Male Reproductive Endocrinology

Male HPG axis — LH pathway

GnRH → LH → Testes (Leydig cells) → testosterone production

Male HPG axis — FSH pathway

GnRH → FSH → Testes (Sertoli cells) → spermatogenesis → sperm

Male HPG axis — unique fact

Concentration of testosterone is 200x higher in testes than in blood

Testes — 2 main components

Leydig cells (testosterone production) + Sertoli cells (sperm production)

Sperm production

30 million/day; ~75-day process

Male hormones — list

Testosterone (95%), DHT (2.5x more potent), Androstenedione (weak), DHEA (weak), 17B-Estradiol

Functions of testosterone

Development of male reproductive structures, male secondary sex characteristics, maintenance of libido + erectile function, maturation of sperm

Primary hypogonadism — definition

Problem in the testes; primary hypogonadism

Primary hypogonadism — lab findings

Low to normal testosterone, poor or no sperm, elevated FSH + LH

Secondary hypogonadism — definition

Hypogonadotropic hypogonadism; lack of LH and FSH from the pituitary

Secondary hypogonadism — lab findings

Low gonadotropins (FSH/LH), low testosterone, no sperm

Secondary hypogonadism — causes

Pituitary adenomas, hypothyroidism (high TRH → hyperprolactinemia), hyperprolactinemia (interrupts GnRH pulse generator)

Testosterone therapy — when appropriate

Primary hypogonadism; secondary hypogonadism when patient does NOT desire fertility

Testosterone replacement — advantages

Restores virilization/masculinization, libido, sexual performance, energy

Testosterone replacement — disadvantages/ADRs

↑BP, ↑CV risk, VTE, ↑risk of prostate cancer, ↑BPH symptoms

Testosterone replacement — monitoring

Symptom improvement + testosterone levels in mid-normal range

Testosterone replacement — fertility warning

Testosterone replacement will NOT produce sperm; NOT appropriate if patient desires fertility

Oral testosterone — why not used much

Hepatotoxicity from first pass effect (methyltestosterone)

Testosterone undecanoate oral (Jatenzo)

Claims to avoid first pass effect

Testosterone — injectable forms

Testosterone cypionate + testosterone enanthate; IM or subQ; every 1–2 weeks

Testosterone — transdermal gel

Androgel, Testim; caution: do not touch skin of other people

Testosterone — intranasal

Natesto metered pump

Testosterone — effect on fertility

Testosterone replacement will NOT produce sperm; not appropriate if fertility desired

Secondary hypogonadism + wants fertility — step 1

Give hCG (same activity as LH); IM 3x/week x 9–12 months; stimulates Leydig cells to make testosterone

Secondary hypogonadism + wants fertility — step 2

Add menotropins (FSH + LH mix) or recombinant FSH; IM 3x/week; monitor sperm count

hCG — physiological activity

Same as LH

BPH — definition

Benign enlargement of the prostate gland that occurs as men age

BPH — 2 growth periods

1. Puberty–age 25-30 (normal size 5–20gm); 2. Restarts ~age 40 through 80

BPH — prostate tissue composition

70–80% smooth muscle; 20–30% glandular epithelial tissue

BPH — what stimulates epithelial tissue growth

DHT (dihydrotestosterone)

BPH — what stimulates smooth muscle growth

Other mechanisms (estrogen); under alpha-adrenergic tone

BPH — pathophysiology

Prostate growth → compresses urethra → ↑ resistance → bladder compensates → becomes irritable → weakens → incomplete voiding → urinary retention

BPH — obstructive LUTS

Hesitancy, weak stream, intermittency, dribbling, bladder fullness

BPH — irritative LUTS

Frequency, urgency, urinary incontinence, nocturia

BPH — complications

Urinary retention, recurrent UTI, irreversible bladder impairment, chronic renal failure

AUA-SI — score interpretation

<8 = mild (watchful waiting); 8–19 = moderate; 20–35 = severe

BPH — watchful waiting appropriate for

Mild symptoms (AUA <8); moderate symptoms (AUA 8–19) if NOT bothered

BPH — when to start drug therapy

Moderate symptoms AND bothered; severe symptoms (AUA ≥20); evidence of complications

PSA — surrogate marker for

Prostate SIZE

PSA — threshold if ≥60 yo

<4 mg/ml

PSA — threshold if <60 yo

<2.5 mg/ml

Alpha-1 blockers — MOA

Relax smooth muscle in bladder neck + prostate → ↑ urinary flow rate

Alpha-1 blockers — advantages

Improves AUA-SI 30–40% in 60–70% of patients; initial therapy for most; equally effective

Alpha-1 blockers — disadvantages

Do NOT decrease prostate size; no effect on PSA levels

Non-selective alpha blockers — drugs

Terazosin (Hytrin), doxazosin (Cardura)

