Hormones, Contraception, and Thyroid

TL;DR. The 2002 Women's Health Initiative trial caused a collapse in HRT use worldwide, and its findings were substantially misapplied: the risks it found were concentrated in women who started HRT long after menopause, and for most women starting near menopause the balance is far more favourable than the 2002 headlines suggested. Contraceptives are among the most effective medicines available, and the gap between "typical use" and "perfect use" failure rates explains almost everything about which methods actually work. Levothyroxine is one of the most absorption-sensitive drugs in the pharmacy, which is why the instructions about food and timing are not optional.

1. Contraception

The single most useful table in this chapter:

The gap between the two columns is the whole story. Methods requiring nothing of the user (long-acting reversible contraception: implants and IUDs) have identical perfect and typical use rates. Methods requiring daily or per-act action have typical failure rates 20 to 30 times their perfect-use rate. This is why guidelines increasingly recommend LARC first, and it is nothing to do with the pharmacology.

Combined hormonal contraception (oestrogen + progestogen)

Mechanism: suppresses the LH surge, preventing ovulation; thickens cervical mucus; thins the endometrium.

Non-contraceptive benefits, which are substantial and under-discussed:

• Lighter, more predictable, less painful periods
• Improved acne
• Reduced ovarian cancer risk by roughly 30 to 50 percent, persisting for decades after stopping
• Reduced endometrial cancer risk by roughly 30 percent
• Reduced colorectal cancer risk
• Treatment for endometriosis, PCOS symptoms, and premenstrual dysphoric disorder

Risks:

• Venous thromboembolism (VTE): the headline risk. Baseline risk in a young woman is roughly 2 per 10,000 per year; on the combined pill roughly 5 to 12 per 10,000 depending on the progestogen. In pregnancy it is roughly 29 per 10,000, and in the postpartum period far higher. That comparison is the one usually missing from the discussion.
• Stroke and myocardial infarction: small absolute increase, concentrated in smokers over 35 and in women with migraine with aura.
• Breast cancer: a small increase in current users, returning to baseline within about ten years of stopping.
• Blood pressure rise in some women.

Absolute contraindications: migraine with aura (stroke risk), smoking over 35, previous VTE or known thrombophilia, uncontrolled hypertension, current breast cancer, and the first six weeks postpartum in breastfeeding women.

Progestogen-only methods

Progestogen-only pill (POP) works mainly by thickening cervical mucus; desogestrel-containing POPs also suppress ovulation. No oestrogen, so no VTE risk, which makes them suitable for smokers over 35, women with migraine with aura, and breastfeeding.

Older POPs had a 3-hour window; desogestrel POPs have a 12-hour window, which matters a great deal in practice.

Implant (etonogestrel, Nexplanon): 3 years, the most effective reversible method there is. Irregular bleeding is the main reason for removal.

Injection (medroxyprogesterone): every 12 to 13 weeks. Reduces bone mineral density, which recovers after stopping, and it carries a delay of up to a year in return of fertility.

Hormonal IUD: 5 to 8 years, very light or absent periods for most users, and it is a first-line treatment for heavy menstrual bleeding in its own right.

Copper IUD: 5 to 10 years, entirely hormone-free, and it makes periods heavier and more painful. It is also the most effective emergency contraception.

Emergency contraception

Both pills work by delaying ovulation. Neither disrupts an established pregnancy, and neither is an abortifacient. They do not work if ovulation has already occurred, which is why the copper IUD is more reliable.

Two practical points that are widely unknown: levonorgestrel is less effective at higher body weight (above roughly 70 to 75 kg), where ulipristal or a copper IUD is preferred. And ulipristal and progestogen contraception interfere with each other: taking ulipristal means waiting 5 days before starting or restarting hormonal contraception, and taking progestogen within 5 days after ulipristal reduces its effect.

What actually affects the pill

The old blanket warning about antibiotics is outdated. Only enzyme-inducing drugs genuinely reduce contraceptive efficacy: rifampicin and rifabutin, several antiepileptics (carbamazepine, phenytoin, topiramate at higher doses), some antiretrovirals, and St John's wort, which is sold as a harmless herbal remedy and causes documented contraceptive failures.

Vomiting within 2 to 3 hours or severe diarrhoea does reduce absorption and requires the missed-pill rules.

2. Menopause and HRT

What happened in 2002

The Women's Health Initiative was a large randomised trial of HRT. In 2002 the combined oestrogen-plus-progestin arm was stopped early, reporting increased breast cancer, stroke, and venous thromboembolism.

