Androgens Flashcards
hypothalamic-pituitary-testes axis: hormones
- hypothalamus produces GnRH → production of FSH & LH from pituitary
2a. FSH regulates Sertoli cell proliferation and Seminiferous tubule growth
2b. LH regulates testosterone synthesis by Leydig cells - testes make:
-testosterone (& dihydrotestosterone)
-Mullerian inhibitory substance / AMH
-inhibin B
-aromatase
testes - 2 important cell types
- Leydig cells: produce testosterone
- Sertoli cells: produce 1) anti-Mullerian hormone (AMH) and 2) inhibin B; express aromatase for estradiol production; support sperm synthesis
Leydig cells & steroidogenesis
*luteinizing hormone (LH) promotes Leydig cell growth & proliferation
*LH also promotes the first step in steroidogenesis (first step in testosterone synthesis)
*Leydig cells (located close to the blood supply) receive LH and then secrete androgens, which direct sex differentiation and pubertal development
*Leydig cells also support fertility b/c developing sperm requires androgens
Sertoli cells - functions
*endocrine functions of Sertoli cells are stimulated by FSH; Sertoli cells also have receptors for androgens
1. during fetal development, Sertoli cells produce AMH → regression of Mullerian ducts
2. later in life, Sertoli cells:
a. produce inhibin (regulates FSH release)
b. produce androgen-binding protein (ABP) to maintain androgen levels in male reproductive tract
c. aromatize testosterone (from Leydig cells) to estradiol for local (paracrine) effects
Sertoli cells & spermatogenesis
*Sertoli cells SUPPORT and REGULATE spermatogenesis
*nourish & protect germ cells by mediating the biochemical environment in which they form
Leydig & Sertoli cell interactions
*growth factors from Sertoli cells have a PARACRINE effect on Leydig cells
1. LH binds Leydig cells and increases testosterone synthesis
2. testosterone goes to bloodstream and to Sertoli cells
3. FSH promotes production of ABP (androgen binding protein), inhibin, & growth factors by Sertoli cells
4. ABP concentrates testosterone in the seminiferous tubules, providing high local concentrations for spermatogenesis
testosterone & inhibin - feedback
1. testosterone (produced by Leydig cells): provides feedback to hypothalamus & pituitary to suppress GnRH & LH release
2. inhibin (produced by Sertoli cells): provides feedback to the pituitary to attenuate FSH release
synthesis of androgens
*LH/ACTH stimulate StAR to transport cholesterol into mitochondria; products are primarily testosterone in the testes (and DHEA / other androgens in the adrenals)
*some tissues (skin, sex organs, prostate) have 5 alpha reductase activity and convert testosterone to dihydrotestosterone
note - DHT is more potent than testosterone, but with a shorter half-life; carries out more local effects
biotransformation of testosterone
*testosterone can undergo biotransformation to:
1. dihydrotestosterone (DHT) via 5 alpha reductase
2. estradiol via aromatase enzyme; estrogens: a) aid in testosterone’s feedback to the brain
b) mediate testosterone’s contribution to epiphyseal closure and bone health
c) are important for other aspects of health and sperm production
androgen receptor binding and signaling
*binding of testosterone or DHT to an intracellular androgen receptor translocates the receptor from cytoplasm to the nucleus where it dimerizes and serves as a transcription factor
note - recall that testosterone & DHT are steroid hormones
blood transport of androgens
*45-60% is tightly bound to sex hormone binding globulin (SHBG)
*40-55% is weakly bound to albumin
*about 2% is free and active
recall: testosterone is a steroid hormone: lipophilic, hydrophobic, requires a binding protein to travel in bloodstream
sex hormone binding globulin (SHBG)
*tightly binds approximately half of the testosterone in the blood
*SHBG is synthesized by the LIVER, and levels can be altered by liver disease & drugs
*SHBG is lower in males than females
*note - estrogen increases SHBG (and lowers free testosterone)
elimination of androgens
*in the liver, androgens are converted to weaker androgens and are also made to be more water soluble via various glucuronidation / sulfonation reactions
*this allows for excretion in the urine by the kidney
testosterone actions in the fetus during gestation
*presence or absence of testosterone determine whether male or female sexual organs develop
*testosterone in the male fetus is responsible for development of epididymis, seminal vesicles, and vas deferens; DHT in the male fetus is responsible for development of penis, scrotum, and prostate
*testosterone drives descent of the testes
*overall: testosterone → INTERNAL male genitalia; DHT → EXTERNAL male genitalia
testosterone activation during puberty
*LH/FSH/testosterone levels are all low prior to puberty
*the pubertal axis is chronically inhibited until puberty, when pulsatile release of GnRH → increased release of LH/FSH → androgen production, Leydig cell maturation, and spermatogenesis
