Endocrinology Quiz 4 Topics 16-21

Compare sexual development in males and females

-In the male, testosterone is synthesized at near-adult levels toward the end of the first trimester ( differentiation of internal and external genitalia) and again at about 2 months after birth (function unknown). The level then remains quite low until puberty, at which point the hypothalamus again becomes active, initially nocturnally, then constantly. The hypothalamus is thought to become less sensi- tive to testosterone inhibition: "resetting the gonadostat" rising testosterone. Growth of the penis, sebaceous glands, long bones, and axillary and pubic hair characterize the adolescent period. Testosterone levels reach a maximum in the mid/late-20s, and then fall gradually thereafter. There is no abrupt hormonal equivalent of menopause ("andropause"). - In the female, estrogen synthesis is seen during gonadal development toward the end of the first trimester, and FSH & LH (& E?) are high 2-3 months after birth (function unknown), but estrogen levels do not rise again until puberty, con- trolled as noted above. The first defining event is breast development (thelarche), followed by the development of axillary and pubic hair (pubarche), and finally the first menstrual period (menarche). Estrogen levels peak monthly after men- arche (except during pregnancy), then periods become irregular (climacteric) and cease around the fifth decade (menopause). Post-menopausal LH & FSH levels are high due to ovarian failure to produce adequate estrogen and inhibin. -In both sexes, long bone growth is augmented by sex steroids (E in the female; T -> E, in the male) but high levels of sex steroids near the end of puberty bring about cessation of long bone growth by epiphyseal plate closure. At 8-10 yrs, the adrenals increase their secretion of androgens (adrenarche), without significant changes in cortisol or ACTH levels. These androgens (from androstendione) contribute to the early stages of the "growth spurt" and to pubic and axillary hair growth, independent of gonadal puberty. Some classic examples of abnormal sexual development -Testicular Feminization or androgen insensitivity syndrome: XY genotype but female external genitalia. Cause: no functional androgen receptors. Y chro- mosome -> testis -> MIH and testosterone, therefore Mullerian ducts regress via MIH action but Wollfian ducts also regress since they can't respond to testos- terone. Leydig -> T but Sertoli cells can't function -> no spermatogenesis. Later, without negative feedback from T, GnRH+ ->LH+ ->A + -> T + -> E (peripheral aromatization) -> breast development -> female phenotype, even though T>E. -5a-reductase-2 Deficiency Syndrome or "Penis at Twelve": XY genotype, begins life with a female phenotype but later reverts to a male phenotype. Cause: one of the two 5a-reductase genes (type 2) is non-functional. Y chromosome -> testes and internal male ducts since T is present but no prostate, penis, or scrotum form since conversion to DHT is required. At puberty, ++T may promote sufficient binding to the receptor, inducing development of external male genitalia and/or the normal 5a-reductase (type 1) present in the prostate and external genital tissues may suffice at very high T levels. -Congenital Adrenal Hyperplasia (CAH): In females: masculinization, e.g. enlargement of the clitoris and fusion of the labia before birth; increased muscular development, facial hair (hirsuitism), irregular menses post-puberty. CAH In males: precocious puberty or supermasculinization. Cause: hypersecretion of adrenal androgens due to a defect in steroid biosynthesis. Most commonly, a 21b- or 11b- hydroxylase deficiency reduces the formation of aldosterone and cortisol, resulting in accumulation of their androgen precursors (see also Adrenal section).

Identify the biochemical properties of each key reproductive hormone

Hypothalamic: Gonadotropin Releasing Hormone (GnRH), is a decapeptide (10 amino ac- ids), released in a pulsatile fashion (1.5-2 hrs), acting on the gonadotropes of the anterior pituitary to induce secretion of both FSH and LH via phospholipase C signaling. Constant level of GnRH -> low FSH & LH due to down-regulation of GnRH receptors. Anterior Pituitary: -Luteinizing Hormone (LH) is a 32 kDa dimeric glycoprotein, acting on "interstitial" steroidogenic (steroid-producing) cells: Leydig cells of the testis and theca cells of the ovary. -Follicle Stimulating Hormone (FSH) is a 32kDa dimeric glycoprotein, acting on "follicular" cells: Sertoli cells of the testis and granulosa cells of the ovary -FSH and LH share a common alpha subunit with TSH and Chorionic Gonadotropin (CG or hCG, human; functionally equal to LH) but each hormone has a distinct alpha subunit. Although the alpha subunit is required for cooperative receptor binding, the unique alpha subunit determines receptor specificity. All four hormones act via adenylyl cyclase / cAMP / PKA signaling. Gonadal: Steroid ("sex") hormones: -Testosterone (T) is produced by the Leydig cells of the testis. It inhibits LH release by the anterior pituitary and decreases GnRH release by the hypo- thalamus. T is converted to the more-potent dihydrotestosterone (DHT) by the enzymes 5-reductase-1 & -2 in target tissues (DHT binds to the T receptor but at higher affinity). -"Estrogens" are estrone (E1), estradiol (E2) and estriol (E3). Their androgen (A) precursors (androstenedione & T) are made by the theca cells of the ovary but converted to the final products in granulosa cells by the FSH-induced enzyme aromatase (also T -> E in peripheral tissues). Aromatase inhibitors are effective against E-dependent cancers. Estriol is a fetal adrenal/liver-placental product. Acting on the hypothalamus and anterior pituitary, moderate, steady levels of estrogen inhibit LH release early in the menstrual cycle but rising levels of estrogen increase LH release before ovulation by increasing the number of GnRH receptors on the gonadotropes (may also increase GnRH release). -Progesterone (P) is produced by the corpus luteum after ovulation (and by the placenta during pregnancy). Synergistic with E2, P inhibits GnRH re- lease. -In plasma, ~98% of sex steroids are bound: ~2/3 of T is carried via Gonadal Steroid Binding Globulin (GBG, or sex hormone binding globulin, SHBG) and ~1/3 by albumin. The opposite ratios are true for E2 in males. Female ratios vary within the menstrual cycle since E increases GBG synthesis. P binds to albumin and Corticosteroid Binding Globulin (CBG), ~4:1. -Androgen Binding Protein (ABP, 90 kDa), produced by the Sertoli cells under stimulation of T and FSH, is secreted into the seminiferous tubules, maintaining very high T levels around sperm maturing in the rete testis and epididymis (~200X > serum). Peptide hormones: Inhibins are 32 kDa dimeric glycoproteins consisting of a 18 kDa beta chain and either of two 14 kDa chains -> inhibins A & B (abA & abB). Inhibins are produced by FSH-stimulated Sertoli or granulosa cells and act on the anterior pituitary to decrease FSH release (classic negative feedback). Inhibin B is pro- duced in the male and during the follicular phase in the female but inhibin A is characteristic of the luteal phase. Inhibins belong to the TGFB gene superfamily.

Sketch the temporal relationship between gamete and ovarian follicle development.

Ovulation occurs when the secondary oocyte, accompanied by the corona radiata and the antral fluid, are expelled from the follicle and freed into the peritoneal space. Normally, fimbriae will quickly "catch" and transport the ball of cells into the oviduct. The mechanism of ovulation is complex, involving many genes and molecular pathways, but the important end-results include increased volume of the follicular fluid, enzymatic breakdown of the follicle wall, and prostaglandininduced contraction of the smooth muscle fibers in the externa. In humans, this process occurs over 32-36 hours. Normally, only one oocyte is released in each cycle. After ovulation, the remaining granulosa cells form the corpus luteum. The follicular wall becomes highly folded, and the follicular basement membrane loses its integrity. The cells increase in size and are known as granulosa lutein and theca lutein cells, derived from the granulosa and the theca interna, respectively The corpus lutein secretes estrogens and progesterone. These hormones prepare the uterus for implantation and inhibit FSH and LH, which prevents development of new follicles. While it may be true that theca lutein cells secrete predominantly estrogen and granulosa lutein cells secrete predominantly progesterone, the biochemical compartmentalization that exists between the granulosa and the theca cells no longer exists in the corpus luteum. In cell cultures, both cell types have been shown to be capable of producing both estrogens and progesterone If pregnancy occurs, the hormone human chorionic gonadotropin (hCG) from the placenta maintains the corpus luteum. It remains the primary source of estrogens and progesterone for the first 8 weeks of pregnancy. If no pregnancy occurs, estrogens and progesterone decrease approximately 12 days after ovulation. The luteal cells autolyse and form the corpus albicans, a white scar of hyaline material that slowly disappears. The great majority of developing follicles do not make it to maturity. Instead, they degenerate at various stages of development, becoming atretic follicles. PCOS CLINICAL: The Graafian follicle is a form of ovarian cyst, i.e. a fluid-filled sac within the ovary. Normally, these cysts either rupture at ovulation or are broken down during atresia. The accumulation of several of these ovarian cysts over one's life is normal, however persistent anovulation leads to polycystic ovary syndrome (PCOS). Although the mechanism is unclear, PCOS correlates with hyperandrogenism and with decreased insulin effect, suggesting it may be primarily an endocrine disorder. Symptoms may be negligible, may be secondary to the underlying hormonal problem, or may include decreased fertility. It is estimated that PCOS affects 5- 10% of all women.

Explain the hormonal and neural control of parturition and lactation

Parturition (birth) After about 30 weeks, rhythmic uterine contractions increase in strength and duration. After about 8 months, the uterine contents shift toward the cervix. After about 8.5 months, dilation and softening ("ripen-ing") of the cervix occurs, mediated by estrogens, the ovarian/placental polypeptide hormone relaxin, (insu- lin/IGF-like) and prostaglandins. Efficacy of progesterone in inhibiting contraction decreases, possibly because E is increasingly synthesized by the placenta from fetal adrenal androgens induced by a placental CRH-like hormone, or the ratio &/or distribution of P receptor isoforms change ("functional progesterone withdrawal"). Uterine muscles, now electrically coupled via E-induced gap junctions, are stimulated by stretch to contract coordinately. Oxytocin receptors, progressively induced by +estrogen, render the uterus in- creasingly more sensitive to oxytocin. Stimulated by stretch receptors in the uterus/cervix, oxytocin (a 9 aa peptide; 2 aa difference from ADH) is released from the posterior pituitary, increasing and synchronizing contractions further (positive feedback), and increasing uterine prostaglandin release. Sufficient dilation and forcible, rhythmic contractions result in expulsion of the fetus and placenta, but specific trigger(s) for the initiation of labor in humans is/are unclear Lactation Estrogen and progesterone (first from the corpus luteum, then the placenta), placental lactogen (PL) and prolactin (PRL), cooperatively stimulate breast de- velopment, creating the components required for milk synthesis, storage and re- lease. Prolactin is a 199 aa protein made by the lactotropes of the anterior pituitary; same gene family as GH and PL. Relevant prolactin functions: 1) mammogenesis - growth and development of mammary gland; 2) lactogenesis - initiation of lactation; 3) galactopoiesis - maintenance of milk production Prolactin release is inhibited by dopamine (DA = PIH, prolactin inhibiting hor- mone). Estrogen stimulates synthesis and secretion of prolactin by the anterior pitui- tary. However, high estrogen and progesterone inhibit milk production until birth, after which the absence of the placenta results in a dramatic decrease in these hormones, allowing milk production to commence (but now with reduced pro- lactin levels since E is lower). The initial secretion is colostrum, containing more protein and less fat than milk Milk-ejection ("let-down") Reflex Suckling results in neural input to the hypothalamus, inhibiting dopamine re- lease. - Decreased dopamine allows the anterior pituitary to release prolactin, which stimulates milk synthesis in the mammary glands. - The posterior pituitary is neurally stimulated to release oxytocin (mainly by suckling; also via audiovisual or anticipatory stimuli). - Oxytocin stimulates the myoepithelial cells of the breast to contract, ejecting milk. - During nursing, neural input and high prolactin inhibit GnRH release, suppress- ing ovulation ("wet-nurse effect"). Similarly, hyperprolactinemia (e.g. from a pituitary adenoma) can result in amenorrhea and galactorrhea.

