Spotlight on Primary Ovarian Insufficiency

When Ovulation Stops Before Age 40

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There is a lot of terminology here, so let’s review it so we are all on the same page.

Menopause occurs when ovulation stops, and this is expected to occur at age 45 or older. The average age is 51-52. Primary ovarian insufficiency, or POI, occurs when ovulation stops or becomes sporadic before age 40, and early menopause is when ovulation stops between ages 40 and 45. 

Surgical menopause is when ovulation stops because of the removal of the ovaries, and premature surgical menopause is < age 40, and early surgical menopause is ages 40-45. 

Some people use a similar term, premature ovarian insufficiency, to encompass POI, premature surgical menopause, and the loss of ovarian function before age 40 that some women experience due to cancer care (from hormone-blocking medications,  chemotherapy, and radiation).

Here, we will focus on POI, but I have upcoming posts planned on surgical menopause and early menopause.

What’s In a Name?

When I was a medical student, and likely when I was a resident, POI was called premature ovarian failure or premature menopause. Premature ovarian failure is awfully pejorative; after all, no one ever tells men that their inability to get or maintain an erection as they age is senile penile failure. Premature menopause is medically not appropriate because menopause is permanent, but some women with POI may ovulate, albeit sporadically, and can have occasional menstrual cycles. In addition, pregnancy is impossible with menopause, but pregnancy rates of 5-15% are reported with POI.

The Scope

Approximately 1-4% of women have either POI or premature surgical menopause. The risk of POI is highest in areas with a lower human development index (which is a measure of a country’s average achievements in health, knowledge, and standard of living). In SWAN (Study of Women’s Health Across the Nation), the rate of POI was 1% for White women and 1.4% for both Black and Hispanic women. Rates of premature surgical menopause also vary. For example, in one study, the rate was 0.4% in the United Kingdom, and in another study, it was just over 2% in the U.S. (this was also just one geographic region of the United States, but it’s important to consider that rates may vary by region due to socioeconomic factors and racism). 

It’s important to know that POI comes with health implications beyond symptoms, such as hot flashes or fertility concerns (although those symptoms and conditions are certainly important). When ovulation stops early, there are higher rates of cardiovascular disease, dementia, and osteoporosis compared with menopause at age 45 and older. In addition, women with POI are more likely to be diagnosed with anxiety and depression, and a recent study suggests that women with POI are more likely to be hospitalized with depression. 

What Causes POI?

Known causes and medical conditions that raise the risk of POI are as follows:

• Genetic: Approximately 30% of women with POI have a genetic cause.

• Autoimmune conditions cause up to 17% of POI cases: autoimmune thyroid disease, Addison’s disease (a disorder of the adrenal gland), and type 1 diabetes have the strongest association, although I think almost every autoimmune condition has only been associated with POI in small studies or case reports. 

• Cancer therapy: certain kinds of radiation and chemotherapy are toxic to the follicles in the ovary. 

• Surgery, including hysterectomy (without removing the ovaries), ovarian surgery (for example, removing a cyst), and a procedure called uterine artery embolization (a treatment for fibroids) are all associated with POI. The belief is that these procedures alter blood flow to the ovaries, or the inflammation from the surgery and healing may play a role. In addition, sometimes, with surgery to remove ovarian cysts, a small amount of normal ovarian tissue, and hence follicles, may be removed. This doesn’t mean that women should not have these procedures if they are medically indicated, but it is a consideration as one of the risks of a procedure, and it’s important to be aware of the association, so if symptoms suggestive of POI develop, there isn't a delay in testing. 

• Infections: 13% of women living with HIV will experience POI. The exact reasons are not known. It may be the infection itself, the medications, co-infection with hepatitis C, socioeconomic factors, and/or higher rates of hysterectomy and other gynecological surgery. Mumps is also associated with POI.

Unfortunately, for one to two-thirds of women with POI, a specific cause will not be identified. 

Vaccination against the human papillomavirus (HPV) is not a cause of POI, although it’s a common Internet myth. 

