Contents

1. Introduction
2. Sex Steroid Hormones
   • Oestrogens
   • Progestogens
   • Androgens
3. Hormonal Contraception
   • The Combined Oral Contraceptive Pill
   • The Progestogen-Only Pill
   • Long-Acting Reversible Contraception
   • Emergency Contraception
4. Hormone Replacement Therapy
5. Selective Modulators
   • Tamoxifen and Raloxifene (SERMs)
   • Ulipristal and Mifepristone (SPRMs)
6. Hormonal Therapy in Cancer
   • Aromatase Inhibitors
   • GnRH Analogues and Antagonists
   • Anti-Androgens
7. Drugs in Obstetric Practice
8. Summary
9. Drug Summary Table
10. Quiz

Abstract

• The sex steroid hormones (oestrogens, progestogens, androgens) bind nuclear receptors and act through gene transcription. Drugs in this area are either analogues, antagonists, or selective modulators with tissue-specific agonist/antagonist action.
• The combined oral contraceptive pill (COCP) contains a synthetic oestrogen and a progestogen and acts mainly by suppressing ovulation. The progestogen-only pill (POP) works mainly by thickening cervical mucus.
• Hormone replacement therapy (HRT) relieves menopausal symptoms and prevents osteoporosis but increases the risk of breast cancer (combined preparations) and venous thromboembolism (oral preparations).
• Selective receptor modulators include tamoxifen (SERM: antagonist in breast, agonist in endometrium and bone) and ulipristal acetate (SPRM: emergency contraception, fibroids).

Core

Introduction

Drugs acting on the reproductive endocrine system are among the most heavily prescribed in the UK, both for women's health (contraception, HRT, cancer treatment) and men's health (prostate disease, hormone-sensitive cancer). This article covers the principal classes at pre-clinical level. The underlying physiology is set out in the SimpleMed Reproductive System articles.

Sex Steroid Hormones

The three main classes: oestrogens, progestogens and androgens: are synthesised from cholesterol via the steroid biosynthetic pathway and act predominantly on nuclear receptors. The receptor-hormone complex translocates to the nucleus and modulates gene transcription, so the effects develop over hours to days rather than seconds.

Oestrogens

Endogenous oestrogens are oestradiol (the most potent), oestrone and oestriol. Synthetic versions used in pharmacology include ethinylestradiol (in the COCP), oestradiol valerate, and conjugated equine oestrogens (in some HRT preparations).

Major actions: development of secondary sexual characteristics in puberty, regulation of the menstrual cycle, maintenance of bone density, and a number of metabolic and vascular effects. Drugs that exploit them include the COCP, HRT, and SERMs.

Progestogens

Endogenous progesterone is produced by the corpus luteum and the placenta. Synthetic progestogens used clinically include levonorgestrel (POP, emergency contraception, intrauterine systems), desogestrel (POP), norethisterone, drospirenone and medroxyprogesterone (depot injection, HRT).

Major actions: preparation of the endometrium for implantation, maintenance of pregnancy, and breast development. Synthetic progestogens differ in their androgenic, mineralocorticoid and glucocorticoid effects, which is why side-effect profiles vary across formulations.

Androgens

The principal androgen is testosterone, with the more potent metabolite dihydrotestosterone (DHT) formed by 5α-reductase. Therapeutic uses include hypogonadism replacement (testosterone preparations) and gender-affirming care.

Hormonal Contraception

The Combined Oral Contraceptive Pill

The combined oral contraceptive pill (COCP) contains an oestrogen (almost always ethinylestradiol) and a synthetic progestogen. Mechanisms:

• Suppression of ovulation: negative feedback on the hypothalamus and pituitary suppresses GnRH, FSH and LH.
• Thickening of cervical mucus.
• Thinning of the endometrium, reducing the chance of implantation.

The contraceptive efficacy with perfect use is very high (around 0.3% failure per year), but typical-use failure is around 9% per year because of missed pills.

Non-contraceptive benefits: the COCP also reduces the risk of ovarian, endometrial and colorectal cancer, regulates the menstrual cycle, and improves acne and dysmenorrhoea.

