Perimenopause and menopause
Premature ovarian insufficiency
When the ovaries stop working before the age of 40
Premature ovarian insufficiency means that the ovaries lose their function before the age of 40. Periods become irregular or stop, FSH rises and estrogen falls. According to the 2024 ESHRE guideline, the condition affects about 3.5-3.7% of women. When the ovaries stop working between the ages of 40 and 45, the condition is called early menopause, and it affects about 12% of women.
Premature ovarian insufficiency is not simply an early menopause. In many women the ovaries still work from time to time, and a spontaneous pregnancy is possible. The diagnosis often comes unexpectedly, at an age when a woman is still planning her family, and it weighs heavily on mental health. In 2024, ESHRE updated its 2016 guideline, with important changes in diagnosis, genetic testing and treatment. The article “Diminished ovarian reserve” explains the difference between the two conditions.
What are the signs?
The first sign is usually periods that become rare or stop. In some girls, periods never start (primary amenorrhea). The lack of estrogen causes the same symptoms as the menopause: hot flashes, night sweats, sleep problems, vaginal dryness, pain during sex, lower sexual desire, mood changes and difficulty concentrating. In other women the symptoms are mild, and the first problem is difficulty becoming pregnant.
How is the diagnosis made?
According to ESHRE, the diagnosis is based on two findings: irregular periods or amenorrhea for at least 4 months, and an FSH above 25 IU/L. A single FSH measurement is now enough, while the 2016 guideline required two measurements 4 weeks apart. FSH does not need to be measured on a specific day of the cycle. When the result is unclear, the doctor repeats the measurement after 4 to 6 weeks.
Before the diagnosis, the doctor rules out pregnancy. The contraceptive pill hides the picture and lowers FSH. For this reason, the woman stops it 2 to 6 weeks before the measurement and uses contraception without hormones in the meantime. Estradiol alone is not enough for the diagnosis. AMH is not the main test, but it can help when FSH does not give a clear answer. Removal of both ovaries before the age of 40 confirms the diagnosis without further tests.
Diagnosis and tests
The diagnosis
Looking for the cause
Why does it happen?
In most women no cause is found, and the condition is called idiopathic. ESHRE nevertheless recommends specific tests in all women, because the cause changes the follow-up and also concerns the family.
Genetic causes. ESHRE recommends a chromosome analysis and a test for a premutation in the FMR1 gene in all women. The chromosome analysis looks for chromosomal changes, such as Turner syndrome. The FMR1 premutation also matters for the family, because in later generations it can cause fragile X syndrome. More than 100 genes have been linked to the condition. Broader genetic testing (next-generation sequencing) is possible after genetic counseling.
Autoimmune causes. Autoimmune diseases are more common in women with premature ovarian insufficiency. ESHRE recommends a test for antibodies against 21-hydroxylase, which point to a risk of adrenal insufficiency (Addison's disease), and a TSH measurement at diagnosis and every 5 years. Antibodies against the ovaries are not reliable, and the doctor does not use them for the diagnosis.
Iatrogenic causes. Chemotherapy, radiotherapy to the pelvis and surgery on the ovaries can cause premature ovarian insufficiency. More in the article Iatrogenic menopause.
The sisters and daughters of a woman with premature ovarian insufficiency have a higher risk and need information. When a genetic cause is found, the family needs genetic counseling.
How does it affect health?
Estrogen protects many organs. Without treatment, premature ovarian insufficiency shortens life expectancy, mainly through heart and blood vessel disease. It increases the risk of coronary heart disease, heart failure and stroke.
The bones lose density and their inner structure changes, with a higher risk of osteoporosis and fractures. Muscle mass and strength may decrease. The risk of memory problems and dementia is higher. Sexual life, mental health and quality of life are often clearly affected.
What does hormone replacement therapy offer?
Hormone replacement therapy is the main treatment. ESHRE recommends it for all women with premature ovarian insufficiency until the usual age of menopause, about 51, even when they have no symptoms. The aim is not only to treat symptoms. Hormone replacement therapy protects the heart, the bones and the brain. It is not a “menopause medicine”, but a replacement for the hormones the body would normally produce at this age.
