Reproduction 1-sexual differentiation & gametogenesis Flashcards
Sexual differentiation begins at ~5-6 wks of gestation. What does Gender Determination depend on?
The presence or absence of the Sex-determining Region of the Y chromosome-SRY gene. SRY protein triggers differentiation of the gonad into testis
What does SRY protein do?
SRY protein triggers differentiation of the indifferent (bipotential) gonad into testis. It starts a cascade of events that lead to differentiation into the male reproductive system.
In a genetice male (XY), what is the significance of antimullerian hormone and what cell produce it?
Antimullerian hormone from the Sertoli cells of the testes causes Mullerian ducts to degenerate
Which cells secrete testosterone and what does testosterone promote?
Leydig cells secrete testosterone which promotes development of the Wolfian duct into male internal urogenital structures and development of male external genitalia.
Genetic females (XX) do not have the SRY gene. In the absence of SRY gene products/proteins, how do the gonads develop?
Gonads develop into ovary,W.ducts degenerate and M. ducts develop into female urogenital structures. Female external genitalia also develop. Estrogen is NOT required for differentiation, bit is needed for growth to normal size.
Testosterone itself stimulates the diff of the internal male genital tract. Testosterone undergoes peripheral activation to Dihydrotestosterone (DHT). What does DHT do?
Allows differentiation of the external genitalia(penis,scrotum) and growth of the prostate gland.
DHT determines facial and body hair distribution, including male pattern baldness, and stimulates sebaceous gland activity.
Under the influence of testosterone, W. ducts grow and differentiate into :
Epididymis Vas Deferens Seminal vesicles Ejaculatory ducts. DHT directs differentiation into penis&scrotum
What do the Mullerian ducts develop into?
Fallopian tubes(Oviducts) Uterus Upper third of Vagina. External: Clitoris Labia majora & minora Lower 2/3 of the vagina
What converts testosterone to DHT are target tissues (peripheral activation)?
5 α-reductase
Testosterone: INTERNAL male genital tract DIFFERENTIATION:
Responds DIRECTLY to testosterone.
DOES NOT REQUIRE 5 Α-REDUCTASE Penis GROWTH Muscle mass Voice Spermatogenesis Libido
Testosterone: EXTERNAL male genital tract DIFFERENTIATION:
REQUIRES 5 Α-REDUCTASE
Prostate GROWTH
Male hair pattern/pattern baldness
Sebaceous glands
What increases the action of P450scc/cholesterol desmolase ?
LH increases P450scc, which catalyzes the first step in steroid synthesis from cholsterol to form pregenenolone.
5 α-reductase deficiency?
Male pseudohermaphroditism (genetic XY)
↑ serum testosterone
↓ DHT
Male phenotypically appears female. Testes secrete testosterone, but structures that require peripheral activation to DHT do not develop male phenotype.
Tx for male pseudohermaphroditism?
continue as woman: remove testes to eliminate source of testosterone, ERT, surgery for vagina, but can’t bear children.
Continue as male:supplemental androgens to complete differentiation and permit growth of external genitalia, facial hair, prostate etc. stuctures requiring peripheral activation of testosterone to DHT.
21β-hydroxylase deficiency?
Congenital Adrenal Hyperplasia
without 21β-hydroxylase, the adrenal cortex does not synthesize mineralocorticoids/aldosterone or glucocorticoids/cortisol. Intermediates/precursors are shunted toward synthesis of adrenal androgens which are then produced in excess.
“Downhill” syntheses are blocked, intermediates shunted to androgen production →virilization in girls.
What are the symptoms of glucocorticoid deficiency?
hypoglycemia, anorexia, wt loss, nausea, vomiting, weakness.
What are symptoms of mineralocorticoid deficiency?
hyperkalemia, metabolic acidosis, hypotension due to decreased ECF volume. Infants with complete deficiency of these hormones would be unlikely to survive.
Cryptochordism, 80 % descend by puberty. If they do not descend by puberty, what happens?
man cannot produce sperm. Spermatogenesis occurs at ~35º or 2º below body Tº
However, the undescended testes still secrete androgens.
Sperm cells are produced in the seminiferous tubules, then where do they go?
