As a woman gets older, the number of viable eggs in the ovary, also known as ovarian reserve, naturally declines. Ovarian activity also declines progressively with age. By the time a woman reaches menopause at age 45 to 55, ovarian reserve and function has diminished, making it almost impossible to get pregnant at this age.

In some women, however, diminished ovarian reserve and impaired ovarian function occur even before 40 years old. This condition is known as primary ovarian insufficiency.

Having ovarian insufficiency is definitely a challenge for women and couples who wish to become pregnant. A diagnosis of ovarian insufficiency prompts women to ask, “Can I still get pregnant?”

Read on to know the answer and to learn more about how ovarian insufficiency affects your fertility journey.

What is ovarian insufficiency?

Primary ovarian insufficiency is a condition that is defined by impaired ovarian function occurring on a continuum with irregular ovulation before the age of 40. This condition can either be transient or progressive, and may ultimately lead to premature menopause, which is menopause that occurs before 40 years old¹. Primary ovarian insufficiency is also used to describe related conditions of the ovary, such as hypergonadotropic hypogonadism, ovarian dysgenesis, and premature ovarian failure².

Women with primary ovarian insufficiency have reduced levels of reproductive hormones and considerable infertility. The resulting infertility is life-changing, especially for those trying to conceive³.

Ovarian insufficiency has been reported in 1 in every 10,000 women by age 20, 1 in every 1000 by age 30, and 1 in 100 women by age 40⁴. Any woman of reproductive age who experiences infertility should be suspected of having primary ovarian insufficiency³.

Causes

For majority of patients diagnosed with primary ovarian insufficiency, the cause is unknown. Some of the proposed underlying causes of ovarian insufficiency are¹:

• genetic disorders
• autoimmune disorders
• metabolic disorders
• infections
• iatrogenic or unexplained causes

Genetic disorders that affect the structure of the X chromosome and the development of the ovary are thought to cause ovarian insufficiency. These disorders include X-chromosome disorders such as Turner syndrome, mutations on the X chromosome such as in Fragile X syndrome, gonadal dysgenesis, and mutations in enzymes and hormones required for reproduction.

The most common autoimmune disease linked to ovarian insufficiency is thyroiditis. Other autoimmune diseases that have been associated with the development of ovarian insufficiency include hypothyroidism, myasthenia gravis, systemic lupus erythematosus, and rheumatoid arthritis.

Abnormalities and mutations in enzymes involved in metabolic pathways have also been linked to ovarian insufficiency. Metabolic disorders such as galactosemia, carbohydrate-deficient glycoprotein deficiency, and deficiencies in enzymes crucial in estrogen production, such as aromatase and 17-α-hydroxylase.

Infections such as mumps and HIV have also been studied as probable causes of ovarian insufficiency. Meanwhile, proposed iatrogenic causes of ovarian insufficiency include chemotherapy and radiotherapy.

Symptoms

Primary amenorrhea, which is the absence of menses at 16 years old, is the first symptom in 10% of women diagnosed with primary ovarian insufficiency. In majority of patients, however, the presenting symptom is irregular menstrual cycles, described as any of the following⁵:

• absence of periods
• infrequent menstrual periods, <6 or 8 periods every year
• heavy menstrual bleeding
• short menstrual cycles
• irregular bleeding

Symptoms of low estrogen levels are also present, such as^1,2:

• hot flashes
• night sweats
• mood swings
• sleep disturbance
• thinning and drying of the vaginal wall, also known as atrophic vaginitis

Women with primary ovarian insufficiency eventually experience infertility. In many cases, the diagnosis is made after evaluation for irregular menses. Still, there are cases when the diagnosis is only made after evaluation for infertility³.     

Aside from these symptoms, women with ovarian insufficiency may also experience other health conditions that are associated with low estrogen levels, such as osteoporosis, cardiovascular disease, and neurocognitive disorders such as dementia⁶.

How is ovarian insufficiency diagnosed?

Primary ovarian insufficiency is diagnosed based on the presence of the following criteria²:

• age below 40 years old
• absent or infrequent periods
• 2 elevated levels of follicle-stimulating hormone (FSH), taken at least one month apart

FSH is a hormone synthesized in the anterior pituitary and is a key hormone for estrogen production and follicle development in females. Increased levels of FSH in females are associated with ovarian dysfunction. For example, in premature ovarian failure, FSH levels remain elevated because of the absence of negative feedback from the ovaries⁷.

Women being evaluated for ovarian insufficiency should be asked about their detailed menstrual history. The doctor should take note of the possible causes of abnormal menstrual cycles, such as polycystic ovarian syndrome, chronic illnesses such as diabetes or celiac disease, thyroid disorders, pituitary lesions, and even pregnancy. Family history, particularly genetic and autoimmune diseases, should be considered. A thorough physical examination focusing on the examination of body habitus and the female genital tract can help in making the diagnosis¹.

Aside from detection of FSH levels, other tests requested during diagnosis may include the following^2,5:

• Karyotype analysis

Karyotyping helps identify whether monosomy X, or Turner syndrome (45,X) is present. Turner syndrome presents with underdeveloped reproductive organs, making it a probable cause of primary ovarian insufficiency. A study also reported that genes that are important for sexual development may be inactivated in the normal X chromosome of patients with Turner syndrome⁸.

• Detection of mutation in the FMR1 gene

Females suspected of having ovarian insufficiency may be tested for the presence of FMR1 gene mutation. Mutation in the X-linked FMR1 gene results in Fragile X syndrome, which is the number 1 genetic cause of cognitive disability. Studies have shown that females with Fragile X syndrome have up to 23% incidence rate of primary ovarian insufficiency¹. Fragile X-associated ovarian insufficiency presents as abnormal follicle function⁹.

