Premature Ovarian Insufficiency

What is Premature Ovarian Insufficiency (POI)?

Premature ovarian insufficiency (POI) refers to a spectrum of conditions that causes impaired or diminished ovarian function before the age of 40. Premature ovarian insufficiency is not the same as premature menopause because ovarian function can wax and wane in women with POI. Some women with POI will stop producing sex hormones completely, but others may intermittently produce levels sufficient for ovulation, normal or irregular menstrual cycles or even pregnancy.

Premature Menopause

The term premature menopause is used when menopause occurs before the age of 40, this can be surgically induced by the removal of both ovaries or via chemotherapy or radiation and is absolute. While POI implies impaired ovarian function which can wax and wane.

Natural Menopause

Natural menopause is divided into three stages:

1. Perimenopause
2. Menopause
3. Post menopause

These phases are tightly regulated by hormones in the brain (LH and FSH) that stimulate the ovaries to produce sex hormones (estrogen, progesterone and testosterone). Perimenopause is the time leading up to the final menstrual cycle and can last up to 10 years. During this time the ovaries make less estrogen and cycles can become erratic. Natural menopause occurs when the ovaries become nearly depleted of ovarian follicles. This causes a drop in the level of sex hormones and cessation of menstrual cycles. For most women, this occurs around age 52 however, natural menopause can occur anytime between the ages of 45 to 58.

Roughly 5% of women will undergo early menopause between the ages of 40-45.

What Causes POI and/or Premature Menopause?

Most cases of POI and premature menopause are idiopathic, in other words there is no specific cause. Other causes for POI include the following:

• Toxic exposures: Chemotherapy and radiation are both commonly used for the treatment of cancer. These therapies can be particularly damaging to the ovaries and can induce POI in young women.
• Injury: In some cases, injury or decreased blood supply during a surgical procedure may induce POI in some women.
• Genetic abnormalities: Genetic and chromosomal defects can cause abnormalities throughout the reproductive system, which can be passed from generation to generation. Most of these syndromes present with specific features that allow them to be identified at an early age. Some of the more common disorders include Turner syndrome and Fragile X syndrome.
• Autoimmune disorders: Autoimmune disorders occur when the body’s immune system (or the body’s natural defense mechanism) mistakenly begins to attack normal tissue/cells. Premature ovarian insufficiency can occur in autoimmune conditions affecting the thyroid gland, adrenal glands, ovaries and other organs as well.

What are the Symptoms of POI?

Women with POI and premature menopause usually progress through the normal stages of puberty and have regular periods before any signs of ovarian insufficiency develop.

1. The first clue for many women is sporadic periods or complete cessation of periods many times in her 30s. Any woman less than 40 years old who misses three or more periods in a row should be evaluated.
2. POI and/or premature menopause often occur during the reproductive years when many women are on some form of birth control. Birth control provides women varying levels of hormones that can mask any ovarian insufficiency in women with premature menopause. Therefore, many women notice the symptoms after stopping birth control.
3. In POI, hormonal contraception does not always suppress ovulation as hormonal contraception was designed for eugondatrophic women, so women may experience irregular bleeding patterns and/or intermittent ovulation. Often times these irregular bleeding patterns are thought to be a side effect of the birth control. When symptoms persist after birth control is stopped, this is a sign that additional evaluation is warranted.
4. Infertility can be a major issue for women with POI. While pregnancy is unlikely, some women may be able to conceive naturally or with the use of donor eggs.
5. Once the ovaries stop producing sex hormones, particularly estrogen, women with POI experience very similar symptoms as women going through menopause. The symptoms can include:
   1. hot flashes
   2. night sweats
   3. vaginal dryness
   4. sometimes painful intercourse

What am I at Risk for with POI?

Women who have premature ovarian insufficiency can have lower levels of estrogen as well as other hormones that are detrimental to their health causing them to be at increased risk of a number of medical conditions.

Symptoms of Menopause

Lower levels of estrogen can lead to hot flashes, night sweats, vaginal dryness, pain during sexual intercourse and low sexual drive just to name a few. Women with POI have difficulties getting pregnant and often seek help from a fertility physician.

Bone Loss and Osteoporosis

Estrogen is essential to bone health. Without estrogen, women with POI often develop osteoporosis and increase their risk of fractures.