When and How to Test for POI

POI should be suspected when any woman who is younger than 40 has missed 3 periods in a row, or she has had 6 months of irregular periods. For women who are no longer having periods, either due to a hysterectomy or an endometrial ablation or because of a hormone IUD, POI should be suspected when someone is under age 40 and has symptoms associated with menopause, such as hot flashes or night sweats. 

Many women will skip three periods or have six months of irregular periods due to other medical conditions that are not POI, so the initial evaluation is screening for POI and as well as looking for other explanations, such as thyroid abnormalities, polycystic ovarian syndrome (PCOS), weight loss, and pregnancy. Medications and other conditions can produce symptoms similar to POI. For example, some antidepressants and sleep apnea can cause night sweats.

The initial testing for POI is the following:

• Follicle-stimulating hormone (FSH): the hormone that stimulates the follicles to produce estradiol. POI should be considered when the FSH is in the menopause range (typically > 25 IU/ml, but it could vary based on the lab). All other causes of missed or irregular periods will have a lower FSH. 

• Prolactin: a hormone produced by the pituitary gland in the brain. An elevated prolactin can cause periods to become irregular or stop.

• TSH, or thyroid-stimulating hormone: to look for a thyroid condition. 

• A pregnancy test, if indicated

• Estradiol level: with POI, it is typically < 25 pg/mL but can be low in other non-POI causes of missed periods, so a low estradiol level isn't always helpful.

If the FSH is elevated, it should be repeated with an estradiol level one month later. When the FSH is elevated on two occasions at least one month apart, and the estradiol is low, the diagnosis of POI is confirmed. At this point, other testing to look for a cause is indicated (except when the cause is chemotherapy or radiation).

Below, you will see the basic testing, but it’s possible that additional testing may be indicated based on other signs, symptoms, and family history:

• A test for diabetes, such as a fasting blood glucose or hemoglobin A1C

• An HIV test

• A blood test for 21-hydroxylase antibodies to screen for autoimmune adrenal insufficiency, the most common cause of Addison’s disease, which is a serious medical condition where the adrenal glands don’t produce enough hormones, including cortisol.

• A blood test called thyroid peroxidase antibodies (TPO) to evaluate the thyroid for an autoimmune condition. 

• Genetic testing, which typically involves a karyotype (examining the number and pairing of chromosomes) and a test for fragile X premutation. Women who carry the fragile X premutation are also at higher risk of several medical conditions, such as anxiety, depression, and tremor-ataxia syndrome, so knowing these test results can be beneficial. There are also potential considerations regarding fertility. A referral to a genetic counselor can be very helpful because they are the real experts and may recommend other testing based on family history. They can also provide detailed and relevant explanations of the results. 

Other testing, regardless of the cause of POI:

• Bone mineral density, given the higher rate of osteoporosis. 

• Lipid profile, given the higher rate of cardiovascular disease.

Treatment of POI

Unless a woman has a contraindication to estrogen, the recommendation is HRT or hormone replacement therapy. Not only can HRT treat symptoms, but estrogen is recommended to reduce the risk of cardiovascular disease, osteoporosis, and dementia. The current recommendation is to take estrogen until 51-52, the average age of menopause. Whether hormones should be continued after that (meaning MHT) will depend on symptoms and risk factors for medical conditions associated with menopause.  

When we discuss menopause hormone therapy (MHT), by default, we mean hormones for those ages 45 and up. POI is associated with different risks than menopause due to the earlier-than-expected decrease in estrogen, and the recommended estrogen replaces what is no longer there, so, in this case, it is medically accurate to use the term hormone replacement therapy or HRT for this specific population. Here, estrogen is truly a replacement therapy. However, HRT should not be the term for women who experience menopause at age 45 and up, as here, a decrease in estrogen is expected, and replacement-level doses are not typically needed.

There are two ways women with POI/early menopause can replace their estrogen: with standard regimens of estrogen and progestogen used in menopause or with the estrogen-containing oral contraceptive pill or COC (Combined oral contraceptive).

