Lecture 2: Male Sexual Development Flashcards
Genotypic sex
The genotypic sex involves the Y chromosome (49, XXXXY genotype is male).
Gonadal Sex
While the gonadal sex: SRY gene encodes testis determining factor (TDF) which is a transcription factor. When the SRY gene is present, indifferent gonads becomes testes AND germ cells develop in spermatogonia (6-8 weeks of gestation)
The phenotypic sex involves
the hormones produced by the gonads that determine the phenotypic sex. This includes development of accessory sex organs, external genitalia (penis, scrotum, urethra) that require the presence of DHT as well as the secondary sex characteristics.
XX Male
SRY gene, which contains the TDF region translocates from the Y chromosome to the X chromosome during male meiosis. The ovum will develop into a male. Crossing over events between normal X and Y chromosome of the father can generate an X-chromatid that contains a substantial portion of the TDF and a Y chromosome that lacks the SRY region (TDF).
XX Male again
If a sperm cell bearing an X-chromosome with a transloctaed TDF feritizes an ovum, the result is a male with a 46, XX karyotype because one of the X chromosomes contains the TDF.
Differentiation of the testis
o When the gonad is still indifferent, it is closely associated with the mesonephros (Wolfian duct) and the excretory duct.
Mesonephros develops into
epididymis
Wolffian duct develops into
Wolfian duct develops in vas deferens, seminal vesicles and ejaculatory duct.
Androgens from Leydig cells promote this and prostate development
Mullerian ducts degenerate (because they would have developed into fimbriae in females). This is controlled anti-Mullerian hormone by from the Sertoli cells
Embryonic gonad affects the development of the INTERNAL GENITALIA
Androgens produced by Leydig cells promote the development of wolffian ducts and its derived structures listed above.
REQUIRES TESTOSTERONE, not DHT
Homologous Regions of Male and Female EXTERNAL GENITALIA
o No testosterone available, the undifferentiated external genitalia is female by default.
o TESTOSTERONE, after conversion to DHT stimulates formation of male external genitalia from the undifferentiated structures.
Hypothalamic-Pituitary-Gonadal Axis
o Regulates spermatogenesis and androgen production
o GnRH stimulation is pulsatile (if it were constant it would prevent LH and FSH release by downregulating receptors…used to treat prostate cancer by lowering Testosterone production). Since GnRH release is pulsatile, LH and FSH release are pulsatile.
o Products of testes negatively feedback on the hypothalamus and anterior pituitary
o GnRH binds GPCR, activating phospholipase C that ultimately causes calcium release, DAG production and protein kinase C activation
H-P-G Axis in the prenatal stage
Leydig cells in the testes make the androgens (sex-steroids). They are the dominant cell types in the testes (Increase in Leydig cells is dependent on maternal hCG in early development and on LH in later development).
H-P-G Axis prior to puberty
o less pulse of GnRH, therefore less LH/ FSH release
o lots of androgens around so they negatively feedback on the hypothalamus and anterior pituitary
o spermatogonia exist in diploid, undifferentiated form in the basal compartment of the testes
H-P-G Axis at Puberty
increased frequency and amplitude of GnRH pulses
• H-P-G axis not as sensitive to negative feedback of testosterone (an androgen) but the gonadotrophs become more sensitive to GnRH which causes increases in LH and FSH production
• Testosterone increases and spermatogenesis begins and you also get the rest of the signs of puberty
Kallman Dz:
lack of the ant pit hormones LH & FSH; patients never enter puberty and hv no sense of smell because the mutation prevents the sensory neurons from extending their axons into the olfactory bulb. GnRH secreting cells walk along these into the brain and then into hypothalamus
The hypothalamic-pituitary-testicular axis
o GnRH causes the gonadotrophs to make and release FSH and LH. LH binds to Leydig cell receptors, upregulating testosterone. FSH binds binds to Sertoli cells upregulating transcription of ABP, growth factors and inhibin.
o Negative Feedback on this axis: Testosterone inhibits pulsatile release of GnRH and LH. And inhibin inhibits the release of FSH by the gonadotrophs in the ant pit.
Physiology of Leydig cells
o Leydig cells have receptors for LH, LH stimulates GPCR to produce cAMP + activate PKA
o Effects include testosterone synthesis, stimulation of rate determining step (cholesterol to pregnenalone, sterol carrier protein and sterol activating protein…for testosterone synthesis
Physiology of Sertoli Cells
Sertoli cells-FSH- activates signaling pathway to LH and increases transcription of 1.androgen binging protein (ABP)—keeps local testosterone high 2. P450 aromatase which produces estrogen, 3. Growth factors that support sperm 4. Inhibin which suppresses Leydig cell proliferation, suppresses FSH secretion 5. Factors that act on Leydig cells. Secondary effects are on the Leydig cells and on sperm (increases motility)
Crosstalk between Leydig and Sertoli cells
Leydig cells make testosterone, which acts on Sertoli cells. These SC cells convert some of the testosterone to estradiol (via aromatase) which comes back to act on Leydig cell. Sertoli cells also generate growth factors that act on Leydig cells to increase LH receptor.
