Nephro/Uro Pharm: Male Repro Drugs

What are the natural androgens?

Testosterone, 5α-dihydrotestosterone (DHT)

What is the role of natural androgens in males?

Development of sex organs and pubertal secondary sexual characteristics

When does GnRH stimulate FSH/LH release?

Pulsatile GnRH

When does GnRH initially stimulate then inhibit FSH/LH release?

Constant GnRH

90% of testosterone synthesis occurs where?

Leydig cells of testes

10% of testosterone synthesis occurs where?

Adrenal cortex

What enzyme converts testosterone to DHT?

5α-reductase

Where is testosterone converted to DHT?

Skin, prostate, seminal vesicle, & epididymis

What enzyme converts testosterone to estradiol (E2)?

Aromatase

Where is testosterone converted to estradiol (E2)?

Liver & adipose

What is the effect of testosterone on the pituitary?

LH inhibition

What is the effect of testosterone on the bone marrow?

Erythropoiesis

What are the effects of testosterone and DHT on bone & skeletal muscle?

Increase in mass & strength

What are the effects of dihydrotestosterone on the prostate?

Prostate growth in elderly

What are the effects of dihydrotestosterone on the hair follicle in adults?

Balding

Where do androgens bind?

Intracellular androgen receptor

What are some pharmacologic effects of androgen receptor agonists on the male reproductive system?

Male sexual differentiation in fetus

growth of prostate & seminal vesicles

maintenance of sexual function, libido & spermatogenesis

pubertal penile and scrotal growth; development of pubic, beard & axillary hair

male pattern baldness

growth of larynx, thickening of vocal cords leading to deepening of voice

What are some anabolic actions of androgen receptor agonists?

↑ protein synthesis and ↓ breakdown

Na+ and water retention

↑ in muscle mass and erythropoiesis

pubertal ↑ in linear skeletal growth and closure of epiphyses

↑ bone mineral density (BMD) but osteoporosis in old age when levels decline

What are some metabolic effects of androgen receptor agonists?

↑ hepatic synthesis of clotting factors

What are "other" effects of androgen receptor agonists in men & women?

Oily skin and acne

What are "other" effects of androgen receptor agonists in women specifically?

Hirsutism, deepening of voice, frontal baldness, acne, clitoromegaly, prominent musculature, suppression of ovulation and irregular menstruation

What are the two activity types of androgens?

Anabolic & androgenic

How do anabolic and androgenic activity of testosterone compare?

Equal

How do anabolic and androgenic activity of anabolic steroids compare?

3x more anabolic activity

What are examples of anabolic steroids?

Oxymetholone, Oxandrolone, Nandrolone decanoate

How is androgen replacement dosed in puberty compared to adulthood & why?

Lower doses to avoid premature epiphyseal closure

What is the clinical use of AR agonists in gender-affirming therapy?

Helps transgender or intersex men develop masculine body features to match gender identity

When are androgen receptor agonists used as protein anabolic agents?

Catabolic states resulting in cachexia (cancer, AIDS-related muscle wasting, trauma, surgery)

What are the effects of AR agonists when used for patients with cachexia?

Improve appetite, resulting in weight gain and a general sense of well-being

What are adverse reproductive effects of AR agonists in men?

Oligospermia, testicular atrophy, infertility, gynecomastia, decreased libido, & growth of prostatic neoplasm

What are adverse reproductive effects of AR agonists in women?

Masculization with anabolic androgens, virilization of female fetus

What are cardiovascular adverse effects of AR agonists?

↑ LDL, ￬ HDL, edema, hypertension

What are hematologic adverse effects of AR agonists?

↑ Hb and Hct

What are psychologic adverse effects of AR agonists?

Aggression, "roid rage," psychotic reactions

What are hepatic adverse effects of AR agonists?

Cirrhosis, jaundice, benign liver tumors (especially oral forms)

What are adverse effects of AR agonists in children?

Precocious puberty

short stature from premature epiphyseal closure

When are AR agonists contraindicated or used with caution?

Pregnancy and lactation

carcinoma of prostate or breast

hypertension and cardiovascular disorders

elderly

liver dysfunction

kidney dysfunction

nephrotic syndrome

CHF

What actions of antiandrogens reduce serum testosterone?

Gonadotrophin suppression

inhibition of testosterone synthesis

inhibition of testosterone to DHT conversion

androgen receptor blockade

When are antiandrogens used clinically?

States of androgen excess (precocious puberty, hirsutism, acne) & androgen dependent tumors (cancer of testis and prostate)

What are the GnRH agonists?

