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Female Sex Hormones: Comprehensive Notes

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1. Natural and Synthetic Preparations of Estrogen

Natural Estrogens

Synthetic Estrogens

Advantages of Synthetic Preparations

1. Oral bioavailability: Natural estrogens (especially estradiol) undergo extensive first-pass hepatic metabolism; synthetic modifications (e.g., ethinyl group in EE) block this degradation, making them effective orally.
2. Greater potency: EE is ~100x more potent than conjugated estrogens on a weight basis.
3. Longer duration of action: Structural modifications reduce hepatic metabolism and prolong half-life.
4. Predictable pharmacokinetics: Consistent absorption, especially from oral route.
5. Tissue/receptor selectivity (newer agents): Allows targeting specific estrogen receptors without systemic effects.
6. Ease of formulation: Stable in tablets, unlike natural hormones which require micronization.
7. Cost: Chemically synthesized preparations are cheaper than extracting conjugated estrogens from animal sources.

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2. Adverse Effects of Estrogenic Preparations

Dose-Dependent Effects

• Nausea, vomiting: Most common; due to direct gastric stimulation; minimized with low-dose preparations
• Breast tenderness and enlargement (mastodynia)
• Fluid retention / edema: Na+ and water retention via mineralocorticoid-like action
• Weight gain
• Headache, including migraine exacerbation
• Breakthrough bleeding / irregular vaginal bleeding

Metabolic and Cardiovascular

• Thromboembolic events: Increased synthesis of clotting factors II, VII, IX, X, XII; increased DVT, PE, and stroke risk - especially with synthetic oral estrogens (EE > transdermal)
• Hypertension: Estrogens increase angiotensinogen production; more prominent with high-dose preparations
• Hyperlipidemia: Increase triglycerides; however, they increase HDL and decrease LDL (net cardiovascular effect complex)
• Gallstones: Increased biliary cholesterol secretion; increased risk of cholelithiasis
• Glucose intolerance: Especially with high-dose synthetic estrogens

Endocrine and Reproductive

• Endometrial hyperplasia and carcinoma: Unopposed estrogen (without progestin) in women with uterus - dose and duration dependent
• Breast cancer: Long-term combined HRT slightly increases risk; pure estrogen therapy in hysterectomized women may be neutral
• Cervical ectopy
• Infertility: Suppression of gonadotropins inhibits ovulation

Other Effects

• Hyperpigmentation (chloasma/melasma): Especially on face during pregnancy or OCP use
• Libido changes
• Hepatic effects: Cholestatic jaundice; increased hepatic protein synthesis (SHBG, clotting factors, angiotensinogen)
• Teratogenicity: DES caused vaginal adenocarcinoma in daughters; ethinylestradiol is contraindicated in pregnancy
• Suppression of lactation at high doses
• Worsening of endometriosis / uterine fibroids
• Contact lens intolerance (corneal curvature change due to fluid retention)

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3. Classification of Progestin Preparations

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A. C21 Steroids (Progesterone Derivatives)

1. Progesterone itself

• Micronized progesterone (Prometrium, Utrogestan): Oral bioavailability improved by micronization; also available as vaginal pessary
• Progesterone injection: Oily solution

2. 17α-Hydroxyprogesterone Derivatives (17-OHP derivatives)

3. Spironolactone Derivatives (C21)

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B. C19 Steroids (Testosterone Derivatives / 19-Nortestosterone Derivatives)

First Generation (Estranes)

Second Generation (Gonanes) - see dedicated section below

Third Generation (Gonanes - reduced androgenic activity)

Fourth Generation (Novel)

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4. Mifepristone as a "Once-a-Month Contraceptive"

Background

Mechanism as Once-a-Month Contraceptive

1. Taken once monthly (at the time of expected menstruation or just before) at a low dose (50-200 mg)
2. Antiprogesterone action: Blocks PR in the endometrium, preventing the secretary transformation necessary for implantation. Even if fertilization has occurred, the endometrium becomes unfavorable for blastocyst implantation.
3. Anti-implantation effect: Progesterone is essential for maintaining the endometrial decidua and promoting implantation. Mifepristone-induced PR blockade causes endometrial shedding.
4. Luteolytic effect: May also cause premature luteolysis, declining progesterone, and menstrual-like bleeding.
5. Effect on cervical mucus: Alters cervical mucus to impede sperm transport.
6. Anti-ovulatory effect at higher doses: Can also delay or inhibit ovulation when taken in the follicular phase.

