Gonadal Hormones and Inhibitors: Androgens

Question 1

Physiology Pharmacology - Hypothalamus Anterior Pituitary Gonad Axes

Answer 1

Question 2

Physiology Pharmacology - Hypothalamus Anterior Pituitary Gonad Axes - Gonadal Steroids Testosterone, Estrogen, Progesterone

Answer 2

Question 3

GnRH, FSH, LH - General notes on release and pulsatile signal amplitude

Answer 3

• GnRH is a decapeptide produced by hypothalamic neurofibers
• Release is influenced by other hormones such as cortisol, insulin, IGF-1, prolactin, gonadal steroids
• GnRH is released in a pulsatile manner to bind to GnRH receptors on the anterior pituitary – LH/FSH

Question 4

Clinical Applications of GnRH

Answer 4

• Suppression – most common use of GnRH
• Leuprolide (generic) used to induce hypogonadism when given continuously
  - Receptor down-regulation on pituitary and reduced LH/FSH production
  - Uses:
  - Prostatic cancer and benign hyperplasia
  - Uterine fibroids, endometriosis
  - Central precocious puberty
  - Assisted reproductive technology procedures

Question 4

Physiology – Pharmacology – Actions of GnRH, FSH, LH

Answer 4

• Continuous stimulation and release of GnRH results in GnRH receptor down-regulation
• Inhibin: produced by the Sertoli cells (testes) and granulosa cells (developing follicles) inhibits further FSH release
• FSH (follicle-stimulating hormone) and LH (luteinizing hormone) are structurally similar glycoproteins
  - Upon release they bind to surface receptors on the cells of the ovaries and testes
  - Ovary:
  - FSH stimulates follicular development
  - LH stimulates ovulation
  - Both LH/FSH are needed for steroidogenesis by the follicular cells
  - Testis:
  - LH is the major regulator of testosterone production via activation of Leydig cells. Testosterone feeds back to suppress LH
  - FSH acts on Sertoli cells → spermatogenesis. Inhibin from Sertoli cells feeds back to suppress pituitary FSH

Question 5

Clinical Applications of FSH analogues

Answer 5

• hMG (Menopur®); FSH-like activity and LH-like activity
  - Human menopausal gonadotropins are extracted from the urine of postmenopausal women
  - Used to stimulate ovarian follicular development in women and spermatogenesis in men
  - Need to be used in conjuction with LH in both sexes
  - Ovulation and implantation in women
  - Testosterone production in men
• Recombinant FSH also available – more expensive

Question 6

Clinical Applications of LH analogues

Answer 6

• hCG (generic); human chorionic gonadotropins
  - Produced by the placenta and excreted in the urine of pregnant women; similar to LH in structure
  - Used in conjunction with hMG for infertility
• Recombinant LH and recombinant hCG is also available – more expensive

Question 7

Physiological Pharmacology - Androgens Synthesis and Release

Answer 7

• In men the most important androgen secreted by the testis (LH stimulated) is testosterone
  - ~95% by Leydig and 5% by adrenals in men
  - Small amounts of dihydrotestosterone, DHEA (anabolic effect) and androstenedione
• In women small amounts of testosterone are derived from the ovaries and adrenals; some converted to estrogens in body fat and bone
• Little to no storage of androgens upon synthesis

Question 8

Physiological Pharmacology - Androgens Actions and Effects

Answer 8

• 98% circulating testosterone bound to SHBG; ~1-2% free
• Testosterone is metabolized in most target tissues
  - Dihydrotestosterone by 5⍺-reductase; many sites
  - Estradiol by aromatase; liver, adipose, bone, brain
• All effects of sex steroids in target cells occur by way of steroid nuclear receptor mechanisms
  - Dihydrotestosterone and testosterone bind to androgen receptor; dihydrotestosterone shows greater affinity
  - Estradiol binds estrogen receptor
• Androgens are responsible for secondary sex characteristics, virilization and growth promotion
  - Spermatogenesis
  - Genitalia and secondary sex glands
  - Deepening of voice; facial hair
  - Libido and behavioural changes
  - Lean body mass
  - Erythropoiesis, decrease HDL
  - Estradiol – closure of growth plates in long bones