Side effects and risks:

• Venous thromboembolism (VTE): the absolute risk is low in healthy young women but rises substantially with smoking, age over 35, obesity and immobility. UK Medical Eligibility Criteria (UKMEC) categorise the COCP as contraindicated in many such patients.
• Stroke and MI: rare in healthy women, but increased by hypertension, smoking and migraine with aura.
• Breast cancer: small increased risk, falling after stopping.
• Cervical cancer: small increase with prolonged use.
• Hypertension, mood changes, breast tenderness, breakthrough bleeding.

Pharmacokinetic interaction: ethinylestradiol is metabolised by hepatic CYP enzymes. Enzyme-inducing drugs reduce contraceptive efficacy: the relevant interactions are with rifampicin and rifabutin, several antiepileptics (carbamazepine, phenytoin, phenobarbital, primidone, topiramate at higher doses), and St John's wort. Standard non-enzyme-inducing antibiotics no longer require additional contraceptive precautions in current MHRA/FSRH guidance, although they were historically thought to.

The Progestogen-Only Pill

The progestogen-only pill (POP) contains a single progestogen (commonly desogestrel or levonorgestrel). The desogestrel POP suppresses ovulation in most cycles; older POPs work mainly by thickening cervical mucus and require strict timing.

The POP is used when the COCP is contraindicated: smokers over 35, women with a history of VTE, breastfeeding mothers, and patients with hypertension, migraine with aura or significant cardiovascular risk.

Long-Acting Reversible Contraception

Long-acting reversible contraception (LARC) methods have failure rates an order of magnitude lower than the COCP and are increasingly the preferred first-line in UK practice:

• Progestogen-only injection (depot medroxyprogesterone acetate, "Depo"): every 12-13 weeks. Concerns about bone mineral density limit prolonged use in adolescents.
• Progestogen-only implant (etonogestrel, Nexplanon): subcutaneous, lasts 3 years. Most effective reversible contraception (failure < 0.05% per year).
• Levonorgestrel intrauterine system (LNG-IUS, Mirena): lasts up to 8 years (newer indications); also used for menorrhagia and as the progestogen component of HRT.
• Copper IUD: non-hormonal; primary action is prevention of fertilisation by copper toxicity to sperm; can be used as emergency contraception.

Emergency Contraception

Three options are available in the UK:

• Levonorgestrel 1.5 mg orally: effective up to 72 hours after unprotected sex; less effective with each passing hour.
• Ulipristal acetate 30 mg orally: a selective progesterone receptor modulator (SPRM), effective up to 120 hours (5 days) after unprotected sex.
• Copper intrauterine device: the most effective option, can be inserted up to 5 days after unprotected sex (or up to 5 days after the earliest expected ovulation).

Hormone Replacement Therapy

Hormone replacement therapy (HRT) replaces oestrogen (and, in women with a uterus, a progestogen) lost at the menopause. Indications are vasomotor symptoms (hot flushes and night sweats), genitourinary symptoms, and osteoporosis prevention.

Two principles to remember:

• Women with a uterus need combined HRT (oestrogen + progestogen): unopposed oestrogen increases the risk of endometrial hyperplasia and cancer.
• Women without a uterus (post-hysterectomy) can have oestrogen-only HRT.

Routes: oral, transdermal patch, gel, vaginal (local). Transdermal preparations avoid first-pass metabolism and have a much lower VTE risk than oral preparations.

Risks:

• Breast cancer: small increase, mostly with combined (oestrogen + progestogen) HRT, related to duration of use.
• VTE: oral oestrogen increases risk; transdermal does not.
• Stroke: small absolute increase with oral preparations.
• Endometrial cancer, with unopposed oestrogen in women with a uterus.
• Cardiovascular disease: HRT does not protect against heart disease (the early observational data were confounded), although starting within 10 years of menopause is not associated with substantial cardiovascular harm.

