Endometriosis and Fibroids: Starving Oestrogen-Driven Disease

One hormone, two diseases

Both conditions are, at heart, oestrogen-dependent growths. In endometriosis, endometrial-type tissue implants outside the uterine cavity — on the ovaries, the peritoneum, the pouch of Douglas. Like the lining inside the womb, it carries oestrogen receptors and responds to the cycle: it proliferates, it bleeds, and because that blood cannot escape it drives inflammation, adhesions, chronic pelvic pain, dysmenorrhoea and subfertility. Uterine fibroids (leiomyomas) are benign tumours of the myometrial smooth muscle; they too are studded with oestrogen (and progesterone) receptors and enlarge under hormonal drive, producing heavy menstrual bleeding and "bulk" symptoms — pressure, a palpable mass, urinary frequency. The molecular biology of oestrogen, progesterone and the hypothalamic–pituitary–gonadal (HPG) axis is taught in full in the Endocrine section; here we take those molecules as given and put them to work as drug targets. The unifying therapeutic idea is simple: reduce oestrogen exposure, or oppose it, and both diseases regress.

Endometriosis: the treatment ladder

Start with symptom relief, then climb into hormonal suppression as the disease demands. The first rung is symptomatic: NSAIDs (such as mebeverine's cousins in the analgesic world — ibuprofen, naproxen, mefenamic acid) reduce the prostaglandin-driven cramping of dysmenorrhoea and are often combined with paracetamol. The second rung is hormonal suppression, whose whole purpose is to abolish the cyclical oestrogen swings that feed the lesions — in effect creating either a "pseudo-pregnancy" (a steady progestogen-dominant state) or a "pseudo-menopause" (a low-oestrogen state). The combined oral contraceptive pill, taken continuously (back-to-back packs, skipping the withdrawal bleed), keeps the endometrium and its ectopic cousins thin and quiet. Progestogens do the same by a different route — oral progestogens (such as norethisterone or dienogest), the levonorgestrel intrauterine system (IUS), or depot medroxyprogesterone acetate (DMPA) injections — all suppress ovulation and decidualise then atrophy the tissue. These same agents are the workhorses of the Menstrual-bleeding and Contraception chapters; here they are re-purposed to silence pain rather than to prevent pregnancy.

When these fail — when pain persists despite continuous pills and progestogens — we climb to the top of the ladder: the GnRH analogues. This is the class that gives this chapter its signature figure, and understanding it is worth more marks in an exam than memorising any drug list. Two families sit here: the GnRH agonists (goserelin, leuprorelin, triptorelin) and the newer oral GnRH antagonists (relugolix, elagolix). Both drive the ovary into a low-oestrogen "medical menopause" — but they get there by opposite routes, and that difference is the whole point.

The GnRH-analogue mechanism: pulses, a flare, and a switch-off

Normal GnRH is a rhythm, not a level — and the rhythm is everything. The hypothalamus releases GnRH in pulses, roughly every 60–90 minutes. Those pulses are what keep the pituitary gonadotrophs alive and secreting FSH and LH, which in turn drive the ovary to make oestrogen. The counter-intuitive fact — the one the figure exists to teach — is that the pituitary responds to the pulsatility, not merely to the presence, of GnRH. Flood it with continuous, unremitting GnRH stimulation and the response is not more FSH/LH but, after a brief burst, far less. A GnRH agonist is a synthetic, long-acting version of the hormone that binds the receptor continuously. At first this causes exactly what you would expect: a flare — a transient surge of FSH and LH, and with it a rise in oestrogen that can briefly worsen symptoms (more pain, a heavier bleed) in the first week or two. Then the receptor, hammered without rest, downregulates and desensitises. FSH and LH fall, the ovary is no longer stimulated, and oestrogen plunges to menopausal levels. The patient is now in a reversible medical menopause.