Question 9

Testosterone as a Prohormone

Answer 9

Question 10

Clinical Applications - Adrogen Preparations

Answer 10

• Testosterone; androgenic and anabolic effects
  - Testosterone has 1:1 androgen: anabolic ratio
  - Attempts have been made to alter preparations to produce more anabolic versus androgenic effects
  - Stanozolol, Nandrolone decanoate, Oxandrolone
• Goal of delivery is to provide reliable drug levels
  - Oral preparations; must by-pass liver
  - Testosterone half-life varied by adding esters; allows for formulation of depot preparations
  - Enanthate, cypionate, undecanoate
  - Transdermal delivery; patch or organogel
• Toxicity and side-effects
  - Prostatic enlargement, acne, mood and behaviour
  - Hepatic dysfunction/cancer
  - Suppression of spermatogenesis – sterility
  - Atherosclerosis and heart disease
  - Women – masculinization
  - Contraindicated in pregnancy

Question 11

Physiological Pharmacology - Androgens and Anabolic steroids (5)

Answer 11

1. Androgen replacement therapy (most common use)
   - Used to replace or augment endogenous androgens secretion in hypogonadal men
   - Testis vs pituitary deficiency
   - Testosterone; PO, IM or transdermal available
   - If spermatogenesis required then gonadotropins used until puberty, then testosterone used
2. Genetic disorders
   - Reduce breast engorgement post-partum (androgens antagonize the growth-promoting effects of estradiol on the breast)
   - Chemotherapy of inoperable breast cancer
   - Endometriosis; Danazol (a weak synthetic androgen)
   - Occasionally combined with estrogens; post-menopausal women – reduce bleeding from estrogens
3. Use as a protein anabolic agent
   - Following a surgery, trauma, debilitating disease
4. Growth stimulators and aging
   - Stimulate growth in boys with delayed puberty
   - Androgens decrease with age; supplementation has shown to increase lean mass and hematocrit while reducing bone turnover in older men
5. Anabolic steroid abuse in sports
   - Increase strength, aggressiveness, performance
   - Side effects: infertility, aggression, depression, liver dysfunction and liver cancer
   - The ‘Duchess’ – a drug cocktail hard to detect
   - Consisted of oral turinabol, oxandrolone and methasterone dissolved in alcohol and swished in mouth to be absorbed by the buccal membrane and spat out
   - Steroids dissolve better in alcohol than water and absorption through buccal shortens the window of detectability

Question 12

Androgen suppression/Antiandrogens

Answer 12

• There are various situations where suppressing androgens with the use of antiandrogens is desirable
• Treatment of male prostatic cancer, benign prostatic hyperplasia, endometriosis: in some women (e.g. women with polycystic ovarian disease and endometriosis) androgens are already high – therefore reduce estrogen e.g. with oral contraceptives, then block excess androgen
• Hirsutism in women; male pattern baldness in men
• Excessive sex drive or behaviours in men; precocious puberty

Question 13

Anti-Androgens Mechanism of Action

Answer 13

1. GnRH agonists; continual delivery - Leuprolide
2. Testosterone synthesis inhibition - Ketoconazole, Spironolactone
3. Inhibition of 5⍺-reductase - Finasteride
4. Androgen receptor antagonists - Flutamide, Cyproterone

Question 14

Androgens: Take Home Messages

Answer 14

• Testosterone (T) is the major androgen produced by the testes. 98% bound in blood by testosterone-estradiol binding globulin
• Responsible for male secondary sexual characteristics – muscle and bone development, facial and body hair, deeper voice, spermatogenesis, fat distribution, sexual behaviour
• 95% from the Leydig cells, controlled by pulsatile hypothalamic GnRH, stimulates pituitary LH release
• Effects amplified by tissue conversion to DHT and estradiol
• Used for anabolic effects in wasting diseases (e.g. cancer), growth promotion in delayed puberty, reducing breast and endometrial growth in women
• Long-acting GnRH analogs suppress LH and T