Common definitions Spermatogenesis refers to the entire process that begins with the primitive germ cell, the spermatogonium, and continues through multiple stages of cell division and ends with the production of the male gametes, the spermatids. The time taken for a spermatogonium to evolve into mature spermatozoa is about 80 days. Spermatogenesis can be divided into the following parts

Spermatocytogenesis: includes all the mitotic divisions of the spermatogonia, eventually producing primary spermatocytes Meiosis: whereby haploid spermatids are generated from primary spermatocytes Spermiogenesis: morphological transformation of spermatids into spermatozoa Spermiation: the release of spermatozoa from the luminal epithelium of the seminiferous tubules

Define sex and its determination, including examples of dysfunction.

-Genetic sex is defined simply by the karyotype: 44 somatic chromosomes plus either XX (female) or XY (male). -Gonadal sex is defined by the internal genitalia and is inherent in the genetic makeup. Downstream action of the SRY (Sex-determining Region of Y) gene product, a transcription factor, induces testis development. Both X's are required for normal ovarian development, although later only one remains active. Aneuploidy of the sex chromosomes can give rise to sexual ambiguity. -XO - Turner syndrome or ovarian agenesis: "streak" gonads, amenorrhea, short stature, webbed neck, lacking secondary sexual characteristics ~1 in 5,000 births. YO is lethal, not found even in karyotypes of early embryonic tissue. -XYY - "Jacobs" or super male syndrome. Seemingly normal male, said to have excess acne, taller than normal, more aggressive, but not supported statistically. -XXY - Klinefelter's syndrome or seminiferous tubule dysgenesis: male genitalia, FSH, LH & E2 but T, sterility, feminization, retardation. This common sex chromosome disorder (>1 per 1,000) is an example of "hypergonado- tropic hypogonadism." -XXX - Triple X syndrome: nearly as frequent as Klinefelter's but these females show no unusual abnormalities since only one X chromosome remains active. -Phenotypic sex is defined by the genital ducts and external genitalia (which can go either way) and by secondary sexual characteristics. -In the male, Sertoli cells produce Mullerian Inhibiting Hormone or Substance or Factor (MIH, MIS, MIF), a 140 kDa dimeric glycoprotein of the TGF superfamily of growth factors. MIH causes regression of the Mullerian ducts (precursor of oviduct, uterus, upper 1/3 of vagina); Leydig cells produce testosterone that supports differentiation of the Wolffian ducts (precursor of epi- didymis, vas deferens, seminal vesicle, ejaculatory duct). After conversion to DHT, testosterone induces the development of the prostate, urethra, penis and scrotum. -In the female, who lacks MIH and testosterone, the Mullerian ducts develop and the Wolffian ducts regress; female external genitalia appear, mainly by labial growth. -In either sex, fetal steroidogenesis is supported by hCG.

Describe potential problems associated with male fertility.

-Oligospermia is defined as having less than 20 million sperm per ml (i.e. <1/5 normal); Causes: decreased GnRH (e.g. because of anabolic steroid abuse; stress), poor nutrition, environmental factors (e.g. heat, toxic chemicals). -Defective sperm: even with sufficient number, some sperm may be physically defective (e.g. double headed, short tailed), not sufficiently motile, or not able to undergo later capacitation, hyperactivation, or the acrosome reaction (see below). >50% defective is considered problematic. -Male contraception? Difficulties: 2-month period for sperm production and the sheer number of sperm. Possibilities: GnRH or gonadotropin antagonists; tes- tosterone analogues; progesterone; inhibitors of sperm motility or function; block- age of sperm-egg recognition. - Impotence (erectile dysfunction) can have a psychological basis, but anticho- linergic drugs, nerve damage, or aging can inhibit arteriolar dilation, which occurs via the NO pathway. Viagra (sildenifil) is a selective inhibitor of phospho- diesterase-5 (PDE5), which hydrolyzes the signaling molecule cGMP involved in Ca++ channel closure: +[cGMP] -> + intracellular [Ca++] -> smooth muscle relaxation -> erection. -Benign prostatic hyperplasia (BPH) and male pattern baldness: since T must be converted to DHT for prostate growth and maintenance, specific inhibition of 5areductase-2 with finasteride (a T analogue) is used to treat BPH. Sub- jects thus treated also showed reversal of scalp hair loss. Consequently, finaster- ide is used at a relatively higher dosage for prostatic hyperplasia (Proscar) and at a lower dosage for male pattern baldness (Propecia).

Describe the mechanisms associated with conception, contraception, and assisted reproduction.

-One can simply observe the menstrual cycle. On average, it repeats every 28 days, with the LH surge and subsequent ovulation and maximum fertility occurring at the 14-15 day mid-point. Since the egg is viable for about 1 day while sperm can live for 2-4 days, there is a very narrow window during which inter- course will likely result in conception (see next section). However, the cycle is not always consistent and other methods have been devised to determine when ovulation is likely to occur. -Influenced by circadian and external factors, an average increase of ~0.5C in basal body temperature occurs after ovulation and persists throughout the luteal phase, a thermogenic effect of progesterone -Before ovulation, vaginal mucus is thin but "stringy" (spinnbarkeit) and a vaginal smear, when dried, forms branching salt crystals ("arborization" or "ferning"); after ovulation, the mucus becomes highly viscous and does not form salt crystals. -Tracking and recording the daily ratio of estradiol and progesterone metabolites (the 3-glucuronides of estrone and pregnandiol) in urine, averaged over several menstrual cycles, is the basis for ClearPlan fertility monitors that graphically predict ovulation. Promoting ovulation / fertilization Ovulation induction: 1) clomiphene (E2 antagonist) -> +GnRH -> +FSH; 2) hMG (human menopausal gonadotropin = FSH+LH) or FSH stimulation; 3) phased protocols involve administration of FSH while blocking the normal cycle with a GnRH antagonist, then terminating with a pulse of hCG (=LH) to trigger (multiple) ovulation. Assisted reproductive technologies (ART): IVF (in vitro fertilization) and ICSI (intracytoplasmic sperm injection) utilize multiple oocytes obtained by induction protocols, fertilized by capacitated or injected sperm, respectively. Hormonal birth control -Progestin-only: continuous: minipill: daily oral dosage; Depo-Provera: DMPA, depomedroxyprogesterone acetate injection 4 per year; Norplant: levonorgestrel implant, lasts 5 years. These lower LH, FSH & E2 to the early/mid- follicular-phase range, suppressing ovulation and also producing thick cervical mucus and a thin, atrophic endometrium. All can allow irregular bleeding. -Combination estrogen + progestin: oral daily protocol (21 days on / 7 days off or placebo); monophasic: constant E/P ratio; biphasic: two different E/P ratios; triphasic: three different E/P ratios. -Phased dosages produce more normal uterine phases, yet still suppress ovulation, sperm entry, and fertilization. E+P can also be given monthly by injection (e.g. Cyclofem) or weekly by transdermal patch (e.g. OrthoEvra); an extended cy- cle oral protocol gives 4 periods per year (e.g. Seasonale). - Morning-after: two doses of a progestin, 12 hours apart, within 72 hours of intercourse (e.g. Plan B), function in essentially the same manner as a conventional progestin-only contraceptive, depending on when it is taken during the menstrual cycle.

Explain the functioning of the hypothalamic-pituitary-gonadal axis.

-Pulse generators stimulate and stress/cortisol inhibits the hypothalamus from releasing GnRH. -The hypothalamus releases GnRH to stimulate the Anterior pituitary. -FSH only or LH only inhibits the anterior pituitary from releasing FSH only or LH only. -FSH and LH stimulate the gonads to release testosterone, estrogen, and androgens. - Testosterone activates sertoli cell and leydig cells in males. Sertoli cells excess increase inhibit which inhibits FSH only. Testosterone excess inhibits LH only through anterior pituitary. -Androgen/Estrogen stimulate theca and granulosa cells. Excess granulosa increases inhibins that inhibit FSH only via Ant Pit. Excess estrogen inhibits LH only via Ant Pit. Estrogen + Testosterone inhibit hypothalamus GnRH release via cortisol. -Sertoli/granulosa (FSH) is for follicular or nurturing gametes -Leydig/theca is for steroidogenic or interstitial tissues.

. Corpus luteum. A huge newly-formed corpus luteum is present on slide 758. The corpus luteum forms following ovulation and expulsion of the oocyte. The size of this structure in the tissue section provides some idea of the size of the Graafian follicle at ovulation. The Graafian follicle collapses upon release of the oocyte and consequent loss of the pressure of antral fluid within the follicle. Blood from broken stromal blood vessels clots within the forming corpus luteum

After the follicle collapses the granulosa cells enlarge and become steroidogenic granulosa lutein cells. The basement membrane surrounding the follicle breaks down and allows small blood vessels to penetrate the previously avascular layer of granulosa cells. Look for the blood vessels among the granulosa lutein cells. Clusters of cells with theca interna morphology are still apparent surrounding this corpus luteum, although some have acquired the more smaller, more densely staining morphology of theca lutein cells.

Clinical correlations - prostate diseases: Approximately 50% of men at age 65 and 90% of men at age 80 show evidence of prostatic enlargement, a condition called benign prostatic hyperplasia (BPH). Usually occurring in the portion of the gland surrounding the urethra, BPH can cause difficulty in urination, as well as increased incidences of urinary tract infection due to incomplete voiding. The digital rectal exam is commonly used in the diagnosis of BPH, as the prostate and rectum share an adventitia. BPH is sensitive to androgens and probably also estrogens. Treatment, when necessary, involves anti-androgen drugs, and/or surgical resection.

An important step in the diagnosis of BPH is to rule out other more serious diseases, such as prostate cancer. Prostate cancer is the second most common type of cancer in American men, next to lung cancer. Unlike BPH, prostate cancer most often occurs in the distal portion of the glands. Prostate-specific antigen (PSA), a normal prostate secretion that functions to liquefy semen, is often overproduced in prostate cancers, so a common diagnostic tool is the testing of blood PSA levels. Similarly, blood acid phosphatase levels can also used to detect prostate cancers, though the PSA test is thought to be more accurate. There is much recent discussion about when and whether to treat prostate enlargement. Simply, it is a matter of weighing the benefits to the patient, in terms of increased life expectancy, against the risks of surgery and unpleasant side-effects which are substantial due to the difficulty of isolating the prostate from its surrounding structures. The bulbourethral glands (Cowper's glands) are small tubuloalveolar mucus glands with ducts and secretory elements of irregular form. The two pea-sized structures are connected with the penile urethra by ducts. The clear viscous secretion may function as lubrication, to displace urine, and/or to provide a basic environment in the urethra, and it is ejected primarily during sexual stimulation prior to ejaculation.