Why "Once-a-Month"?

• Single administration at the end of the luteal phase (Day 25-28) is sufficient to prevent pregnancy for that entire cycle
• Does not require daily administration like conventional OCPs
• Induces menstruation regardless of whether pregnancy has occurred
• Clinical trials (Bygdeman, 1994; Webb 1992) showed a single monthly dose of 200 mg taken late in the luteal phase is effective

Advantages

• High compliance (single dose)
• Does not suppress the pituitary-ovarian axis persistently
• Avoids daily pill burden

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5. Mifepristone as a "Multipurpose Contragestational Agent"

A. Contraceptive Actions (Pre-fertilization / Pre-implantation)

1. Anti-ovulatory: At doses of 2-5 mg/day, delays or inhibits ovulation by suppressing LH surge
2. Cervical mucus alteration: Increases viscosity, impeding sperm penetration
3. Endometrial modification: Makes endometrium unfavorable for implantation even before fertilization

B. Interceptive Action (Post-fertilization, Pre-implantation)

1. Anti-implantation: Single post-coital dose (10-50 mg) within 72 hours prevents implantation by blocking endometrial progesterone receptors (morning-after use)

C. Abortifacient Action (Post-implantation)

1. Medical abortion: 200-600 mg mifepristone + misoprostol (prostaglandin E1 analogue) causes:
   • Decidual breakdown (anti-PR)
   • Uterine contractions (sensitizes uterus to prostaglandins by blocking PR)
   • Cervical softening
   • Effective up to 63 days gestation; success rate >95% with misoprostol

D. Cervical Ripening (Pre-operative)

1. Cervical dilatation: Used pre-operatively before surgical abortion or induction of labor (sensitizes uterus to prostaglandins)

E. Anti-glucocorticoid Actions (Non-contraceptive Uses)

1. Cushing's syndrome: 300-1200 mg/day; used for hyperglycemia associated with hypercortisolism when surgery is not possible (approved by FDA as Korlym)
2. Uterine fibroids and endometriosis: Reduces fibroid size; anti-estrogenic indirect effect
3. Breast cancer: Anti-PR action investigated in hormone-receptor positive breast cancer
4. Meningioma: PR-positive meningiomas may respond

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6. SERMs and SERDs - Definitions, Examples, and Indications

SERM - Selective Estrogen Receptor Modulators

Examples and Indications:

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SERD - Selective Estrogen Receptor Degraders (also: Downregulators)

Examples and Indications:

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7. Action and Indications of Individual Agents

a. Clomiphene Citrate

• Binds to hypothalamic ERs and blocks estrogen negative feedback
• The hypothalamus "perceives" low estrogen and increases GnRH pulse frequency
• Increased GnRH stimulates pituitary FSH and LH release
• Elevated FSH recruits ovarian follicle development and ovulation
• Also has direct weak estrogenic and anti-estrogenic effects at peripheral tissues

1. Anovulatory infertility (especially PCOS) - first-line agent; dose 50-150 mg/day for 5 days (Day 2-6 of cycle)
2. Hypogonadotropic hypogonadism (select cases)
3. Oligospermia in men: Off-label; increases LH/FSH to boost testosterone and spermatogenesis
4. Luteal phase defect
5. Diagnosing hypothalamic-pituitary competence

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b. Tamoxifen

• Competitive antagonist at ER-alpha in breast tissue
• Recruits corepressors (NCoR, SMRT) instead of coactivators - blocks transcription of estrogen-responsive genes
• Agonist at ER in uterus and bone (via ER-beta and different coactivator profiles)