Seminiferous tubules are continuous with the epididymis→continuous with vas deferens→enters abdominal cavity and empties into urethra.
Where do sperm undergo maturation?
epididymis! They they are expelled into vas deferens at time of ejaculation.
Sperm makes up 10% of the ejaculate, what makes up the other 90%?
Seminal Vesicles
Prostate gland
bulbourethral glands
What is BPH treated with and how does it work?
Finasteride, a 5α-reductase inhibitor that blocks peripheral activation to DHT, which stimulates growth of of prostate. Prostate cancer is 2nd most common in men.
What is Proscar?
Finasteride prescribed in 5mg doses
What is Propecia?
Finasteride prescribed in 1mg doses.
Inhibits allopecia-an additional benefit. 5α-reductase inhibitors require time to remove tropic effect of dihydrotestosterone and shrink the prostate tissue.
What are Sertoli Cells?
Provide nutrients to sperm, secrete the luminal fluid, hormones e.g. inhibin and proteins e.g. Androgen Binding Protein-concentrates testosterone in the aq luminal fluid.
Secrete antimullerian hormone.
spermatogenesis, FSH
What forms the Blood-Testes barrier?
Sertoli cells-form tight junctions with each other b/w the basal lamina/BM and the lumen.
Spermatogenesis (continuous throughout life): what is produced by the first meiotic division?
1º spermatocyte divides into two 2º spermatocytes.
Spermatogenesis: what is produced by the 2nd meiotic division?
Each 2º spermatocyte divides into 2 spermatids which will differentiate into 4 mature, haploid sperm.
What occurs during the process of differentiating into sperm cells (64days)?
lose most of cytoplasm, develop flagella, form the acrosome which contains enzymes important in fertilization.
Sperm produced in the seminiferous tubules cannot swim, how are pushed into the epididymis?
by hydrostatic pressure. In the epididymis they undergo further maturation and are stored
What do higher levels inhibit inhibit?
Inhibin, secreted by the sertoli cells inhibits FSH through negative feedback.
Hypothalamic and anterior pituitary hormones influence the functions of Leydig cells and Sertoli cells. The arcuate nucleus of the hypothalamus pulsatile secretion of GnRH which acts on the Ant. Pit. to secrete LH and FSH. What do FSH and LH do?
LH stimulates the Leydig cells to produce and secrete testosterone. Testosterone acts as a paracrine in the testes by reinforcing the action of FSH on Sertoli cells-they secrete inhibin and inhibits ant pit from secreting more FSH. LH and FSH are tropic to the testicular tissue
What is the effect of steroid abuse on spermatogenesis?
Large amounts of exogenous testosterone, negative feedsback to hypothalamus and ant. pit to reduce secretion of GnRH and FSH/LH. In the absence of tropic FSH/LH, the testes become small and soft, sperm production is reduced.
Where do the GnRH originate?
Olfactory epithelium. Normal migration of sensory and GnRH neurons from olfactory epithelium to hypothalamus. Disrupted migration of sensory and GnRH neurons result in Kallmann’s syndrome.
What is Kallmann’s Syndrome (KS)?
Anosmia(inability to smell) and hypogonadotropic hypogonadism (HH).
XL, or AD inherited genetic condition
What happens in Kallmann’s syndrome?
In HH, the GnRH neurons do not migrate to the hypothalamus where normally secrete GnRH into the capillary bed of the median eminence, which feeds feeds into the portal system of the ant. pit. In the absence of GnRH neurons and GnRH, the pituitary gonadotrophs do not secrete gonadotropins FSH/LH, and the gonads do not develop.
What does antimullerian hormone do? Secreted by?
secreted by fetal sertoli cells, cause atrophy of mullerian ducts so that they don’t develop into internal female genital tract.
Testosterone and estrogen play major roles in bone formation. Osteoblasts secrete OSTEOCALCIN that stimulates testosterone synthesis by Leydig cells. How does osteocalcin fxn?
Osteocalcin secreted by the osteoblasts, enhances Leydig cell production of testosterone. Both Osteocalcin and LH bind to their respective GPCRs→via AC→cAMP production→phosphorylation events lead to testosterone synth.
How have investigators concluded that bone mass, energy metabolism, and reproduction may all be regulated by hormonal signals secreted by osteoblasts?