A GnRH antagonist skips the drama. Instead of over-stimulating the receptor into exhaustion, it simply blocks it from the first dose — competitively occupying the GnRH receptor so the hypothalamus's own pulses can't get through. FSH, LH and oestrogen fall immediately, with no initial flare. That is the practical advantage of relugolix and elagolix over goserelin and leuprorelin: no transient worsening, oral dosing, and a dose-dependent control of just how much oestrogen you suppress. The identical flare-versus-no-flare distinction reappears in the Oncology / prostate chapter: there, a GnRH agonist is used for androgen-deprivation therapy in prostate cancer, and its testosterone flare can transiently worsen the tumour — which is why an anti-androgen is given as "cover" for the first weeks, or a GnRH antagonist is chosen to avoid the flare altogether. Same mechanism, different gland, same clinical footnote.

The price of hypo-oestrogenism — and "add-back"

A medical menopause works because oestrogen starves the disease — but oestrogen also protects bone, blood vessels and mood, so removing it has a cost. Patients get menopausal symptoms: hot flushes, night sweats, vaginal dryness, mood change. More importantly, sustained hypo-oestrogenism causes loss of bone mineral density, so GnRH-agonist therapy is time-limited (classically capped around six months when used alone). The elegant solution is add-back therapy: giving a small amount of hormone back — low-dose combined oestrogen/progestogen, or tibolone (a synthetic steroid with weak oestrogenic, progestogenic and androgenic activity) — alongside the GnRH analogue. The relugolix combination product bundles this in directly (relugolix with oestradiol and norethisterone). There is a therapeutic window here: enough oestrogen to protect bone and quell flushes, but not enough to re-feed the endometriosis. This is exactly the reasoning of the Menopause chapter, where hypo-oestrogenism, its bone consequences and hormone replacement are covered in depth — here we simply borrow a slice of HRT to make a medical menopause tolerable long-term.

Fibroids: controlling bleeding, then shrinking the mass

The two problems fibroids cause — heavy bleeding and bulk — call for two different pharmacological answers. For heavy menstrual bleeding the first-line non-hormonal options are tranexamic acid — an antifibrinolytic that stabilises the clot in the bleeding endometrium (taken only on the days of heavy flow) — and NSAIDs, which also reduce prostaglandin-mediated blood loss and pain. The most effective device is the levonorgestrel intrauterine system (IUS), which thins the endometrium locally and can dramatically cut menstrual loss; these bleeding tools are shared verbatim with the Menstrual-bleeding chapter. To shrink the fibroid itself — for instance to correct anaemia and reduce operative difficulty before surgery — a GnRH agonist is used pre-operatively: three months of goserelin or leuprorelin lowers oestrogen, shrinks the fibroid and lets the haemoglobin recover so the woman goes to theatre in better shape (and sometimes allows a smaller operation). Ulipristal acetate, a selective progesterone-receptor modulator (SPRM) that directly blunts the progesterone drive to fibroid growth and bleeding, is effective and was once widely used — but a signal of serious liver injury led regulators to restrict it sharply, so it is now reserved for narrow circumstances with liver-function monitoring. Aromatase inhibitors, which block the peripheral conversion of androgens to oestrogen, are used in selected refractory cases.

Medicine buys time and improves conditions; it rarely cures the anatomy. It is worth being honest about the limits of drug therapy. Hormonal suppression controls symptoms and can shrink lesions, but stop the drug and the oestrogen returns and so, often, does the disease — endometriosis in particular tends to recur once suppression is lifted, and fibroids regrow after a GnRH agonist is stopped. That is why the medical strategy is framed around goals: relieving pain, controlling bleeding, correcting anaemia, preserving fertility, or bridging a woman to surgery or to the natural fall in oestrogen at menopause (when both diseases quieten on their own). When symptoms are severe and refractory, when a fibroid is very large, or when fertility is the priority and endometriosis is distorting the pelvis, medical therapy gives way to surgery — but that decision, and the operative technique, belong to the gynaecology-surgery literature rather than this pharmacology chapter.