• Detection of adrenal antibodies via immunoprecipitation or indirect immunofluorescence

About 4% of women with ovarian insufficiency have adrenal antibodies. A positive test for adrenal antibodies suggests that the ovarian disorder is due to autoimmune processes that involve steroidogenic cells and lymphocytes¹⁰.

• Pelvic ultrasound

A pelvic ultrasound will help identify the presence of cysts in the ovaries, which is a prominent feature of women with deficiency in the enzyme 17,20-desmolase, an important enzyme for the formation of the female hormones 17-hydroxyprogesterone and 17-hydroxypregnenolone. Multiple cysts in the ovary are also present in autoimmune oophoritis and polycystic ovary syndrome, which are probable underlying causes of primary ovarian insufficiency¹⁰.

• Bone mineral density

Ovarian insufficiency is a risk factor for the development of bone¹¹. Evaluation of bone mineral density helps in assessing the risk and identifying the presence of osteoporosis and other bone diseases. Early identification is important in preventing long-term complications of decreased bone health⁵.

Can I still get pregnant if I have ovarian insufficiency?

Yes, you can still get pregnant even if you have been diagnosed with ovarian insufficiency. In some women, normal ovarian function resumes even without treatment, thus allowing pregnancy¹². Reports reveal that approximately 5 to 10% of women were able to naturally conceive and deliver a baby even after being diagnosed with the condition².

Still, a vast majority of women with ovarian insufficiency experience infertility. Inability to conceive causes not only physical stress, but also considerable emotional stress to women and their partners.

Fortunately, several strategies that promote pregnancy in the setting of ovarian insufficiency are now available. With a wider set of treatment options, new fertility modalities provide hope for women desiring of pregnancy.

Treatment for ovarian insufficiency

The following are the treatment options currently recommended for women with ovarian insufficiency who are desirous of pregnancy¹³:

• Oocyte donation

Oocyte donation is the preferred treatment for women with ovarian insufficiency who want to get pregnant¹³. Oocyte donation involves a female donor and the female recipient who wishes to conceive. Unlike sperm donation, oocyte donation is an invasive procedure that involves surgical retrieval of mature oocytes from the ovaries of the donor, who is put under local anesthesia¹⁴. In the United States, oocyte donation makes up about 10% of all assisted reproductive technology (ART), with more than 50% live birth rate every cycle¹⁵.

• Hormone replacement therapy (HRT)

HRT is a common treatment approach for primary ovarian insufficiency. The aim of HRT is to restore normal estrogen levels in women. It is recommended that HRT be started at the time of diagnosis of primary ovarian insufficiency until menopause¹⁶. A sample HRT regimen is daily 50-100 μg transdermal estradiol, which is a form of estrogen, supplemented with 5-10 mg of medroxyprogesterone acetate for 12 days per month¹.

HRT, combined with ovarian stimulation, has resulted in a huge number of pregnancies¹³. HRT also provides protection against diseases linked to ovarian insufficiency, such as osteoporosis, cardiovascular diseases, dementia, and genitourinary syndrome¹⁶.

• Ovarian stimulation

Ovarian stimulation involves the administration of key female hormones, such as FSH and luteinizing hormone (LH) above normal levels. This allows the maturation of multiple oocytes, which can then be retrieved during each IVF cycle. The oocytes can then be used for embryo culture, embryo transfer, and implantation. Spare embryos may also be cryopreserved to increase chances of future pregnancies, without the need for another round of ovarian stimulation and retrieval of oocytes¹⁷.

• Dehydroepiandrosterone (DHEA) administration

A relatively new modality in promoting pregnancy in women with ovarian insufficiency is the use of DHEA. DHEA was shown to improve the ovarian environment, promote estrogen and progesterone production, and increase the number of receptors for FSH. These effects result in the growth of more pre-antral and small antral follicles. Multiple studies have reported that DHEA administration resulted in enhanced ovulation and successful pregnancies¹³.

Aside from these techniques, two new emerging technologies are being explored to increase fertility rates in women with ovarian insufficiency¹³:

• In vitro activation (IVA)

Women diagnosed with primary ovarian insufficiency may have irregular or absent menstrual cycles, but they still have dormant follicles in the ovaries. IVA rescues these residual dormant follicles by manipulating the processes involved in their maturation. IVA therefore helps women become pregnant using their own egg cells¹⁸.

• Stem cell therapy

Stem cell injection has also been explored recently as a means to induce pregnancy in women with ovarian insufficiency. A recent study showed that injection of umbilical cord mesenchymal stem cell to the ovaries plus HRT resulted in 2 pregnancies out of 14 women who participated in the study¹⁹.

Can ovarian insufficiency be prevented?

Primary ovarian insufficiency that is caused by genetic or autoimmune disorders may be impossible to prevent, but it is possible to predict whether other relatives would also present with ovarian insufficiency. Genetic analysis and family studies can help identify family members who are at risk of having ovarian insufficiency.

Meanwhile, primary ovarian insufficiency due to chemotherapy or radiotherapy may be prevented by considering other therapeutic options, especially for women who strongly desire to become pregnant. If there are no other options, patients could opt for cryopreservation of oocytes prior to chemotherapy or radiotherapy.

References

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• Ding, L., Yan, G., Wang, B., Xu, L., Gu, Y., et al. (2018). Transplantation of UC-MSCs on Collagen Scaffold Activates Follicles in Dormant Ovaries of POF Patients with Long History of Infertility. Science China Life Sciences. 2:1554-1565.