1. ER+/PR+ breast cancer: Adjuvant treatment in pre- and postmenopausal women (5-10 years; reduces recurrence by ~50% and mortality by ~30%)
2. Metastatic ER+ breast cancer: First-line hormonal therapy
3. Breast cancer chemoprevention: High-risk women (BRCA1/2 carriers, atypical hyperplasia)
4. Ductal carcinoma in situ (DCIS)
5. Male breast cancer
6. McCune-Albright syndrome (off-label)
7. Gynecomastia (off-label)

• Endometrial cancer (due to uterine agonist activity - 2-3x increased risk with long-term use)
• Thromboembolic events (DVT, PE)
• Hot flushes, vaginal discharge, menstrual irregularities
• Cataracts (long-term use)
• BRCA-related: Liver toxicity with high-dose

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c. Raloxifene

• Antagonist at ER-alpha in breast and uterus (recruits corepressors)
• Agonist at ER in bone (maintains BMD) and liver (beneficial lipid effects - decreases LDL without increasing TG as much as estrogen)
• Does NOT stimulate endometrial proliferation (no uterine agonism) - key advantage over tamoxifen

1. Osteoporosis prevention and treatment in postmenopausal women (increases BMD; reduces vertebral fracture risk by 30-50%)
2. Breast cancer risk reduction in postmenopausal women at high risk (non-inferior to tamoxifen in STAR trial, with better uterine safety profile)
3. Cardiovascular risk reduction in postmenopausal women with osteoporosis (reduces LDL)

• Worsening of vasomotor symptoms (hot flushes) - does NOT relieve hot flushes unlike estrogen
• DVT/PE (risk comparable to tamoxifen)
• Leg cramps
• Does NOT cause endometrial cancer (unlike tamoxifen)

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d. Ormeloxifene (Centchroman)

1. Inhibits implantation: Desynchronizes the endometrium from the ovarian cycle; the blastocyst arrives at a hostile endometrium
2. Anti-proliferative on endometrium: Opposes estrogen-induced endometrial proliferation
3. Anti-estrogenic in uterus: Accelerates uterine motility, moving the blastocyst faster than normal through the tube
4. Cervical mucus changes: Inhibits sperm transport
5. Does NOT inhibit ovulation: Cycles remain ovulatory
6. Agonist on bone: Maintains bone density

1. Oral contraception (Saheli, Centron): 30 mg twice weekly for first 3 months, then once weekly; no estrogen = no estrogen-related side effects; approved in India
2. Dysfunctional uterine bleeding (DUB): 60 mg twice weekly used as medical management of menorrhagia/DUB
3. Endometrial hyperplasia
4. Fibrocystic disease of breast (experimental)

• No estrogen component (safer in women intolerant of estrogen)
• Once-weekly dosing (high compliance)
• Does not suppress ovulation (menstrual cycle preserved)
• Does not affect lactation
• Relatively low incidence of side effects

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8. Mechanism of Action and Uses of Mifepristone

Chemical Structure

Mechanism of Action

• Binds progesterone receptor (PR-A and PR-B) with 3-4x higher affinity than progesterone
• Acts as competitive antagonist: occupies PR without activating it
• Recruits corepressors (NCoR, SMRT) to the PR-DNA complex, preventing transcriptional activation
• Causes endometrial shedding, cervical ripening, and sensitization of myometrium to prostaglandins
• In pregnancy: decidual degeneration, trophoblast cell death, increased prostaglandin sensitivity leading to uterine contractions

• Binds glucocorticoid receptor (GR) with high affinity (2-3x that of dexamethasone)
• Pure antagonist at GR - blocks ACTH-driven cortisol effects
• Used in Cushing's syndrome to block cortisol end-organ effects

Pharmacokinetics

• Oral bioavailability ~70%; peak plasma 1-2 hours
• Highly protein bound (albumin + alpha-1 acid glycoprotein)
• Extensively metabolized by CYP3A4; three active metabolites
• t½ = 18-20 hours (long-acting)