The response was dramatic: HRT use fell by 50 to 80 percent worldwide within a few years, and a generation of women and clinicians came to regard it as dangerous.

What was subsequently understood:

• The average participant was 63 years old, more than a decade past menopause. Many were in their 70s. This is not the population that typically starts HRT.
• The oestrogen-only arm (in women who had had a hysterectomy) actually showed reduced breast cancer and reduced mortality in younger participants.
• Age at initiation matters enormously. The "timing hypothesis" holds that starting HRT within 10 years of menopause or before age 60 carries a favourable risk-benefit profile, including possible cardiovascular benefit, whereas starting much later does not.
• Absolute risks were small and were widely reported as relative increases. The breast cancer signal amounted to roughly 8 extra cases per 10,000 women per year.
• Route matters: transdermal oestrogen (patches, gel, spray) does not carry the VTE risk that oral oestrogen does, because it bypasses first-pass hepatic metabolism. This was not known at the time of WHI, which used oral preparations.
• Micronised progesterone appears to carry a lower breast cancer signal than the synthetic progestins used in WHI.

Current guidance (NICE, the British Menopause Society, the North American Menopause Society, and the International Menopause Society) is broadly that for symptomatic women under 60 or within 10 years of menopause, the benefits of HRT generally outweigh the risks, and that treatment should be individualised rather than time-limited by an arbitrary rule.

What HRT does well: vasomotor symptoms (hot flushes and night sweats) with large effect sizes, genitourinary symptoms, sleep, mood in some women, and prevention of osteoporotic fracture.

Vaginal oestrogen is a separate case worth knowing: low-dose topical oestrogen for genitourinary symptoms has minimal systemic absorption, is not subject to the same risk discussion, can be used long term, and is appropriate for most women including many with a history of breast cancer after discussion. It is markedly under-prescribed.

Non-hormonal options for vasomotor symptoms include SSRIs/SNRIs, gabapentin, clonidine, and the newer neurokinin-3 receptor antagonists (fezolinetant), plus CBT, which has genuine evidence for symptom impact.

Testosterone is used off-label in some countries for low sexual desire in postmenopausal women, with reasonable evidence for that specific indication.

3. Thyroid

Hypothyroidism and levothyroxine

Levothyroxine (T4) is synthetic thyroxine, replacing what the thyroid is not making. It is one of the most prescribed drugs in the world.

It is also unusually sensitive to how you take it, which is why the instructions are so specific:

Take levothyroxine on an empty stomach, with water, at least 30 to 60 minutes before food, and separated by at least 4 hours from:

• Calcium (supplements, antacids, calcium-fortified foods)
• Iron supplements
• Proton pump inhibitors (reduced acid impairs absorption)
• Soy products (Chapter 47)
• High-fibre foods and supplements
• Coffee, which measurably reduces absorption when taken at the same time

Bedtime dosing, at least 3 hours after the last food, works as well or better in trials and is easier for many people to keep consistent.

Consistency matters more than the exact timing. The same routine every day produces stable levels; erratic timing produces erratic results.

Monitoring: TSH is checked 6 to 8 weeks after any dose change and then periodically. Because levothyroxine's half-life is about a week, changes take weeks to show, which is why frequent dose adjustments are counterproductive.

Doses need increasing by 25 to 50 percent in pregnancy, usually as soon as pregnancy is confirmed, because maternal thyroid hormone is essential for fetal brain development in the first trimester. This is one of the more important items in this chapter and is easy to miss.

Levothyroxine is a narrow-therapeutic-index drug, and switching between brands or formulations can shift levels enough to matter; guidance in several countries advises staying on the same product where possible.

T3 (liothyronine) and desiccated thyroid extract are contested. A minority of people report feeling better on combination T4/T3 therapy, trials have generally not shown benefit over T4 alone, and there is ongoing debate about whether trial design has adequately captured the subgroup who might benefit. Desiccated thyroid extract has variable hormone content and is not recommended by most guidelines.

Hyperthyroidism

Carbimazole (or methimazole) and propylthiouracil block thyroid hormone synthesis.

The one thing to know: both can rarely cause agranulocytosis, a sudden loss of white blood cells.

If you develop a sore throat, mouth ulcers, or fever while taking carbimazole or propylthiouracil, stop the drug and get an urgent blood count. This is not a wait-and-see situation.

Beta blockers control the symptoms (tremor, palpitations, anxiety) while waiting for the antithyroid drug to work. Radioactive iodine and surgery are definitive options, both usually resulting in lifelong levothyroxine.