Describe the specifics of reproductive endocrinology in the male

Anatomy of Male Reproduction System -Spermatogonia (= germ cells): The sperm-producing stem cell line. -Leydig cells (= interstitial cells): Stimulated by LH, they synthesize and secrete T. -Sertoli cells (= follicular cells): Stimulated by FSH (and T, to produce ABP), they surround and "nurse" the developing sperm. Interconnected laterally by tight junctions, Sertoli cells form a "blood-testis barrier," thus protecting developing sperm cells. Sertoli cells contain abundant aromatase and can convert T to E2. - Seminiferous tubules: formed by the above cells, for sperm production (com- bined length about 250 meters). -Rete testis: collects sperm from multiple seminiferous tubules. - Efferent ductules: conducts sperm to epididymis. - Epididymis: passage wherein sperm undergo maturation (about 6 meters long). - Vas (ductus) deferens: exit for sperm to seminal vesicles. - Seminal vesicle: drains into vas deferens above the prostate, thus forming ejaculatory duct; produces fructose (major sperm nutrient) and prostaglandins (stim- ulate uterine/ovarian contractions); accumulates hormones and sperm-coat proteins. - Prostate gland: joins ejaculatory ducts with the urethra; produces buffered secretions to aid sperm in motility and fertilization. - Bulbourethral (Cowper's) gland: drains into urethra; produces lubricating mucus. -Urethra: the common urogenital passage through the penis. -Scrotum: external pouch that suspends testes away from the body. Normal body temperature (37C) is inhibitory to sperm development, destroying the germinal epithelium, but not to testosterone production; 32-34C is optimal. In cryptorchidism, the testes remain in the abdomen; the person is infertile but virile. Spermatogenesis and sperm maturation -Spermatogonium -> continual mitosis -> primary spermatocyte (2n / 2DNA) -> 1st meiotic division -> 2 secondary spermatocytes (1n / 2DNA) -> 2nd meiotic division -> 4 spermatids (1n / 1DNA) -> loss of cytoplasm -> 4 spermatozoa (sperm). -Primary spermatocyte to fully-formed spermatozoa takes ~2 months. - Passage through the epididymis takes ~12 days for full maturation, during which size, shape, metabolic, and cell surface/acrosomal protein changes take place (but sperm can't fertilize until they undergo capacitation in the female tract). - Sperm pathway: seminiferous tubules -> rete testis -> efferent ductules -> epididymis -> vas deferens -> ejaculatory ducts -> prostate gland -> urethra -> intersected by ducts from seminal vesicle, bladder, and bulbourethral glan - The average male produces ~30 million sperm per day, continuously, and ejaculates ~3 ml at 100 million/ml. Testosterone Effects -Fetal: induces the Wolffian-derived duct system directly; induces the prostate and the urethra / penis / scrotum via DHT (through 5a-reductase-2). -Puberty: induces facial, pubic and axillary hair; sebaceous glands (all mainly via DHT); sperm production; larynx development; fat and muscle distribution; promotion of bone growth during puberty but cessation of bone growth with in- creasing T post-puberty (T likely acts indirectly on bone growth by aromatase- mediated conversion to E). -Adult: sex drive ("libido" in both sexes; Intrinsa T-patch for women?); mus- cle growth & maintenance (T is an anabolic steroid); +erythropoiesis (hence higher male hematocrit); +male pattern baldness (via DHT); +cholesterol, with its negative cardiovascular consequences. -Pulses of GnRH stimulate the gonadotropes of the anterior pituitary to secrete pulses of both LH and FSH -FSH stimulates the Sertoli cells to produce factors (e.g. ABP; perhaps activins) that nurse the developing sperm cells they surround and also to produce inhibin- B, (abB), which inhibits FSH release by the anterior pituitary (negative feedback). - LH stimulates the Leydig cells to produce testosterone, required by the developing sperm cells, but testosterone inhibits LH release by the anterior pituitary and also inhibits GnRH release by the hypothalamus (negative feedback). - Testosterone is converted in non-gonadal target tissues to a more potent andro- gen, dihydrotestosterone (DHT), by the enzyme 5a-reductase, which has two forms that are differentially expressed. -Aromatase in peripheral tissues, particularly adipose tissue, converts androgens to estrogens. In the male, 80-95% of E2 & E1 is formed by peripheral aromatization, with most of the remainder occurring in the testes.

Describe key maternal, placental and fetal hormones and their variation during pregnancy.

Chorionic Gonadotropin (CG or hCG) is produced by the trophoblasts al- most immediately after their invasion into the endometrium (arrow). It serves as a signal from the embryo that implantation has occurred. Structurally and functionally similar to LH, CG maintains the corpus luteum for up to 2 months, strongly stimulating P and E production, preventing further ovulation. CG peaks after ~2 months, then declines to a near-constant level until delivery. Detection of CG in the urine is the basis for home pregnancy tests. - Progesterone (P) is made initially by the corpus luteum and later by the pla- centa. It is critical for maintaining the uterus in a receptive condition for implan- tation, for breast development, and for inhibiting uterine contraction during preg- nancy. After corpus luteum degeneration, the level progressively rises, but the efficacy of inhibition decreases as parturition approaches (Local +E? &/or change in PR-A/B expression? -> "Functional progesterone withdrawal"). -RU486 (mifepristone; "French abortion pill") is a competitive inhibitor of pro- gesterone (binds to but doesn't activate P receptor), causing endometrial degrada- tion and myometrial contraction. If administered with a prostaglandin (miso- prostol), it will result in expulsion of the fetus. - Estrone/Estradiol (E1/E2) are cooperative products of maternal or fetal ad- renal synthesis of dehydoepiandrosterone sulfate (DHEAS) from placental preg- nenolone; Estriol (E3) is produced by fetal liver hydroxylation of fetal adrenal DHEAS to 16a-OH-DHEAS, each followed by placental conversion to estrogens: -maternal cholesterol -> placenta -> pregnenologe -> fetal adrenal -> DHEAS fetal adrenal DHEAS -> placenta -> DHEA -> androstenedione -> E1 and E2 fetal adrenal DHEAS -> fetal liver -> 16a-OH-DHEAS -> placenta -> 16aOH-DHEA -> E3 Sulfation of DHEA eiliminates any androgenic effects of high DHEA on fetus Estrogens promote breast development but inhibit actual milk production be- fore birth. Their levels rise at near-constant rates throughout pregnancy. Before the advent of ultrasound, the level of E3 served as a measure of fetal health. - Placental Lactogen (PL or hPL) is a 18.5 kDa protein, similar to GH and prolactin (PRL). hPL facilitates breast development, maintains positive protein balance, mobilizes fats for energy, and promotes the high glucose levels required for nourishing the fetus (i.e. it is said to be diabetogenic). Its level rises at a near- constant rate throughout pregnancy.

Testis The testes are the primary reproductive organs, or gonads, in the male. They are suspended outside the abdominal cavity within the scrotum, a specialization that creates a lower temperature to facilitate spermatogenesis. The scrotum consists of thin skin, without subcutaneous fat, and with a smooth muscle layer (dartos muscle [dartos G., flayed, skinned]) that can actively alter the testicular temperature by wrinkling the overlying skin. Internal to the scrotum, there is also a skeletal muscle, the cremaster muscle (G., a suspender), which functions to raise or lower the testis within the scrotal sac.

Delicate connective tissue septa divide the testis into about 250 cone-shaped lobules. Within each lobule are 1-4 tortuous seminiferous tubules, each around 200 µm in diameter, and 30-70 cm in length. The seminiferous tubules are lined with a special seminiferous (germinal) epithelium consisting of cells producing spermatozoa and testicular fluid (the exocrine secretions of the testis). The spaces between the seminiferous tubules are occupied by a highly vascular connective tissue containing Leydig cells (interstitial cells of Leydig). They secrete testosterone into the blood stream.

Outline how the attempts to manipulate gender identity in the past lead to our current understanding of the relative durability of gender identity

Diagnosis Because some children who present as transgender will go on to not be transgender as adults, early treatment carries significant risk. The issue is problematic because individuals who wish to avail themselves of transgender treatment will find it easier at a younger age; prior to the need to reverse opposite sex characteristics developed in puberty. A paradigm to address the tension is to use GnRH analogs which delay puberty. Such intervention need only be considered at the first signs of puberty; there is no indication for medical intervention for pre-pubertal children. Note that pre-pubertal children do not require any medical intervention. Because of the biological nature of gender identity, there does not seem to be any reason for parents to fear allowing pre-pubertal children to explore and even to live as transgender. The parents can be reassured that non-transgender children will not be convinced to be transgender any more than transgender children can be convinced to not be transgender. In addition, there is modest but active investigation into the brain regions that might be associated with gender identity. The purpose of such research is aimed to help provide objective corroboration of gender identity and to learn biological mechanisms rather than to identify areas of the brain to manipulate.

. Distinguish gender identity from external sexual anatomy and sexual orientation.

Diagnosis of transgender identity is straightforward among adults. Most individuals who recognize that there is a choice will be able to determine a gender identity without much doubt. Whether and how a given individual with a transgender identity wants to address the mismatch is a very personal decision relating to many other factors in life. In order to avoid a rare instance of a psychiatric condition confounding the situation to such a degree that sexual identity is not clear,

The cervix in pregnancy

During pregnancy, the cervix takes on the function of first preventing premature expulsion of the fetus and subsequently allowing for its delivery. Despite the bulk of the uterine myometrium, it is the cervix that is most important in controlling the timing of delivery. The bulk of the cervix consists principally of a fibromuscular stroma. In contrast to the body of the uterus, there is much less muscle tissue present, with collagenous (type I and III) connective tissue making up about 80% of the cervix. During delivery, biochemical "remodeling" of this connective tissue is the principal means by which the cervix dilates in preparation for expelling the fetu During the course of pregnancy, the cervix goes through four distinct phases: softening, ripening, dilation and repair. These changes provide a nice illustration of the interdependence of connective tissue cells, fibers, and ground substance. The softening stage begins at the start of pregnancy and continues slowly over the first 32 weeks. During this stage, endocervical cells proliferate greatly. In the connective tissue, the rates of collagen synthesis and breakdown both increase. Increasing collagen turnover has the effect of decreasing the amount of cross-linking between fibrils, thus of gradually thinning the matrix. The ripening stage occurs over several weeks prior to the onset of labor. The rate of collagen turnover continues to increase, but most important to this stage is a marked increase in the production of ground substance (especially heparan sulfate and hyaluronic acid) that effectively decreases the collagen concentration and increases the tissue hydration. The dilation stage occurs immediately prior to parturition (commonly over several hours), and is correlated with an influx of leukocytes into the tissue. These leukocytes produce collagenases and proteases that cause a more rapid increase the fluidity of the matrix. Various substances influence ripening and dilation in a clinically-useful way, including progesterones, prostaglandins, and the peptide relaxin, but the natural mechanism remains uncertain. Finally, in the repair phase, all the above changes are reversed. Leukocytes decrease, ground substance decreases, and the rate of collagen synthesis and breakdown decrease, resulting in a net increase in collagen density and cross-linking. Nevertheless, the original architecture of the cervix is not completely restored after pregnancy. One easily observed change is that the external os, a round opening in a nulliparous woman, adopts a slit-like configuration in a multiparous woman.