Cardiovascular Morbidity and Mortality

Cardiovascular disease is the leading cause of death for both men and women. A decline in natural estrogen has been linked to increased risk of heart disease in women. Lower levels of estrogen at a young age can negatively affect cholesterol ratios, blood pressure and may increase the risk of hardening of the arteries.

Sexual Dysfunction

Decreased levels of estrogen and testosterone contribute to lack of sexual desire, reduced arousal, vaginal dryness, painful sex, and difficulties in achieving orgasm.

Skin and Hair Changes

Dryness and thinning can occur due to low estrogen.

Anxiety and Depression

Hormonal changes can lead to poor sleep which may contribute to anxiety or lead to depression.

Impaired Cognition

Estrogen has a positive effect on the brain. Studies have shown that women who undergo oophorectomy (surgical removal of the ovaries) at a young age are at an increased risk of cognitive impairment or dementia, which may be explained by a deficit in hormones.

Low Thyroid Function

Low levels of thyroid hormones can affect your well-being, energy level, mental health, and metabolism and menstruation.

How is POI Diagnosed?

Diagnosis of POI involves comprehensive medical history taking, including:

• Menstrual cycle
• Prior ovarian surgery, chemotherapy, or radiation
• Symptoms of primary adrenal insufficiency: anorexia, weight loss, vague abdominal pain, weakness, fatigue, salt craving
• Personal or family history of autoimmune diseases: hypothyroidism, Grave’s disease, primary adrenal insufficiency, vitiligo, myasthenia gravis, hypoparathyroidism, recurrent mucocutaneous candidiasis, type 1 diabetes, celiac disease, autoimmune oophoritis
• Family history of POI
• Family history of fragile X syndrome (mutation in FMR1) with a family history of male mental retardation, developmental delay, Parkinsonism, intention tremor, ataxia, and/or dementia
• Deafness

Your doctor may recommend one or more of the following tests depending on your history:

• Pregnancy test
• Follicle -stimulating hormone (FSH) test. Abnormally high levels of FSH can suggest POI- which means that the growth of follicles in the ovaries is absent at that time it is checked.
• Estradiol test. Lower levels of estrogen suggest POI- which means that ovarian function is absent.
• Prolactin test. High levels of prolactin can lead to problems with ovulation.
• Karyotype test. This test examines your 46 chromosomes for abnormalities.
• FMR1 gene testing. The FMR1 gene is the gene associated with Fragile X Syndrome- an inherited disorder that could cause intellectual problems.
• Pico Anti-Mullerian Hormone (AMH) Elisa test. This test helps to determine a woman’s menopausal status and ovarian reserve.

How is POI Treated?

Treatment of POI can include hormonal and non-hormonal approaches. In women with primary ovarian insufficiency, the goal of treatment is to replace the hormone that the ovaries are no longer making realizing that INTERMITTENT ovarian function may occur independent of therapy. Systemic hormone replacement therapy (HRT), administered orally or transdermally, is an effective approach to treat the symptoms of estrogen deficiency and mitigates long-term health risks if there are no contraindications to treatment.

Hormone replacement therapy is indicated to reduce the risk of osteoporosis, cardiovascular disease, and urogenital atrophy and to improve the quality of life of women with primary ovarian insufficiency.

Treatment for all women with primary ovarian insufficiency should continue at least until the average age of natural menopause is reached (average age 51 years). Hormonal contraception can be used as HRT, however NOT for contraception which is RARE on or off hormonal contraception.

Estrogen/Progestin Therapy

Estrogen relieves symptoms of estrogen deficiency, including symptoms of menopause. Your doctor will typically recommend hormone replacement therapy (HRT). This combination regimen does NOT provide effective contraception and thus, a more effective method of birth control is warranted such as a barrier method and/or an intrauterine device if the rare chance of pregnancy needs to be prevented. Adding progesterone protects the lining of the uterus from precancerous changes caused by taking estrogen alone.

Long-term estrogen/progestin therapy use has been shown to be beneficial in reducing risks of cardiovascular disease, osteoporosis, cognitive decline, and sexual dysfunction in those women with POI.

Low bone mass in women with primary ovarian insufficiency is managed most appropriately with HRT in addition to adequate dietary calcium and a vitamin D supplement and regular exercise.

For those who desire pregnancy, a small percentage of women could still get pregnant on their own. For those who can’t get pregnant on their own or in women anticipating cancer treatment during their childbearing years, you can still get pregnant with new-age technologies in fertility-preservation. Ask your doctor about seeing a fertility specialist.