4. Other hormone treatments

Testosterone replacement for genuine hypogonadism (confirmed low morning testosterone plus symptoms) is appropriate and effective. The direct-to-consumer "low T" industry substantially over-treats men with normal levels and age-related decline. Effects include polycythaemia (raised haematocrit), acne, sleep apnoea, testicular shrinkage, and suppression of sperm production, which matters for anyone wanting children. The cardiovascular question was long uncertain; the 2023 TRAVERSE trial found no increase in major cardiovascular events in men with hypogonadism.

Anabolic steroid misuse is a separate matter and carries serious risks: cardiomyopathy, hypertension, dyslipidaemia, liver injury with oral 17-alkylated agents, infertility, mood disturbance, and, on stopping, a hypogonadal state that can persist for months to years.

Corticosteroids are covered in Chapter 78.

Bisphosphonates for osteoporosis (alendronate, risedronate, zoledronic acid) have specific and non-negotiable administration rules: take on an empty stomach with a full glass of plain water, and remain upright and do not eat for 30 to 60 minutes, because they cause severe oesophageal ulceration if they lodge. Rare effects with long-term use include osteonecrosis of the jaw (strongly associated with dental extraction, hence dental assessment before starting) and atypical femoral fracture, which is why drug holidays are considered after 3 to 5 years.

5. The bottom line

• The gap between perfect and typical use is what decides contraceptive effectiveness. Implants and IUDs perform identically in both columns; pills and condoms do not.
• The combined pill raises VTE risk from about 2 to about 5 to 12 per 10,000 per year, against 29 per 10,000 in pregnancy. It also substantially reduces ovarian and endometrial cancer risk for decades.
• Only enzyme-inducing drugs, notably rifampicin and St John's wort, genuinely reduce contraceptive efficacy. The general antibiotic warning is outdated.
• The copper IUD is the most effective emergency contraception, and levonorgestrel is less effective at higher body weight.
• The 2002 WHI findings were misapplied. For symptomatic women under 60 or within 10 years of menopause, HRT's benefits generally outweigh its risks, and transdermal oestrogen avoids the VTE risk of oral.
• Levothyroxine on an empty stomach, away from calcium, iron, coffee, soy, and PPIs, and the dose needs increasing in pregnancy.
• Sore throat or fever on carbimazole means stop and get a blood count urgently.

Sources and notes

Doses, cautions, and interactions follow the British National Formulary and the electronic Medicines Compendium; US figures follow FDA labelling. Contraceptive failure rates by perfect and typical use follow Trussell's tables in Contraceptive Technology and CDC reporting. Non-contraceptive benefits, including ovarian and endometrial cancer risk reduction, follow the Collaborative Group on Epidemiological Studies of Ovarian Cancer, The Lancet, 2008, and Iversen et al.'s RCGP cohort. VTE risk by progestogen and the comparison with pregnancy follows the FSRH and MHRA reviews. Breast cancer risk follows Morch et al., NEJM, 2017. Emergency contraception comparative efficacy, the body weight effect on levonorgestrel, and the ulipristal-progestogen interaction follow FSRH guidance and Glasier et al., The Lancet, 2010. Enzyme-inducing drugs as the genuine contraceptive interaction, and the obsolescence of the general antibiotic warning, follow FSRH clinical guidance. The Women's Health Initiative is Rossouw et al., JAMA, 2002, with the oestrogen-only arm reported by Anderson et al., 2004; the timing hypothesis follows Manson et al.'s later analyses and the ELITE and KEEPS trials. Current positions follow NICE NG23, the British Menopause Society, and the North American Menopause Society 2022 position statement. Transdermal oestrogen and VTE follows Vinogradova et al., BMJ, 2019. Vaginal oestrogen safety follows NICE and BMS guidance. Levothyroxine absorption interactions and bedtime dosing follow Bolk et al., Archives of Internal Medicine, 2010, and BNF. Pregnancy dose increase follows ATA guidance. Carbimazole agranulocytosis warning follows MHRA advice. Testosterone cardiovascular safety follows TRAVERSE, Lincoff et al., NEJM, 2023. Bisphosphonate administration rules, osteonecrosis, and atypical fractures follow NICE and the ASBMR task force reports.

Open questions. Whether combination T4/T3 therapy benefits a genuine subgroup of hypothyroid patients is unresolved, and trial design may not have captured it. The optimal duration of HRT remains individualised rather than evidence-based.

👉 Next: the rest of the cabinet.