Osteocalcin enters the circulation during bone resorption. Osteocalcin was shown to stimulate β-cell proliferation and insulin secretion and to favor whole-body glucose balance and energy expenditure.
Does osteocalcin affect estrogen synthesis?
NO, ovarian cells do not express the osteocalcin receptor.
What is a primary oocyte?
Once An oogonium starts meiosis, it is called an primary oocyte. (oogonia start meiosis but don’t finish, remain in Prophase:diplotene arrest)
When is the first meiotic division completed?
at ovulation
When does the second meiotic division occur?
2nd meiotic division won’t happen at all unless unless fertilization takes place.
What does the cortex of the ovary contain?
all stages of follicles. The mature/Graffian follicle expels the oocyte and becomes corpus luteum. BOTH the follicle (before ovulation) and corpus luteum (after ovulation) secrete hormones.
What is hilum? What does the medulla of the ovary contain?
The hilum is the root, the entry for arteries etc.
The medulla contains various cell types, but no hormone-secreting cells.
What are the ovarian phases of the menstrual cycle?
follicular: 1-14
ovulation: @ DAY 14 REGARDLESS!!!
luteal: 15-28,corpus luteum fxns
What are the uterine phases of the menstrual cycle?
Menstrual:1-5
proliferative: 5-14, cells ↑ in #, capillaries and glands develop, endometrium thickens
secretory: 15-28, glands secrete mucus, nutritive substances.
What is ovulation preceded by?
A peak in estrogen secretion by the granulosa cells. The peak of estrogen exerts Positive feedback at the hypothalamus and ant pit to produce the surge of LH secretion, which triggers the ovulation and luteinization into the corpus luteum.
What is the luteal phase characterized by?
HIgh amounts of progesterone> (and estrogen) secreted by cells of the corpus luteum.
How does the woman’s body temp increase by ~.3º C during the luteal phase?
By action of progesterone on the hypothalamus, changing the temperature set-point.
What is the HPG axis? present in both male and female repro.
Hypothalamus, Pituitary, and Gonad
Irregular menses can be a result of?
Stress, anorexia, athletes etc can affect the neural input to GnRH cells, which can lead to reduced secretion of GnRH and the gonadotropins FSH and LH.
Which enzyme converts Testosterone to ESTRADIOL?
Aromatase
Which cells coordinate to produce Estradiol?
Theca cells and granulosa cells.
What type of receptors do Theca cells express?
LH receptors-LH stimulates theca cells to produce androgens/testosterone which diffuse to the Granulosa cells
What type of receptors do Granulosa cells express?
FSH receptors-FSH stimulates the granulosa cells to androgens to estrogen via Aromatase enzyme.
What estrogen intermediate is elevated in PCOS?
Androstenedione
In theca cells, LH increases the action of what enzyme?
cholesterol desmolase /P450scc
FSH stimulates what enzyme in the granulosa cells to convert testosterone to estradiol?
aromatase.
Early Follicular phase: Role of Estrogen (E)
E→Uterus starts out early with E receptors.
1) E binds to endometrial E Receptors causing endometrial proliferation and thickening of the endometrium.
2) later, E stimulates the endometrials to develop receptors for progesterone which is important in the luteal phase to accomplish ovulation.
Follicular phase: Positive feedback within ovary:
FSH and E (paracrine) in ovary→ ↑granulosa cells (mitosis)→ ↑E (endocrine fxn)
Gr cells proliferate and each secrete estrogen leading to ↑plasma[E]→pos feedback to ant pit and hypothalamus→LH surge
Note: FSH and E also stimulate gr cells to synthesize and incorporate receptor molecules for LH (ovulation)
Follicular phase targets include:
E(paracrine) + FSH: incorporate LH receptors in gr cells.
↑E(endocrine) @ hypothal/ant pit→LH surge
↑E(endocrine) @ cervix:watery mucus to permit sperm entry at time of ovulation.
E(endocrine) in uterus: incorporate progesterone receptors in endometrial cells
Late Follicular phase:
↑[estradiol]→surge of LH (and FSH)→ovulation. As gr cells increase in number, the overall secretion of estradiol also increases.
