Primary Ovarian Insufficiency

The age at which menopause occurs in Western populations of women is 50 ± 4 years.¹ 

Primary ovarian insufficiency (POI), also known as premature ovarian failure, premature menopause, hypergonadotropic amenorrhea, hypergonadotropic hypogonadism, and ovarian insufficiency, refers to the loss of ovarian function before the age of 40 years. The condition is present when a woman, less than 40 years old, has had amenorrhea for more than 4 months; with two serum FSH levels in the menopausal range (>40 UI), obtained at 1-month distance.² In contrast with menopause, in which the loss of ovarian function is physiological and irreversible, in women with POI the ovarian function is varying in almost 50% of cases and up to 5–10% of women conceive after having been diagnosed. Thus, the definition suggested by Welt of “ovarian insufficiency”, while being more acceptable to patients, meets the need to describe a continuum of impaired function rather than a dichotomous state.³

The condition affects approximately 1% of women, occurring in 10–28% of women with primary amenorrhea and 4–18% in those with secondary amenorrhea.⁴ POI may be developed as a result of many pathogenic mechanisms such as chromosomal or genetic abnormalities, autoimmune, infectious, or iatrogenic causes. In 90% of cases no cause is found and they are classified as idiopathic.⁵

Although some patients will report hot flashes and/or vaginal dryness, the most common presentation of POI is primary or secondary amenorrhea. However, any abnormal bleeding patterns such as oligomenorrhea, dysfunctional uterine bleeding and polymenorrhea, can be an early sign of POI. Therefore, any change from regular to irregular menses for 3 or more consecutive months should be investigated for all potential causes, such as pregnancy, polycystic ovary syndrome, hypothalamic amenorrhea, thyroid dysfunction, and POI.⁶ The initial laboratory work up should include serum FSH, estradiol, prolactin and thyroid stimulating hormone (TSH) to rule out pregnancy, hyperprolactinemia and thyroid disease. If FSH levels are in the menopausal range (above 40 mUI/ml), a repeated FSH measurement should be done in 1 month. If the results still indicate high FSH levels, the diagnosis of POI can be made. The progestin-withdrawal test is not indicated as it could be misleading, since ovarian function can be intermittent (thus hypoestrogenism), and almost one-half of women with POI will respond to the progestin challenge, thus delaying the diagnosis.⁷

Antimüllerian hormone (AMH) is currently being evaluated to determine its value in the diagnosis of POI. AMH could become of great importance in assessing the ovarian reserve in women at risk of developing POI, such as women with cancer undergoing chemotherapy, before extensive ovarian surgery, or females with a family history of early menopause.⁸

Once a diagnosis of POI is established, further testing is indicated to investigate possible etiologies.

POI may be developed as a result of many pathogenic mechanisms such as chromosomal or genetic abnormalities, autoimmune, infectious, or iatrogenic causes (Table 1).

Table 1 Etiology of premature ovarian insufficiency

Chromosomal and genetic causes

In 50% of patients with primary amenorrhea as a result of POI, an abnormal karyoptype is associated.⁹ Among women with secondary amenorrhea, 13% also have been noted to have an abnormal karyotype.⁷ Familial as well as non-familial X chromosome abnormalities have been described in women with POI. Monosomy X (Turner’s syndrome) leads to ovarian dysgenesis with primary amenorrhea.¹⁰ However, patients with Turner’s syndrome due to mosaicism (45X/46XX and 45X/47XXX), are more likely to menstruate and can do so several years before developing POI. It is believed that X trisomy has no effect on fertility; however, association with POI has been reported. Balanced X/autosomal translocations, and X chromosome deletions can also lead to POI.⁵

Fragile X syndrome is the most common form of hereditable mental retardation.⁶ It is an X-linked triplet repeat disease that occurs when the number of CGG repeats in the 5' untranslated region of the FMR1 gene reaches more than 200.³ A number of repeats between 6 and 40 is considered normal, 41–60 repeats are gray-zone, 61–200 are premutated, and the full mutation occurs above 200 repeats.⁵ Women who carry the full mutation have mental retardation but a normal reproductive lifespan; on the contrary, POI occurs in premutated carriers in 13–26% of cases, and the age at menopause is decreased in proportion to the number of repeats.¹¹