Penis The penis is an elongate organ consisting principally of the urethra and three parallel cavernous bodies. The skin of the penis is very thin, free of fat, and hairless distally. Sebaceous glands are absent and sweat glands are sparse

Emptying directly into the vascular spaces of the corpora cavernosa are the helicine arteries that are irregularly coiled when the penis is in a flaccid condition. The inelastic tunica albuginea surrounding the corpora cavernosa penis fuse in the midline to form a septum in the penis that becomes incomplete distally so that the two cavernous bodies connect. The incomplete septum allows the pressure to equalize in the corpora cavernosa. The albuginea enclosing the spongiosum is thinner and contains circularly arranged smooth muscle fibers and more elastic fibers than that of the paired cavernous bodies. Penile erection is a hemodynamic event that is controlled by parasympathetic neural input to both arterial muscle and smooth muscle in the walls of the erectile tissue in the penis. Erection occurs when the corpora cavernosa fill with blood through relaxation of the helicine arteries and compression of the draining veins and arteriovenous shunts via compression against the surrounding tunica albuginea. Clinical correlations - erectile dysfunction: Recently, several drugs (Viagra™, Levitra™ and Cialis™) have been developed that promote the maintenance of an erection. The parasympathetic innervation that initiates an erection is mediated by nitric oxide (NO), a gaseous neurotransmitter. NO activates a second messenger cascade in target cells that is mediated by cGMP. A specific phosphodiesterase (PDE-5), which degrades cGMP in the penis, can be inhibited through pharmacological intervention. Thus, a PDE-5 inhibitor prolongs the action of a given amount of cGMP and NO. The normal function of NO in causing an erection is relaxation of smooth muscle in the tunica media of helicine arteries.

Identify the benefits and problems associated with hormone replacement therapy.

Estrogen supplements can be administered to alleviate menopausal symptoms and preserve bone mass, but long-term HRT can increase the risk of certain breast and endometrial cancers, and can have adverse cardiovascular consequences (MI, stroke, pulmonary emboli, DVT). Breast cancer in hysterectomized women is not significantly increased by estrogen supplements; E+P is required to minimize uterine cancer risk in normal women but at an increased risk of breast cancer (ref. WHI).

Explain the roles of estrogen and progesterone throughout life

Estrogens stimulate growth and maintenance of the reproductive tract, female body configuration, bone growth and maintenance, epiphyseal plate closure, distinctive pubic hair pattern, cervical mucus secretion, breast development and function, prolactin secretion, and myometrial contractions. Estrogens inhibit GnRH release (moderate E in early to mid-follicular; E+P in luteal), the milk- producing effects of prolactin, and atherosclerosis (--cholesterol?). Progesterone stimulates breast glandular growth, uterine secretion, cervical mucus thickening; and an increase in body temperature. Progesterone inhibits GnRH release, myometrial contractions, and the milk-producing effects of prolactin. -Negative feedback parallels the male in the early follicular stage: +inhibin B (abB) -> - FSH; moderate levels of E -> -GnRH -> -LH. -Theca cells produce androgens (A); granulosa cells have aromatase, convert- ing A to E. -E stimulates follicle cell growth, -> +A -> +E -> further growth (autocrine/paracrine actions). -E (+FSH) stimulates granulosa cell production of LH receptors, rendering them responsive to the later LH surge. -In the mid/late follicular phase, high rising E -> +LH due to increased sensitivty of ant. pit. to GnRH (GnRH receptors on AP increased by high E) -the mid/late follicular phase is a self-limiting, positive feedback loop. -High LH -> ovulation since now granulos cells respond to LH releasing lytic factors - the LH surge and/or the loss of follicular communication with the expelled oocyte may serve as a metabolic system switch. -ovulation -> corpus luteum -> + P,E, and inhibin A -In the luteal phase, P (+E) strongly lower LH & GnRH, leading to corpus luteum degeneration since LH is required for luteal function; inhibin A keeps FSH low. -the luteal phase is a self-limiting, negative feedback loop. -P, E, and inhibin decrease -> High FSH & LH. Cycle continues as all oocytes are spend on menopause. The timing within the menstrual cycle is ovarian, not hypothalamic, but the cycle itself cannot be initiated without GnRH stimulation of FSH release (low GnRH -> amenorrhea, "hypogonadotropic hypogonadism").

The Uterine Tube (Fallopian tube; oviduct) A pair of oviducts occur in the woman's body; they are also known as the fallopian tubes (named after G. Fallopius, an Italian anatomist of the mid 1500's). Each oviduct extends from its origin near the ovary, toward the midline to the lumen of the uterus. The tube is divisible into four contiguous parts. From lateral to medial, beginning with the fimbriated end of the infundibulum (fimbria, L. fringe), the four regions are the infundibulum (funnel-shaped opening), the ampulla, the isthmus, and the intramural (L., within the wall) portion that traverses the uterine wall. The structure of this tube is basically similar throughout. The mucosal folds and the relative thickness of the encircling muscularis progressively change from its distal to its proximal end.

Examine slide 762, a transversely sectioned human oviduct, to study the basic structure of the oviduct. Observe that the tube is supported by the mesosalpinx, the part of the broad ligament that carries the blood vessels and nerves to it (meso + G. salpinx, trumpet). The rest of the oviduct's outside surface is covered by a simple squamous mesothelium overlying a highly vascularized loose connective tissue layer. In this tissue section, the mesothelium is abraded in all but a few places. The thickness of the encircling muscular layer changes along the oviduct, being thinnest at the infundibulum and becoming progressively thicker as it approaches the wall of the uterus. The diameter of the tube simultaneously decreases along this distance. Along most of the length of the oviduct the muscularis has an inner circular layer and an outer longitudinal layer of smooth muscle, both somewhat spiraled as they encircle the wall. Further along the tube, toward the uterus, an internal longitudinal layer is present. The muscle fibers in the two thin layers tend to intermingle, which you can see in this tissue section. Observe the zone within and beneath the muscle layer: it is very rich in vessels, especially veins and lymphatic vessels. The mucosa is covered by a simple epithelium of ciliated, secretory, and peg cells. The cilia beat toward the uterus, moving a viscous mucous secretion that covers the luminal surface of the oviduct. Scan the luminal surface and observe the patches of ciliated cells. The relative numbers of ciliated cells is greatest at the fimbriated end of the oviduct and least at the intramural end. Secretory cells generally show the opposite distribution, reaching maximum density towards the uterine end. These cells are most easily recognized by their mucus product, which in this slide can often be seen extravasating to the lumen. Until recently, there was confusion over the categorization of peg cells, with many sources lumping them together with secretory cells. It is now becoming clear that the cells originally described as "peg cells" are the true stem cells, which differentiate to either ciliated or secretory cells based on hormonal state and location within the oviduct. The true peg cells have a thinner columnar morphology and are otherwise nondescript; we will not require you to recognize them. Importantly, they are distributed like the ciliated cells, most numerous towards the fimbria, and may account for the increased indicence of tubal cancers found at that end. At low power examine the intricately folded character of the mucosa in this tissue section. There are four to five major longitudinal ridges of well-vascularized mucosa, upon whose surface are many highly branched secondary and tertiary folds. This folding is especially complex in the infundibulum and the ampulla, where the height of the mucosal folds is greater than the thickness of the muscularis layer.

Vagina

Examine slide 780, a section of vagina wall, with the lumen at the top. The vagina is a fibromuscular sheath that extends from the cervix to the external genitalia. It is lined with a mucosa that has transverse rugae (L. ruga, a wrinkle). Examine the mucosa of this organ. The epithelium is a stratified squamous nonkeratinized epithelium that is rich in glycogen, especially in the surface cells. During the preparation of this tissue the glycogen dissolves out of the cells, leaving unusually clear images of the shapes of these cells. Connective tissue papillae project into the underside of the epithelium and when sectioned oblique to their long axis, the tips of the papillae may appear as islands of connective tissue within the epithelium. The papillae increase the surface area for attachment between these two tissues as well as carry blood vessels deeper into the epithelium. Look to see capillaries looping into these papillae. The mucosal connective tissue is a dense irregular connective tissue that is more cellular than the dense connective tissue in most other organs. Assess the distribution of the blood vessels and lymphatic vessels in this connective tissue: the number and size of these vessels is also unusually high for a dense connective tissue. The muscularis layer consists mainly of longitudinal smooth muscle with some inner circular fibers. Fascicles of these muscles intermingle. The adventitia is mostly an adipose tissue that links the vagina to the body wall.

Uterus The uterus is a hollow, thick-walled, and muscular organ, situated in the pelvis between the urinary bladder (anterior) and the rectum (posterior). In its upper part (where the fundus meets the body of the uterus), the oviducts open into its lumen, one on each side. The uterine lumen is continuous with the lumen of the vagina (L., sheath), through its lower part, the cervix (L., neck).

Examine slide 820 to observe a section of the human uterine wall. This tissue section includes a small centrally located uterine lumen bordered on all sides by mucosa; all five outside surfaces of this tissue section are cut surfaces. Look carefullyat this tissue section and attempt to visualize its plane of section. Observe the thick pale-staining mucosal layer surrounding the lumen. The organizational pattern of the uterus is similar to that of other hollow organs, but the layers have uterus-specific names: endometrium for the mucosa/submucosa, myometrium for the thick surrounding muscularis layer, and perimetrium for the serosa covering the outer surface (G. metra, uterus). This section does not include the full thickness of the myometrium, and thus no perimetrium is present. The endometrial epithelium is a simple columnar luminal epithelium, with occasional groups of ciliated cells; it lines the lumen and also lines the simple tubular uterine glands that extend through the thickness of the endometrium, typically branching basally. Observe the very regular spacing of these glands in regions where the endometrium is sectioned obliquely (toward the right side). The connective tissue surrounding the endometrial (uterine) glands is called the endometrial stroma. It is quite cellular and contains reticular fibers. Observe that in many places, especially deep in the endometrium, the glandular epithelium is artifactually separated from the supporting connective tissue along the basement membrane interface. The endometrium is subdivided into two functionally distinct parts. The stratum functionalis and the stratum basalis (functional layer and basal layer), which are identified primarily by location and relative thickness: there is no distinct morphological line of separation. The stratum functionalis (pars functionalis) is the superficial layer and the one that undergoes cyclic changes in the hormone-driven uterine cycle. The stratum basalis (pars basalis) is the thinner, deeper, permanent region containing the basal portions of the uterine glands; it is retained during menstruation and subsequently gives rise to the new stratum functionalis. The myometrium consists of interlacing bundles of smooth muscle obscurely arrayed in three layers. Branches of the uterine arteries within the uterus form arcuate arteries located about midway through the thickness of the myometrium. Do not attempt to identify these large arteries. The arcuate arteries give rise to radial branches that supply the endometrium.

