Flashcards in Unit 7 - Male Reproductive Endocrinology Deck (47)
male genotypic VS gonadal VS phenotypic sex
genotypic - Y Xm makes male
gonadal - SRY in Y Xm encodes testis determining factor (TDF) transcription factor (presence in gonad turns into testes)
phenotypic - hormones made in testes make phenotypic sex (development of accessory sex organs, external genitalia, and secondary sex characteristics)
what is the XX male?
SRY gene translocates to X Xm during male meiosis
-ovum getting this X Xm with SRY gene develops into a male (1:100,00 births)
-normal testes never made
what is the XY female?
similar to XX male, but if sperm carries the Y Xm that lacks the SRY gene (no TDF)
-result is XY person that looks female
contains germ cells
-the genotype of germ cells determines fate of gonad
-considered indifferent before it differentiates into testes or ovary
what makes androgens and what do they do?
made by Leydig cells, and prmoote:
-differentiation of Wolffian (mesonephric) duct
-prostate (DHT only), epididymis, VDs, seminal vesicles, ejaculatory duct (testosterone)
what makes anti-Mullerian hormone and what does it do?
made by Sertoli cells and causes female Mullerian ducts to degenerate
how does the prostate develop?
series of endodermal buds located proximal to urethrea
transformation of genital ducts in males
1. when gonad is indifferent, it's closely associated with mesonephros and excretory duct (mesonephric or Wolffian) that lead from mesonephros to urogenital sinus
-parallel to Wolffian are paramesonephric/Mullerian ducts, that merge caudally to form uterovaginal primordium
2. in males, mesonephros develop into epididymis, and Wolffian into VDs, seminal vesicles, and ejaculatory duct
-Mullerian degenerate (but in females, would make fallopian tubes, uterus, and cervix)
what is DHT needed for?
make external genitalia (penis, scrotum, urethra) and prostate
how does the hypothalamic-pituitary-gonadal axis work in males generally?
regulates spermatogenesis and androgen production
-GnRH stimulation is pulsatile, causing pulsatile LH and FSH
-constant levels of GnRH prevent LH and FSH release (used to treat prostate cancer to lower testosterone production)
-products of testes (mainly sex hormones and inhibin) have negative feedback on hypothalamus and anterior pituitary
how does the hypothalamic-pituitary-gonadal axis work in the prenatal stage?
Leydig cells make up more than half the testes by 60 days gestation, and are the source of sex steroid production
-increase is dependent on hCG (early development) or embryonic LH (late development)
how does the hypothalamic-pituitary-gonadal axis work prior to puberty?
few GnRH pulses, and low FSH and LH levels
-hypothalamus and pituitary are very sensitive to negative feedback inhibition by androgens
-spermatogonia exist in diploid, undifferentiated form in basal compartment of testes
how does the hypothalamic-pituitary-gonadal axis work in puberty?
frequency and amplitude of GnRH pulses increase, so sensitivity of HP axis to negative feedback of testosterone decreases
-gonadotroph sensitivity to GnRH increases
-LH and FSH production increases
-testosterone increases and spermatogenesis starts
-androgen-driven changes characteristic of puberty occur
what hormones act on Sertoli and Leydig cells? what are their hormone products?
FSH and LH from anterior pituitary act on Sertoli and Leydig cells respectively
-inhibin from Sertoli negatively feedback to AP
-testosterone from Leydig negatively feedback to AP and hypothalamus
what does LH do on Leydig cells?
stimulates GPCR to make cAMP and activate PKA to increase transcription of:
-enzymes involved in testosterone synthesis
-stimulates rate-limiting step (chol --> preg)
-sterol carrier PRO and sterol activating PRO (also in testosterone synthesis)
what does FSH do on Sertoli cells?
stimulates GPCR to increase AC to increase cAMP to activate PKA to increase transcription of:
-androgen binding PRO (keep local testosterone levels high)
-P450 aromatase (make estrogen)
-growth factors (support production of sperm)
-inhibins (suppress Leydig cell proliferation)
-factors that act on Leydig cells
what kind of secondary effects does FSH have?
on Leydig cells and sperm (increase motility)
crosstalk between Leydig and Sertoli cells
-Leydig make testosterone that acts on Sertoli cells, which convert to estrogen to act on Leydig cells
-Leydig also make beta-endorphins, which inhibit Sertoli cell proliferation
-Sertoli makes growth factors to increase LH receptors on Leydig
what is Kallmann syndrome? main danger?
-development of both olfactory cells and GnRH-making cells is the olfactory epithelium (latter migrates to brain)
-mutations in KAL-1 (X-linked), FGFR1 (autosomal dominant), and PROK(R)2 prevent neurosensory neurons from extending axons into brain, thus preventing migration of GnRN neurons into hypothalamus
-main danger is osteoporosis, so treat with hormone replacement therapy (b/c also have little/no sexual maturation)
rate limiting step of androgen synthesis
desmolase (regulated by LH) in mitochondria of Leydig cells
-removes side chain from cholesterol to make pregnenolone
what does aromatase do and where?
converts androstenedione to estrone, or testosterone to estradiol in Sertoli cells
what does 5 alpha reductase do and where?
converts testosterone (made in Leydig cells, moved to Sertoli) to DHT in peripheral tissue
how much testosterone and DHT do the testes make? where else are androgens made?
95% of testosterone, but only minor fraction of DHT
-also made in adipose, skin, and adrenals
what are 2 causes of male pseudohermaphroditism?
any deficit in mechanism by which androgens act in genetic males:
1. 5 alpha reductase deficiency
-DHT levels reduced, testosterone levels OK
-failure in DHT-dependent development (urogenital sinus and external genitalia)
2. androgen insensitivity syndrome
-normal levels of testosterone and DHT, but androgen receptors are absent/defective
-urogenital sinus and external genitalia develop female, Wolffian ducts degenerate, but AMH is normal to suppress Mullerian development so look female, but are sterile
what are androgen's actions divided into?
affect nearly every tissue in body
1. androgenic - maturation of sex organs (especially penis)
-develop secondary sex characteristics (deep voice, beard, and axillary hair)
2. anabolic - promote PRO 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, RBCs, etc.
--bone maturation occurs indirectly through estradiol metabolites, and is more gradual in men than women
--men have larger brain, but women have more dendritic connections
do men or women have higher FSH?
men have 8x higher FSH levels
-regulated by combined action of E2, T, and DHT
free form of testosterone is active, and enters cells by diffusion (only 2% is free; usually bound by sex hormone binding globulin and albumin)
-binds homodimeric receptor (AR/AR)
-directs transcriptional activity of target genes
-DHT binds the same receptor with greater activity
testosterone decreases with age (especially ~40 years; 30% experience by mid-50's)
-begins to fall by 10%/year starting in 30s
-quantity and quality of sperm decrease
-FSH and LH levels increase
-unlike menopause, no abrupt loss of fertility
-causes decreased bone formation, muscle mass, appetite, libido, Hct
effects of low testosterone
small percentage of men have levels <300 ng/dL
-low sex drive, erectile dysfunction, loss of muscle mass, mood problems, fatigue, sleep disturbances, loss of body/facial hair
-most will benefit from testosterone treatment, but not if have prostate or breast cancer
--can worsen sleep apnea, worsen BPH and CHF, or cause erythrocytosis