Among the genetic disorders than can be associated with POI the most frequent is galactosemia. It results from the mutation of the galactose 1-phosphate uridyl transferase (GALT), the enzyme that converts galactose to glucose.¹² Patients that carry the classic mutation have no GALT enzyme activity and buildup galactose metabolites, which cause cell damage. The disease presents with mental retardation, liver failure and kidney insufficiency. Retrospective analysis of a large number of patients showed that POI occurs in 75–96% of homozygous galactosemic women.¹³ A galactose-free diet eliminates the clinical symptoms, although ovarian compromise cannot be completely reversed by the diet alone.¹²

An extensive discussion over all the candidate genes for POI goes beyond the scope of this chapter, and readers are referred to Goswami and Conway for a comprehensive review.⁵ Briefly, other genetic diseases associated with POI are the mutations of the FSH receptor (FSHR), the blepharophimosis/ptosis/epicantus inversus syndrome, the ataxia telangectasia, alterations of the inhibin alpha gene (INHA), of the bone morphogenetic protein 15 (BMP15), the Diaphanous 2 Drosophila Homologue (DIAPH2), and the polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (AIRE gene).⁵

Autoimmune diseases

Autoimmune diseases are characterized by the presences of organ and non-organ specific autoantibodies. Autoimmune ovarian insufficiency can be present in three different situations: (1) associated with adrenal autoimmunity, (2) associated with non-adrenal autoimmunity, and (3) isolated idiopathic autoimmunity.¹⁴

The association of POI with autoimmune Addison disease (adrenal insufficiency) can occur in the context of two types of autoimmune polyendocrine syndromes (APS): type I (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy) and type II (a polygenic syndrome with Addison disease and hypothyroidism).¹⁵ The incidence of POI in APS type I is approximately of 60% and in APS type II is 10% of cases.¹⁶ In steroidogenic cell autoimmunity, the mechanism responsible for the ovarian failure is autoimmune lymphocytic oophoritis which is characterized by mononuclear inflammatory cell infiltrate in the theca cells of growing follicles, with early stage follicles without lymphocytic infiltration.¹⁵ The infiltrate includes plasma, B and T cells and may also involve perivascular and perineural regions.¹⁷ As the immune reaction affects the steroid-producing cells but not the granulosa cells, estradiol production is ended but inhibin B levels are normal. In the absence of estradiol, FSH levels rise, stimulating follicular growth, which leads to the formation of cyst and high levels of inhibin B.³ Serum ovarian antibodies can be detected by indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA); however, ovarian antibodies lack specificity and testing for them is not warranted.¹⁸ Much better markers of autoimmune POI are adrenocortical autoantibodies such as 21-hydroxylase (CYP21Ab) and steroid cell autoantibodies (SCAb). These antibodies should be measured in all women with POI because they are predictive of adrenal failure in 50% of adult cases;¹⁹ they are uncommon in non-adrenal autoimmunity and in isolated idiopathic POI.

The POI may also be associated with non-adrenal disorders such as thyroid diseases, hypoparathyroidism, type 1 diabetes mellitus, systemic lupus erythematosus (SLE), Sjögren’s syndrome, rheumatoid arthritis, immune thrombocytopenic purpura, autoimmune hemolytic anemia, pernicious anemia, vitiligo, celiac disease, primary biliary cirrhosis, glomerulonephritis, multiple sclerosis and myasthenia gravis.¹⁵ The presence of these diseases in women with POI is higher than in the general population, suggesting that autoimmune mechanisms are involved in the pathogenesis of up to 30% of POI cases.⁵

Iatrogenic

Almost any pelvic surgery that affects the ovarian blood supply can be responsible of the development of POI. Extensive or repeated ovarian surgery, even for a benign disease such as endometriosis, can be responsible of POI. According to Busacca and colleagues there is a rate 2.4% postsurgical ovarian failure in patients undergoing laparoscopic excision of bilateral endometriomas.²⁰

