Endometriosis
Hormonal treatment of endometriosis
What the options are, how they work and how the right treatment is chosen for each woman
Endometriosis is an estrogen-dependent disease. The lesions of endometriosis outside the uterus respond to the hormones of the cycle, just like the lining inside the uterus. With every cycle, small bleeds and inflammation occur in them. This is why the pain is so closely linked to the period, and this is why hormonal treatment is the basis of care.
Hormonal treatment does not make endometriosis disappear. It does, however, reduce estrogen production or block the effect of estrogen on the endometriosis lesions. The lesions “calm down”, the inflammation settles and the pain eases. The 2022 international guideline of ESHRE recommends hormonal treatment for endometriosis pain and considers it the first choice for most women, before surgery.
What should be clarified before treatment starts?
Treatment can start without a laparoscopy. According to the guideline, the symptoms, the medical history and the imaging findings are enough. Before choosing a medicine, the doctor considers a few basic questions. Does the woman want to become pregnant now or later? Does she need contraception? Are there risk factors for thrombosis, such as smoking, migraine with aura or a previous thrombosis? Is there a history of depression or sleep problems? How important is a regular period to her?
The answers to these questions shape the treatment more than the extent of the disease itself. No single treatment is best for every woman. The guideline does not rank one first-line medicine above another. The choice depends on the woman's preferences, side effects, effectiveness, cost and availability.
The steps of hormonal treatment
First line
Combined contraceptives or progestins: pill, hormonal IUD, implant.
Effective and suitable for long-term use.
Second line
GnRH agonists or antagonists, always with added hormones (add-back).
When first-line treatment is not enough or not tolerated.
Resistant forms
Aromatase inhibitors, only together with another hormonal treatment.
For persistent pain, after other treatments.
Review
Checking pain, side effects and quality of life.
Every 6 to 12 months, and whenever her needs change.
How do combined hormonal contraceptives help?
Combined contraceptives contain an estrogen and a progestin. They stop ovulation, reduce menstrual bleeding and limit the hormonal stimulation of the endometriosis lesions. They are available as a pill, a skin patch and a vaginal ring.
For women with severe period pain, the guideline recommends considering continuous use, without a monthly break. With continuous use there is no period, and so no period pain. Some women have light, irregular bleeding, especially in the first months.
Combined contraceptives are not suitable for every woman. They should not be used after a thrombosis, with migraine with aura, in smokers over 35 and in some other situations. In these cases, progestin-only treatment is the safer choice.
How do progestins work?
Progestins mimic the action of progesterone. They turn the tissue of the lesions into inactive tissue, reduce inflammation and, in most women, stop the period. They are also suitable for women who cannot take estrogen.
Dienogest at a dose of 2 mg a day is the best-studied progestin for endometriosis. In a randomized trial of 252 women, dienogest relieved pain as effectively as leuprorelin, a GnRH agonist. Bone density in the spine, however, rose by 0.25% with dienogest and fell by 4.04% with leuprorelin. Other options are norethisterone acetate and desogestrel tablets.
The levonorgestrel hormonal IUD releases the progestin mainly inside the uterus. It reduces period pain and bleeding and protects against pregnancy for several years. It is especially useful when adenomyosis or increased bleeding during periods is also present. The etonogestrel implant is another long-acting option.
The most common side effects of progestins are irregular bleeding, especially in the first months, acne, fluid retention, mood changes and lower sexual desire. Medroxyprogesterone injections reduce bone density. For this reason, they are not a first choice for teenagers and young women.
What are GnRH agonists and antagonists?
GnRH agonists and antagonists act on the pituitary gland. They stop the signal from the brain to the ovaries, and estrogen falls to menopausal levels. They are very effective against pain. The guideline nevertheless keeps them as a second-line treatment, for women in whom combined contraceptives or progestins have not helped or were not tolerated.
GnRH agonists such as leuprorelin, triptorelin and goserelin are given as an injection every one or three months. The guideline recommends adding a small dose of estradiol and a progestin from the start (add-back therapy). This addition protects the bones and prevents the symptoms of low estrogen caused by the sudden fall in estrogen, such as hot flashes, night sweats, sleep problems and vaginal dryness. The addition does not make the treatment less effective.