Distinguish the various terms used to describe gamete and follicle development

Maturation of the ovarian follicles Ovarian follicles mature in the ovarian cortex, occupying space gradually closer to the medulla as they grow. Each follicle is composed of a single oocyte surrounded by follicular cells, which have an uncertain embryonic origin, deriving in utero either from cords of cells extending from the germinal epithelium, or possibly from the rete ovarii, part of the degenerating mesonephros homologous to the rete testis, which ascends from the future medullary region. Mesenchymal cells (and eventually vasculature) infiltrate and disrupt this network, resulting in each developing follicle (oocyte and associated follicular cells) being individually separated within a basement membrane from the ovarian stroma. Subsequent growth of the follicle during the reproductive years occurs under the influence of follicle stimulating hormone (FSH), which is secreted from the anterior pituitary gland. There are five main types of follicles: primordial, primary, pre-antral, antral, and mature (Graafian) follicles, defined as follows primordial follicle: the "resting" stage, lasting between 12-50 years. Commonly, they are found just beneath the tunica albuginea. primary follicle: the first stage of follicular maturation that occurs during the reproductive years, and persists for several reproductive cycles. -oocyte becomes active and enlarges -follicular cells proliferate and become cuboidal granulosa cells -zona pellucida is a PAS positive region that is rich in GAGs and glycoproteins and is secreted by the oocyte -theca folliculi: sheath of stromal cells surrounding the follicle. It is subdivided into the: -theca interna: inner, highly vascularized; ovoid secretory cells secrete estrogen precursors (probably androstenedione) that are converted into estrogens by the granulosa cells. -theca externa: connective tissue layer containing smooth muscle cells, collagen fibers pre-antral follicle: (historically, primary multilaminar follicle) a primary follicle in which many of the dividing granulosa cells lose contact with the follicular basement membrane. antral follicle: (historically, secondary follicle) follicle grows to approximately 5-8mm diameter. Accumulating fluid in the extracellular space surrounding the granulosa cells coalesces into a central area. This stage also persists over several reproductive cycles. Antral follicles larger than about 2mm form a pool of selectable follicles from which Graafian follicles can potentially develop. -antrum: space with antral fluid, known as liquor folliculi. -corona radiata: granulosa cells immediately surrounding the oocyte. These cells send processes through the zona pellucida to communicate with the oocyte via gap junctions. (Technically, the corona radiata consists of the granulosa cells that accompany the oocyte at the time of ovulation. These form at least one, and probably several layers around the oocyte.) -cumulus oophorus: granulosa cells connecting the corona radiata with the mural granulosa cells, effectively suspending the structures to be ovulated within the antral space Graafian (mature, tertiary) follicle: a further state of maturation of the antral follicle, occurring within one reproductive cycle, marked by a rapid expansion in follicular size in preparation for ovulation. This stage ends with the mid-cycle surge in LH inducing completion of the first meiotic division of the oocyte and triggering ovulation within 24 hours. At this time, luteinization begins to occur, and the granulosa and theca cells begin to produce progesterone. Prior to ovulation, the granulosa cells also secrete enzymes that erode the ovarian tunica albuginea, creating a visible thin spot on the ovarian surface called a stigma. At ovulation, in humans the average size of a Graafian follicle is 23mm. (The size of the second largest follicle, which is usually destined for atresia, averages 12mm.)

Describe the development of the female gamete (ovum) from its embryological origin through fertilization.

Ovaries and Oocyte Development The two major functions of the ovaries are gametogenesis and steroidogenesis. Gametogenesis, or production of gametes, is called oogenesis in the female. Properly, the developing gamete is called an oocyte and the mature, post-meiotic gamete is called an ovum (plural, ova), although the term "ovum" is also commonly used to refer to the female gamete without specification of its developmental stage. The primary hormones produced by the ovaries are estrogens and progesterone. Estrogens promote growth and maturation of sex organs and promote formation of female secondary sex characteristics. Progesterone prepares the uterus for implantation and pregnancy and prepares mammary gland for lactation. Maturation of the oocyte It is important to distinguish between maturation of the oocyte and maturation of the follicles since these two processes occur over different time courses. Primary oocytes are formed in the developing female embryo. At 6 weeks post fertilization (PF), a small number of primordial germ cells (oogonia) migrate to the genital ridge and begin to undergo rapid mitosis. By 5 months PF, there are 5- 6 million presumptive oocytes. Between 5 and 7 months PF each oocyte becomes surrounded by follicle cells and begins the first meiotic division. Meiosis is arrested at prophase I (in diplotene stage) and does not resume again until after 12- 50 years have passed. At each cycle, just prior to ovulation, one or more primary oocytes are stimulated to complete meiosis I. The division is unequal, and the two resulting cells are a secondary oocyte and a first polar body. The secondary oocyte immediately begins the second meiotic division but becomes arrested in metaphase II. Thus the oocyte at ovulation has not yet completed the second meiotic division. The second meiotic division (and production of the second polar body) is triggered by the entry of a spermatozoon.

Describe the role of female reproductive structures in oocyte fertilization

Oviducts (uterine tubes, Fallopian tubes) Just prior to ovulation the infundibulum moves to overlie the site of the Graafian follicle in order to capture the emerging oocyte. The ciliated cells of the fimbriae sweep the oocyte into the infundibulum. The ratio of ciliated to nonciliated secretory cells lining the oviducts is under hormonal control. Estrogen stimulates the growth of cilia, and progesterone increases the number of secretory cells. The epithelium is thicker at the time of ovulation than it is at the onset of menstruation. The longest portion of the oviduct is the ampulla, which is usually the site of fertilization. The function of the ampulla is to nourish both the oocyte and the sperm and to retain them to optimize chances for fertilization. In the ampulla, the primary means of moving the ovum switches from beating cilia to peristalsis. As a result, the following gradual changes are observed: the epithelial cells become shorter and fewer of them are ciliated, the mucosa becomes thrown into less convoluted folds, and the muscularis becomes thicker. The final portions of the oviduct move the fertilized ovum into the uterus by peristalsis. As a result, the isthmus and the intramural portion have a small lumen, short non-ciliated epithelial cells, few mucosal folds, and a thick muscularis.If the oviduct does not function properly, the embryo can implant outside of the uterus, resulting in an ectopic pregnancy. The most common kind of ectopic pregnancy is tubal pregnancy, where implantation occurs in the oviduct. Ectopic pregnancies are often the result of a tubal obstruction that prevents normal movement of the fertilized ovum. For example, ectopic pregnancies have been seen (rarely) in persons who have had tubal ligation surgery, a method of female birth control that involves tying, cauterizing, or otherwise blocking the fallopian tubes. Uterus The uterus is a hollow, pear-shaped organ, about 7cm in length, which provides an environment for the developing embryo and functions to expel the baby at birth. It is divided into the fundus, body, and the cervix. The myometrium of the fundus and body is an extremely thick muscle layer that is loosely organized into three layers. It serves to protect the developing fetus and to expel the baby at birth. The uterus expands up to 100 times its nonpregnant size during pregnancy so the muscle grows accordingly. The size of muscle fibers increases (hypertrophy) significantly and new muscle cells are produced (hyperplasia).The myometrium also undergoes an increase in collagen content during pregnancy. The endometrium is divided functionally into the stratum functionalis and the stratum basalis. The stratum functionalis proliferates and degenerates during the menstrual cycle. The stratum functionalis is very highly vascularized with abundant spiral arteries that are important during menstruation. The stratum basalis underlies the stratum functionalis and is retained during menstruation. Cells in the stratum basalis act as stem cells to regenerate the stratum functionalis with each cycle. Although the spiral arteries pass through the stratum basalis on their way to nourish the stratum functionalis, the stratum basalis is itself nourished by short straight arteries. Both the straight and the spiral arteries arise from radial arteries in the myometrium. CLINICAL: Endometriosis is a fairly common condition in which endometrial tissue is present in the peritoneal cavity. It can be very painful and can lead to ectopic pregnancies Endometriosis can be treated with hormone therapy or by laser ablation of the tissue. Cervix The cervix is the lower one third of the uterus. It differs from the rest of the uterus in that it does not contain spiral arteries and its epithelium is not sloughed off during menstruation. The function of the cervix is to provide a tight opening to the uterus that allows sperm to enter but provides a barrier to infection. The mucosa of the endocervix is continuous with the endometrium and is composed of mucus-secreting cells. The plica palmatae are complex crypts that are sometimes imprecisely referred to as cervical glands. The mucus produced by the epithelial cells helps to protect against bacterial invasion. The chemical composition of the mucus changes over the reproductive cycle. A thinning of the mucus (literally a change in the macromolecular arrangement of the various mucin molecules) that facilitates the entry of sperm occurs over the last days of the proliferative period. Also, thick cervical mucus contains immunoglobulins, protease inhibitors, and other compounds that normally serve to impede the passage of sperm (and other foreign microorganisms). The ectocervix is the external surface of the portio vaginalis. Changes in ectocervical epithelial cells can give an early indication of cervical cancer, therefore screening these cells, by a technique such as the Papanicolou (Pap) smear, is an important part of a gynecologic exam. The abrupt squamocolumnar junction between the endocervical and ectocervical epithelia typically occurs at the external os. However, this junctional area may migrate: in many young women, the endocervix is everted, and the squamocolumnar junction is visible during physical examination of the vagina and cervix; by the time of menopause, the squamocolumnar junction has migrated into the cervical canal and is not visible during physical examination. It is quite common to see a metaplastic squamous epithelium replacing the columnar epithelium where it has been chronically exposed to the acidic vaginal contents. Thus pathologists may use the terms "original columnar" and "original squamous" when describing the cervix epithelium.

Describe the coupled ovarian and uterine events of the menstrual cycle. Fimbriae: ciliated finger-like structures on the funnel-like end (ampulla) of the oviduct; receives the ovum from the topologically-separate ovary. Oviduct (= uterine tube = Fallopian tube): transports the ovum from the ovary to the uterus; provides an appropriate environment for fertilization. Uterus: site of implantation and growth of the embryo; lining renewed in each cycle. Cervix: constricted base of uterus, separating it from vagina. Vagina: accepts penis; with dilated cervix, forms the birth canal. Only one egg is produced per primary oocyte (vs. 4 spermatozoa per con- tinuously-produced primary spermatocyte). There are 2-4 million eggs at birth -> 200,000-400,000 at puberty -> 400-500 ovulated over a lifetime

