male repro endocrinology howell Flashcards
how to make a male
- genotypically: y chromosome makes a male genotype
- gonalal sex SRY gene encodes testis determining factor TDF trascription factor. SRY makes indifferent gonads into testes, and germ cells into spermatogonia.
- phenotypic sex: hormones made by gonads determine phenotypic sex. phenotypic sex includes development of accesory sex organ, external genitalia, of penis, scrotum, urethra. this requires dihydrotestosterone DHT
- XX male is when SRY gene translocates to X chromosome.the oxum will be XX but develop into a male. so will appear to be make even though XX karyotype
differentiation of testes
-mesencephros becomes epidydimis in males
-mesensephric duct=wollfian duct. in males, wolffian duct becomes vas deferens, seminal vesicles, and ejaculatory duct. wollfian duct degenerates in women.
-paramesencepharic duct=mullerian duct. degenerates in men and in women develops into fallopian tubes, uterus, and cervix.
-at first though the duct system is indifferent. genotype of germ cells determines fate of gonad.
-Leydig cell angrogens promote 1. differentiation of Wollfian mesonephric duct that beomces the vas deferens, seminal vescles and ejaculatory duct. 2. prostate development
- leydig cells also promote anti-mullerian hormone from Sertoli cells, causing the mullerian ducts to degenerate. these require testosterone, not DHT.
prostate required DHT
-in absense of testosterone, undifferentiated external genitalia develop into female structures. in presence of testosterone, testosterone is converted to DHT and DHT stimulates formation of male external genitalia. starts at 10 weeks
hypothalamic pituitary gonad axis
- regulates spermatogenesis and androgen production
- GnRH stimulation is pulsatile
- LH and FSH is also pulsatile based on GnRH.
- constant GnRH prevents release of LH or FSH which is a treatment for prostate cancer to decreases testosterone levels. constant levels downregulate receptors
- testes products like testosterone and inhibin have negamitve feedback to the hypothalamus and anterior pituitary
-hypothalamic pituitary gonaldal axis
- prenatal: leydig cells are source of testosterone in tested. make up more than half of testes by 60 days gestation. increase in leydig cells is dependant on momther hCG early in development or embryonic LH late in development
- only i aa diff bw hCG and LH
- prior to puberty, boys have few GnRH pulses and low FSH and LH. the hypothalamus and piuitary are sensitive to negative feednack from androgens. spermatogonia eist in diploid, undifferentiated form in basal compartment of testes
- at puberty: freq and amplitude of GnRH increases. senstivity to negative feedback to testosterone and inhibins decreases. gonadotrophs become more sensitve to GnRH and LH and FSH production increases. testosterone increases and spermatogeneiss begins. androgen changes of puberty occur
axis
hypothalamus releases GnRH that stimulates anterior pituitary. anterior pituitary makes FSH that acts on Sertoli cells to release inhibin. inhibin can only negative feedback on anterior pituitary, it cant go to ypothalamus.
-anterior pitutary also releases LH that acts on leydig cells to release testosterone. testosterone also stiluleases sertoli cells to release inhibins. testosterone also causes anterior pituitary and hypothalamus negaitve feedback.
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leydig and sertoli cell physiology
- leydig cells respond to LH. H stimulates g protein couples receptors to produce cAMP and activate PKA. increases transcription of enzymes in testosterone synthesis, stimulates rate limiting step cholesterol to pregnenolone, and sterol carrier protein transcription.
- FSH acts on sertoli cells. similar g protein linked pathway. increases transcription of androgen binding proteins to keep local testosterone levels high, P450 aromatase to make estrogen, growth factors for the producction of sperm, inhibins to supress leydig cell proliferation and supress FSH secretion, and factors that act on Leydig cells.
crosstalk bw Leydig and Sertoli cells
- leydig cells make testosterone that acts on sertoli cells to increase release in inhibns
- leydig cells also make beta endorphins that inhibit sertoli cell proliferation.
- sertoli cells make estrogen that prevents the proliferation of leydig cells
- sertoli cells also make growth fctors that increase LH receptors on leydig cells
Kallmann syndrome= hypogonadotropic hypogonadism
- mutation on Kal-1, FGFR1, PROK1, PROKR2
- lack pituitary hormones LH anf FSH anf have no small anosmia bc of agenesis of olfactory lobes.