Selective Modulators

Tamoxifen and Raloxifene (SERMs)

Selective oestrogen receptor modulators (SERMs) bind the oestrogen receptor but produce tissue-specific effects: agonist in some tissues, antagonist in others. The key examples:

Tamoxifen:

• A pro-drug; metabolised in the liver (mainly by CYP2D6) to 4-hydroxytamoxifen and endoxifen, which compete with oestrogen at the ER.
• Antagonist in breast tissue: the basis of its use in oestrogen-receptor-positive breast cancer (adjuvant therapy in pre-menopausal women, typically for 5-10 years).
• Agonist in endometrium: increases the risk of endometrial hyperplasia and cancer.
• Agonist in bone: preserves bone mineral density.
• Increases VTE risk.

Raloxifene:

• Antagonist in breast and endometrium.
• Agonist in bone.
• Used for osteoporosis prevention in post-menopausal women.

Ulipristal and Mifepristone (SPRMs)

Selective progesterone receptor modulators (SPRMs) bind the progesterone receptor with similar tissue-specific behaviour:

• Ulipristal acetate: emergency contraception (delays or inhibits ovulation up to 120 hours post-coitus). Was also used for uterine fibroids until concerns about hepatotoxicity restricted that use.
• Mifepristone (RU-486): progesterone receptor antagonist with significant antiglucocorticoid activity. Used (with misoprostol) in medical termination of pregnancy, and in selected cases of Cushing's syndrome where its glucocorticoid receptor blockade is exploited.

Hormonal Therapy in Cancer

Aromatase Inhibitors

Anastrozole, letrozole and exemestane inhibit aromatase, the enzyme that converts androgens to oestrogens. They suppress oestrogen synthesis in peripheral tissues (the main source of oestrogen in post-menopausal women) and are first-line adjuvant therapy for oestrogen-receptor-positive breast cancer in post-menopausal women.

Side effects relate to oestrogen deprivation: hot flushes, joint pains (common and limit adherence), accelerated bone loss requiring bisphosphonates or denosumab, and a small adverse effect on lipid profile.

GnRH Analogues and Antagonists

GnRH analogues (goserelin, leuprorelin) initially stimulate the pituitary, then desensitise it, ultimately suppressing FSH and LH and producing a "medical castration". The initial flare is clinically important; patients with metastatic prostate cancer can experience worsening symptoms in the first weeks unless co-prescribed with an anti-androgen during this period.

Indications:

• Prostate cancer (androgen deprivation therapy).
• Pre-menopausal hormone-sensitive breast cancer.
• Endometriosis and uterine fibroids.
• IVF protocols.

GnRH antagonists (degarelix) act immediately without the flare, and have largely replaced agonists in metastatic prostate cancer.

Anti-Androgens

• Bicalutamide, flutamide, cyproterone acetate: competitive antagonists at the androgen receptor; used in prostate cancer and (cyproterone) in severe acne and hirsutism.
• Finasteride and dutasteride: 5α-reductase inhibitors; reduce DHT formation. Used in benign prostatic hyperplasia and male-pattern baldness. Side effects include reduced libido and erectile dysfunction.
• Spironolactone: antagonist at the mineralocorticoid receptor with off-target androgen receptor activity, used for hirsutism in women.

Drugs in Obstetric Practice

A handful of obstetric drugs are routinely tested at pre-clinical level:

• Oxytocin: given intravenously to induce or augment labour, and as an intramuscular injection in active management of the third stage. Synthetic preparation is Syntocinon; combined with ergometrine as Syntometrine for postpartum haemorrhage.
• Ergometrine: uterine smooth muscle constrictor; used for postpartum haemorrhage.
• Misoprostol: a prostaglandin E₁ analogue; uses include induction of labour, postpartum haemorrhage, and (with mifepristone) medical termination of pregnancy.
• Tocolytics: suppress uterine contractions in preterm labour: nifedipine (calcium channel blocker, first-line in UK), atosiban (oxytocin antagonist), beta-agonists (less commonly used).
• Magnesium sulfate: first-line for eclampsia and severe pre-eclampsia; also offered for fetal neuroprotection in threatened or imminent preterm delivery between 24⁺⁰ and 29⁺⁶ weeks (consider between 30⁺⁰ and 33⁺⁶ weeks if delivery is expected within 24 hours), per NICE NG25.
• Antihypertensives in pregnancy: labetalol first-line, nifedipine and methyldopa as alternatives. ACE inhibitors and ARBs are contraindicated.
• Anti-D immunoglobulin: given to RhD-negative women after potential sensitising events to prevent haemolytic disease of the fetus and newborn.