Review of components of female reproductive system Cells of the ovary: -Oogonia (= germ cells): The counterpart of the spermatogonia in the testis, oo- gonia exist only during fetal life, generating a fixed number of primary oocytes by birth. -Theca cells (= interstitial cells): The steroidogenic counterpart of Leydig cells in the testis, they are stimulated by LH to produce androstenedione. Theca cells are low in aromatase and cannot effectively convert androgens to estrogens. -Granulosa cells (= follicular cells; surround and "nurse" developing oocytes): The counterparts of Sertoli cells, granulosa cells are stimulated by FSH to produce abundant aromatase and thus can convert theca cell androstenedione to estrogen Oogenesis -Oogonia -> continual mitosis only until birth -> fixed number of primary oocytes (2n / 2DNA); reduced 10-fold through atresia (= apoptosis = programmed cell death) by the time of puberty. - Primary oocyte -> 1st meiotic division -> secondary oocyte (1n / 2DNA) plus polar body at ovulation. - Secondary oocyte -> 2nd meiotic division -> "egg" (1n / 1DNA) plus polar body at fertilization, at which point the haploid egg (ovum) and sperm nuclei fuse to produce the diploid zygote ("conceptus" -> embryo -> fetus). Ovarian Events during the Menstrual Cycle -Primary oocytes (25 um) are each surrounded by a single layer of granulosa cells (primordial follicles). -Secreting a clear, protective zona pellucida, a cohort of a dozen or so oocytes grows while granulosa cells multiply (-> primary follicles); granulosa cells are connected to each other and to the oocyte via gap junctions. -Surrounding connective tissue differentiates into a theca cell layer as granulosa cells and oocytes grow further (preantral follicles). -After oocytes reach their final size (~150 um), granulosa cells secrete fluid, forming a fluid-filled space, the antrum (-> early antral follicles) -Typically, one follicle (dominant follicle) develops more robustly than the others, which undergo atresia or apoptosis (atetric follicles), ~ day 7. - The dominant follicle enlarges, mainly via an expanding antrum, and the oocyte, encompassed by a sphere of granulosa cells (cumulus oophorous), protrudes into the antrum (antral follicle). -After growth to 1-2 cm, the mature ("Graafian") follicle is palpable at the sur- face of the ovary and ready for ovulation, ~day 14. - As ovulation approaches, the first meiotic division concludes (-> secondary oocyte), cytoplasm matures, and the cumulus begins separating from the follicle wall -The remaining follicular cells (~80% granulosa + ~20% theca = "luteal" cells) enlarge and form a glandular structure, the corpus luteum (yellow body). - If fertilization and implantation do not occur, the corpus luteum develops max- imally by ~day 25, then rapidly degenerates by apoptosis (-> corpus albicans, white body); after ~28 days, a new cohort of primary oocytes begins to develop. Hormonal Changes in Menstruation -In the female, not only do the levels of hormones change in a monthly fashion but the nature and control of their effects change as well. The steps below correspond to the days numbered on the following figure, beginning on "day 1" of the menstrual cycle (~14 days before ovulation). -Early follicular (days 1-5) Having been strongly inhibited by progesterone, es- trogen and inhibin A in the previous cycle, LH and FSH rise as their respective inhibitors fall. No longer supported by progesterone, the uterine lining degenerates -> menstruation. Stimulated by rising FSH, a new cohort of follicles begins to develop. Proliferating granulosa cells now secrete inhibin B. -Mid-follicular (days 6-10) - Rising inhibin B begins to suppress FSH release. As FSH decreases, one follicle becomes dominant while the others undergo atresia. Estrogen levels increase as a result of LH-stimulated theca cell production of androgens and subsequent granulosa cell conversion of androgens to estrogen via FSH-induced aromatase. Estrogen stimulates further growth of granulosa and theca cells via autocrine / paracrine actions. -Late follicular (days 11-14) - Estrogen-induced growth of the follicle results in rapidly rising estrogen levels, which stimulate further follicular growth. Rising estrogen renders the anterior pituitary increasingly more sensitive to GnRH by inducing more GnRH receptors on the gonadotropes, an apparent "pos- itive" feedback. Consequently, LH release increases dramatically (and GnRH may also increase). Estrogen (+ FSH) induces LH receptors on the granulosa cells that encompass the oocyte. -Ovulation (day 14) - The rapid increase in LH triggers ovulation through action on the now-LH-sensitive granulosa cells, which release lytic enzymes and prosta- glandins to expel the oocyte. There is passive release (co-secretion) of FSH and a subsequent inhibin B re- sponse.The LH surge also induces completion of the oocyte's first meiotic division, preparing it for fertilization. -Early luteal (days 15 20) - The LH surge and the loss of oocyte signaling to the follicle result in a metabolic shift, after which the remaining "luteal" cells pro- duce less estrogen and inhibin B but increasing amounts of progesterone and inhibin A. -Mid-luteal (days 21-25) - As the corpus luteum grows under LH stimulation, pro- gesterone, estrogen and inhibin A rise maximally. But, the resulting high proges- terone, together with estrogen, inhibit both GnRH and LH release while inhibin A inhibits FSH. If implantation occurs, the trophoblasts of the embryo produce hCG (= LH), which maintains the corpus luteum through the first 8-10 weeks of pregnancy. -Late luteal (days 26-28) - The corpus luteum, lacking LH (the luteinizing hor- mone) degenerates. Consequently, progesterone, estrogen and inhibin A levels fall rapidly, releasing both the hypothalamus and the anterior pituitary from inhibition. -End cycle/recycle - Lacking inhibition, FSH and LH begin to rise, stimulating a new cohort of follicles. Uterine Events during the Menstrual Cycle -Menstrual phase (days 1-5): from the initiation to the completion of bleeding; the epithelial lining of the uterus - the endometrium - degenerates and sloughs off, resulting in menstrual flow (menses). -Proliferative phase (days 5-14): under the influence of increasing estrogen, the endometrium regenerates, thickens and forms glandular structures. Induced by rising estrogen, progesterone receptors appear on the endometrial cells. The un- derlying myometrium (smooth muscle) thickens and also acquires progesterone receptor -Secretory phase (days 14-28): under the influence of increasing progesterone, mucus and fluid secretion, glycogen synthesis and vascularization increase while progesterone inhibits myometrial contraction, all in preparation for implantation. - Mid-cycle: under the influence of estrogen, cervical mucus initially is thin, allowing sperm movement, but under the influence of increasing progesterone, the cervical mucus thickens and becomes acidic, thus preventing sperm movement and bacterial invasion. - End-cycle: the fall in estrogen and progesterone deprive the endometrium of support, causing constriction of uterine blood vessels, much-reduced blood flow, prostaglandin secretion, and eventual death of the tissue. Lacking inhibition by progesterone, the myometrium rhythmically contracts, and the endometrial blood vessels dilate, resulting in hemorrhage through weakened capillary walls.

The Uterine Tube (Fallopian tube; oviduct) Part II

Slide 764 has been digitized from the original microscope slide illustrated in its entirety in large format below. Examine this syllabus image in color. Only the parts of the slide within the green lines have been compiled for our VM database of images. Relate what you can see in your VM slide to the large unscanned areas of the tissue section. This slide illustrates how the complexity of the mucosal folds changes with distance from the infundibulum (1 in the photomicrograph) to the ampulla/isthmus (the section below section 4). Only three tissue sections and part of the infundibulum are scanned at higher magnifications and appear on your VM slide 764. You can identify the infundibulum in sections where there is an obvious discontinuity in the surrounding muscularis. Dashed lines on the photomicrograph above indicate the open lumen of the infundibulum (1). Although you cannot use adequately high magnification to see it, the columnar epithelium of the fimbria (the extensive finger-like "fringe" of the infundibulum) is continuous with the serosal mesothelium on the outside of this infundibulum. Section 2 is very close to the infundibular opening since the muscle layer does not completely encircle the lumen, although the serosa does. Most of the remaining tissue sections on this slide are of the ampulla, which comprises nearly two-thirds of the length of the oviduct. Since the height of the mucosal folds decrease with increasing proximity to the uterus, the height of the mucosal folds will range from being very much greater than the relatively thin muscularis at the distal end of the oviduct to only slightly greater in height than the thickness of the muscularis layer as it nears the isthmus, and then considerably shallower than the thickness of the muscularis as the isthmus approaches the uterus wall. The tissue section at the bottom middle of this original slide appears smaller than the others. This tissue section has somewhat simpler mucosal folds than the others and the height of its mucosal folds appears to be less than the thickness of the surrounding muscularis. On this basis, this section is likely very close to the isthmus region of the oviduct. The intramural portion of the oviduct, which we do not examine, has very shallow mucosal ridges. It is embedded within the wall of the uterus and therefore will be surrounded by the uterine myometrium in place of a serosa.

Cervix The cervix is the neck of the uterus, but differs in structure, function, and mucosal lining from the body (corpus) of the uterus. The cervix is about 2.5 cm long and is more cylindrical and narrow than the corpus. Its distal portion extends into the vagina. The narrow cervical canal opens into the uterine lumen at an aperture known as the internal os, and opens into the lumen of the vagina at the external os.

Slide 772 is one wall of a longitudinally sectioned human cervix. During preparation the normally straight wall of this cervical canal has become artifactually concave. The part of the cervix that bulges into the vaginal cavity is the portio vaginalis, and its outer mucosal surface (facing the vagina) is the ectocervix. The lumen of the cervix is the cervical canal. The epithelium of the cervical canal is not well preserved here, but you can see enough detail to identify it as a simple columnar secretory epithelium. Observe the distinctly indented surface to the right side of this tissue section: this is part of the lumen of the vagina and like the vagina is lined with a stratified squamous nonkeratinized epithelium. Observe, therefore that the outside of the portitio vaginalis is covered with a stratified squamous nonkeratinized epithelium, while the lumen of the portio vaginalis (as is all the cervical canal) is lined with a simple columnar epithelium. Although artifactually abraded on this section, there is an abrupt demarcation line between the epithelia of the cervix and that of the vagina. The abrupt change in epithelial type marks the border between ectocervix and endocervix, and typically occurs just inside the opening of the cervical canal into the vagina (at the external os of the cervix) Notice that the mucosa (endocervix) lining the cervical canal forms very complex, deep furrows or compound clefts, known as the plicae palmatae. The folds are irregularly arranged and often misinterpreted to be a system of branching tubular glands, and so are also known as endocervical or cervical glands. The epithelium consists of tall columnar cells with basal nuclei; some of the cells are ciliated, but most are mucoid, secreting a substance that occludes the opening of the cervical canal protecting the uterus from bacteria. On occasion, the necks of these branching "glands" become occluded and the deep portions fill with secretion, eventually causing atrophy of the surrounding epithelium; these dilatations are called Nabothian cysts. The thick wall of the cervix is unlike that of the rest of the uterus in that it consists mostly of dense collagenous and elastic fibers among which are distributed a relatively few smooth muscle cells.

Spermiogenesis Capacitation The glycoprotein coat acquired by spermatozoa in the ductus epididymis facilitates long-term storage in the male reproductive tract. This coat is removed through contact with the uterine epithelium in a process termed capacitation, which may occur over several hours. Capacitation may be considered the final step in sperm maturation.

Spermiogenesis is the final stage of production of the germ cells. No cell division occurs in this stage. Haploid spermatids begin as small spherical cells with small dense nuclei (early spermatids). They gradually mature into pointed cells with flagella (late spermatids) that are embedded in the apical cytoplasm of Sertoli cells. The first recognizable change is the formation of the acrosome (an organelle derived from coalesced Golgi complexes, containing hydrolytic enzymes known to dissociate cells of the corona radiata and digest the zona pellucida which surround the oocyte). The acrosome shapes the condensing nucleus into an elongate form. The remainder of the cytoplasm also deforms under control of a specialized cylindrical sheath of microtubules called the manchette. Further development includes synthesis of the flagellum (a cilium with an intracellular motor attached), packaging of mitochondria, and the loss of much of the cytoplasm in the residual bodies. The spermatids' intercellular bridges are also lost in the excreted residual bodies. When spermiogenesis is complete, the late spermatids are released from the enveloping apical cytoplasm of the Sertoli cell into the lumen of the seminiferous tubule as mature spermatozoa.