GnRH antagonists are taken by mouth and act immediately. A newer medicine, relugolix, is approved in Europe for endometriosis. The tablet already contains the added estradiol and progestin. In two large randomized trials (SPIRIT 1 and 2), after 24 weeks 75% of women on relugolix had a clear improvement in period pain, compared with 27% on placebo. Pain outside the period improved in 66% compared with 43%.
When are aromatase inhibitors used?
The lesions of endometriosis can produce estrogen themselves, through an enzyme called aromatase. Aromatase inhibitors, such as letrozole and anastrozole, block this production. The guideline suggests them only for women with resistant pain, when other treatments have not helped. They are always given together with a combined contraceptive, a progestin or a GnRH analogue, because on their own they stimulate the ovaries in women of reproductive age.
What treatment follows surgery?
After surgical removal of an endometrioma, the disease often comes back. For women who do not want to become pregnant soon, the guideline recommends long-term hormonal treatment after surgery, for example with the levonorgestrel hormonal IUD or with combined contraceptives for at least 18 to 24 months. This lowers the risk of new cysts and of another operation, and it protects the ovaries.
For women who want to become pregnant, the guideline recommends the opposite. Hormonal treatment after surgery, with the sole aim of improving the chances of pregnancy, does not help and delays trying to conceive.
Does hormonal treatment affect pregnancy?
The available studies do not show a higher live birth rate when a woman takes hormonal treatment to suppress endometriosis before trying to conceive. Hormonal treatment can slow the progression of the disease and limit its anatomical complications, but no official guideline states that it helps a woman become pregnant and give birth sooner. Depending on their composition, some hormonal treatments also work as contraception, so each treatment needs to be adapted to the woman's needs. More in the article “Endometriosis and infertility”.
How can treatment affect mood, sleep and sex life?
Hormonal treatments control pain, but they are not neutral for mental health. A large Danish study of more than one million women showed that hormonal contraception is linked to greater use of antidepressants, especially in teenagers. In everyday life, some women describe low mood, irritability, poorer sleep or lower sexual desire during treatment.
These symptoms are not a reason to give up treatment. They are, however, a reason to talk about them openly. A change of progestin, dose or form often solves the problem. A woman's quality of life is part of the outcome of treatment, not a minor detail.
How is endometriosis treated in adolescence?
For teenagers with severe period pain, the guideline recommends combined contraceptives or progestins as the first choice. GnRH agonists are used only after careful consideration, for a limited time and always with add-back, because adolescence is when bone mass is built. Treatment in adolescence is not only about today's pain. It also lowers the risk of central sensitization, in other words, the risk that the pain becomes chronic.
How long does treatment last?
Hormonal treatments control the symptoms for as long as they are taken. After stopping, the pain often returns, usually within a few months. For this reason, treatment is long-term, often for years, until the woman wants to become pregnant or until the menopause. Long-term use of combined contraceptives and progestins is considered safe, with regular review. The doctor checks effectiveness, side effects and the woman's needs, which change over the years.
The practice's approach
At the practice, hormonal treatment is the basis of endometriosis care. It starts with the consent of each woman, after detailed information. The medicine is chosen together with her, taking into account pain, the need for contraception, plans for pregnancy, risk factors and mental health.
Side effects on mood, sleep and sex life, which are often underestimated, receive particular attention. A treatment that controls pain but harms quality of life is not successful. The woman's wishes are heard and respected, even beyond what the guidelines set out.
The aim is a treatment that is effective for pain, safe for the bones and the heart, and compatible with the woman's life and plans, so that she can keep it up for years.
Sources: Becker CM et al., ESHRE guideline: endometriosis, Human Reproduction Open 2022. National Institute for Health and Care Excellence (NICE), Endometriosis: diagnosis and management (NG73). Strowitzki T et al., Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial, Human Reproduction 2010. Giudice LC et al., Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2), The Lancet 2022. Skovlund CW et al., Association of hormonal contraception with depression, JAMA Psychiatry 2016.