Uses / Indications

1. Medical termination of pregnancy (MTP): 200 mg mifepristone + misoprostol 400-800 mcg (24-48 hrs later); up to 63 days gestation; WHO essential medicine
2. Cervical priming before surgical abortion or labor induction
3. Emergency contraception: Single 10 mg dose within 120 hours; effective and well-tolerated
4. Cushing's syndrome (FDA-approved as Korlym): 300-1200 mg/day for hyperglycemia associated with hypercortisolism when surgery not possible
5. Uterine leiomyomas (fibroids): Long-term low-dose (5-25 mg/day) reduces fibroid volume and symptoms
6. Endometriosis: Anti-progestational + weak anti-estrogenic (suppresses local estrogen production) effects reduce lesion activity
7. Unresectable meningioma: PR-positive meningiomas (weak evidence)
8. Breast cancer: Adjunct in PR+ breast cancer (experimental)
9. Labor induction in intrauterine fetal death
10. Once-a-month contraceptive: 200 mg at luteal phase end (experimental)

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9. Classification of Aromatase Inhibitors (AIs)

What is Aromatase?

Classification

Type I: Steroidal (Irreversible) - "Aromatase Inactivators"

• Also called Type I inhibitors or mechanism-based inhibitors
• Bind to the active site of aromatase covalently; permanently inactivate the enzyme
• Recovery requires new enzyme synthesis

Type II: Non-Steroidal (Reversible) - "Aromatase Inhibitors"

• Bind to the heme iron of CYP19 via a nitrogen atom (imidazole or triazole)
• Reversible, competitive inhibition
• No structural similarity to androgens; no androgenic side effects
• Further divided by generation:

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Indications of Aromatase Inhibitors

1. Postmenopausal ER+ breast cancer:
   • Adjuvant treatment (preferred over tamoxifen in postmenopausal women in many guidelines)
   • Neoadjuvant treatment to downsize tumor before surgery
   • Metastatic breast cancer
   • Switch strategy: Tamoxifen 2-3 years then AI for remaining 2-3 years
   • Extended adjuvant: Letrozole after 5 years of tamoxifen
2. Ovulation induction: Letrozole (2.5-7.5 mg, Day 3-7) now considered first-line for PCOS-related infertility (superior to clomiphene in PCOS; NEJM 2014 Legro et al.)
3. Endometriosis: Off-label; reduces local estrogen production in lesions
4. Uterine fibroids: Off-label
5. Gynecomastia: Short-term
6. McCune-Albright syndrome in girls with precocious puberty
7. Male hypogonadotropic hypogonadism with high estrogen:testosterone ratio

Adverse Effects of Aromatase Inhibitors

• Arthralgia and myalgia (20-50% of patients; "AI-associated musculoskeletal syndrome")
• Bone loss / osteoporosis (estrogen deprivation removes bone protection; DEXA monitoring required; bisphosphonates indicated)
• Fractures

• Worsening lipid profile (anastrozole and letrozole increase total cholesterol and LDL; exemestane may be more favorable)
• Increased cardiovascular risk (debated)
• Hypertension

• Hot flushes, night sweats (estrogen deprivation)
• Vaginal dryness, dyspareunia (genitourinary syndrome)

• Headache
• Cognitive complaints, "chemo brain" (debated)
• Depression, fatigue

• Carpal tunnel syndrome
• Nausea (less than tamoxifen)
• Alopecia
• In premenopausal women used without ovarian suppression: AIs stimulate gonadotropin rise and are ineffective/potentially harmful (not used alone in premenopausal women without GnRH agonist co-treatment)

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10. Role and Limitations of HRT in Menopausal Women

Background

Role / Benefits of HRT

• Hot flushes and night sweats: Estrogen is the most effective treatment; reduces frequency and severity by 75-90%
• Improves sleep quality
• Most effective for this indication; no other treatment comes close

• Vaginal dryness, dyspareunia, urinary urgency
• Local (vaginal) estrogen highly effective with minimal systemic absorption
• Systemic HRT also helps

