Primary ovarian insufficiency- an overview: Part 1 definition, aetiology, clinical relevance

Definition

Premature ovarian insufficiency is a clinical syndrome defined by loss of ovarian activity before the age of 40 and is characterized by menstrual disturbance (amenorrhea or oligomenorrhea) with raised gonadotropins and low estradiol. (ESHRE 2016).^[5]

Cessation of ovarian function in women aged between 40 and 45 is termed early menopause.^[5]

Prevalence

There are not many studies to find out the prevalence of POI and most are from old literature. The longitudinal cohort study of Coulam and colleagues, which aimed at establishing the age-specific incidence of POI, found that 1% of women entered natural menopause before the age of 40 (Coulam, et al., 1986). The prevalence of early menopause (in the 40 to 44 age group) is ten times higher (Coulam, et al., 1986).^[6] Luborsky and colleagues reported a 1.1% prevalence of POI in a cross-sectional survey of women aged 40-55 years (Luborsky, et al., 2003).^[7]

Prevalence of POI is greatly influenced by ethnicity, lifestyle, genetics, and familial and socio-economic factors, Luborsky found that the prevalence of POI in the USA was higher in African-American and Hispanic women than in Caucasians, and the prevalence was lower in women with Chinese and Japanese ancestry.^[7] Regular smoking can lead to earlier menopause.^[8] Those who exercise regularly are likely to attain menopause later.^[9] Women with lower IQ and cognitive scores in childhood reached menopause earlier than women with higher IQ scores.^[10]

Idiopathic POI

Almost 90% of POI are idiopathic^[3] but the exact number of women diagnosed with idiopathic POI has not been established, as it is largely dependent on the setting, patient population, and the available investigations for identifying causation. As our knowledge grows on POI it is more likely that the number of idiopathic cases will reduce. “In a significant number of women with POI, the cause is not identified and these women are described as having unexplained or idiopathic POI”.^[12] (ESHRE 2016)

Environmental POI

Smoking, alcohol, nutrition, and exposure to endocrine disruptors are implicated as influencing the age of menopause, but are not readily diagnosable causes of POI. It is recommended that women at risk of POI discontinue smoking.^[12] Some observational studies have revealed that smoking may cause early menopause in women.

Iatrogenic POI

Radiotherapy and chemotherapy can lead to POI. Alkylating agents are gonadotoxic in childhood as well in adulthood.^[13] The gonadotoxic effect of chemotherapy is largely drug-and dose-dependent and is related to age. There are studies indicating a relation between early menopause in women who had undergone a hysterectomy and in women who had undergone tubal sterilization compared with women without surgery.^[14]

Infectious POI

Many viruses like mumps, rubella, EBV, HIV, herpes zoster, cytomegalovirus, tuberculosis, malaria, varicella, and shigella can harbor in the ovary but only mumps oophoritis has been considered a cause of POI, explaining 3-7% of POI cases.^[15] There is no indication for infection screening in women with POI.

Autoimmune POI

POI is more common in women with specific autoimmune illnesses, and POI is more common in POI than in the general population. Approximately 25% of individuals with isolated spontaneous POI are positive for autoimmune markers but there is poor sensitivity and/or specificity of the common autoantibodies.

The most clinically important association is with autoimmune Addison’s disease, in the context of the autoimmune polyendocrine syndrome (APS). POI of adrenal autoimmune origin is the most frequent type observed in 60 to 80% of patients with autoimmune POI.^[16], ^[17]

At present, only the detection of SCA (steroid-cell autoantibodies) can ensure the accurate diagnosis of POI caused by autoimmune ovarian damage, and ovarian biopsy is not indicated for the diagnosis of autoimmune POI as in the absence of autoantibodies, no infiltration of ovaries by immune cells has been documented. Major autoantigens recognized by SCA are 17α-hydroxylase (17α-OH) and cytochrome P450 side-chain cleavage enzyme (P450SCC).^[18] In women with Addison's illness, circulating SCA may indicate a high chance of POI years before clinical diagnosis. ACA and 21-hydroxylase autoantibodies (21OH-Ab) are the most sensitive markers for autoimmune POI. In nearly 90% of instances, cryo-sections of ovaries with peripheral 21OH-Ab show SCA, 17α-hydroxylase antibodies, and/or P450SCC antibodies. Without 21OH-Ab, fewer than 0.5 percent of POI patients will test positive for SCA, 17α-OH-Ab, or P450SCC-Ab, which is similar to the general population.^[19] The predictive value of a commercially available serum anti-ovarian antibody test (an indirect immunofluorescence assay using cynomolgus monkey ovary) to identify these women is poor. ESHRE 2016 recommended that adrenocortical antibodies (ACA) and/ or 21OH-Ab should be measured in every POI patient because of the possibility of subclinical or latent Addison’s disease in POI patients and POI patients with a positive 21OH-Ab/ACA test should be referred to an endocrinologist. In women negative for 21OH-Ab/ACA, there is no indication to analyse these autoantibodies in the future, in the absence of clinical signs or symptoms suggestive of adrenal insufficiency.^[20]

POI is associated most commonly with thyroid autoimmunity (14–27%) when adrenal autoimmunity is absent. At present, the most sensitive assay to detect an autoimmune thyroid process is the analysis of TPO-Ab. ESHRE 2016 recommended screening for thyroid antibodies (TPO-Ab) should be performed in women with POI. In patients with a positive TPO-Ab test, thyroid-stimulating hormone (TSH) should be measured every year and a referral to an endocrinologist should be considered. In the case TPO-Ab is negative, in the absence of clinical signs or symptoms of hypo- or hyperthyroidism, follow-up of thyroid function should be applied to the general population of women.

