59: Male Reproductive Endocrinology Flashcards
Genotypic sex = ____, gonadal sex = ___ which encodes testes determining transcription factor, & phenotypic sex = hormones produced by _____ = masculinization via ______.
Genotypic sex = Y chromosome, gonadal sex = SRY gene which encodes testes determining transcription factor, & phenotypic sex = hormones produced by the gonads = masculinization via testosterone.
In rare cases, the SRY gene translocates to the _ chromosome during male meosis. The ovum getting the X chromosome with the SRY gene wil develop into a male with an __ genotype. __ male is infertile. Conversely, if the sperm cell carries a Y chromosome lacking its TDF, the result can be a 46, XY individual that appears to be _____.
In rare cases, the SRY gene translocates to the X chromosome during male meosis. The ovum getting the X chromosome with the SRY gene wil develop into a male with an XX genotype. XX male is infertile. Conversely, if the sperm cell carries a Y chromosome lacking its TDF, the result can be a 46, XY individual that appears to be female.
Transformation of the genital ducts.
A) When the gonad is still ______, it is closely associated with the mesonephros, as well as the excretory duct (mesonephric or Wolffian duct) that leads from the mesonephros to the _____ sinus. Parallel to the Wolffian ducts are the paramesonephric or Müllerian ducts, which merge caudally to form the ______.
B) In males, the mesonephros develops into the _____. The ______ duct develops into the vas deferens, seminal vesicles, and ejaculatory duct. The Müllerian ducts degenerate. (In females the Mullerian ducts develop into the fallopian tubes, uterus and cervix.)
Transformation of the genital ducts.
A) When the gonad is still indifferent, it is closely associated with the mesonephros, as well as the excretory duct (mesonephric or Wolffian duct) that leads from the mesonephros to the urogenital sinus. Parallel to the Wolffian ducts are the paramesonephric or Müllerian ducts, which merge caudally to form the uterovaginal primordium.
B) In males, the mesonephros develops into the epididymis. The Wolffian duct develops into the vas deferens, seminal vesicles, and ejaculatory duct. The Müllerian ducts degenerate. (In females the Mullerian ducts develop into the fallopian tubes, uterus and cervix.)
______ produced by the Leydig cells promote the development of 1) the ____ ducts and derived structures (epididymis, vas deferens, seminal vesicles, ejaculatory duct. This requires _____ NOT DHT. 2) the prostate develops from a series of endodermal buds located proximal to the urethra; requires _____.
Prostate & external male genitalia dependent on _____. Testosterone is converted to ____, a testosterone derivative. DHT leads to beard _____ & DHT also leads to _____.
Androgens (testosterone) produced by the Leydig cells promote the development of 1) the wolffian (mesonephric) ducts and derived structures (epididymis, vas deferens, seminal vesicles, ejaculatory duct. This requires testosterone NOT DHT. 2) the prostate develops from a series of endodermal buds located proximal to the urethra; requires DHT.
Prostate & external male genitalia dependent on DHT (dihydrotestosterone). Testosterone is converted to DHT, a testosterone derivative. DHT leads to beard growth & DHT also leads to baldness.
Differentiation of the External Genitalia: In the absence of testosterone, the undifferentiated external genitalia develop into the ____ structures. Testosterone, after conversion to dihydrotestosterone, stimulates the formation of male external _____ from the undifferentiated structures. Begins at about 10 weeks of gestation.
Differentiation of the External Genitalia: In the absence of testosterone, the undifferentiated external genitalia develop into the female structures (internal genitalia). Testosterone, after conversion to dihydrotestosterone, stimulates the formation of male external genitalia from the undifferentiated structures. Begins at about 10 weeks of gestation.
The hypothalamic-pituitary-gonadal axis regulates: spermatogenisis & androgen production. GnRH stimulation is _____, therefore, LH & FSH release is _____. GnRH binds G-protein coupled gonadotroph receptors and activates phospholipase C (PLC) that ultimately causes Ca2+ release, DAG production and protein kinase C activation.
Constant supply of GnRH _____ receptors and fails to induce LH or FSH secretion – used to treat prostate cancer to lower testosterone production.
Products of the testes, sex hormones & inhibins, have a _____ feedback on the hypothalamus & anterior pituitary. GnRH is secreted into the portal vein to the anterior pituitary.