Leuprolide, goserelin, histrelin, triptorelin

What are the GnRH antagonists?

Degarelix, relugolix

What are the AR antagonists?

Flutamide, bicalutamide, apalutamide,

enzalutamide, darolutamide

What are the 5-α-reductase inhibitors?

Finasteride, dutasteride

What is the 17-α-hydroxylase and 17,20-lyase inhibitor?

Abiraterone

What is the mechanism of action of GnRH agonists when given continuously?

Suppress the release of FSH, LH from pituitary (initial agonistic effect) then testosterone production ￬ once the GnRH receptors desensitize

What are the clinical uses of GnRH agonists?

Precocious puberty, Benign Prostatic Hypertrophy (BPH), & androgen-sensitive prostate cancer (palliative)

reversible pharmacologic orchiectomy

What are the adverse effects of GnRH agonists?

Hypogonadism, ￬ libido,

erectile dysfunction

What is the mechanism of AR antagonists?

non-steroidal competitive antagonism at androgen receptors

blocks effects of androgens at target tissues

Which AR antagonist(s) are weak partial agonists?

Most (except Enzalutamide)

Which AR antagonist is a "pure" antagonist with no partial agonistic effect?

Enzalutamide

What drug is useful for "castration-resistant" prostate cancer?

Enzalutamide

What is the clinical use of AR antagonists?

Administered in combination with GnRH agonists for treatment of prostatic cancer

What causes the adverse effects of AR and GnRH antagonists?

Low serum testosterone

What are the adverse effects of AR and GnRH antagonists?

Decreased libido, gynecomastia, decreased muscle strength, osteoporosis, hot flashes

What is the mechanism of action of GnRH antagonists?

Blocks GnRH action on anterior pituitary gonadotrophs, inhibiting LH secretion testosterone secretion from Leydig cells (without initial testosterone flare)

What is the clinical use of GnRH antagonists?

Androgen-sensitive prostate cancer (palliative)

What is the mechanism of action of 5-α-reductase inhibitors?

Blocks tissue conversion of T to DHT

What is the action of α1A adrenoceptor blockers?

Relaxes prostate and bladder neck smooth muscle, assisting urinary flow and suppressing the dynamic component of obstructive uropathy

How are 5-α-reductase inhibitors used in MPB?

block production of DHT, which enhances hair growth

What are the clinical uses of 5-α-reductase inhibitors?

MPB & BPH

5-α-reductase inhibitors are usually given in combination with what drug for relief of obstructive symptoms?

Tamsulosin

Finasteride inhibits which 5-α-reductase type(s)?

Type-2 only

Dutaseride inhibits which 5-α-reductase type(s)?

Both Type-1 and Type-2

What are the adverse effects of 5-α-reductase inhibitors?

Gynecomastia, impotence, decreased libido, sperm count, & ejaculatory volume

What is the mechanism of action of abiraterone?

Inhibits 17-α-hydroxylase and 17,20-lyase (CYP17), halting the synthesis of androgens & cortisol

What is the clinical use of abiraterone?

Castration-resistant advanced prostate cancer

What are the adverse effects of abiraterone?

Adrenal insufficiency (must be given with corticosteroid supplementation)

What does NO release stimulate in the erection pathway?

Parasympathetic neurons

NOm—> vasodilation —> erection

What is the mechanism of action of PDE-5 inhibitors?

Inhibits PDE-5

increases t1/2 of cGMP, leading to vasodilation promoting erection in the presence of sexual stimulation

What is the onset of action of Sildenafil & Vardenafil?

30-60 minutes

What is the onset of action of Tadalafil?

30-120 minutes

What is the onset of action of Avanafil?

15-30 minutes

What is the maximum duration of action for Sildenafil?

12 hours

What is the maximum duration of action for Vardenafil?

10 hours

What is the maximum duration of action for Tadalafil?

36 hours

What is the maximum duration of action for Avanafil?

6 hours

Which PDE-5 inhibitor can also be used for BPH?

Tadalafil

Which PDE-5 inhibitor can be taken as a daily low dose?

Tadalafil

Why are PDE-5 inhibitors used for pulmonary hypertension?

Inhibition of PDE-5 prolongs NO-induced vasodilation lowering pulmonary

vascular pressure

What are the adverse effects of PDE-5 inhibitors?

Headache, facial flushing, bluish discoloration of vision (PDE6 inhibition of sildenafil and vardenafil)

What are the DDIs for PDE-5 inhibitors?

Hypotension when used with organic nitrates (nitroglycerin) or with α- blockers (prazosin, doxazosin etc.)