lecture 7: androgens and tx of impotence

5 alpha reductase

testosterone is converted to DHT via what enzyme?

aromatase

testosterone is converted to estradiol via what enzyme?

-puberty related changes in males

-increase muscle mass/strength

effects of androgens

a)Hypogonadism (e.g., due to advanced age)

b)Hypopituitarism prior to adolescence

indications for androgen replacement therapy

-reduce postpartum breast engorgement

-endometriosis

-post menopausal

-breast tumor chemo

off label uses of androgen therapy (gynecologic disorers)

danazol: weak androgen with anti-estrogen activity

androgen therapy to treat endometriosis

•Methyltestosterone

•Fluoxymesterone

name the oral preparations of testosterone

•Testosterone enanthate

•Testosterone cypionate

parenteral preparations of testosterone (preferred form for replacement)

testosterone

topical preparation of testosterone

Testosterone undecanoate

tesosterone formulation associated with liver tumors (not recommended)

oIneffective androgen effects

oNegative lipid effects

oHigh risk of hepatic adverse effects

disadvantages of oral testosterone therapy

-higher CV risk than topical

o"Roller-coaster" pharmacokinetics

oFluctuations in mood, libido

oSite reactions

oPulmonary oil microembolism reaction (undecanoate)

oHigher CV risk than topical products

disadvantages of parenteral testosterone

breast or prostate cancer

-BPH

-pregnancy

contraindications to testosterone replacement therapy

•BP increases with oral testosterone undecanoate and subcutaneous testosterone enanthate

BBW of testosterone

testosterone replacement can cause fluid retention; avoid inn poorly controlled HF

relationship of testosterone replacement and heart failure

-sodium retention

-hepatotoxicity (oral), polycythemia (parenteral)

adverse effects of testosterone replacement

Paclitaxel

don't take _____ with testosterone replacement, bc testosterone inhibits CYP2C8

-GnRH agonists

-GnRH antagonists

-steroid synthesis inhibitors

-receptor inhibitors

pharm options for androgen suppressionn

relugolix

first oral hormone GnRH anatgonist used in pts for treatment of advanced prostate cancer

-dopamine is proerectogenic

-a2 adrenergic stimulation causes penis to remain flaccid

hypothalamic influence on erection

S2-S4 (parasympathetic and somatic)

nerve roots of proerectogenic neuros

•Prolongation or sustainment of erection occurs by venous outflow occlusion from the corpora

•Compressed subtunical venules against the tunica albuginea by the swollen corpora

how does the penis maintain an erection?

phosphodiesterase 5 in cavernosal tissue

cGMP is metabolized by

enhances the activity of adenyl cyclase, decreasing intracelllular calcium to enable erection

effect of prostaglandin E on erection

•Peripheral vascular disease, arteriosclerosis, HTN, smoking

vascular causes of erectile dysfunction

neurologic

diabetes mellitus is a ______ cause of ED

Smoking

Diabetes

Hypertension

Obesity

most common preventable risk factors of ED

-antiandrogens

-5 alpha reductase inhibitors

-antihypertensives

-anti-arrhythmics

-recreational drugs

-psychotropics

medications contributing to erectile dysfunction

phosphodiesterase 5 inhibitors

first line ED therapy in most men

alprostadil-intracavernous injection

-vacuum erection device, penile implant

if PDE5 inhibitors can't be used, consider

-ED and coronary artery disease frequently coexist

-treatment increases risk of MI during sex

why must you do a CV risk assessment before treating ED?

testosterone replacement

tx for ED secondary to hypogonadism

PDE 5 inhibitors

indications:

•Erectile dysfunction, pulmonary arterial hypertension

•Off label: Raynaud phenomenon

7 to 8 doses; titrate to max dose

what is an adequate trial of PDE 5 inhibitor?

•Competitive reversible inhibitors of phosphodiesterase isoenzyme type 5 (PDE-5)

- Decreases degradation of cGMP to enhance smooth muscle relaxation and inflow of blood into corpus cavernosum

MOA of PDE 5 inhhibitors

the --afils

name the PDE-5 inhibitors

fatty meals

absorption of PDE-5 inhibitors is impaired by

tadalafil (24-36 hours)

longest lasting PDE-5 inhibitors

hypotension

adverse effects of slidenafil and vardenafil

•Prostaglandin E1

•Stimulates adenyl cyclase to increase cAMP, which ↓ intracellular calcium concentration and causes smooth muscle relaxation

MOA of alprostadil

intracavernosal injection, or intraurethral pellets

administration of alprostadil

onset within 5-15 min, duration up to 1 hour

onset and duration of intracavernosal injection

onset 5-10 min; duration 30-60 min

onset and duration of intraurethrall injectionnn

-local anesthesia

-aspiration if not due to injection

-sympathomimetic agent if due to injection

management of ischemic priapism

•Patients with contraindications or lack of response to PDE-5 inhibitors, or patient preference

•Combination therapy

indication of vacuum erection device

primary hypogonadism

testicular failure

secondary hypogonadism

hypothalamic or pit. dysfunction

decreased libido, erectile dysfunction, and loss of spontaneous morning erections

3 cardinal symptoms of hypogonadism

•Serum testosterone <230 ng/dL (<8 nmol/L)

•Serum testosterone between 230-350 ng/dL (8.0-12.2 nmol/L) + symptoms

criteria for testosterone replacement

yohimbine

central alpha 2 adrenergic atagonist to treat ED

-increase catecholamines and improves mood

papaverine

•Nonspecific PDE5 inhibitor; used as a vasodilator for arterial vasospasm to treat ED

•Intracavernosal injection

phenotolamine

•Competitive nonselective α-adrenergic blocking agent; used for extravasation of vasopressors and for settings of catecholamine excess

•Intracavernosal injection