PMCOL 343 Androgens

Flutamide

- Antiandrogen that is an AR blocker

- Competitive antagonist of AR. It binds to AR and prevents translocation tot eh nucleus and prevents downstream signalling

- Several AR mutations cause resistance to the flutamide treatment with patients

Leydig cels

- Responsible for androgen production

- Synthesize 95% if testosterone

- 5% of dihydrotestosterone (DHT)

- Also synthesizes estradiol

Seminiferous tubules

Responsible for production of spermatozoa

What is gametogenesis regulated by

Hypothalamic-Pituitary-Gonadal axis

Male Hypothalamic-Pituitary-Gonadal axis

- Hypothalamus secretes GnRH

- GnRH stimulates anterior pituitary to secrete LH and FSH

- LH stimulates Leydig cells to secrete testosterone

- FSH stimulates Sertoli cells to secrete hormone-binding protein

- Testosteorne, FSH, and androgen-binding protein stimulate spermatogenesis

Negative feedback loops of Male Hypothalamic-Pituitary-Gonadal axis

- Testosterone inhibits GnRH secretion from hypothalamus

- FSH stimulated Sertoli cells release inhibin which activates a negative feedback inhibiting FSH secretion

Describe testosterone levels throughout life

- In prenatal phase, in peaks during first trimester for male differentiation and then it falls

- In Neonatal phase, there is a surge in androgens around 3 months after birth then falls close to zero,, the reason for it is not understood

- Puberty and adulthood phase, testosterone peaks in puberty, then has a very slow drop off into later stages of life

3 forms of circulating testosterone

- Free testosterone, 1-2%, active

- Testosteorne + albumin, 20-40%, mildly active

- Testosterone + SHBG, 60-80%, inactive

Slow Classic genomic mechanism of androgens

- Androgen dependent pathway (activated at high androgen levels)

- Androgen-independent pathway (Activation of AR by phosphorylation mediated by receptors downstream growth factor receptors

- Testosterone enters cell, is converted to DHT via 5⍺-reductase, which then binds to AR which translocates to nucleus and either does direct or indirect DNA binding to influence gene transcription

Rapid non-genomic mechanisms of androgens

- Activated when androgen levels are low

- cytokines or growth factors bind to receptors which cause phosphorylation of AR. This then causes activation of second messengers which will lead to non-genomic effects

Amplification pathway of testosterone

- 5⍺-reductase converts T to DHT. It then binds to androgen receptors

- In the external genitalia, it causes differentiation during gestation, maturation during puberty, and increases prostate size and development

- In hair follicles it increases facial and body hair in puberty and causes male pattern baldness

Direct pathway of testosterone

- Testosterone simply binds to androgen receptor

- In internal genitalia it causes differentiation of wolffian ducts during gestation and causes spermatogenesis during puberty

- Increases mass and strength of skeletal muscle

- Also effects lipid0, sexual function, erythropoiesis, bone growth

Diversification pathway of testosterone

- aromatase converts testosterone to E2 which will bind to estrogen receptors

- In bones it causes epiphysis closure and increased density

- also has an effect on Libido, sexual function, and reduced body mass

Inactivation pathway of testosterone

Hepatic oxidation and conjugation, renal excretion

Describe relationship of testosterone and DHT

- They interact differently at androgen receptors

- T has a lower affinity than DHT and has a higher dissociation rate

- selective ARE sequences may play an important role in differentiation

Benefits of optimal testosterone

- Stronger muscle and bones

- Confident

- Strong boners and libido

- happy

- Sharp mind

Negatives of low testosterone

- tired

- increased risk of Alzheimers

- depressed

- increased fat

- increased risk of erectile dysfunction and low libido

- increased risk of osteoporosis

Physiological effects of testosterone

- Sex organ development, sperm production, prostate growth, ED

- Development and maintenance of secondary sexy characteristics

- Red blood cell productions

- Increased muscle mass and strength

- Bone density, maintenance, and epiphyseal closure

- Sex drive, sense of well being, confidence, cognition and memory

- Growth of facial and body hair, collagen growth, androgenic alopecia

Pharmacological uses of Androgens

- Androgen replacement therapy for hypogonadism, pituitary deficiency, and aging

- As a protein anabolic agent for trauma, after surgery, or debilitating disease

- Osteoporosis

Pharmacological uses of antiandrogens

- Benign prostatic hyperplasia (BHP) (prostate enlargement)

- Prostate cancer

- Precocious puberty

- hair loss

- Hirsutism

SARMs

- No FDA approved indications

- Promise for the safe use of treatment in BHP, prostate cancer, male hormonal contraception, cachexia, breast cancer

Primary hypogonadism

- Primary testicular failure

- Reduced testosterone which results in increased FSH and LH due to reduced negative feedback

- Treated with androgen replacement therapy

Secondary hypogonadism

- Problems in the hypothalamus or pituitary

- Results in low testosterone and FSH and LH

-Treated with androgen replacement therapy

Andropause

- decrease in testosterone level in aging male

- treated with androgen replacement therapy

Prostate cancer

- Before disease and at early stages, testosterone therapy might reduce risk

- With advancing disease, suppression of androgen receptor signalling is required

Prostate physiology and testosterone levels

- Low testosterone levels are associated with causing prostate cancer. However with advancing prostate cancer, androgen deprivation therapy can have life-extending benefits

Antiandrogens

- suppress the production of androgen

- Used for androgen deprivation therapy to reduce circulatory levels of androgens in androgen responsive tissue

Ketoconazole

- Antiandrogen that is a testosterone synthesis inhibitor

- Inhibits 17⍺-hydroxylase, which prevents the conversion of cholesterol to testosterone

Abiraterone acetate

- Antiandrogen that is a testosterone synthesis inhibitor

- inhibits 17⍺-hydroxylase and 17,20 lyase

- Inhibitng these enzymes prevents the conversion of many precursors to testosterone

- effective in androgen dependent prostate cancer

- May cause cortisol deficiency

Finasteride

- Antiandrogen

- 5⍺-reductase inhibitor, stops the conversion for Testosterone to DHT in the cell

- Used in BPH and PC

- Lower chance to cause impotence, infertility, and loss of libido due to no interference with Testosterone

Darolutamide

- Antiandrogen that is an AR blocker

- more potent AR binding

- Inhibits wild-type AR as well as clinically relevant AR mutations

- More effective in preventing nuclear translocation of AR

PROTACs for Androgen Receptors

- demonstrate efficacies toward AR protein degradation and anti-proliferation of prostate tumours in animal studies

- Eliminate all active AR proteins regardless of high hormone environment

Selective androgen receptor modulators (SARMs)

- Bind to AR and display tissue selective activation of androgenic signalling

- Range from full agonists to full antagonists depending the tissue

- Highly attractive for doping in sports and illegal bodybuilding

- To date, none have been clinically approved

Risk of SARMs

- increased risk of heart attack or stroke

- psychosis/hallucinations

- sleep disturbances

- sexual dysfunction

- liver injury and acute liver failure

- infertility

- pregnancy miscarriage

- Testicular shrinkage

Anabolic Androgenic Steroids (AAS)

- AAS mimic the testosterone physiological effects via the AR

- Rationale is to increase muscle mass and strength

- action o skeletal muscle is not entirely known

- Crazy amount of side effects