• Estrogen prevents postmenopausal bone loss; reduces osteoporotic fracture risk by ~30-35%
• However, no longer first-line for osteoporosis prevention given risks (bisphosphonates preferred); used when HRT is already prescribed for vasomotor symptoms

• Perimenopausal depression responds to estrogen
• "Window of opportunity" hypothesis: HRT initiated early in menopause may reduce Alzheimer's disease risk; late initiation may worsen it

• The "timing hypothesis" (Manson, Rossouw): HRT initiated within 10 years of menopause or before age 60 may be cardioprotective; initiated later increases risk
• WHI study (initiated late, average age 63): Increased MI, stroke, DVT/PE, breast cancer

• Decreased joint pain and myalgias
• Improved skin collagen content
• Reduced colorectal cancer risk (combined HRT; CEE+MPA in WHI)
• Relief of psychological symptoms (irritability, poor concentration)

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Limitations and Risks of HRT

• Combined estrogen-progestin HRT: Increased risk after 3-5 years use (~24% increase in WHI; attributable risk ~8 extra cases per 10,000 person-years)
• Estrogen alone: Possibly no increase or slight reduction (WHI estrogen-only arm showed possible breast cancer risk reduction in some analyses)
• Risk returns to baseline within 2-5 years after stopping

• WHI showed increased MI risk with combined CEE+MPA, especially in older women or those with existing cardiovascular disease
• Thromboembolism: DVT/PE risk doubled (most pronounced in first year; oral EE >> transdermal estrogen)
• Stroke: Increased with oral combined HRT

• Unopposed estrogen causes endometrial hyperplasia/cancer (5-10x risk increase)
• Completely prevented by adequate progestogen addition
• Only applicable to women with intact uterus

• 1.5-2x increase in gallstones and cholecystitis (increased biliary cholesterol secretion)

• Absolute contraindications: Active/prior breast cancer, active coronary artery disease, unexplained vaginal bleeding, active liver disease, prior DVT/PE, pregnancy, estrogen-dependent tumors (endometrial carcinoma)
• Duration: Most guidelines recommend using lowest effective dose for shortest duration; reassess annually
• Contraindications limit use in many high-risk women
• Variable response and tolerability
• Progestogen side effects (PMS-like: bloating, mood changes, irregular bleeding) reduce adherence

• HRT is appropriate for symptomatic women under 60 or within 10 years of menopause (benefit-risk generally favorable)
• For women over 60 or >10 years post-menopause, risks generally outweigh benefits unless symptom burden is high
• Transdermal estrogen has lower thrombotic risk than oral
• Micronized progesterone preferred over synthetic progestins (lower breast cancer and cardiovascular risk)

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11. Non-Hormonal Agents for Menopausal Symptoms (with Pharmacological Basis)

A. For Vasomotor Symptoms (Hot Flushes and Night Sweats)

B. For Genitourinary Symptoms

C. For Bone Loss

D. For Mood and Cognitive Symptoms

E. Phytoestrogens (Controversial)

• Isoflavones (genistein, daidzein from soy; biochanin A from red clover): Bind ER with weak estrogenic activity; modest reduction in flush frequency; safety in breast cancer survivors debated
• Black cohosh (Cimicifuga racemosa): Mechanism unclear (possibly serotonergic; NOT estrogenic); some evidence for vasomotor symptoms; hepatotoxicity risk

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12. Gonanes: Examples, Structural Peculiarity, Pharmacological Actions, and Indications

Definition

Structural Peculiarity

1. C13 ethyl group: Gonanes uniquely have an ethyl group at C13 (instead of the methyl group found in estranes). This single structural modification accounts for their increased potency and altered pharmacology.
2. No C19 methyl group: Like all 19-nortestosteroids, they lack the C19 angular methyl group (hence "nor")
3. 17α-ethinyl group: Present in most gonanes to prevent first-pass metabolism and ensure oral activity
4. Active isomer: Levonorgestrel is the active L-isomer; the D-isomer (dextronorgestrel) is pharmacologically inactive