Young women usually need higher doses than women in the menopause. For the bones, ESHRE suggests at least 2 mg of estradiol by mouth or 100 micrograms through the skin per day. Women with a womb also need a progestogen, for example micronized progesterone (natural progesterone), to protect the womb lining. The hormonal coil is also an option. A late start or irregular use reduces the protection of the bones.
The contraceptive pill is an alternative, mainly when a woman also needs contraception. ESHRE then recommends taking it continuously or with fewer breaks, so that the bones do not lose mass. Pills with a low dose of estrogen may not be enough for the bones, and the pill has not been studied specifically in premature ovarian insufficiency.
For vaginal dryness, ESHRE recommends local estrogen, also together with systemic treatment when that is not enough. For low sexual desire, testosterone through the skin can be considered, at doses that match the normal levels for the woman's age. When hormone replacement therapy is not possible, for example after breast cancer, there are non-hormonal treatments for hot flashes, such as venlafaxine, escitalopram, gabapentin, fezolinetant and cognitive behavioral therapy. More in the article Menopausal hormone replacement therapy.
Doses of hormone replacement therapy
Usual dose in the menopause
Dose in premature ovarian insufficiency
What about fertility?
Premature ovarian insufficiency clearly lowers the chance of a natural pregnancy, but not to zero. Depending on the study, natural conception is reported in fewer than 5-15% of women. The chance is higher when the diagnosis is recent, FSH is lower and AMH can still be measured. Hormone replacement therapy does not prevent conception. A woman who does not want a pregnancy therefore needs contraception.
No treatment has been shown to increase ovarian function or the chance of a natural pregnancy. The most reliable route to pregnancy is egg donation. Eggs from a sister may carry the same genetic cause, and the stimulation cycle is cancelled more often. Before cancer treatment, the doctor should discuss fertility preservation early, for example freezing eggs or ovarian tissue.
A natural pregnancy after idiopathic premature ovarian insufficiency or after most chemotherapies carries no higher risk than other pregnancies. Pregnancies after egg donation, after radiotherapy to the womb and in Turner syndrome, however, are high-risk and need specialist obstetric care. In Turner syndrome and after anthracyclines or radiotherapy to the heart, a cardiology check is also needed before pregnancy.
What follow-up is needed?
ESHRE recommends a bone density scan (DXA) at diagnosis. If bone density is low, the doctor repeats the scan every 1 to 3 years. If it is normal and the woman takes hormone replacement therapy regularly, a new scan within 5 years has little value. The doctor checks blood pressure, weight and smoking at least once a year, blood lipids and blood sugar at diagnosis and then according to risk, and TSH every 5 years. The doctor also asks about mental health, sexual life and quality of life.
Information and psychological support are part of the treatment. The doctor gives the diagnosis with sensitivity and with time for questions, and the woman needs continuity of care. ESHRE also recommends contact with support groups.
The practice's approach
The doctor makes the diagnosis according to the 2024 ESHRE guideline and systematically checks for genetic and autoimmune causes. The doctor explains to the woman what the diagnosis means for her health, her fertility and her family.
Hormone replacement therapy is given at an adequate dose and for as long as needed, until the usual age of menopause. The doctor follows the bones, the heart, metabolism and mental health and works, when needed, with endocrinology, cardiology, genetics and a fertility center. The aim of the practice is for the woman to have the same health and quality of life as other women of her age.
Sources: Panay N et al., Evidence-based guideline: premature ovarian insufficiency (ESHRE), Human Reproduction Open 2024 (also Climacteric and Fertility and Sterility 2024). ESHRE – Premature Ovarian Insufficiency guideline, Toolkit for healthcare professionals, 2024. ESHRE Guideline Group on POI, Webber L et al., ESHRE Guideline: management of women with premature ovarian insufficiency, Human Reproduction 2016.