After anticancer therapy, the incidence of amenorrhea has been reported to vary between 40% and 68%.^{21, 22} The frequency of ovarian failure seems to depend on the type, dose, and duration of the therapy.²³ Alkylating agents and procarbazine are responsible for the highest incidence of acute ovarian failure after chemotherapy. Whole-body, whole-brain, pelvic and spinal irradiation also increase the risk of losing ovarian function. Another risk factor for ovarian failure is the age of the patient, with older women having a much higher incidence of permanent sterility than younger women.^{21, 24} Nevertheless, even survivors of childhood malignancies who experience a spontaneous pubertal development, regular menstrual cycles, and normal early follicular FSH levels, show significantly lower uterine volume and more elevated resistance at the level of the uterine arteries compared with control patients, suggesting an accelerated decline of fertility.²⁵  

Infectious and toxic causes

Mumps oophoritis has been considered to be a cause of POI.²⁶ Cigarette smoking is associated with a decrease in age of menopause of at least 1–2 years compared to the general population. However, the association between the effects of chemicals, cigarette smoke, heavy metals, and female reproduction is still dubious and further studies are required before drawing any conclusions.

When managing a patient diagnosed with POI various issues have to be considered. First of all, menopausal symptoms have to be relieved and long-term health sequel of estrogen deficiency prevented. Second, associated pathology has to be assessed and treated. Finally, patients have to be helped to deal with the loss of fertility and the emotional challenge that this entails.

Hormone replacement therapy

Regardless of the etiology, patients with POI are estrogen deficient. Thus, hot flashes, vaginal dryness, difficulty sleeping, mood swings, and sexual disturbance can be relieved by the use of hormone replacement therapy (HRT). Moreover, hypoestrogenism is responsible of osteoporosis and cardiovascular disease. As very well stated by Nelson and colleagues: “it is not scientifically valid to apply results of the Women’s Health Initiative study, a study on older menopausal women, to young women with POI who experience pathologically low estradiol serum levels compared to their peers who have normal ovarian function”.¹⁸ In these patients the hormonal treatment focuses on replacing the hormones that the ovary has stop producing, so that the metabolic paths that are estrogen dependent are kept functioning, as in contrast with menopausal women in which HRT is meant to alleviate menopausal symptoms. Once POI patients reach normal menopausal age (50 years or so), therapy management can be revised.¹⁸

In young girls with incomplete breast development, estrogen therapy should be initiated and increased slowly before administration of progesterone dosages until breast development is completed.⁶ Once pubertal development is completed, ongoing therapy will be necessary. Young women may need higher dosages of estrogen than menopausal women to ensure an adequate replacement. The transdermal route is recommended to avoid the first-pass effect on liver with transdermal E2 patches (100 µg/day). Micronized progesterone (200 mg/day) for 12 days each month is considered protective against endometrial hyperplasia. Combined oral contraceptives (COCs) can be used in patients who suffer from cysts development or in those who desire contraception.³ Nevertheless, despite containing higher doses of estrogen than are necessary, COCs may not protect towards the hot flashes during the placebo week. Furthermore, since FSH levels can be extremely elevated, COCs are not fully reliable in women who do not wish to get pregnant, so they are not recommended as first-line hormonal therapy in patients with POI.¹⁸

Bone loss

Young women with POI have significantly lower bone mineral density (BMD) compared to regularly menstruating women.²⁷ Thus, BMD should be measured and patients should be advised on lifestyle (daily exercise, calcium intake – 1200/1500 mg/day, vitamin D intake) and therapy. Although the literature does not clearly establish the best HRT for women with POI, Popat and colleagues have recently demonstrated that continuous transdermal estradiol and oral progestin therapy, not only maintains BMD, but it can also restore BMD back to normal levels in this population.²⁷ In this study, HRT increased significantly bone formation markers. In contrast, oral contraceptives may have inferior bone effects compared to cyclic progesterone and continuous transdermal estradiol.²⁷

Biphosphonates are not advised in POI patients since they have a long skeletal half-life and may have teratogenic effects in patients wishing to become pregnant.