The hypothalamic-pituitary-gonadal axis regulates: spermatogenisis & androgen production. GnRH stimulation is pulsatile, therefore, LH & FSH release is pulsatile. GnRH binds G-protein coupled gonadotroph receptors and activates phospholipase C (PLC) that ultimately causes Ca2+ release, DAG production and protein kinase C activation.
Constant supply of GnRH downregulates receptors and fails to induce LH or FSH secretion – used to treat prostate cancer to lower testosterone production.
Products of the testes, sex hormones & inhibins, have a negative feedback on the hypothalamus & anterior pituitary. GnRH is secreted into the portal vein to the anterior pituitary.
Kallmann Syndrome = hypogonadotropic hypogonadism as patients lack the pituitary hormones ___ and ___ and have congenital _____ (complete inability to ____) due to the agenesis of the olfactory lobes. Patients fail to enter puberty. The genes KAL-1 (X-linked), FGFR1 (autosomal dominant) and PROKR2 have been implicated in the disease. Happens to men & women.
The link to the loss of smell is the developmental origin of the odor receptor cells (primary neuroscensory cell) and the GnRH producing cells. Both develop in the olfactory _____ in the rudimentary nose. The primary neurosensory cells extend axons into the olfactory bulb and the GnRH-secreting cells migrate along these axons into the brain then into the hypothalmus. The mutations mentioned above prevent the neurosensory neurons from extending their axons into the brain and this failure prevents the migration of the GnRN neurons into the _____.
The main danger for patients with this syndrome is osteoporosis. Treatments usually include hormone replacement therapy.
Kallmann Syndrome = hypogonadotropic hypogonadism as patients lack the pituitary hormones LH and FSH and have congenital anosmia (complete inability to smell) due to the agenesis of the olfactory lobes. Patients fail to enter puberty. The genes KAL-1 (X-linked), FGFR1 (autosomal dominant) and PROKR2 have been implicated in the disease. Happens to men & women.
The link to the loss of smell is the developmental origin of the odor receptor cells (primary neuroscensory cell) and the GnRH producing cells. Both develop in the olfactory epithelium in the rudimentary nose. The primary neurosensory cells extend axons into the olfactory bulb and the GnRH-secreting cells migrate along these axons into the brain then into the hypothalmus. The mutations mentioned above prevent the neurosensory neurons from extending their axons into the brain and this failure prevents the migration of the GnRN neurons into the hypothalamus.
The main danger for patients with this syndrome is osteoporosis. Treatments usually include hormone replacement therapy.
______ cells, the source of sex-steroid (testosterone) production in the testes, make up more than half the testes by day 60 of gestation. Increase in Leydig cells is dependent on maternal chorionic gonadotropin ____ or _____
Prior to puberty there are few GnRH pulses & low FSH & LH levels, the hypothalamus & pituitaty are very sensitive to _____ feedback inhibition by testosterone, spermatogonia exist in a ____ undifferentiated form in the testes.
hCG & LH are very _____ hormones, 1 AA difference.
Leydig cells, the source of sex-steroid (testosterone) production in the testes, make up more than half the testes by day 60 of gestation. Increase in Leydig cells is dependent on maternal chorionic gonadotropin hCG or embryonic leutinizing hormone LH.
Prior to puberty there are few GnRH pulses & low FSH & LH levels, the hypothalamus & pituitaty are very sensitive to negative feedback inhibition by testosterone, spermatogonia exist in a diploid undifferentiated form in the testes.
hCG & LH are very homologous hormones, 1 AA difference.
