Female and Male Reproductive Pharmacology

Estrogen

Produced in ovaries & adrenal glands; drives female reproductive development & secondary sex characteristics

Progesterone

Produced in ovaries, adrenals & placenta; prepares uterus for implantation

Estradiol (E2)

Most potent estrogen; premenopausal women; made in ovaries

Estrone (E1)

3x less potent than E2; postmenopausal women; stored as estrone sulfate

Estriol (E3)

80x less potent than E2; made by placenta during pregnancy

Follicular Phase

↑LH & FSH → follicle development + ovulation; estrogen rebuilds endometrium

Luteal Phase

Corpus luteum → ↑progesterone & estrogen; endometrium preps for implantation

No Implantation

Corpus luteum → corpus albicans → ↓hormones → menstruation

Implantation

hCG maintains corpus luteum → placenta takes over progesterone production

Estrogen + uterus

Rebuilds endometrium (proliferation & differentiation)

Estrogen + fallopian tube

↑ muscle contractility → affects ovum transit time

Estrogen + cervical mucus

↑ amount & water content → helps sperm penetrate cervix

Progesterone + endometrium

↓ proliferation; ↑ secretion → implantation prep

Progesterone + menstruation

↓ progesterone → ↓ GnRH pulses → menstruation begins

Progesterone + mammary glands

Develops & proliferates acini

Progesterone + CNS

↑ body temperature at ovulation

ERα

Female repro tract, mammary gland, hypothalamus, endothelial cells → genomic

ERβ

Prostate, ovaries, lung, brain, bone → genomic

GPER (GP30)

Membrane receptor → rapid non-genomic effects

PR-A

Truncated; mediates inhibitory effects; recruits co-repressors

PR-B

Full-length; mediates excitatory effects; recruits co-activators

Progesterone membrane receptor

GPCR → non-genomic, fast effects

Estrogen effect on PR

Upregulates PR → ↑ progestin effects

Progestin effect on ER

Downregulates ER → ↓ estrogen effects

Estrogen ADME: Administration

Oral

Estrogen ADME: Absorption

Rapid; significant first-pass metabolism

Estrogen ADME: Protein binding

SHBG (~60%), albumin (~38%); only 2-3% free/active

Estrogen ADME: Metabolism

Hepatic CYP enzymes; converted to estrone

Estrogen ADME: Excretion

Urine (sulfate & glucuronide metabolites)

Progesterone ADME: Administration

Oral (micronized = better bioavailability)

Progesterone ADME: Protein binding

Albumin (50-54%), transcortin (43-48%)

Progesterone ADME: Metabolism

Hepatic CYP450; t½ = 5 min

Progesterone ADME: Excretion

Urine (sulfate & glucuronide metabolites)

COC MOA

↓LH/FSH → no ovulation; thins endometrium; ↑ cervical mucus viscosity

POP MOA

↓LH → suppresses ovulation; thickens cervical mucus; thins endometrium

COC

Ethinylestradiol + progestin (e.g. norethindrone, levonorgestrel, drospirenone)

POP (mini-pill)

Progestin only; norethindrone

Monophasic

Same E/P dose 21 days + 7 days placebo

Triphasic/Quadriphasic

Doses change to mimic natural cycle

Extended cycle

84 days active + 7 days placebo → period every 3 months

Continuous cycle

Active pills only, 1 year → no period

COC common SE

Sore breasts, nausea, headache, hypertension

COC serious SE

MI, stroke, DVT, pulmonary embolism (rare)

COC boxed warning

No use in women >35 who smoke; avoid with DVT/PE, stroke, CAD, hormone-sensitive cancer history

POP SE

Breakthrough bleeding, amenorrhea (after 1+ yr), acne

DDIs that ↓ contraceptive efficacy

Rifampin, carbamazepine, phenytoin, barbiturates, St. John's wort, tobacco, colesevelam

1st gen progestins

Norethindrone acetate, ethynodiol diacetate; moderate estrogen & androgen activity

2nd gen progestins

Levonorgestrel, norgestrel; strongest progestin & androgen activity

3rd gen progestins

Desogestrel, gestodene, norgestimate; fewer androgenic effects than 2nd gen

4th gen progestins

Drospirenone, dienogest; antiandrogen; drospirenone from spironolactone

Mifepristone (RU-486)

PR antagonist; detaches blastocyst + ripens cervix; + misoprostol 48h later = 90% effective termination