Glands: Seminal Vesicle, Prostate, Bulbourethral Gland

The abundant viscous secretion formed in the seminal vesicles represents a substantial portion of the whole ejaculate (70 to 85%) and contains many substances that serve as spermatozoa-activating substances. The most important of these are fructose and prostaglandins. The fructose produced by the seminal vesicles serves as the principal energy source for the spermatozoa. It is speculated that the function of prostaglandins in semen may be to increase smooth muscle motility in the female reproductive system. The prostate is the largest of the accessory glands of the male reproductive system. It can be divided into several zones that have clinical relevance: the central zone occupies 25% of the gland's volume and surrounds the ejaculatory ducts, the peripheral zone (70% of the gland) comprises the outermost portion which is the major site of prostatic cancer, and the transitional zone surrounds the prostatic urethra proximal to the ejaculatory ducts which is where most benign prostatic hyperplasia originates. The secretion is a yellowish fluid rich in proteolytic enzymes, including fibrinolysin and acid phosphatase as well as citric acid. Historically, measurement of acid phosphatase levels was used to assess prostatic function and pathology. In the lumens of the individual glands may be found concentric layers of condensations of secretory material, called prostatic concretions or corpora amylacea. These increase in number with age and are present in the ejaculate. Their significance is not known. A small, blind outpouching of the urethra, the prostatic utricle, occurs at the junction of the ejaculatory ducts and prostatic urethra. It is occasionally enlarged in cases of insufficient anti-Müllerian hormone action in utero, providing evidence that it is a vestige of the paramesonephric (Müllerian) duct that forms many of the female reproductive structures, The structure and function of both the seminal vesicle and the prostate gland depend on the level of testosterone. The abundant smooth muscle of the seminal vesicle and the prostate gland is innervated by the sympathetic nervous system, which stimulates the contractions that empty these glandular structures during ejaculation.

Explain how the histology of the ovary, fallopian tubes, uterus, and vagina supports their functions.

The internal organs of the female reproductive system are situated within the woman's pelvis, (specifically, the lesser pelvis) and include the ovaries, uterine (fallopian) tubes ( a.k.a. oviducts), uterus, and vagina. The ovaries and oviducts are paired bilaterally-symmetric structures, while the uterus and vagina are single midline structures.

Explain the difference between spermatogenesis and spermiogenesis, and describe the morphological changes in the germ cells during these stages.

The male reproductive system consists of the two testes and the penis, the duct system between the testes and the penis, and accessory sexual structures that include the glands that contribute fluid secretions to the semen upon ejaculation. It is a bilaterally symmetric system, but becomes a single midline system when it connects to the urethra.

List the events associated with fertilization, implantation and placenta formation.

The sperm After ejaculation, sperm must undergo critical changes in the female reproductive tract to enable them to function: Capacitation: epididymis-derived proteins are stripped off; transmembrane proteins are rearranged; metabolism and motility increase (also required for IVF). Hyperactivation: receptor-mediated calcium influx converts slow, wave-like beating to rapid, whip-like beating, triggered by proximity to the egg - a paracrine signal from a yet-unidentified egg factor for which sperm have receptors. Acrosome reaction: sperm head binding to zona pellucida triggers exocytosis of a trypsin-like proteolytic enzyme (acrosin) from the acrosome, clearing a path for the sperm head to fuse with the egg plasma membrane. Of ~250 million sperm deposited in the vagina, ~100,000 reach the uterus, but several orders of magnitude fewer reach the ampulla of the oviduct. Sperm can live in the female tract for 2-4 days. The egg After ovulation, the ovum is transported quickly from the fimbriae to the ovi- duct by ciliary movement and smooth muscle contractions, then slowly through the oviduct by ciliary movement, requiring nearly 4 days to reach the uterus. Unless fertilized, the egg is only viable for about 12-24 hours. Fertilization usually takes place in the distal portion of the oviduct, the ampulla, 1-2 days after ovulation. Specific sperm-egg receptor binding -> membrane fusion -> exocytosis of cortical granules releases enzymes beneath zona pellucida -> block to polyspermy & egg activation; 2nd meiotic division -> haploid female pronucleus -> union with male pronucleus -> mitosis -> beginning of cleavage stage. The cleaving zygote passes through the oviduct and enters the uterus as a morula (no cavity), 3-4 days post-ovulation. The zygote differentiates to the blastocyst stage: an outer layer of cells (the trophoblast, destined to become the fetal portion of the placenta), an inner cell mass (destined to become the embryo/fetus), and a central, fluid-filled cavity (the blastocyst cavity, or blastocoel). The zygote sheds its zona pellucida (~day 6) in preparation for implantation. The embryo implants in the uterine wall ~7 days post-ovulation (implantation stage), during a "window of receptivity" before or after which implantation may fail. This specific recognition and signaling process appears to be analogous to leukocyte attachment to and penetration of blood vessel walls (leukocyte extrav- asation). If transport is delayed, implantation can occur in the oviduct wall or, if the fer- tilized egg escapes the fimbriae, in the abdominal wall (-> ectopic pregnancy). Implantation / Placenta formation Contact between blastocyst and endometrium triggers proliferation of an outer layer of syncytial trophoblast cells (syncytiotrophoblasts), which penetrate be- tween endometrial cells, aided by proteolytic enzymes, thus embedding the blastocyst in the uterine wall. The syncytiotrophoblasts form finger-like projections (chorionic villi) into the endometrium; these develop extensive capillaries linked to the embryo's circula- tory system. Under the influence of an invading villus, the surrounding endometrial cells form a sinus of blood supplied by maternal arterioles. This modified maternal endometrial tissue (decidua) plus the fetal chorion (synctiotrophoblasts, meso- derm cells and the cytotrophoblasts from which both arose) interlock to form the placenta. Umbilical arteries and veins form, in turn forming the umbilical cord attaching the developing embryo to the placenta. By 5 weeks, the fetal heart is functioning. Meanwhile, a fluid-filled space - the amniotic cavity - forms around the embryo itself. By the 4th month, genetic screening can be done on fetal cells in fluid withdrawn from the amniotic cavity (amniocentesis); chorionic villus sampling (needle bi- opsy) can be done by the 3rd month.

Relate the changing appearance of the reproductive organs from the embryo through senescence to their underlying causes. Hormonal control of the menstrual cycle

The three phases of uterine proliferation are under the control of hormonal changes during the menstrual cycle. The standardized cycle is 28 days with day 1 being the first day of menstruation. Keep the days of the menstrual cycle distinct from the days of embryo development (days post fertilization). The menstrual phase (day 1-4) is influenced by the decline in estrogens and progesterone as the corpus luteum degenerates. The spiral arteries begin to contract as progesterone levels decline, causing the stratum functionalis to become ischemic. The surface epithelium is disrupted and blood vessels burst. Blood, uterine fluid, and sloughing epithelial and stromal cells from the stratum functionalis constitute the menstrual flow. As the menstrual phase ends, the proliferative phase begins again. The proliferative or follicular stage (day 5-15) is influenced by estrogen from the developing ovarian follicles. At the beginning of this phase, the stratum functionalis is absent and the stratum basalis is only 1 mm thick. The endometrium rapidly proliferates to a thickness of 5-7 mm. Epithelial cells from the base of the glands residing in the stratum basalis reconstitute the uterine glands and the endometrial surface. Stromal cells proliferate and spiral arteries regenerate into the lower two thirds of the stratum functionalis The secretory or luteal phase (day 16-28) is influenced mainly by progesterone and begin to secrete a thick, glycogen-rich fluid. Spiral arteries lengthen, become more coiled, and extend nearly to the surface. Human endometrial stromal cells undergo decidualization beginning after day 23. Cells swell, occupying more of the connective tissue space, and produce specific cytokines in preparation for a potential implantation. In most other animals, decidualization occurs in response to implantation, so it will be discussed further with "Organs of Pregnancy".

Vagina Illustrate the morphological changes in the reproductive organs that accompany hormonal changes of the menstrual cycle and pregnancy. The internal reproductive organs in the female consist of paired ovaries and oviducts and the uterus and vagina. The external genitalia consist of the clitoris, labia majora, and labia minora. Together they provide for the production of gametes and reproductive hormones, the fertilization of the ovum, sexual function, and the protection, nourishment, and expulsion of the embryo. After puberty, the ovaries, oviducts, and uterus undergo significant structural and functional changes due to neural and hormonal signals during the menstrual cycle and during pregnancy Describe the process and purpose of atresia of ovarian follicles (at the level presented here). Describe the formation, morphology, and function of the corpus luteum.

The vagina is a fibromuscular tube that connects the uterus to the outside of the body. It acts in transport of sperm to the uterus and in expulsion of the newborn. The nonkeratinized stratified squamous lining epithelium has no glands so there is no mucus secretion present other than that of the endocervix. The lamina propria has an unusually high density of thin-walled blood vessels that contribute to diffusion of vaginal fluid across the epithelium. The vaginal epithelium responds to hormonal changes during the menstrual cycle. Glycogen is stored in the epithelial cells and reaches maximal levels at ovulation, after which time the glycogen-rich superficial layer of epithelium is shed. Breakdown of the glycogen by bacteria in the vagina produces lactic acid, causing the vaginal environment to have an acidic pH of about 3. This inhibits growth of other bacteria, bacterial pathogens, and fungus. It also limits the time in which sperm can survive in the vagina Changes with aging While the symptoms of menopause are primarily understandable as a response to altered hormonal levels, the precipitating cause of menopause is the complete lack of selectable ovarian follicles. However, even before menopause occurs, fertility decreases significantly as a function of age. Many of the female reproductive organs, notably the ovaries, uterus, and vagina accumulate connective tissue with age. Especially in the uterus, the change in the ratio of connective tissue to muscle tissue may underlie the age-related decrease in fertility, may serve to complicate childbirth, and may play a role in diseases such as endometriosis

The Aging Male

To a first approximation, male sexual potential remains unchanged with advancing age. Testicular volume, sperm counts, etc. change very little as a function of age. Semen volume, sperm motility, and morphology do show age-related changes, and some studies suggest that birth defects also show a correlation with the age of the father. But these changes are relatively minor concerns, clinically. Empirically, there are numerous documented instances of men fathering children while in their 90s. (Pablo Picasso fathered a child at age 68, Marlon Brando at age 74.) More important are the concerns of BPH and prostate cancer, the prevalence of which increases with age to the point where some researchers consider these diseases to be "normal" consequences of aging. Also, the incidence of erectile dysfunction is known to increase markedly. Androgenic alopecia (male balding) is apparently due age-related changes in androgen sensitivity within hair follicles. Senescent gynecomastia (enlargement of the breasts) correlates with changes in the estrogen to androgen ratios. (Testosterone levels show a mild decrease with aging, while estrogen (E1 and E2) levels remain relatively constant.) As with prostate enlargement, gynecomastia in an elderly person may arise either from benign or serious, acute or chronic underlying causes. Thus it is clinically important to be sensitive to these agerelated diseases in males.

The Duct System The exit route from the lumen of the seminiferous tubule proceeds sequentially through the following series of tubes: -tubuli recti (straight tubules) at the end of seminiferous tubule -rete testis (a network of channels in the mediastinum) -ductuli efferentes (10-15 tubules) -ductus epididymis -ductus deferens -ampulla -ejaculatory duct -prostatic urethra -penile urethra Sperm are transported through the duct system by several different means. A current, produced from fluid produced in the testes and absorbed further along the duct, first carries sperm. The ductuli efferentes contain cilia that may be important in moving sperm. Finally, an increasingly thick layer of smooth muscle, which contracts forcibly during ejaculation, propels sperm. The sperm's own flagellar motor is largely reserved for movement after ejaculation. Although secretions of the prostate and seminal vesicle make up over 99% of the ejaculate by volume, the prior elements of the duct system predominately contain sperm.