In general, the first line recommendation is HRT, starting with a 100 mcg estradiol patch (or other transdermal equivalent) or 2 mg of oral estradiol, as this dose approximates the average estrogen production of the ovary in the 30s and early 40s. Some women may need a 150 mcg patch or 3 mg of oral estradiol. Women with a uterus will need to take progesterone or progestin (a synthetic progesterone) to protect their uterus. The optimal progesterone/progestin dose for long-term use of this dose of estradiol hasn’t been determined, and some healthcare professionals may recommend 200 mg of progesterone a day here instead of 100 mg, so this needs to be personalized. A progestin, such as norethindrone or medroxyprogesterone, may also be appropriate based on the baseline risk for endometrial cancer. Another great option is the levonorgestrel IUD, as that will protect the uterus and also offer contraception (if that is a concern). Standard HRT, as described above, does not provide contraception.  

The main reason to take a COC is it is needed for contraception, and some younger women with POI may also prefer a COC as they may be bothered by the association of HRT with menopause. The recommendation is to skip the placebo pills and take the active pills every day. If the placebo pills were taken, that means symptoms of hot flashes could emerge in the week without hormones, and taking a COC 3 out of 4 weeks means that 25% of the time, there is insufficient estrogen to protect the heart and bones. 

There is a potential concern that pills with ethinyl estradiol, the most common estrogen is the pill, may not protect the bones as well as estradiol. This is likely a greater concern for women in their 20s, when they are still building bone mass than for those in their 30s (this does not apply to women in their 20s with normal ovulation using the pill for contraception). The oral contraceptive pill Zoely® has 1.5 mg of estradiol and the progestin nomegestrol acetate. This pill has the same type of estrogen as in HRT, so it avoids any potential concerns with ethinyl estradiol. Zoely® isn’t available in the US and Canada but is available in many other countries. The estradiol is slightly less than recommended for POI, but it is still a very reasonable option. 

Unfortunately and inexcusably, many women with POI don’t get the right medical care— about half are not taking the recommended hormone therapy. Some women are given the correct diagnosis, but if they’re not interested in assisted reproduction (fertility therapy), they aren’t offered the appropriate therapy to reduce their health risks. This focus on fertility while ignoring the increased risk of death associated with POI is a consequence of medical professionals and society viewing women’s health in terms of reproductive function instead of ovarian function. Other women are dismissed, as based on their age, they simply “can’t be menopausal.” Some women are offered therapy but decline it as the importance of HRT in protecting the heart, brain, and bones was never stressed.

Women with POI who are hoping to get pregnant should be referred to an infertility specialist. 

Summary:

• Primary ovarian insufficiency, or POI, is a condition when ovulation stops or becomes sporadic before the age of 40. 

• POI can be genetic, related to autoimmune conditions, caused by previous cancer therapy or surgery on the uterus or ovaries, or associated with certain infections, but often no cause is identified.

• An elevated FSH level is essential for the diagnosis. 

• Women with POI should be offered estrogen therapy at least until the average age of menopause to reduce their risk of cardiovascular disease, dementia, and osteoporosis.

• While pregnancy rates are lower with POI, it is not impossible. 

References

Stuenkel CA, Gompel A. Primary Ovarian Insufficiency NEJM 2023;388:154-63.

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Rocca WA, et al. Frequency and type of premature or early menopause in a geographically defined American population. Maturitas. 2023;170:22.

Hormone therapy in primary ovarian insufficiency. Committee Opinion No. 698. American. College of Obstetricians and Gynecologists. Obstet Gynecol 2017;129.

Primary ovarian insufficiency in adolescents and young women. Committee Opinion No. 605. American College of Obstetricians and Gynecologists. Obstet Gynecol 2014;123. 

Menopause Practice, A Clinician’s Guide 6th Edition. Crandall CJ Editor-in-Chief. The North American Menopause Society. 2019

Andany N, Kaida A, de Pokomandy A, et al. Prevalence and correlates of early-onset menopause among women living with HIV in Canada. Menopause 2019;27.

Pan M-L, Chen L-R, Tsao H-M, Chen K-H. Polycystic ovarian syndrome and the risk of subsequent primary ovarian insufficiency: a nationwide population-based study. Menopause 2017; 24.

Christ JP, Gunning MN, Palla G, et. al. Estrogen deprivation and cardiovascular disease risk in primary ovarian insufficiency. Fertility and Sterility 2018:109.