Non-selective alpha blockers — SE

Hypotension, dizziness, first dose syncope; start low and titrate; monitor BP

Selective alpha blockers — drugs

Tamsulosin (Flomax), silodosin (Rapaflo)

Selective alpha blockers — advantage

Selectively block α-1A receptors (~70% of prostate receptors); less dizziness + hypotension; low incidence of sexual SE

Alfuzosin (Uroxatral) — type

Functionally selective α1; concentrated in prostate; less dizziness + hypotension; lower incidence of sexual SE

5-alpha reductase inhibitors — MOA

↓ conversion of testosterone to DHT → reduces prostate size by ~25%

5-alpha reductase inhibitors — appropriate for

Prostate size ≥40gm OR PSA ≥1.5; can use +/- alpha blocker

5-alpha reductase inhibitors — sexual SE

↓ libido, ejaculatory dysfunction (3–15%), erectile dysfunction (3–5%)

5-alpha reductase inhibitors — PSA concern

Decrease PSA by 50% → get baseline PSA before starting; if not remembered → delay in prostate cancer diagnosis

5-alpha reductase inhibitors — time to effect

Takes 6–12 months for full effect; monitor/follow up in 3 months

Finasteride (Proscar) — details

5mg daily; Type II 5α-reductase inhibitor; suppresses DHT ~70%

Dutasteride (Avodart) — details

0.5mg daily; non-selective (Type I+II); suppresses DHT ~90%

ED — definition

Inability to achieve or maintain an erection to allow for satisfactory intercourse

ED — prevalence

20–30 million American men; 40–49 yrs ~12%; 50–59 yrs ~26%; 60–69 yrs ~46%

ED — classification

Psychogenic, drug-induced, organic (~80%)

ED — organic causes

Hormonal (hypogonadism, hyperprolactinemia), neurologic (stroke, peripheral neuropathy), vascular (atherosclerosis, HTN, diabetes)

ED — drug-induced causes

Anticholinergics, dopamine antagonists, antidepressants, BP meds

Physiology of erection

Parasympathetic stimulation → acetylcholine → nitric oxide → guanylate cyclase → ↑cGMP → relaxes cavernosal smooth muscle → blood flow → erection

PDE5 — role

Metabolizes cGMP; PDE5 is most abundant PDE enzyme in cavernosal tissue

PDE-5 inhibitors — MOA

Inhibit PDE5 → prevent metabolism of cGMP → ↑cGMP → initiate + maintain erection

PDE-5 inhibitors — all metabolized by

CYP3A4

PDE-5 inhibitors — effectiveness

Considered equally effective

PDE-5 inhibitors — adequate trial

7–8 doses; if one fails switch to another; assess correct use (timing, foreplay)

Avanafil (Stendra) — details

Onset 15–30 min; t½ ~5hrs; duration >6hrs; starting dose 100mg; take 15–30 min before; max 1 dose/24hrs

Sildenafil (Viagra) — details

Onset ~1hr; t½ ~4hrs; duration ~4hrs; starting dose 50mg (25mg if >65); take 60 min before; max 1 dose/24hrs

Vardenafil (Levitra) — details

Onset ~1hr; t½ ~4hrs; duration ~4hrs; starting dose 10mg (5mg if >65); take 60 min before; max 1 dose/24hrs

Tadalafil (Cialis) — details

Onset ~2hrs; t½ ~18hrs; duration 24–36hrs; starting dose 10mg; take 30 min before; max 1 dose/24hrs; daily dosing 2.5mg FDA approved

Tadalafil — unique advantage

Only PDE-5 inhibitor FDA approved for once daily dosing; also approved for BPH with accompanying ED

PDE-5 inhibitors — ADRs

Headache, flushing, nasal congestion, heartburn, cyanopsia (blue vision from PDE-6 inhibition), ↓BP ~10/5 mmHg

PDE-5 inhibitors — contraindication

Organic nitrates (nitroglycerin, isosorbide dinitrate) → severe hypotension

PDE-5 inhibitors — alpha blocker precaution

Additive hypotension; OK if patient on stable alpha blocker dose + stable BP; start PDE-5i at lowest dose

Priapism — definition + management

Erection lasting >4hrs; medical emergency; immediate attention required; risk of permanent erectile dysfunction

Alprostadil (prostaglandin E1) — MOA

Stimulates adenyl cyclase → ↑cGMP → relaxes smooth muscle → ↑blood flow → erection

Alprostadil — effectiveness

Intracavernosal injection (Caverject); 70–90% effectiveness

VED (vacuum erection device) — details

Negative vacuum pump creates erection; band placed at base to maintain; satisfaction rate 60–80%

Penile prostheses — details

Surgically inserted; 2 styles: bendable rods or saline pump; >90% satisfaction; lasts ~7–10 years; risk of infection + device failure

Non-PDE5 ED treatments — list

Alprostadil (intracavernosal injection), VED (vacuum erection device), penile prostheses