In Puberty:
- Frequency and amplitude of GnRH pulses ____
- Sensitivity of H-P axis to negative feedback of testosterone _____
- Gonadotroph sensitivity to GnRH ______
- LH and FSH production _____
- Testosterone _____ and spermatogenesis _____
- Androgen-driven changes characteristic of puberty occur
In Puberty:
- Frequency and amplitude of GnRH pulses increase
- Sensitivity of H-P axis to negative feedback of testosterone decreases
- Gonadotroph sensitivity to GnRH increases
- LH and FSH production increases
- Testosterone increases and spermatogenesis begins
- Androgen-driven changes characteristic of puberty occur
The hypothalamic-pituitary-testicular axis. Small-bodied neurons in the arcuate nucleus and preoptic area of the hypothalamus secrete GnRH, a decapeptide that reaches the gonadotrophs in the anterior pituitary through the long portal veins. Stimulation by GnRH causes the gonadotrophs to synthesize and release FSH and LH. The LH binds to receptors on the _____ cells, thus stimulating the transcription of several proteins involved in the biosynthesis of testosterone. FSH binds to receptors on the basolateral membrane of the _____ cells, thereby stimulating gene transcription and protein synthesis. These proteins include ABP, aromatase, growth factors, and inhibin.
Negative feedback on the hypothalamic- pituitary-testicular axis occurs by two routes. First, ______ inhibits the pulsatile release of GnRH by the hypothalamic neurons and the release of LH by the gonadotrophs in the anterior pituitary. Second, ____ inhibits the release of FSH by the gonadotrophs in the anterior pituitary.
The hypothalamic-pituitary-testicular axis. Small-bodied neurons in the arcuate nucleus and preoptic area of the hypothalamus secrete GnRH, a decapeptide that reaches the gonadotrophs in the anterior pituitary through the long portal veins. Stimulation by GnRH causes the gonadotrophs to synthesize and release FSH and LH. The LH binds to receptors on the Leydig cells, thus stimulating the transcription of several proteins involved in the biosynthesis of testosterone. FSH binds to receptors on the basolateral membrane of the Sertoli cells, thereby stimulating gene transcription and protein synthesis. These proteins include ABP, aromatase, growth factors, and inhibin.
Negative feedback on the hypothalamic- pituitary-testicular axis occurs by two routes. First, testosterone inhibits the pulsatile release of GnRH by the hypothalamic neurons and the release of LH by the gonadotrophs in the anterior pituitary. Second, inhibin inhibits the release of FSH by the gonadotrophs in the anterior pituitary.
Useful mnemonics: “L” for LH and ____, “S” for FSH and ____
LH stimulates G-protein coupled receptor to produce cAMP and activate PKA. This increases the transcription of: 1) enzymes involved in _____ synthesis, 2) stimulates the rate-limiting step ______ to _____, 3) _____ protein, sterol activating protein (also involved in T synthesis).
FSH-primary action on Sertoli cells, activates a similar signaling pathway to LH and increases transcription of: 1) __________ protein- keeps local testosterone levels high, 2) ______ produces estrogen (estradiol), 3) ____ factors that support production of sperm 4) ______ that suppress Leydig cell proliferation, suppress FSH secretion 5) factors that act on Leydig cells.
Secondary effects on Leydig cells and on sperm (increases _____).
The Leydig cells make _____, which acts on the Sertoli cells. Conversely, the Sertoli cells convert some of this testosterone into ______ (product of aromatase), which acts on the Leydig cells. The Sertoli cells also generate growth factors that act on the Leydig cells.
Useful mnemonics: “L” for LH and Leydig, “S” for FSH and Sertoli–both S in fSh & Sertoli
LH stimulates G-protein coupled receptor to produce cAMP and activate PKA. This increases the transcription of: 1) enzymes involved in testoterone synthesis, 2) stimulates the rate-limiting step (cholesterol to pregnenolone), 3) sterol carrier protein, sterol activating protein (also involved in T synthesis).
FSH-primary action on Sertoli cells, activates a similar signaling pathway to LH and increases transcription of: 1) androgen binding protein- keeps local testosterone levels high, 2) P450 aromatase produces estrogen (estradiol), 3) growth factors that support production of sperm 4) inhibins that suppress Leydig cell proliferation, suppress FSH secretion 5) factors that act on Leydig cells.
Secondary effects on Leydig cells and on sperm (increases motility).
The Leydig cells make testosterone, which acts on the Sertoli cells. Conversely, the Sertoli cells convert some of this testosterone into estradiol (product of aromatase), which acts on the Leydig cells. The Sertoli cells also generate growth factors that act on the Leydig cells.
First step of androgen synthesis occurs in the mitochondria: _____ removes the side chain of cholesterol. _____ produces pregnenolone–this is the rate limiting step and it is up-regulated by LH. Testes produce approximately 95% of testosterone, but only minor fraction of the body’s DHT. Other sites of androgen production include adipose tissue, skin, adrenals.