- pateints dont enter puberty.
- odor receptor cells and and GnRH producing cells both develop in olfacory epithelium in rudimentary nose.
- mutations in the genes prevent neurosensory neurons from extending their axns into the brain and failure prevents migration of GnRH neurons into the hypothalamus.
- main danger is osteoporosis. treatment has hormone therapy.
- GnRH neurons never reaches hypothalamus, no puberty
androgen synthesis
- rate limiting step is conversion of cholesterol to pregnenolone by desmolase P450 side chain cleavage enzyme. Activity of desmolase is upregulated by LH.
- androstedione is banned and illegal now. used to be able to get it at health stores.
- testosterone is made by leydig cells. uses 5alpha redctase to make testosterone into dihydrotestosterone (DHT). this occurs in peripheral tissues, not in testes.
- in sertoli cells of testes, you have aromatase. aromatase makes androstedione and testosterone into estone and estradiol .
- 95% of testosterone is made in testes.
male pseudohermaphroditism- any deficit in mechanism by which androgens act in genetic laes causes this
- cause 1: 5alpha reductase deficiency: DHT levels will be reduced and testosterone levels are OK. this is a problem bc you need DHT to make prostate and external male genitalia
- cause2: androgen insensitvity syndrome: normal level of testosterone and DHT. androgen receptos defectove/absent. urogenital sinus and external genitalia develop according to female pattern, – wolffian ducts degenerate. (mullerian ducts are present in women) but these mutations have AMH so you supress mullerian development. look female but are sterile
- androgens actions affect almost every tissue in body. either androgenic or anabolic
androgenic vs analbolic affects of androgens
- androgenic: maturation of se organs and penis. also development of secondary sex characteristcs, deepening of voice, growth of beard and axillary hair
- anabolic affects: protein synthesis and tissue expression of androgen receptors. growth of muscle and increase in strength. increase bone density, strength, linear growth and maturation. lager hearts, liver, lungs, erythrocytes, etc. bone maturation indirectly through estradiol metabolites- mroe gradual in men than women. men have larger brain, women have more dendritic connections.
effects of androgens on organs
- testosterone is more prevelant circulating androgen in men
- FSH levels are 8X higher in men. male gonadotropin pattern regulated by T, DHT, and estradiol E2
- androgens increase expression of erythropoitin from kidneys leads to higer hmatocrit in men
- estrogens regulate men sex behavior
- penis, seminal vesciles, and prostate get bigger in puberty. dependent on indicated hormones.
androgen receptors
- free form of testosterone enters cells through diffusion. bind homodimeris receptor and direct the transcriptional activity of target genes.
- DHT binds the same receptors as testosterone w/ greater 30X more affinity.
- testosteorne is bound by sex hormone binding globulin and albumin.
- 2% of testerone is free and biologically active
plasma testosterone vs age in males
- testosterone high at fertiliztion then goes down. after birth it beaks again and goes down again. at puberty it rises and then as an adult to senescene at aorund 40 it stays up until it starts to fall.
- the spike at birth is important for male specific neural circuitry
- senescence: andropause. not an abrupt loss in fertility. testosterone decreases w/ age above 40. quality and quantitiy of sperm also decreases. FSH and LH levels increase just like in female menopause.
- less testosterone will cause aging problems like less bone formation, less muscel mass, apetite, leibido, blood hematocrit
- testosterone level falls by 10% a year starting at 30
low testosterone
-some men have very low testosterone. symptoms are low sex drive, erectle dysfinction, loss of muscle mass, mood issues, fatigue, sleep issues and loss of body and facial hair. alot of them will benefit from treatment.
-men w/ prostate or bone cancer should not be treated for testosterone
-finasteride is a drug for balding propecia. same effects as low testosterone. blocks production of DHT, and is used to treat male pattern balding. side effects are impotence, abnormal ejaculation, and depression.
-testosterone can worsen sleep apnea, prostate cancer, congestive heart failure, and high rbc counts. can cause increased hematocrit and hair loss. hair loss treated with propecia which blocks DHT prodcution
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