Unit 7 - Male Reproductive Endocrinology Flashcards
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
primordial gonad
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
-needs DHT
transformation of genital ducts in males
- 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 - 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?
hypogonadotropic hypogonadism
- 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:
- 5 alpha reductase deficiency
- DHT levels reduced, testosterone levels OK
- failure in DHT-dependent development (urogenital sinus and external genitalia) - 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
- androgenic - maturation of sex organs (especially penis)
- develop secondary sex characteristics (deep voice, beard, and axillary hair) - 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
androgen receptors
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
senescence (andropause)
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
what does Finasteride (Propecia) do?
block production of DHT (used to treat male pattern baldness) by blocking 5 alpha reductase
-side effects include impotence, abnormal ejaculation, and depression
effects of anabolic steroid abuse
- reduced sperm count, shrinkage of testes (b/c negative feedback causes decreased LH, so less T made in testes)
- permandent damage to heart, liver, kidneys, psychiatric problems
- increase LDL and decrease HDL
- irreversible breast enlargement in men
- excessive body hair and deep voice in women
what is Kennedy’s disease (spinobulbar muscular atrophy)?
X-linked lower motor neuron disease caused by mutation in androgen receptor
- expansion of CAG repeat in gene causes polyglutamine expansion in androgen receptor, causing toxic gain of function (onset related to size of expansion)
- patients have progressive weakness due to degeneration of motor neurons in brain stem of spinal cord, but rarely causes death
- early signs are weakness of tongue and mouth muscles, fasciculations, and progressive weakness of limbs
interaction of Sertoli cells and sperm
spermatogenesis initiated at puberty through FSH and LH
- single Sertoli spans from basal lamina to lumen of seminiferous tubule
- adjacent Sertoli connected by tight junctions (barrier to prevent toxins from interfering with spermatogenesis) and surround developing germ cells
- from basal lamina to lumen of tubule, gradual maturation of germ cells occurs
when does spermatogenesis start?
at puberty by FSH via Sertoli cells
- further supported by LH driven increases in testosterone and Sertoli cell growth factors
- ~120 million/day
sperm maturation
after spermiation, spermatids move passively into rete testes and epididymis
- testosterone-dependent maturation needed for fully mobile/fertile sperm (~70 days)
- after ejaculated, undergo several physiological changes in female genital tract to activate for fertilization
- during capacitation, they become hyperactive
- acrosome provides protection and carries enzymes for acrosomal reaction that dissolves jelly coat of egg during fertilization
- mitochondria provide energy for swimming
seminal fluid production
by male accessory glands (only 10% is sperm, so >20 million sperm/L)
- contains sugars and ions from seminal vesicles, prostate, and bulbourethral glands
- -seminal vesicles provide 70% volume and fructose
where do sympathetic fibers arise and what do they do?
T11-L2 segments of spinal cord
- reach genitals via mesenteric, hypogastric, and pelvic plexi, and hypogastric and cavernous nerves
- responsible for emission, ejaculation, and detumescence (flaccid state)
where do parasympathetic fibers arise and what do they do?
S2-S4 segments of spinal cord
- travel via pelvic nerve to pelvic plexus
- post-ganglionic fibers reach penile corpora and vasculature via cavernous nerves
- responsible for corporeal vasodilation and corporeal smooth muscle relaxation leading to tumescence (erection)
somatic fibers to penis?
travel via pudendal nerve to striated muscles
sensory fibers to penis?
afferent fibers carried in dorsal nerve of penis, which reaches spinal cord via pudendal nerve, compression of which (like biking) causes temporary sexual dysfunction
vascular components of penis?
pudendal artery
how is NO related to erection?
nerve terminals release ACh and NO
- ACh acts through M3 receptors on endothelial cells to make NO as well
- NO relaxes smooth muscles, causing vasodilation of arteries, and increases intracellular cGMP levels
- decrease in sympathetic tone allows relaxation of corpora
what does Sildenafil (Viagra) do?
treats erectile dysfunction by inhibiting cGMP-specific phosphodiesterase 5 to keep cGMP levels high
- stimulates erection only during sexual arousal
- side effects cause blue vision, and if taken with other vasodilators will cause sudden death
mechanics of erection
parasympathetic fibers in cavernous nerve cause dilation of arteriolar smooth muscle
- decrease in sympathetic tone to vascular smooth muscle
- increased blood flow to corpora
- increased somatic fiber stimulation causes striated muscle contraction, causing decreased venous outflow (to keep blood engorged)
- sinusoids of corpora expand to cause erection
mechanics of emission
movement of ejaculate into urethra
- sympathetic stimulation of hypogastric nerve causes contraction of smooth muscle of distal epididymis, VDs, and accessory glands
- semen propelled into prostatic urethra
- internal sphincter of bladder prevents retrograde flow of sperm
mechanics of ejaculation
rapid spinal reflex expulsion of semen from urethra
- stimulated by entry of semen into bulbous urethra
- response mediated by spinal regions S2-S4 and somatic motor fibers of pudendal nerve
- initiates rhythmic contractions of striated muscles of perineal area (ischiocavernosus, bulbospongiosus)
- followed by refractory period
anejaculation
pathological inability to ejaculate due to:
- sexual inhibition
- pharmalogical inhibition
- ANS malfunction
- prostatectomy
- ejaculatory duct obstruction