Androstenedione = andro = _____ anabolic steroid = is converted to testosterone in the next step.
______ converts testosterone to DHT.
First step of androgen synthesis occurs in the mitochondria: P450 side chain cleavage enzyme (P450 scc, Desmolase) removes the side chain of cholesterol. Desmolase produces pregnenolone–this is the rate limiting step and it is up-regulated by LH. Testes produce approximately 95% of testosterone, but only minor fraction of the body’s DHT. Other sites of androgen production include adipose tissue, skin, adrenals.
Androstenedione = andro = indirect anabolic steroid = is converted to testosterone in the next step.
5a-reductase converts testosterone to DHT.
Male pseudohermaphroditism is a deficit in the mechanism by which androgens act in genetic males.
Potential causes include:
1) ______ deficiency, which causes reduced DHT levels with normal testosterone levels. There is faliure of DHT-dependent development of the urogenital sinus & external genitalia
2) Androgen insensitivity syndrome:
• normal levels of testosterone and DHT
• androgen receptors ________
• urogenital sinus and external genitalia develop according to female pattern, Wolffian ducts degenerate
• Normal levels of AMH suppress Müllerian development
Male pseudohermaphroditism is a deficit in the mechanism by which androgens act in genetic males.
Potential causes include:
1) 5a reductase deficiency, which causes reduced DHT levels with normal testosterone levels. There is faliure of DHT-dependent development of the urogenital sinus & external genitalia
2) Androgen insensitivity syndrome:
• normal levels of testosterone and DHT
• androgen receptors are absent or defective
• urogenital sinus and external genitalia develop according to female pattern, Wolffian ducts degenerate
• Normal levels of AMH suppress Müllerian development
Androgens affect nearly every tissue in the body & have anabolic or androgenic effects.
____ effects = maturation of the penis, development of secondary sex charictaristics, deepening of voice, and growth of hair.
_____ EFFECTS:
• Promote protein synthesis and growth of tissues expressing androgen receptors
• Growth of muscle and increase in strength
• Increase in bone density and strength, ______ growth and maturation
• Males have larger hearts, lungs, liver, erythrocytes, etc.
• Bone maturation occurs indirectly through ______ metabolites and is more gradual in men than women.
• Men have a larger brain but women have more ______.
Androgens affect nearly every tissue in the body & have anabolic or androgenic effects.
Androgenic effects = maturation of the penis, development of secondary sex charictaristics, deepening of voice, and growth of hair.
ANABOLIC EFFECTS:
• Promote protein synthesis and growth of tissues expressing androgen receptors
• Growth of muscle and increase in strength
• Increase in bone density and strength, linear growth and maturation
• Males have larger hearts, lungs, liver, erythrocytes, etc.
• Bone maturation occurs indirectly through estradiol metabolites and is more gradual in men than women.
• Men have a larger brain but women have more dendritic connections.
Androgens increase the expression of erythropoietin from the kidneys which leads to a higher _______ in men (42-52% vs 36- 46%).
Paradoxically _____ regulate male sexual behavior.
Men have 20-40% _____ muscle mass than females.
The penis, seminal vesicles and prostrate increase in size during ______.
Androgen Receptors:
• Free form of testosterone enters cells by diffusion
• Binds _______ receptor (AR/AR)
• Directs transcriptional activity of target genes
• DHT binds the ______ receptor (has greater activity)
Testosterone is bound by sex hormone-binding globulin and albumin. Only 2% of testosterone is _____ and this is the biologically active fraction.
Androgens increase the expression of erythropoietin from the kidneys which leads to a higher hematocrit in men (42-52% vs 36- 46%).
Paradoxically estrogens regulate male sexual behavior.
Men have 20-40% more muscle mass than females.
The penis, seminal vesicles and prostrate increase in size during puberty.
Androgen Receptors:
• Free form of testosterone enters cells by diffusion
• Binds homodimeric receptor (AR/AR)
• Directs transcriptional activity of target genes
• DHT binds the same receptor (has greater activity)
Testosterone is bound by sex hormone-binding globulin and albumin. Only 2% of testosterone is free and this is the biologically active fraction.