Androgen Synthesis
Occurs in mitochondria….cells uses cholesterol from LDL to produce pregnenalone which is upregulated by LH. Androstendione→testosterone→DHT via 5-α-reductase. Androstendione and testosterone are converted to estradiol and estrone via aromatase.
Male Pseudohermaphroditism - any mechanism that prevents androgens from working correctly:
2 causes
5-α-reductase deficiency:
androgen insensitivity:
5-α-reductase deficiency:
DHT levels REDUCED; testosterone OK so any DHT-dependent development fails (urogenital sinus, external genitalia)
androgen insensitivity:
androgen receptors are absent but the levels of testosterone and DHT are normal. Urogenital sinus and external genitalia develop according to female pattern and the Wolff ducts degenerate because no testosterone to turn them on. Since they produce and respond to FSH, this will suppress Mullerian ducts which will lead to ovaries forming. Normal AMH????
Androgenic effects of Androgens -
maturation of the penis; voice depens, beard grows; axillary hair grows
Anabolic effects of Androgens-
Anabolic effects of Androgens- muscle growth, strength increase, increase in bone density, linear growth, larger lungs, heart, liver and RBCs and brains but women have more dendritic connections. Bone maturation occurs indirectly through estradiol metabolites and is more gradual in men than
Androgens (Testosterone) Effects on Organs
o Increases in liver to produce more VLDL and LDL (bad) while decreasing HDL, increases RBC, muscle mass, upper body fat, skeleton, larynx, epididymis, vas deferens and scrotum.
o Testosterone via estradiol and DHT: imprint made of gonadotropins (LH & FSH), sex drive and behavior,
o Testosterone via DHT: feedback suppression of gonadotropin secretion; penis, scrotum, urethra, prostate, male pattern baldness, sweat cells/acne, seminal vesicles
Androgen Receptors
Androgen receptors are in the cytoplasm binds and homodimerizes increasing transcription of target genes. DHT binds the same receptors with greater affinity. In the plasma testosterone is bound by sex hormone-binding globulin and albumin
Plasma testosterone v age in males
Testosterone levels remain low until puberty (small spike after birth
Andropause (Senescence)-
slower loss of fertility, unlike menopause and the quality and quantity of sperm decreases. FSH and LH levels increase. Reduced testosterone causes some of the aging problems: decreased bone formation, muscle mass, apetite, libido and blood hematocrit
o Low testosterone <300ng/dL blood)-sympthoms include ED, loss of muscle mass, mood problems, sleep disturbances, loss of body ad facial hair.
Taking steroids/abusing steroids:
reduced sperm count (due to testosterone negative feedback on ant pit and it is also a consequence of testosterone being bound up by ABP), shrinks testicles, permanent damage to heart, liver, kidneys, psychiatric problems, breast enlargement (irreversible), excessive body hair voice deepens
Kennedy Dz:
mutated androgen receptor causes LMN dz. Mutation due to expanded glutamine repeat; tongue and mouth muscle weakness that progresses to limbs. Larger repeat, earlier onset; more androgen receptor dysfunction:gynecomastia, ED, impotence
Spermatogensis and Sperm Development
o Sertoli cells promote sperm development
o Testosterone needed for maturation of sperm…take 70 days…activated in female genital tract for fertilization
o Sex glands produce the seminal plasmid: seminal fluids contain sugars (to mobilize for energy and is derived from seminal vesicles, prostate gland and bulbouretheral glands
Sympathetic component:
emission, ejaculation and flaccid penis
Parasympathetic component
Erection
Nerve terminal release
acetylcholine and nitrous oxide (NO) which relaxes smooth muscle of the arteries increasing blood flow
Viagra works by
inhibiting cGMP phosphodiesterase, keeping cGMP around longer to promote vasodilation
o Mechanics of erection
increased arterial flow; decreased venous flow
o Somatic:
pudendal nerve..blood supply is primarily pudendal artery
Emission:
is the movement of ejaculate into urethra; sympathetic stimulation of hypogastric nerve causes contraction of smooth muscle of distal epididymis, vas deferens and accessory glands
Ejaculation:
expulsion of semen thru urethra; a spinal reflex/pudendal nerve, often accompanied by orgasm (CNS involvement)
