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Causes of Anovulation: WHO Class 3

Sophie Christin-Maitre and Jean-Pierre Siffroi

Introduction

WHO class 3 anovulation is characterized by hypergonadotropic hypogonadism or primary ovarian insufficiency, and is also called premature ovarian insufficiency (POI). POI (MIM 311360) is diagnosed in adolescents with primary amenorrhea or in adolescents or young women presenting with secondary amenorrhea lasting more than 6 months and occurring before the age of 40. In all cases, plasma gonadotropins are in the postmenopausal range, and estradiol levels are low (1). Classically, FSH serum levels, measured twice, at least 1 month apart, are higher than 40 IU/L. ESHRE guidelines recommend an elevated FSH level >25 IU/L on two occasions >4 weeks apart (2). In most cases, the antral follicle count (AFC) evaluated by pelvic ultrasound examination is diminished, and AMH serum level is very low (LOE 2a).

Overview of Existing Evidence

POI affects 1%–3% of reproductive-age women (LOE 3). POI should be distinguished from diminished ovarian reserve (DOR). Indeed, women with DOR have infertility associated with antral follicular counts below 10, but they are still menstruating. Furthermore, their FSH levels are only slightly elevated and not in the menopausal range. The term POI is more accurate than premature ovarian failure (POF) or premature menopause. Indeed, the term menopause suggests a definitive arrest of ovarian function, and variable degrees of ovarian function are preserved in a subset of patients with POI. Second, hormonal replacement therapy (HRT) is necessary for women with POI in order to avoid effects related to estrogen deficiency. Finally, the term POI is less stigmatizing. Among the different etiologies of POI, genetic causes should be distinguished from infectious, surgical, and toxic causes.

Among the toxic causes, chemotherapy and radiotherapy are becoming frequent causes of POI due to a growing population of childhood/adolescent cancer survivors (3). Alkylating agents remain some of the most toxic drugs as they induce POI in 40%–50% of treated women. Sixty to eighty percent of women treated with cyclophosphamide, methotrexate, and 5-fluorouracil will develop POI. Chemotherapeutic agents damage the ovary by increasing follicle loss (3). This phenomenon can be due to direct damage to the oocytes and direct damage to somatic cells as well as an increased rate of follicle growth initiation (3). The impact of radiotherapy is dependent on dose, age at treatment, and on the radiation therapy field. Many occupational exposures to chemicals have been shown to induce POI in animal models (4). However, in humans, environmental causes are difficult to identify. A study has reported an adjusted RR of POI of 3.24 (1.06–9.9) in hairdressers using dyes without gloves (5).

Cases of POI have been reported after ovarian surgery or uterine artery embolization. A potential detrimental effect of surgery has been described mainly in patients operated for bilateral ovarian endo-metriomas (6). The laparoscopic stripping of recurrent ovarian endometriomas has been associated with a high risk of ovarian failure. Furthermore, endometriosis by itself could influence ovarian aging and increase the risk of POI (LOE 3).

In the absence of previous chemotherapy, radiotherapy, or ovarian surgery, genetic causes of POI need to be investigated (1). Some genetic causes of POI are syndromic (Table 6.3). Most of them are linked to X chromosomal abnormalities. They include abnormal numbers as well as structural defects of the X chromosomes. The most common is Turner syndrome with 45, X karyotype, 45,X/46,XX mosaicism or Xq isochromosome. Clinical features of Turner syndrome include small height and ovarian insufficiency. Around 30%–40% of patients with Turner syndrome enter puberty, but less than 10% have spontaneous menses and more than 95% will develop POI (7). Among patients with Turner syndrome, the diagnosis is established in adults in 10% of cases. In POI, apart from Turner syndrome, the karyotype can also reveal Xq deletions as well as X;autosomal translocations or trisomy X. By studying patients with Xq deletions, it has been demonstrated that two different regions located on the long arm of the X chromosome are necessary for the maintenance of ovarian follicles. Those regions, named POF1 and POF2, are able to escape X inactivation (8). Therefore, in case of haplo-insufficiency, ovarian follicle loss is accelerated. In X;autosome translocations, most breakpoints concern desert gene regions, thus suggesting underlying mechanisms different than gene mutations. A position effect on autosomes translocated on the X chromosome and, more recently, epigenetic effects on the long arm of the X chromosome have been suggested (9). Taken together, X chromosome abnormalities represent around 10%–15% of POI (LOE 2a).

POI is associated with familial or personal history of autoimmune diseases in 4%–5% of POI cases (LOE 3). It belongs to autoimmune polyendocrinopathy syndromes (APS). APS type 1 stands for autoimmune polyendocrinopathy candidosis ectodermal dystrophy syndrome (APECED). It is related to autosomal recessive AIRE gene mutations (10). In type 2 APS, patients present with type 1 diabetes mellitus, adrenal insufficiency, and hypothyroidism. POI is present in 10%–25% of APS-2 patients. In APS type 4, patients have vitiligo, systemic lupus erythematosus, and chronic atrophic gastritis. An Italian study has shown that in all cases of APS, Addison disease occurs at an earlier age than POI (11). Genes involved in APS-2 and APS-4 have not been identified so far. In autoimmune POI, cases of serum LH levels may be higher than FSH levels (12). Furthermore, in autoimmune POI, the numbers of ovarian follicles and AMH levels are higher than in non-autoimmune POI (13). Autoimmunity seems to induce selective theca cell destruction, preserving granulosa cell function (LOE 2a). Very few cases of POI, apart from autoimmune causes, are associated with high AMH levels. In those cases, impaired folliculogenesis is probably involved (14).

TABLE 6.3

Syndromic POI

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