The prevalence of undetected diabetes in POI is 2.5%^[21] and it is thought Type 1 DM patients are prone to POI. At present insufficient evidence to recommend routine screening of POI women for diabetes. (ESHRE 2016)

The diagnosis of autoimmune oophoritis can be made based on:

Clinical evidence of primary ovarian insufficiency (POI), including menstrual dysfunction, low estradiol, and high serum gonadotropin concentrations.

The presence of steroidogenic cell autoantibodies.

The exclusion of other causes of POI such as X chromosome defects and the FMR1premutation.

Testing for the presence of 21-hydroxylase autoantibodies or adrenal autoantibodies is sufficient to make the diagnosis of autoimmune oophoritis in a woman with proven spontaneous POI. Autoimmune thyroid illness does not always mean the POI is autoimmune. Anti-21-hydroxylase antibodies by immunoprecipitation test or indirect immunofluorescence utilising adrenal tissue as substrate are the only approved markers for autoimmune oophoritis.

Ovarian biopsy for autoimmune oophoritis is no longer advised. Autoimmune oophoritis ovarian biopsies with lymphocytic infiltration of secondary and antral but not primordial follicles. Resistant ovary syndrome is clinically similar to POI, although the ovary has normal ovarian reserve for its age owing to receptor block from medications, antibodies to gonadotrophins, or post-receptor abnormalities.

Chromosomal POI

10-12% of women diagnosed with POI have chromosomal abnormalities, of which the majority (94%) are X chromosomal abnormalities (X structural abnormalities or X aneuploidy).^[21] In the presence of a Y chromosome, there is an elevated risk of developing gonadal neoplasia (45%).^[22] Every woman with a Y chromosome, whether or not she has an SRY gene mutation, should be counseled about the risk of development of a gonadal tumor and gonadectomy should be advised. ESHRE 2016 recommended that all women with POI not caused by medical intervention should have chromosomal study done.

In Turner syndrome, there is accelerated atresia of the primordial follicles during later fetal life. Subsequently, the ovarian follicle pool is depleted by the time of puberty among those with the 45 XO genotype and they present with primary amenorrhoea. Among those with a mosaic genotype such as 45XO/46XX (when the X chromosome is missing in some cells but not in others), the rate of atresia, although accelerated, is relatively slower and these women present with secondary amenorrhoea.

Another X chromosome disorder in which POF is well described is fragile X syndrome premutation, where the prevalence of POF is 13–26%.^[23] Unlike the classical fragile X syndrome, where the FMR-1 gene contains >200 repeats of the CGG codon, in premutation the individual is phenotypically normal and there are 55–200 repeats. The mechanisms by which FMR-1 premutation causes POF are not clearly understood. One hypothesis is that the increase in FMR-1 transcription results in excess RNA protein clusters, causing premature degradation of ovarian follicles.^[24] Most cases of the syndrome result from the expansion of a CGG trinucleotide repeat located in the 5′ UTR of the FMR1 gene to more than 200 repeats. Alleles of FMR1 that include this extended repeat are known as the complete mutation. Locus-specific hypermethylation and chromatin remodelling due to the expanded repetition silence the FMR1 gene epigenetically. Many premutation alleles (55–199 CGG repeats) are unstable and at risk for complete mutation expansions in one generation. 94% of alleles with 90+ repetitions get fully mutated. Expansion to a complete mutation usually always happens from mother to kid.

Fragile-X testing is indicated in all women with POI, not only to establish the causation of POI but also because the presence of the mutation could have major implications for herself and her family. Family members may be carriers too and therefore have a risk of developing POI and a risk of having (grand) children with the fragile-X syndrome. In addition, the patient herself may already have daughters, who may be carriers. This requires careful counselling before the test is performed, including permission from the patient to perform the test.

For this reason, in some countries, women who wish to avoid the risk of having a child affected with FXS are offered preconception genetic screening for FMR1 premutation. Currently, FMR1 premutation carriers who wish to conceive and avoid the risk of having an affected child have three options:

To conceive using In Vitro Fertilization and preimplantation genetic testing for monogenic gene diseases (IVF-PGT-M).

II. Spontaneous conception and prenatal genetic diagnosis during pregnancy by either chorionic villous sampling (CVS) or amniocentesis (AC).

Using a donor oocyte.

Spontaneous conception carries a risk of bearing an affected child and the need to perform a termination of pregnancy. Termination of pregnancy involves medical, emotional, and ethical issues. On the other hand, IVF using PGT-M avoids the need for a termination of pregnancy and offers the opportunity to transfer only non-carrier embryos. However, this procedure arouses financial and emotional difficulties and is not the obvious choice for a fertile couple, especially considering the higher prevalence of ovarian dysfunction and reduced ovarian response observed in FMR1 premutation carriers undergoing IVF compared to non-carrier women. For women who are known cases of POI due to this condition or daughters of a mother with FMR1 premutation, we can take advantage of the latest developments in the rapidly evolving field of fertility preservation. 

An additional reason to counsel about Fra-X testing is the risk of fragile-X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurological problem predominantly in male carriers of the Fra-X-mutation.

Galactosaemia is associated with a higher risk of developing POI. In galactosemia, mechanisms involved in the pathogenesis of POF include direct toxicity from increased metabolites (galactose-1-phosphate and galactitol); aberrant glycosylation of glycoproteins, and glycolipids involved in ovarian function; and activation of apoptosis of oocytes and ovarian stromal cells.^[25]

Autosomal genetic testing is not at present indicated in women with POI except in POI patients presenting with typical phenotype characteristics of a specific gene mutation.^[26]