Summary

• Sex steroid drugs act on nuclear receptors via transcription: effects are slow but durable.
• The COCP contains ethinylestradiol and a progestogen; works mainly by suppressing ovulation; risk profile dominated by VTE and breast cancer; efficacy reduced by enzyme-inducing drugs (rifampicin, antiepileptics, St John's wort).
• The POP is the contraceptive of choice when oestrogen is contraindicated.
• Long-acting reversible contraceptives (implant, IUS, IUD, depot) have the lowest typical-use failure rates.
• Emergency contraception: levonorgestrel up to 72 hours; ulipristal up to 120 hours; copper IUD most effective.
• HRT relieves menopausal symptoms and prevents osteoporosis; oral preparations carry meaningful VTE risk; combined HRT increases breast cancer risk; women with a uterus need a progestogen to prevent endometrial cancer.
• Tamoxifen is a SERM: antagonist in breast (cancer treatment), agonist in endometrium (cancer risk) and bone (bone preservation).
• Aromatase inhibitors (anastrozole, letrozole) are used in post-menopausal ER-positive breast cancer.
• GnRH analogues produce medical castration: used in prostate cancer, endometriosis and fibroids.
• Key obstetric drugs: oxytocin, ergometrine, misoprostol, nifedipine (tocolytic), magnesium sulfate (eclampsia), labetalol (hypertension in pregnancy), and anti-D immunoglobulin.

Drug Summary Table

Class	Examples	Use	Key points / side effects
Combined OCP	Ethinylestradiol + progestogen	Contraception, cycle regulation, acne	VTE, ↑ BP, breast & cervical cancer; ↓ ovarian/endometrial cancer; reduced by enzyme inducers
POP	Desogestrel, levonorgestrel	Contraception when oestrogen contraindicated	Irregular bleeding
LARC (progestogen)	Implant (Nexplanon), depot (Depo-Provera), LNG-IUS (Mirena)	Long-acting contraception, menorrhagia, HRT progestogen	Lowest typical-use failure rates; depot: bone density concern
Emergency contraception	Levonorgestrel (≤72 h), ulipristal (≤120 h), copper IUD (≤5 d)	Post-coital prevention	Copper IUD most effective
HRT	Oestradiol ± progestogen	Menopausal symptoms, osteoporosis prevention	Combined ↑ breast cancer; oral ↑ VTE; transdermal preferred where possible
SERM	Tamoxifen, raloxifene	ER+ breast cancer (tamoxifen, pre-meno); osteoporosis (raloxifene)	Tamoxifen ↑ endometrial cancer & VTE
SPRM	Ulipristal acetate; mifepristone	Emergency contraception (ulipristal); medical TOP & Cushing's (mifepristone)	Mifepristone has antiglucocorticoid activity
Aromatase inhibitors	Anastrozole, letrozole, exemestane	Post-menopausal ER+ breast cancer	Joint pain, osteoporosis (need bone protection)
GnRH analogues / antagonists	Goserelin, leuprorelin (agonists); degarelix (antagonist)	Prostate Ca, breast Ca (pre-meno), endometriosis, fibroids, IVF	Initial flare with agonists; medical castration symptoms
Anti-androgens	Bicalutamide, cyproterone (AR antagonists); finasteride, dutasteride (5α-reductase inhibitors)	Prostate Ca (bicalutamide); BPH, hair loss (finasteride)	Reduced libido, erectile dysfunction
Obstetric drugs	Oxytocin, ergometrine, misoprostol, nifedipine, magnesium sulfate, labetalol, anti-D Ig	Labour induction/augmentation, PPH, tocolysis, eclampsia, HT in pregnancy, RhD prophylaxis	Misoprostol contraindicated unless TOP intent; Mg toxicity

Reviewed by: Dr. Marcus Judge

Quiz

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