• Estrane backbone: C13-methyl; C18 total carbons
• Gonane backbone: C13-ethyl; C18 + extra ethyl = effectively C19 carbon framework

Examples

• Levonorgestrel (LNG): The prototype; most extensively studied progestin
• Norgestrel (racemic; L-isomer = LNG)
• D,L-Norgestrel

• Desogestrel: 11-methylene group; prodrug converted to etonogestrel (active) by 3-keto and delta-4 reductase
• Gestodene: Most potent progestin available; direct oral activity; 11-methylene group; slight mineralocorticoid activity
• Norgestimate: 3-oxime and 17-acetate groups; prodrug converted to levonorgestrel and norgestrel; minimal androgenicity

Pharmacological Actions

• Transform proliferative endometrium to secretory phase
• Oppose estrogen-induced endometrial proliferation (prevent hyperplasia)
• Increase basal body temperature (thermogenic)
• Make cervical mucus hostile to sperm (thick, scanty, cellular)
• Suppress LH surge (anti-ovulatory at contraceptive doses)
• Promote implantation-ready endometrium at lower doses
• Inhibit myometrial contractility (uterine quiescence)

• Second-generation gonanes (LNG): Significant androgenic activity; may cause acne, seborrhea, hirsutism, adverse effects on HDL lipids
• Third-generation (desogestrel, gestodene, norgestimate): Markedly reduced androgenicity (~60-70% less than LNG); better lipid profiles; preferred in women with acne/hirsutism

• Down-regulate endometrial estrogen receptors
• Oppose estrogenic effects on endometrium and breast

Indications

1. Oral contraceptive pills (OCP): Combined (with EE) as low-dose 20-35 mcg EE pills; widely used globally
   • LNG: 150 mcg/day in 30 mcg EE pill
   • Desogestrel: 150 mcg + EE 20-30 mcg (Marvelon, Mercilon)
   • Gestodene: 75 mcg + EE 20-30 mcg (Femodene)
2. Progestin-only pill (POP): Desogestrel 75 mcg/day (Cerazette); does inhibit ovulation (unlike norethindrone POP); suitable for lactating women
3. Emergency contraception (EC):
   • Levonorgestrel 1.5 mg single dose within 72 hours (Plan B, I-Pill); can be used up to 120 hours
   • Mechanism: Primarily delays/inhibits ovulation; does NOT act post-fertilization when used before LH surge
4. LNG-Intrauterine System (LNG-IUS; Mirena, Kyleena):
   • 52 mg LNG releasing 20 mcg/day; effective 5-8 years
   • Reduces menstrual blood loss by 90%; treats heavy menstrual bleeding, endometriosis, fibroids
   • Used in HRT as endometrial protection (progestogen component)
5. Subdermal implant: Etonogestrel (Implanon/Nexplanon); 68 mg; 3-year contraception; inhibits ovulation
6. Injectable contraception: Norethindrone enanthate (NET-EN) - closely related
7. Endometriosis: LNG-IUS reduces endometriotic pain and lesion activity
8. Menorrhagia/DUB: LNG-IUS is highly effective
9. Endometrial protection in HRT: LNG-IUS preferred over oral progestins in some regimens

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13. Indications for Estrogen and Progestin Preparations

a) Indications for Estrogen Preparations

1. Primary hypogonadism (Turner syndrome, gonadal dysgenesis)
2. Secondary hypogonadism (Kallmann syndrome, hypopituitarism)
3. Premature ovarian insufficiency (POI) / premature menopause
4. Castration (surgical or radiation-induced)

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b) Indications for Progestin Preparations

1. Combined OCP (with estrogen)
2. Progestin-only pill (mini-pill; norethindrone, desogestrel)
3. Emergency contraception (LNG 1.5 mg)
4. Long-acting reversible contraception: Injectable (Depo-Provera/MPA 150 mg IM 3-monthly), implant (etonogestrel), IUS (LNG-IUS/Mirena)
5. Post-coital contraception

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