Tubuli Recti and Rete Testis Seminiferous tubules connect with the rete testis by straight, short tubuli recti: only Sertoli cells line the tubules. This very short portion ends abruptly at the rete testis. Ductuli Efferentes Two types of epithelial cell line the ductuli efferentes: tall columnar ciliated cells, their cilia beating toward the epididymis, and shorter cells that are absorptive in function. The activity of the ciliated cells and the fluid absorption together create a flow of fluid from the rete testis that carries the spermatozoa toward the ductus epididymis. Ductus Epididymis and Ductus Deferens Some of the final differentiating steps in sperm development occur in the ductus epididymis. Spermatozoa leaving the testis exhibit weak, random, circular motion, while spermatozoa taken from the distal end of the epididymis, after many days in transit, have a strong unidirectional motility although maximal motility is not achieved until they reach the female reproductive tract. The ductus epididymis is approximately 16 feet long. The ductus epididymis, along with connective tissue and blood vessels forms the body (corpus) and tail (cauda) of the epididymis. The head (caput) of the epididymis contains primarily the ductuli efferentes. The ductus epididymis is approximately 16 feet long. The ductus epididymis, along with connective tissue and blood vessels forms the body (corpus) and tail (cauda) of the epididymis. The head (caput) of the epididymis contains primarily the ductuli efferentes. Any remaining fluid generated in the testis is absorbed in the epididymis; the epithelium also participates in the elimination of any residual bodies that have accompanied the spermatozoa. The cells secrete glycoproteins and other materials essential for the maturation of the spermatozoa. Maturing spermatozoa are stored in the lumen of the ductus epididymis. The thin peripheral smooth muscle sheath becomes progressively thicker as the epididymis is followed distally towards its junction with the ductus deferens. Contractions of this muscle during arousal move the spermatozoa into the ductus deferens for ejaculation. The ductus deferens (older name: vas deferens) is a thick walled tube that is a continuation of the epididymis. Its lumen is rugose (i.e., highly folded) and lined by a pseudostratified epithelium with stereocilia; this epithelium is similar to that in the epididymis but the principal cells are not as tall nor are the stereocilia as long. The most striking feature of this duct is the three-layered muscular coat, 1 to 1.5 mm thick. Peristaltic contraction moves the spermatozoa into the urethra via the ejaculatory ducts of the prostate. The ductus deferens forms part of the spermatic cord. In addition to the ductus deferens, the spermatic cord contains arteries (including the testicular artery to the testis and epididymis) and a complex of veins, the pampiniform plexus, which drain the testis and epididymis. These veins carry blood cooled in the periphery of the scrotum and "precool" the arterial blood traveling to the testis. This aids in maintaining the lower temperature required for the production of spermatozoa in the testis. Ampulla and Ejaculatory Duct. Before entering the prostate gland, each ductus deferens dilates into a region called the ampulla. The epithelium in the ampulla is thicker than that of the distal ductus deferens and extensively folded. In the final portion of the ampulla, the seminal vesicle joins the duct. After the seminal vesicle joins the duct, the duct enters the prostate gland as the ejaculatory duct. The muscular coat of the ampulla is lost after the seminal vesicle joins it and the tube becomes the ejaculatory duct. The ejaculatory ducts open into the prostatic urethra within a central elevation of the urethral mucosa known as the seminal colliculus. From this point, the bilaterally symmetrical components of the male reproductive system become a single midline structure. Urethra. The epithelial lining of the urethra varies. Near its origin, the epithelium is transitional, like that of the urinary bladder. The prostatic urethral epithelium is largely transitional. This gives way to a largely pseudostratified or stratified columnar arrangement in the penile urethra. Within the penis, patches of stratified squamous epithelium are present. Along the course of the urethra, occasional mucus goblet cells are found. Some of the recesses in the lumen wall continue into mucous acinar structures, the glands of Littré. These occasional intraepithelial nests of clear cells exhibit the staining reactions of mucus.

Explain the evidence for the organic nature of gender identity

What we think we know about the biology of gender identity Opposite to the dogma of many years, gender identity appears durable. While individuals may make choices related to other inputs in their lives, there do not seem to be external manipulations that truly cause individuals to change gender identity. Because gender identity is fixed, treatment can only be to support an individual who wishes to change external appearance to match self-perceived gender Evidence Because conventional medical dogma was so certain that gender identity was malleable (either a passive response to external anatomy, a social construct, or something that could be manipulated in childhood perhaps by parents), the standard treatment for individuals born with ambiguous genitalia was that they would be best treated by assigning them to the sex that fit the easiest surgical maneuver. Typically, the surgery for a neo-vagina was considered most optimally accomplished and the individuals were often raised as girls. If we apply the current rough estimates for transgender individuals in the population (0.6% of the population), raising XY individuals as girls would be predicted cause incongruence between gender identity and external anatomy the overwhelming majority of the time. Indeed, in the few instances when XY individuals raised as girls have been carefully interviewed, the majority report male gender identity.

Ovarian Follicles All the oocytes that a woman is ever to have are present in her ovaries at her birth. The growth and full maturation process of the oocyte occurs through a series of stages that begins with a primordial follicle and ends with the ovulation (expulsion) from a Graafian follicle. Many oocytes begin the maturation process, a fewer number survive to form the "selectable pool" and typically (in humans) only one follicle per cycle is selected to mature into a preovulatory Graafian follicle. Ovarian follicles, at any stage of maturation, may cease development and undergo a degenerative process, known as atresia. As the ovarian follicles mature, the oocyte itself remains a primary oocyte until just before ovulation when it completes meiosis I and enters meiosis II. The oocyte-containing ovarian follicles are embedded in the connective tissue stroma of the cortex of the ovary. Return to slide 751, the ovary. To view the development of the ovarian follicles, examine also 753 (Mallory's trichrome, described below) and 755.

primordial follicle (oocyte, stromal cell, folicular cell): a single layer of flattened follicular cells surrounds the small oocyte. A basement membrane separates the follicular cells from the surrounding connective tissue. The oocyte typically has a large round euchromatic nucleus with a prominent dark nucleolus; if the plane of section is not mid-cell, you will not see the nucleus and/or the nucleolus. These numerous small follicles tend to be located in the superficial cortex, beneath the dense tunica albuginea. primary follicle (basal lamina, zona pellucida forming, granulosa cells). : The oocyte has grown in size and is surrounded by cuboidal to columnar granulosa cells (the former follicularcells), which begin as a single layer (unilaminar) and then stratify (pre-antral, below). The basement membrane persists The zona pellucida, secreted by the oocyte, is a glycosaminoglycanrich zone that forms between the granulosa cells and the oocyte. b.The theca folliculi (theca, G. a box) develops in the immediately surrounding stroma, with a fibromuscular layer (theca externa) and a steroidogenic layer (theca interna) that is well vascularized. The theca interna contains clusters of foamy-appearing theca interna cells. The theca folliculi is especially well illustrated in slide 753 (described below). pre-antral follicle: a primary follicle with more than one stratum of granulosa cells, but prior to any significant accumulation of extracellular fluid antral follicle: This stage in follicle development is marked by the formation of an extracellular fluid-filled space (antrum) that appears among the granulosa cells. This space is filled with antral fluid (liquor folliculi). The membrana granulosa can now be separated into: the mural granulosa (a "wall" lining the antral space), the cumulus oophorus (the pedestal of cells upon which the oocyte rests), and the corona radiata (the layer of granulosa cells that surrounds the oocyte). A subset of the larger antral follicles form a pool of selectable follicles. Graafian follicle: This follicle is also known as a preovulatory or selected follicle. It is a very large follicle (nearly 2 cm in diameter) that ovulates. Note: although there are numerous antral follicles on these slides there are no Graafian follicles present. 6. atretic follicle: In atretic follicles, the granulosa cells of follicles at any stage of development undergo degeneration by apoptosis; distinctly small, dense, pyknotic nuclei appear among the normal granulosa cell nuclei. Most atretic follicles are completely phagocytosed by macrophages. This tissue section and the following tissue sections are fixed well enough so that you can distinguish between healthy ovarian follicles and atretic (degenerating) ones. There are many good examples of atretic follicles in slide 755. Though atretic primordial and primary follicles can be recognized, you are only responsible to distinguish follicles that become atretic from the antral stage.

Spermatogenesis

Sertoli cells are the supporting cells of the seminiferous tubules. They are important in the function of the testis in the following ways. They: provide support, protection, nutrition, and developmental regulation for spermatozoa, phagocytose excess spermatid cytoplasm, continuously secrete a fluid that is used for sperm transport in the proximal genital ducts, secrete two hormones; androgen binding protein (ABP) which concentrates testosterone in cells lining the reproductive duct, and inhibin which serves to inhibit FSH production by the pituitary, produce the anti-Müllerian hormone during fetal development, inhibiting the development of female reproductive structures, and form a blood-testis barrier that protects the haploid gametes from blood-borne noxious agents and contact with the immune system. Spermatogenesis begins with activation of a single peripherally located resting Type A dense (or dark) spermatogonium. There are three populations of spermatogonia: Type A dense spermatogonia are reserve cells that may enter the cell cycle and divide to produce two daughter cells. One remains as a Type A dense to maintain the reserve stem population and the other becomes a Type A pale. Eventually, of the daughter cells of the Type A pale spermatogonia, one is induced by testosterone to proliferate and differentiate, eventually dividing into two Type B spermatogonia. Thus the Type A spermatogonia are stem cells and the Type B spermatogonia are progenitor cells. In humans, the Type B spermatogonia undergo four additional mitotic divisions, the final one giving rise to primary spermatocyte daughter cells. The primary spermatocytes will undergo the first meiotic division, resulting in secondary spermatocytes. The secondary spermatocyte divides again to produce germ cells that no longer divide, but rather begin morphological differentiation, at which point they are termed spermatids. Roughly 10 mitotic divisions, plus those of meiosis 1 and 2, produce a total of about 1000 to 4000 spermatids from a single Type A dense spermatogonia. Because of crossing-over events and random segregation of chromosomes, the 1000- 4000 spermatozoa are genetically distinct from each other. The seminiferous epithelium is divided into two compartments, largely for the purpose of preventing immune recognition of the genetically distinct post-meiotic spermatocytes, spermatids, and spermatozoa. This blood-testis barrier is formed by the connection of neighboring Sertoli cells with each other via co-localized tight and adhering junctions. Primary spermatocytes pass through these junctions, from the basal (abluminal: ab- = away from) compartment to the adluminal (ad- = near) side, as they enter the leptotene stage of meiotic prophase. (More precisely, the Sertoli cells form new tight junctions basal to the primary spermatocytes, and then break the more apical junctions to allow spermatocytes into the adluminal compartment as they become haploid.) Thus, primary spermatocytes reside exclusively in the basal compartment and secondary spermatocytes in the adluminal compartment The initial Type A spermatogonia divide and produce separate daughter cells. Once committed to differentiation, the progenitor Type B cells and all subsequent divisions (both mitosis and meiosis) stay connected by intercellular cytoplasmic bridges. These cytoplasmic continuities produce synchronous cell division and differentiation through all cell divisions. The spermatozoa can be considered to be isolated cells only after they are separated from the residual bodies.