Ulipristal (Ella)

PR modulator; emergency contraception; delays ovulation up to 5 days; better than Plan-B

Mifepristone high dose

Also blocks glucocorticoid receptor (↓ cortisol effect)

Testosterone

Main male androgen; produced by Leydig cells in testes

DHT (dihydrotestosterone)

Active metabolite of testosterone; made by 5α-reductase; drives prostate & external genitalia development

Estradiol (male)

Made from testosterone via aromatase (CYP19); 85% of circulating estradiol in men

Testes

Produce sperm & secrete androgens

Leydig cells

Located between seminiferous tubules; secrete testosterone

Sertoli cells

Supporting cells; secrete inhibin & ABP; form blood-testes barrier

Spermatogenesis

Spermatogonia → spermatocytes → spermatids → spermatozoa

GnRH (pulsatile)

Stimulates LH & FSH release from anterior pituitary

LH

Stimulates Leydig cells → ↑ testosterone

FSH + testosterone

Stimulate Sertoli cells → activate spermatogenesis

Inhibin

Secreted by Sertoli cells; regulates FSH & sperm production rate

Testosterone 1st trimester

Fetal testes secrete testosterone (stimulated by hCG) → male sexual differentiation

Testosterone childhood

Low levels

Testosterone puberty

Reaches adult levels; ↑ muscle, bone, hair, libido, erythropoiesis

Testosterone adulthood

Gradual decline with age

Testosterone senescence

↓ energy, libido, muscle mass, bone density; insulin resistance

5α-reductase

Converts testosterone → DHT (active)

Aromatase (CYP19)

Converts testosterone → estradiol (active)

Liver metabolism of testosterone

Converts to androsterone & etiocholanolone (inactive)

Testosterone direct (AR)

Internal genitalia, skeletal muscle, erythropoiesis, bone

DHT (via AR)

External genitalia, prostate, hair follicles

Estradiol from testosterone (via ER)

Bone density, libido

Why not oral testosterone?

Rapid first-pass hepatic metabolism → ineffective

Transdermal testosterone

Patch (Androderm), gel (Androgel), buccal tablet (Striant)

Testosterone esters (IM)

Enanthate, cypionate; t½ 4-5 days; hydrolyzed to free testosterone at injection site

Testosterone undecanoate

Oral (lymphatic absorption, bypasses liver); IM t½ = 20-30 days

17α-Alkylated androgens

Oral; alkyl group slows hepatic metabolism; less androgenic; some anabolic effects

Testosterone patch SE

Minimal unless levels exceed normal range

17α-Alkylated androgens SE

Hepatotoxicity, cholestasis, peliosis hepatis

General androgen SE

Acne, gynecomastia, aggression, prostatic hyperplasia

BPH

Prostate enlargement → compresses urethra → ↓ urine flow, ↑ urinary frequency

DHT role in BPH

DHT causes prostate to enlarge

BPH treatments

5α-reductase inhibitors + selective α1A antagonists

Finasteride (Proscar/Propecia)

Blocks testosterone → DHT; oral; t½ 5-6h; SE: impotence

Dutasteride (Avodart)

Same MOA as finasteride; oral; t½ 5 weeks

5α-reductase inhibitors effect

↓ DHT → ↓ prostatic volume → ↑ urine flow

α1A antagonists MOA

Relax smooth muscle in prostate & bladder neck → ↑ urine flow

Tamsulosin (Flomax)

Oral; onset 1-30 min; t½ 9-13h; SE: orthostatic hypotension

Silodosin (Raplafo)

Oral; onset 2-30 min; t½ 13h

α1A antagonists key point

Minimal effect on blood pressure (prostate-selective)

Vascular ED

Impaired blood delivery to penis

PDE5 inhibitors

Sildenafil, Tadalafil, Vardenafil, Avanafil

PDE5 inhibitor MOA

Block cGMP breakdown → ↑ cGMP → ↓ Ca²⁺ → smooth muscle relaxation → erection

Sildenafil (Viagra)

Onset 30-50 min; duration 4-5h; food affects absorption

Tadalafil (Cialis)

Onset 30-45 min; duration up to 36h (longest)

Vardenafil (Levitra)

Onset 30-60 min; duration 4-5h; food affects absorption

Avanafil (Stendra)

Onset 15-30 min (fastest); duration 6-12h