Premature ovarian insufficiency (POI) affects more women than previously thought, with serious long-term ramifications if it’s not identified and managed—including a 2-fold increased risk of dementia and osteoporosis and reduced life expectancy.

Recent guidelines from the European Society of Human Reproduction and Embryology (ESHRE)—developed in partnership with Monash University, the American Society for Reproductive Medicine, and the International Menopause Society—provide updated advice about diagnostic criteria, investigations and management of this often-distressing condition, explains endocrinologist Dr Sonia Davison, clinical fellow at Jean Hailes for Women’s Health and past president of the Australasian Menopause Society.

Clinical presentation

Formerly known as premature menopause, POI is marked by loss of ovarian function in women aged under 40.

It has a prevalence of approximately 3.7%, and most affected women present with secondary amenorrhea—although some present with primary amenorrhea, or oligoamenorrhea with occasional periods, Dr Davison says.

“And that’s a tricky one because women might have no periods for years, and think, oh, this is very convenient. And they might escape medical attention.”

Women may also present with signs and symptoms of the underlying cause, and may or may not have oestrogen deficiency symptoms, Dr Davison adds.

She notes mood swings are common in POI, reported by seven in 10 women—compared to five in 10 who report the classical flushes and sweats associated with menopause.

Many have psychological distress, and symptoms are typically more severe in women with iatrogenic POI.

Risk factors and aetiology

Several factors increase the likelihood of developing POI, including family history, known genetic causes (such as Turner syndrome and carriage of the fragile X premutation), smoking, and ethnicity—with a lower prevalence in Asian women.

Autoimmune diseases have a bidirectional relationship with POI. Women with conditions such as rheumatoid arthritis and inflammatory bowel disease are at higher POI risk, while those with POI are at higher risk of developing autoimmune conditions. Hypothyroidism affects one in four women with POI, while adrenal insufficiency and type 1 diabetes each affect around 3% of this population.

Iatrogenic causes include surgical removal of the ovaries, chemotherapy, and radiotherapy for cancer treatment.

Other risk factors include earlier menarche, shorter cycle length, lower socioeconomic circumstances, and possibly exposure to environmental toxins.

In most women, however, a cause cannot be identified.

Diagnostic approach

Diagnosis relies primarily on clinical presentation, Dr Davison explains.

“They’re either not having periods or they’re having infrequent periods, and they’re below the age of 40,” she says.

Women younger than 40 who’ve had both their ovaries removed automatically receive the diagnosis and no further testing is needed, Dr Davison explains.

Otherwise, diagnosis is based on the presence of oligo/amenorrhoea for at least four months and an FSH of > 25IU/L (rather than the previous threshold of 40). A low oestradiol concentration, while not necessary to make the diagnosis, helps confirm it.

If diagnosis remains uncertain, you can repeat FSH testing in four to six weeks.

Anti-Müllerian hormone (AMH) testing is not necessary for diagnosis, Dr Davison says, noting there are issues with assay sensitivity.

Importantly, women need to cease hormonal contraception or hormone therapy for four to six weeks before any of these tests are done.

Other investigations

Other possible causes must be excluded, particularly hypothalamic amenorrhoea, which can “definitely masquerade as POI,” Dr Davison says.

“Think of this in someone with a type A personality, high levels of exercise, low caloric intake, low body weight, a bit of a stress head—and they will have low FSH and LH. They will also have low estradiol, but that low FSH is the real thing that will tell you that that’s a different diagnosis.”

It’s also important to exclude thyroid dysfunction, pregnancy, and polycystic ovary syndrome, she adds.

In addition to FSH/LH and oestradiol, she recommends testing:

• TSH
• testosterone
• prolactin
• DHEAS
• cortisol
• thyroid antibodies
• adrenal antibodies
• fasting blood glucose
• vit B12
• beta-hCG.

A good-quality pelvic ultrasound can provide information about ovarian morphology and endometrial status.

Consequences of untreated POI

Women of reproductive age typically have average oestradiol levels of approximately 400 picomoles per litre, which drops to about 20 at menopause, Dr Davison explains. When this drop occurs before the age of 40, “there will be ramifications and complications for the body,” Dr Davison says.

