH is required for a) ______ cell function, and b) ______ production*. At early stages of graafian follicle development, theca cells differentiate via androgen production (androstenedione). The theca interna layer is richly vascularized to deliver hormones (FSH, LH), required for the growth and differentiation of the oocyte and granulosa cells.

a) theca b) androgen

Estrogens Are Agonists or Antagonists? at Estrogen Receptors (ER)

agonists note: NOT GPCR receptors--> they occupy--> dimerize--> transport to nucleus--> gene transcription

protein: albumin what binds to it? binding affinity low or high? binding capacity low or high?

all low high

progesterone: Breast development Induction of secretory _____ (pregnancy)

alveoli

During the luteal phase (day 15-28), the follicle remnant transforms into a corpus luteum. In response to LH, the large & small luteal cells (formerly 'theca' & 'granulosa' cells) in the corpus luteum produce progesterone to support the endometrium. The large increase in LH inhibits _____ production, thus estradiol levels decline from the pre-ovulatory peak.The corpus luteum also secretes significant amounts of inhibin A. Corpus luteum function depends primarily on pituitary LH secretion throughout the luteal phase.

androgen

FSH released by what? fxn?

ant pituitary stimulates follicle dev

Folliculogenesis... At the start of a menstrual cycle, the anterior pituitary gland secretes increasing amounts of follicle-stimulating hormone (FSH). This FSH reaches the ovaries & it allows a cohort of antral follicles to survive. From this cohort, a 'dominant' follicle emerges (selection). *Those antral follicles with insufficient FSH stimulation undergo _______ *. Only the dominant follicle undergoes final growth & maturation into a Graafian follicle destined for ovulation.

apoptosis (atretic follicles)

Granulosa cells express FSH receptors. FSH stimulates expression of ______ enzyme activity required for estrogen synthesis

aromatase

androstenedione & testosterone --> estradiol via what 2 enzymes?

aromatase & 17 beta hydroxylase

If fertilization does not occur, the corpus luteum shrinks and levels of both estrogen and progesterone decrease. The withdrawal of estrogen and progesterone cause the blood vessels of the endometrial (uterine) lining to "_____" resulting in vaginal bleeding (menstruation). The average menstrual cycle is 28-35 days, and menstrual flow usually continues for three to seven days, although there are variations among women.

break

A key feature of the model is cell type specific expression of gonadotrophic hormone receptors & steroid biosynthetic enzymes in theca and granulosa cells, and the 'coupling' of FSH and LH receptors with estrogen and androgen biosynthesis, respectively b/c of _______

compartmentalization

protein: CBG what binds to it? binding affinity low or high? binding capacity low or high?

corticoids, progesterone, 17 alpha-OH-prg high low

Around day 25 there is a preferential rise in FSH, while LH remains 'constant'. FSH seems to be slightly more sensitive to estradiol negative feedback than LH. Thus, the rise in FSH may reflect the rapid inc or dec? in estradiol. The rise in FSH may also reflect differential effects of GnRH pulse frequency on the synthesis of LH and FSH, as a lower pulse frequency favors FSH β subunit synthesis, and a larger pool of FSH would be available for release at the end of this period.

dec

By mid-follicular phase, there is an incremental increase in LH receptors, in androgens, & in estrogens, which induce FSH receptors in the granulosa cells of the dominant follicle. *Thus, the developing follicle generates its own _____ microenvironment*, which promotes further granulosa cell growth directly through its mitogenic activity. FSH also acts as a survival factor by stimulating cellular proliferation and by inhibiting apoptosis.

estradiol

A 28 day menstrual cycle can be divided into three discrete phases what are they and how many days to they last?

follicular phase: Day 1-13 Mid-Phase (Ovulation): Day 13-15 Luteal Phase: Day 15-28

how is estrogen cleared?

hepatic metabolism --> conjugates it to make it more water sol --> excreted in urine (can measure estrogen metabolite to get estrogen clearance)

A hallmark of a dominant follicle is acquisition of LH receptors & differentiation of a theca layer that can synthesize androgens in response to LH. These androgens are converted to estradiol in the granulosa cell layer, which contains aromatase. *Serum estradiol levels begin to inc or dec? as a result of the emergence of the dominant follicle*. The rising estradiol, initially (day 1-12), restrains FSH levels to nullify maturation of the other follicles in the cohort, which undergo final atresia.

inc

Progesterone affects the hypothalamic thermoregulatory center, provoking a dec or inc? in basal body temperature.

inc

Specificity involves receptor recognition of particular DNA sequences. Progesterone actions are primarily mediated by an intracellular progesterone receptor, whose numbers dec or inc? in the presence of estrogen.

inc

progesterone released by what? fxn?

ovaries (CL), adrenal cortex Maintains endometrium for implantation or during pregnancy

estrogens released by what? fxn?

ovaries- granulosa cells Regulates menstrual cycle & lactation & acts on other target organs

androgens released by what? fxn?

ovaries-thecal cells Transferred to granulosa cells For conversion to estradiol

*Following ovulation, the ruptured follicle transforms into the corpus luteum, a glandular mass that continues to produce some estrogen and high levels of _________*. This causes the endometrium to thicken, preparing it for implantation of a fertilized egg. If fertilization occurs , progesterone hormonal levels remain high, essential for the maintenance of the pregnancy. Progesterone also stops menstruation for the duration of the pregnancy.

progesterone

_______ dominates the luteal phase of the menstrual cycle, *adapting the uterus for possible implantation of a fertilized ovum.* this increases secretory activity by the endometrial glands and causes changes in the cervical mucus, to a thicker more viscous state. Progesterone provides "pregnancy help" by reducing the chances of contraction in the uterine muscles, as well as by briefly inhibiting female immune response so that a pregnancy is accepted by the body.

progesterone

protein: α1-Acid glycoprotein (orosomucoid) what binds to it? binding affinity low or high? binding capacity low or high?

progesterone low high

Steroid hormones secreted into the circulation are bound to specific proteins, what are those 3? All steroids bind to albumin with low affinity but high capacity. In contrast, SHBG binds with high affinity but low capacity to the sex steroids, including estradiol. CBG binds with high affinity but low capacity to corticosteroids, progesterone, and 17-hydroxyprogesterone

sex hormone-binding globulin (SHBG) corticosteroid-binding globulin (CBG) and/or albumin

Feedback effects of ovarian steroid hormones _____ with the stage of the menstrual cycle. Estradiol and progesterone may have stimulator or inhibitory activities depending on the stage of the menstrual cycle and the target tissue (anterior pituitary, uterus).

vary

what 2 things happen in the follicular phase?

• Folliculogenesis - Oogenesis • Endometrium Proliferation