Chapter 12- Androgens

Anatomy of male repro system

Testes, ducts and accessory structure

Seminiferous tubules

Sertoli cells secrete inhibin- FSH control, leydig cells produce testosterone-LH control

Natural and synthetic androgens

Testosterone and 5a-dyhydrotestosterone

Androgen main functions

Develop and maintain male reproduction and anabolic skeletal muscle effects

Androgen antagonists

Synthetic analogs of testosterone that bind to the androgen receptor without androgenic effects

Androgen biosynthesis

Cleavage of cholesterol to yield testosterone occurs in leydig mitochondria

Unmodified pathway

Testosterone to androgen receptor in muscle

Amplification pathway

Testosterone to 5a-reductase to DHT to androgen receptor in skin and prostate

Diversification pathway

Testosterone to aromatase to E2 to estrogen receptor in bone and brain

Aromatization of testosterone to estradiol

Critical in bone to close epiphyseal plate and feedback loop to brain to decrease GnRH secretion

Free testosterone

Binds to inactive cytoplasmic receptors to be transported into the nucleus to bind the androgen responsive element of DNA to initiate transcription

Bound testosterone

Most testosterone is bound to albumin or steroid hormone binding globulin

Degradation of androgens

In liver, testosterone and DHT undergo catabolism, testosterone is conjugated with glucuronic acid, released into circulation and is removed through urine or bile

Hypothalamic pituitary-testis axis

Hormonal control of testis, feedback control and prolactin

Luteinizing Hormone (LH)

Leydig cells, site of production of testosterone, paracrine interactions with seminiferous tubules for spermatogenesis

LH binds to plasma membrane receptor on leydig cell

Increase of cyclic AMP within the cell activates protein kinase A and StAR to initiate steroidogenesis

Follicle stimulating hormone (FSH)

FSH and T act on sertoli cells to initiate spermatogenesis, binds to G-protein coupled receptor to increase inhibin and ABP production

Androgen binding protein (ABP)

Concentrates androgens in the seminiferous tubules to deliver steroid hormones to spermatocytes and spermatids

Kisspetin

Contain androgen and estrogen receptors, T or E2 repress kisspeptin gene expression and decreases GnRH levels

Inhibin

Gonads produce inhibin in response to FSH in the sertoli cells to inhibit FSH

Activins

Stimulate secretion of FSH, important in testis development and spermatogenesis

Prolactin

Half the amount of females, PRL high levels feedback to hypothalamus to inhibit GnRH secretion, thus LH and FSH and T production

Androgen receptor

Widely expressed, on the X chromosome, nuclear receptor, bound to ligand or complexed with chaperone proteins, occupied receptor acts as a transcription factor

Sex determination

Development of the gonad based on chromosomal complement, SRY on the Y chromosome confers male sexual development

Klinefelter syndrome

XXY, small testis with few sperm, tall stature, obesity and cognitive disability

Turner syndrome

X, Steak gonad, immature ovary, lymphedema, short stature, web neck, cardiac defects, hearing loss

Mixed gonadal

X/46, XY, Testis or dysgenic testis, increased dysgenesis risk of gonadal tumors

Ovotesticular DSD

XX/46, XY, Testis, ovary or ovotestis, increased risk of gonadal tumors

Puberty

Growth spurt, pubic hair, increase in testis and penis size, voice change, acne and facial hair

Signals for onset of puberty

Increase in pulsatile GnRH and kisspeptin

Spermatogenesis

Commitment of a spermatogonium to maturation take 74 days in human, mitotic phase, meiotic phase and transformation into mature spermatozoa

Maturation of the spermatid

Loss of cytoplasm, development of acrosome, organization of mitochondria and elaboration of the flagellar tail

Estrogen in males

Arise from aromatization of T in adipose tissue, bone, brain, breast, blood vessels, liver, leydig and sertoli cells, critical for epiphysial plate closure and negative feedback on GnRH

Androgen abuse

Steroid use may result in increased mortality, cardiac pathology, abnormal plasma lipoprotein levels, liver pathology and behavioral changes

Prostate cancer

Androgens promote prostate growth, aromatization of testosterone to estradiol continues lifelong which can result in prostate cancer, treatment involves surgical or chemical castration