Left untreated, POI can lead to a:

• 40% increased risk of cardiovascular disease
• 2-3-fold increased risk of osteoporosis and fracture
• 2-fold increased risk of cognitive decline and dementia
• reduced life expectancy.

“That’s why we want to treat with some form of oestrogen—so that we can reverse those risks,” she says.

POI management

Unless it is contraindicated (e.g. in women with hormone-dependent cancers), hormone replacement is the cornerstone of POI management.

“We want them to have some form of oestrogen—and progestogen if they still have a uterus—until the age of natural menopause,” Dr Davison explains.

Options include MHT or a COCP, which may be more acceptable to women under 40 than “menopausal” treatment.

Women with POI usually need higher medication doses to achieve the hormone levels expected for their age, Dr Davison says. Oestrogen-wise, transdermal patches at 25-100 microgram strengths, topical gels at 1.5-2 sachets daily, or gel pump preparations at 3-4 pumps daily may be necessary.

“And if we are on higher levels of estrogen, we do need a higher dose of progestogens. And if they’ve got side effects, we just need them to have whatever level of hormone therapy or the combined pill that they are comfortable with.”

Importantly, you can reassure women who have concerns about possible risks associated with hormone replacement—including breast cancer—that these risks do not apply to them, Dr Davison says.

Vaginal oestrogen, moisturisers and lubricants can be helpful, and you can use testosterone if lowered libido is causing distress.

For women with hormone-dependent cancers, non-hormonal approaches for vasomotor symptoms include cognitive behavioural therapy, hypnotherapy, selective serotonin reuptake inhibitors, gabapentin, and fezolinetant (although this has not been studied in younger women).

Contraception and fertility considerations

About 15% of women with autoimmune POI can conceive naturally, so you’ll need to discuss contraception if they do not want a pregnancy. In this case, the COCP can serve as both hormone replacement and contraception. The levonorgestrel intrauterine device combined with oestrogen therapy is another option.

Fertility management in women with POI is complex and Dr Davison recommends early referral of women who wish to conceive.

Genetic implications

If a genetic cause of POI is identified, the woman’s female relatives have a 3-18-fold increased risk, Dr Davison says. She recommends offering genetic testing and counselling to both male and female family members, ideally through specialist genetic services.

Long-term monitoring and care

Women with POI need regular monitoring. Yearly reviews should focus on treatment compliance, symptom management, and screening for associated conditions.

Bone density scans should be performed at diagnosis to get a baseline, then every two to five years—with five-yearly intervals acceptable for women stable on treatment. Women who cannot use hormone therapy may need osteoporosis medications.

Given the increased autoimmune risk, yearly thyroid function and cortisol testing are prudent. Standard cardiovascular and diabetes screening applies, along with appropriate breast and cervical screening.

It’s also important to remember that POI can have a significant impact on psychological function, sexual health and quality of life, Dr Davison stresses.

Depending on a woman’s symptoms and risk factors, referrals to various specialists—such as a psychiatrist/psychologist, endocrinologist or cardiologist—may be warranted.

Key takeaways:

• POI involves loss of ovarian function before the age of 40 and affects 3.7% of women.
• Diagnosis requires FSH >25 IU/L (updated from 40 IU/L) with oligomenorrhoea or amenorrhoea for at least four months.
• Exclude other causes including hypothalamic amenorrhoea, thyroid dysfunction, PCOS, and pregnancy.
• Hormone replacement until natural menopausal age is essential unless contraindicated to prevent cardiovascular disease, osteoporosis, and cognitive decline.
• Higher hormone doses are required compared to typical menopausal hormone therapy.
• Early referral for fertility counselling is advised in women with POI who are hoping to conceive.
• Genetic counselling is advised if a hereditary cause is identified.
• Annual review should include monitoring of treatment compliance, oestrogen deficiency symptoms, cardiovascular risk factors, and bone, psychological and sexual health.

More information

ESHRE POI Guideline | Healthcare professional toolkit (which has algorithms for diagnosis, identifying the cause, and management)