Male Hormones Flashcards
- Explain age-related changes in the levels of GnRH, LH, FSH, and testosterone (hypothalamic-pituitary-gonadal axis) during fetal development, onset of puberty, reproductive maturity, and senescence.
Fetal development: testes descend into integumentary pouch.
Puberty– androgens from testes are driving force behind secondary sexual development.
Although the levels of both total and free testosterone decline with age, levels of LH are frequently not elevated. This finding is believed to indicate that some degree of hypothalamic-pituitary dysfunction accompanies aging.
- Explain what is required for male sexual differentiation.
Androgens play two major roles in male phenotypic differentiation: (1) they trigger conversion of the wolffian ducts to the male ejaculatory system, and (2) they direct the differentiation of the urogenital sinus and external genitalia. The wolffian phase of male sexual differentiation is regulated by testosterone itself and does not require conversion of testosterone to DHT. In contrast, virilization of the urogenital sinus, the prostate, the penile urethra, and the external genitalia during embryogenesis requires DHT, as does sexual maturation at puberty.
- List the functions of the Leydig and Sertoli cells in the process of spermatogenesis
After formation of the testicular cords, the Sertoli cells produce AMH, which causes the müllerian ducts to regress. The cranial end of the müllerian duct becomes the vestigial appendix testis at the superior pole of the testis. Shortly after the initiation of AMH production, the fetal Leydig cells begin producing testosterone. The embryonic mesenchyme contains androgen receptors and is the first site of androgen action during formation of the male urogenital tract. The Sertoli cells also produce a substance referred to as androgen-binding protein (ABP). It is possible that ABP binds and maintains a high concentration of testosterone locally. These high local levels of testosterone stimulate growth and differentiation of the medulla of the gonad into the rete testes, as well as differentiation of the wolffian ducts into the epididymis, the vas deferens, the seminal vesicles, and the ejaculatory duct. Testosterone also promotes development of the prostate from a series of endodermal buds located at the proximal aspect of the urethra. Cells of the wolffian ducts lack 5α-reductase and therefore cannot convert testosterone to DHT. Thus, the internal male ducts respond to testosterone per se and do not require the conversion of testosterone to DHT. In the absence of testosterone, the wolffian system remains rudimentary, and normal male internal ductal development does not occur.
- Describe the process and hormonal regulation of steroidogenesis in the male.
- The pathway for testosterone synthesis begins in the mitochondria, where P-450scc (also called 20,22desmolase) removes the long side chain (carbons 22 to 27) from the carbon at position 20 of the cholesterol molecule (27 carbon atoms). The rate-limiting step in the biosynthesis of testosterone, as for other steroid hormones, is the conversion of cholesterol to pregnenolone. LH stimulates this reaction and is the primary regulator of the overall rate of testosterone synthesis by the Leydig cell. LH appears to promote pregnenolone synthesis in two ways. First, it increases the affinity of the enzyme for cholesterol. Second, LH has long-term action in which it increases steroidogenesis in the testis by stimulating synthesis of the SCC enzyme.
- The product of the SCC-catalyzed reaction is pregnenolone (21 carbon atoms). In the smooth ER (SER), 17α-hydroxylase (P-450c17) then adds a hydroxyl group at position 17 to form 17αhydroxypregnenolone.
- In the SER, the 17,20-desmolase (a different activity of the same P-450c17 whose 17α-hydroxylase activity catalyzes the previous step) removes the side chain from carbon 17 of 17α-hydroxypregnenolone. That side chain begins with carbon 20. The result is a 19-carbon steroid called dehydroepiandrosterone (DHEA).
- In the SER of the Leydig cell, a 17β-hydroxysteroid dehydrogenase (17β-HSD, which is not a P-450 enzyme) converts the ketone at position 17 to a hydroxyl group to form androstenediol.
- Finally, 3β-HSD (not a P-450 enzyme) oxidizes the hydroxyl group at position 3 of the A ring to a ketone to form testosterone.
