Gonadal Hormones and Inhibitors: Androgens

Hypo-Ant Pit-Gonad axes

what is GnRH

a decapeptide produced by hypothalamic neurofibers

what is GnRH release influenced by

other hormones such as cortisol, insulin, IGF-1, prolactin. gonada steroids

in which manner is GnRH released

a pulsatile manner to bind to GnRH receptors on the anterior pituitary -LH/FSH

what does continuous stimulation and release of GnRH result in

GnRH receptor down-regulation

what is inhibin

produced by the Sertoli cells (testes) and granulosa cells (developing follicles) inhibits further FSH release

FSH and LH

FSH (follicle stimulating hormone) and LH (luteinizing hormone) are structurally similar to glycoproteins

• upon release they bind to surface receptors on the cells of the ovaries and testes

Ovary and hormones

• FSH stimulates follicular development

• LH stimulates ovulation 

• both LH/FSH are needed for steroidogenesis by the follicular cells

testes and hormones

• 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

GnRH stimulation

• gonadorelin - used in both sexes for infertility caused by hypothalamic hypogonadotropic hypogonadism  — less popular now

• pulsatile therapy via a portable pump; programmed for pulsatile delivery about every 90 mins

GnRH suppression - most common use of GnRH

• Leuprolide → 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

FSH analogues

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 conjunction with LH in both sexes

• ovulation and implantation in women

• testosterone production in men

recombinant FSH also available - more expensive

LH analogues

hCG - human chorionic gonadotropins

• produced by the human 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

what is the most important androgen secreted by the testes (LH stimulated)

testosterone

what is testosterone secreted by

95% by Leydig cells and 5% by adrenals in men

small amounts of what also produced by the testes

dihydrotestosterone, DHEA and androstenedione also produced by testes

in women, small amounts of testosterone are derived from what? and what is it converted to

derived from ovaries and adrenals; some converted to estrogens in body fat and bone

is there storage of androgens

little to no storage of androgens upon synthesis

androgens actions and effects

circulating testosterone bound to what

SHBG; approx 1-2% free

where is testosterone metabolized

in most tissues

what metabolizes testosterone

• dihydrotestosterone by 5a-reductase; many sites

• Estradiol by aromatase; liver, adipose, bone, brain

how do all affects of sex steroids in target cells occur

by way of steroid nuclear receptor mechanisms

what receptor do dihydrotestosterone and testosterone bind

androgen receptor

what hormone binds the androgen receptor with greater affinity

dihydrotestosterone

what receptor does estradiol bind

estrogen receptor

androgens actions and effects

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

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

• stanazolol, Nandrolone decanoate, Oxandrolone

goal of delivery is what

to provide reliable drug levels

• oral preparations; must pass by liver

• testosterone half-life varied by adding esters; allows for formulation of depot preparations → enanthate, cyprionate, undecanoate 

• transdermal delivery; patch or organogel

toxicity and side effects of androgen preparations

• prostatic enlargement, acne, mood and behaviour

• hepatic dysfunction/cancer

• suppression of spermatogenesis - sterility 

• atherosclerosis and heart disease

• women - masculinization - contraindicated in pregnancy

androgen replacement therapy - most common use

• used to replace or augment endogenous androgens secretion in hypogonadal men (testes versus pituitary deficiency)

• testosterone; PO, IM or transdermal available

• if spermatogenesis required, then gonadotropins used until puberty, then testosterone used

2. Gynecological disorders

• reduce breast engorgement post-partum (andorgens antagonize the growth-promoting effects of estradiol on the breast)

• chemotherapy of inoperable breast cancer

• enometriosis; Danazol (a weak synthetic androgen)

• occasionally combined with estrogens; post-menopausal women - reduce bleeding from estrogens

3. use as a protein anabolic agent

following surgery, trauma, debilitating disease

4. growth stimulators and aging

• stimulate growth in boys with delayed puberty 

• androgens decrease witha ge; supplementation has shown to increase lean mass and hematicrit 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 which was dissolved in alcohol

• swished in mouth to be absorbed by the buccal membrane and spat out 

• shortens the window of detectability

when would you use Androgen suppressors/antiandrogens

• treatment of male prostatic cancer, benign prostatic hyperplasia, endometriosis: in some women (e,g, women with PCOS and endometriosis) androgens are already high - therefore, reduce estrogen e.g. with oral contraceptives, then block the excess androgen 

• hirsutism in women; male pattern baldness'

• excessive sex drive or behaviours in men; precocious puberty

anti androgens

• leuprolide

• Ketoconazole, spironolactone 

• finasteride

• flutamide, cyproterone

mechanism of action of leuprolide

GnRH agonists; continual delivery

Ketoconazole, sprionolactone mechanism of action

testosterone synthesis inhibition

flinasteride mechanism of action

inhibition of 5a-reductase

Flutamide, Cyproterone mechanism of action

androgen receptor antagonists

what is the major androgen produced by the testes? what percent is bound in blood and what to

testosterone; 98% bound by testosterone-estradiol binding globulin

what is testosterone responsible for

male secondary sexual characteristics - muscle and bone development, facial and body hair, deeper voice, spermatogenesis, fat distribution, sexual behaviour

what is testosterone released from and what manner

95% from the Leydig cells, controlled by pulsatile hypothalamic GnRH, stimulates pituitary LH release

what are the effects of T amplified by

tissue conversion to DHT and estradiol by 5a-reductase 

used for what

anabolic effects in wasting diseases (e.g. cancer), growth promotion in delayed puberty, reducing breast and endometrial growth in women

what are the side effects of testosterone abuse

cardiovascular effects and infertility

what suppresses LH and T

long acting GnRH analogs