Comorbidities

Hypothyroidism is present in nearly 20% of POI patients at diagnosis. Thyrotropin levels and the presence of thyroid peroxidase antibodies should be checked. If negative, a thyroid disease should not be definitively ruled so it is reasonable to measure thyroid values annually. Anti-adrenal antibodies should also be evaluated, but if negative, in absence of any adrenal symptom, there is no need to repeat the testing. Other autoimmune diseases (lupus erythematosus, rheumatoid arthritis, diabetes, etc.), may be associated with POI, however, in the absence of specific symptoms, no testing is advocated. As such, except from a karyotype to identify Turner’s syndrome and testing for Fragile X syndrome, no other genetic disorder should be investigated unless symptomatology raises suspicion.  

Women affected by POI have an increased risk of cardiovascular mortality.²⁸ Patients with Turner's syndrome have an additional risk, including aortic aneurism. All patients experiencing an early loss in ovarian function should be advised on healthy lifestyle (no smoking, physical exercise, appropriate diet, etc.), which also includes regular medical checkups in order to measure blood pressure and lipid levels. As stated above, HRT is recommended since there is currently no evidence that these patients are at increased risk of cardiovascular adverse effects from hormonal therapy.²⁹   

Fertility and contraception

As POI is an intermittent condition, chances of conceiving are not zero, but can reach 5–10%. However, resumption of fertility is unpredictable and no therapies can improve this rate. Only IVF with egg donation has demonstrated high success rates and is currently considered the treatment of choice in these patients. Nevertheless, Turner’s syndrome patients should consult with a cardiologist prior to undergoing an egg donation process, since they have a higher risk of aortic dissection.¹⁰

Resumption of ovarian function may occur after regression of the autoimmune status and control of the coexistent endocrine disease. Thymectomy in women with myasthenia gravis can lead to resumption of menses, corticosteroids administration can restore fertility in patients with polyglandular endocrinopathy syndrome.⁵ However, long-term therapy with immunomodulators is not recommended due to the associated complications such as osteonecrosis.⁵

Cryopreservation of ovarian tissue, oocytes or embryos (if a male partner is present), is another option for women who are likely to develop POI, such as patients who have to undergo chemoradiotherapy or ovarian surgery. Age at diagnosis is a determining factor in establishing the best option. In prepubertal girls, cryopreservation of ovarian tissue is the only viable option. Donnez reported in 2004 the first live birth after orthotopic transplantation of cryopreserved ovarian tissue.³⁰ However, patients with possible metastasis to the ovary, or with ovarian cancer, should not be offered this option for safety reasons. IVF with oocyte/embryo cryopreservation is a safer solution, although it can only be offered to adult women. According to Devesa and colleagues the ovarian response in women with cancer undergoing controlled ovarian hyperstimulation for fertility preservation purposes, is as expected according to an age-specific nomogram.³¹ Moreover, it has been proven that mature oocytes can be efficiently obtained before cancer treatment irrespective of the phase of the menstrual cycle.³² Thus, fertility preservation does not delay significantly the beginning of chemo- or radiotherapy.³¹

Women with POI, who do not seek pregnancy, may use oral contraceptives, although anecdotal reports of women conceiving while complying with the pill have been published.³³

POI is a unique condition that requires special care on behalf of the physicians who attends the woman. Therefore, these patients should be treated for the loss of the ovarian function with HRT and, if necessary, for the associated comorbidities. They should also be advised on the proper lifestyle they should maintain in order to improve their cardiovascular and bone health. Finally, healthcare practitioners should bear in mind that in addition to the stressful event of the diagnosis, these women also face the loss of the opportunity to have children, so emotional support to help them deal with the diagnosis and its consequences is also required.

This work was performed under the auspices of the “Catedra d’Investigación I Ginecología” of the Department of Obstetrics, Gynecology and Reproduction, Hospital Universitario Quirón-Dexeus, Universitat Autónoma de Barcelona