Androgens and antiandrogens

Testis

Gonads- gametogenesis is regulated by hypothalamic-pituitary-gonadal axis

Male HPG axis

• Hypothalamus secretes GnRH in a pulsatile manner

• GnRH stimulates ant. Pituitary cells to secrete LH and FSH

• LH stimulates Leydig cells to secrete testosterone

• FSH stimulates Sertoli cells to secrete steroid hormone binding protein

• Testosterone, FSH, and androgen binding protein stimulate spermatogenesis

Testostérone and GnRH

Testostérone inhibits GnRH secretion

What does FSH stimulate

Sertoli cells, secrete inhibin, activates negative feedback inhibiting FSH secretion

Testosterone synthesis

Pre curser is cholesterol derived from different sources, de novo synthesis, LDL

Adrenal cortex and peripheral organs- small amount of T

Leydig cells most

What do Leydig cells synthesize

95% of testosterone, 6% a-dihydroxytestosterone (DHT)

T levels throughout life

• Transient increase during first trimester- development of sex organs

• Perinatal surge

• Huge surge at puberty

• Continually after puberty

• Gradual decrease after middle age

T binding

• 1-2% free

• Albumin 2040% (mildly active)

• SHBG- 60-80% (inactive)

Slow classic genomic mechanism

• Androgen dependent: dimer transcription factor

• Androgen independent: activation of AR by phosphorylation mediated by receptors downstream growth factor receptors

Rapid non genomic mechanism

Active when androgen levels are low

Growth factors and cytokines

Doesn’t enter nucleus so response is variable

DHT path

Amplification pathway, much higher affinity

Gonads, prostate, skin, hair

5a-reductase

T path

Direct pathway

Liver, muscle, adipose tissue

E2

ER receptors, brain and bone

Inactivation path

Hepatic oxidation and conjugation

Renal excretion

Actions of DHT

• external genitalia- differentiation in gestation, maturation during puberty, prostate size and development

• Hair follicles- increased facial and body hair growth during puberty, male astern baldness

Actions of T

• Internal genitalia- differentiation of Wolffian ducts, spermatogenesis during puberty

• Skeletal muscles- increased mass and strength

• Libido

• Sexual function

• Erythropoiesis

• Bone growth

Actions of E2

• Bone- epiphysis closure, increased density

• Libido

• Sexual function

• Reduced body mass

Benefits of optimal testosterone

Strong bones

Energy/shrper mind

Increased muscle

Healthy heart

Happy

Pharmacological use of androgens

• Androgen replacement therapy: hypogonadism, pituitary deficiency, aging

• As protein anabolic agents: trauma, after surgery or prolonged immobilization, debilitating disease

• Osteoporosis

Pharmacological use of antiandrogens

• Benign prostatic hyperplasia

• Prostate cancer

• Precocious puberty

• hair loss

• Hirsutism

Pharmacological use of SARMS

No fda approval but maybe

• BHP

• Prostate cancer

• Male hormonal contraception

• Cachexia

• Breast cancer

Primary hypogonadism

Primary testicular failure, decreased T, increased FSH and LH

Secondary hypogonadism

Problem in hypothalamus or pituitary, decreases testosterone, decreased FSH and LH

Androgen replacement for primary and secondary hypogonadism

Both respond well

Only can restore fertility in primary

Treatment only uses T- doesn’t convert to DHT or E2

Andropause

Decrease in T level in agin male

Low sex drive, erectile dysfunction, decreased energy, depression, reduced muscle mass, increased body fat

Prostate cancer

• Could maybe be reduced in early stages if treated with T

• In advanced stages need suppression of androgen receptor signaling

Low testosterone in early and intermediate prostate cancer

Favors obesity, diabetes mellitus, metabolic syndrome

Ketaconazole

Antifungal drug inhibits gonadal and adrenal steroid syntheis

Inhibits 17a-hydroxylase

low potency

Abiraterone acetate

• First second generation anti androgen approved

• Inhibits 17a-hydroxylase, and 17 and 20 lyase

• Effective in androgen dependent prostate cancer

• May cause cortisol deficiency

Finasteride

Inhibits conversion of T to DHT

Inhibits 5a-reductase

Treatment of BPH

Lower chance to cause impotence, infertility, and loss of libido

Flutamide

First gen nonsteroidal competitive antagonist of AR

Binds to AR and prevents translocation

Several mutations causes resistance

Darolutamide

Second generation AR blocker

More potent

Inhibits wild type and clinically relevant AR mutations

More effective in preventing translocation

PROTACS for AR

Several have been found to target AR, show efficacy in protein degredation and anti-proliferation of prostate tumours in animal studies, eliminate all active AR proteins regardless of high hormone environment, decent oral availability and strong anti tumour efficacy

SARMs

• Full agonist to full antagonist depending on tissue

• Originally to treat muscle wasting conditions, osteoporosis, breast cancer, prostate cancer

• Similar anabolic agents, reduced and organic properties

• Highly attractive for doping in sports

Risk of SARMs

• Increased risk of heart attack or stroke

• Psychosis/hallucinations

• Sleep disturbances

• Sexual dysfunction

• Liver injury/acute liver failure

• Infertility

• Pregnancy miscarage

• Testicular shrinkage

Anabolic androgen is steroids (AAS)

Mimic effects via AR

Used by athletes at high doses

Theory: androgens influence differentiation of multipotent stem cells, promote myogenic lineage in detriment of adipose if lineage

Adverse AAS effects

Reproductive, liver cardiovascular, endocrine, neuro, urinary, integument, muscoskeletal