- List the major target organs and describe the biosynthesis, transport, metabolism, and actions of testosterone and dihydrotestosterone
LH secreted by the anterior pituitary gland is essential for testosterone production by the testis. The interstitial cells of the testis, the Leydig cells, are the primary source of testosterone production in the male. Leydig cells synthesize androgens from cholesterol by using a series of enzymes that are part of the steroid biosynthetic pathways.
LH binds to specific high-affinity cell surface receptors on the plasma membrane of Leydig cells (Fig. 54-3). Binding of LH to this G protein-coupled receptor on the Leydig cell stimulates membrane-bound adenylyl cyclase, which catalyzes the formation of cAMP and thus activates protein kinase A (PKA). Activated PKA modulates gene transcription and increases the synthesis of enzymes and other proteins necessary for the biosynthesis of testosterone. Two of these other proteins are the sterol-carrier protein (SCP-2) and the steroidogenic acute regulatory protein or (StAR or STARD1). SCP is a 13.5-kDa protein that appears to transport cholesterol from the plasma membrane or organellar membranes to other organellar membranes, including the outer mitochondrial membrane
- Discuss the role of the hypothalamic-pituitary-testicular axis in regulation of hormone secretion and spermatogenesis
The male HPT axis controls 2 primary functions: 1. production of male gametes (sprematogenesis) in the seminiferous tubules and 2. androgen biosynthesis in the leydig cells in the testes. They hypothalamus produces GnRH, which stimulates the gonadotrophs in the anterior pituitary to secrete the two gonadotropins, LH and FSH., which control the leydig and sertoli cells of the testes
- Describe the endocrine regulation of testicular function, including the biological effects of the following hormones: GnRH, LH/FSH, Androgens (testosterone, dihydrotestosterone), Inhibin
GnRH stimulates the release of both FSH and LH from the gonadotroph cells of the anterior pituitary. FSH and LH are the primary gonadotropins; in males, they stimulate testicular function. The cell surface of the pituitary gonadotrophs is the site of high-affinity membrane receptors for GnRH. These receptors are coupled to the G protein Gαq, which activates phospholipase C (PLC). PLC acts on membrane phosphoinositides to liberate inositol 1,4,5-triphosphate (IP3), which triggers Ca2+ release from internal stores, and diacylglycerol (DAG), which stimulates protein kinase C. The results are the synthesis and release of both LH and FSH from the gonadotrophs. Because secretion of GnRH into the portal system is pulsatile, secretion of both LH and FSH by the gonadotrophs is also episodic. The frequency of pulsatile LH discharge in men is ∼8 to 14 pulses over a 24hour period. FSH pulses are not as prominent as LH pulses, both because of their lower amplitude and because of the longer half-life of FSH in the circulation.
Products of the testes, particularly sex steroids and inhibin, exert negative feedback control on hypothalamic and anterior pituitary function. Neural elements in the arcuate nucleus respond to sex steroids. Sex steroids alter the frequency and amplitude of the LH secretory pulses in both men and women. Androgens also exert powerful influences on higher brain function, as evidenced by alterations in sex behavior.
spermatogenesis requirements
What, then, is required for optimal spermatogenesis to occur? It appears that two testicular cell types (the Leydig cells and the Sertoli cells) are required, as well as two gonadotropins (LH and FSH) and one androgen (testosterone). First, LH and the Leydig cells are required to produce testosterone. Thus, LH, or rather its substitute hCG, is used therapeutically to initiate spermatogenesis in azoospermic or oligospermic men. Second, FSH and the Sertoli cells are important for the nursing of developing sperm cells and for the production of inhibin and growth factors, which affect the Leydig cells. Thus, FSH plays a primary role in regulating development of the appropriate number of the Leydig cells such that adequate testosterone levels are available for spermatogenesis. During early puberty in boys, both FSH and LH levels increase while, simultaneously, the Leydig cells proliferate and plasma levels of testosterone increase