LH surge initiates:
Completion of first meiotic division:
- Fluid accum in antrum→follicle expands to a diam of 1.5 cm.
- Gr cells secrete enzymes that weaken and rupture the wall of the ovary.
- Ovulation(oocyte is expelled from follicle)
- Gr cells begin to secrete progesterone and decrease their secretion of estrogen.
- Remaining follicle cells convert to luteal cells of the corpus luteum.
Treatments for infertility:stimulate growth of follicle to maturity. Tx with
Gonadotropin or Clomiphene=
Clomiphene
A selective E receptor modulator (SERM). It decreases the number of estrogen receptors at the hypothalamus and ant pit, making neg feedback by estrogen less effective at those sites. With less neg feedback, gonadotropin release will continue, promoting increased estrogen secretion at the ovary, follicular growth, and ovulation.
What if the follicle grows, but does not rupture? Tx?
Use HCG to trigger ovulation. hCG binds to LH receptors. It is used in preference to LH, because it was a longer half-life than LH.
What secretes hCG?
the conceptus secretes hCG to rescue the corpus luteum.
PolyCystic Ovary Syndrome? (PCOS)
Follicles develop but are arrested at 5-7mm.
None mature to ovulate.
Accum of immature follicles→ ↑ ovary size
Clinical signs of PCOS?
obese, hirsute, irreg periods, ↑plasma glucose, insulin resistance, acanthosis nigrans(gray-brown thickened skin in axillae), ↑androstendione,infetiity
What effect does insulin have on the ovaries?
↑insulin stimulates ovaries to secrete excess androgens: possibly by ↑pulse freq of GnRH and ↑LH/FSH ratio.
Adipose tissue
has aromatase, converts androstendione to estrone and testosterone to estradiol.
Excess adipose in obese women
creates excess androgens→virilization and continuously present plasma estrogens. Continuous Estrogens inhibit FSH/LH by neg feedback and contribute to irregular periods and infertility(prevents LH surge)
When does the first meiotic division terminate?
after the first polar body is ejected. The 2nd meiotic division begins with arrest in the metaphase.
What are the fxns of the processes on gr cells?
they transferred substances to the oocyte, ie yolk?
What is the pervitelline space?
Forms b/w the oocyte and the pellucid zone. This space is necessary for allowing division of the oocyte and for holding the first polar body. The gr cells loosen in the vicinity of the cumulus oophorus and proliferate. Gr cells increase their production of progesterone, which increases in concentration in the follicle fluid.
What is luteinization?
when the theca and gr cells undergo morphological and biochemical changes to become luteal cells.
What do luteal cells secrete?
Progesterone, smaller amounts of estrogen, and inhibin.
Corpus luteum secretes hormones that reduce hypothalamic and ant. pit secretions by negative feedback. Progesterone is important in making the womb ready for implantation:
- stimulates secretions by glands and increases blood vessels
- Inhibits contractions of sm. m. of uterus and oviducts.
- Makes cervical mucus sticky (prevents sperm and bacteria from entering uterus)
If fertilization does not occur, what happens?
after~12days, corpus luteum ceases to fxn. Luteal cells stop secreting estrogen and progesterone, now called c. albicans and menstration ensues.
Menstruation
↓ estrogen ↓progesterone→ prostaglandins→constriction of endometrial vessels, depriving endometrium of oxygen and nutrients & contractions of myometrium→ sloughing of surface endometrium. NSAIDs inhibit the enzymes that synthesize prostaglandins. During menses, overproduction of prostaglandins can cause overly strong contractions→cramps
GnRH of hypothalamus do not express receptors for FSH/LH(sex steroids). So, how is negative feedback accomplished?
Via Kisspeptin(Kiss1) neurons. Kisspeptins express steroid receptors. The Kiss1 neurons integrate the steroid feedback info and relay it to the GnRH neurons, which do have receptors for kisspeptin.
In females, high levels of estrogens and progesterone stimulate kisspeptin neurons of AVPV to stimulate the preovulatory surge of GnRH/LH. They inhibit . . ?
kiss1 action in the ARC.
In males, GnRH and FSH/LH release are negatively regulated by . . .
circulating testosterone, partly through the activity of kisspeptin neurons of the ARC.
