Premature ovarian insufficiency

Premature ovarian insufficiency (POI) refers to ovarian dysfunction arising from an inherent defect within the ovary itself, with resultant dysfunction or depletion of the resting follicle pool. It affects 1% of women and carries significant medical and psychosocial consequences for affected women, their partners and their families.

POI is diagnosed in women who present before the age of 40 with:

• amenorrhoea for at least four months;
• oestrogen deficiency (menopausal symptoms); and
• evidence of raised follicle-stimulating hormone (FSH) concentrations of over 40IU/L on two occasions at least one month apart.

Most women present with secondary amenorrhoea (absence of three or more menstrual periods in a person who previously had menstrual periods) or oligomenorrhoea (fewer than six to eight periods per year).

In 10% of those with POI, primary amenorrhoea – the complete absence of menstrual periods at any point – is the presenting feature, with or without delayed puberty. In these cases, the condition presents in adolescence, often to paediatric endocrinology.

A POI diagnosis has devastating implications for reproductive potential. Although pregnancy rates of 5%–10% have been reported in women with POI, affected patients are typically infertile.

Assessment for known causes of non-iatrogenic POI is recommended at diagnosis, as per the list below.

• Endocrine assessments:
  • FSH and luteinizing hormone (LH) levels on two occasions at least four weeks apart; and
  • oestradiol levels.
• Genetic assessments:
  • karyotyping; and
  • fragile X screening.
• Autoimmune screening:
  • thyroid antibodies; and
  • adrenocortical antibodies and/or 21-hydroxylase antibodies.
• Bone health assessment:
  • bone densitometry scan.

Causes

• Known and postulated causes of POI include iatrogenic POI (secondary to surgical oophorectomy, chemotherapy or radiotherapy), environmental toxins and autoimmune mechanisms.
• A proportion of POI is genetically mediated. Within clinical contexts, approximately 5%–10% of women with POI have a causative genetic mechanism identified. These include sex chromosome aneuploidies, such as Turner syndrome, as well as pathogenic variants in autosomal and sex chromosome genes.
• In general, over 80% of people with this condition do not currently have an underlying cause of POI identified.
• POI can occur in isolation or as part of a multi-system condition (such as Bloom syndrome, blepharophimosis syndrome, galactosaemia and Perrault syndrome).
• POI can be sporadic, occurring in just one person within a family. Up to 30% of cases are familial, affecting two or more first-degree relatives within a family. Often, though not always, this occurs within consanguineous pedigrees.

• Genetically, POI is remarkably heterogeneous. Next-generation sequencing studies have related pathogenic variants in more than 100 genes to the molecular pathogenesis of both syndromic and non-syndromic POI. The functional evidence supporting these associations varies. However, it has become clear in recent years that a much higher proportion of POI is genetically influenced than was previously thought. Some of the key genes associated with the pathogenesis of POI are listed below.
  • Genes associated with primordial germ cell development and maintenance:
    • NANOS3 (development);
    • NOBOX (maintenance); and
    • SOHLH1 (maintenance).
  • Genes associated with ovary formation:
    • FOXL2;
    • SOX8; and
    • SALL4.
  • Genes associated with meiotic homologous recombination:
    • MSH4;
    • MSH5;
    • BRCA2;
    • ZSWIM7;
    • MCM8; and
    • MCM9.
  • Genes associated with meiotic pachytene progression:
    • YTHDC2.
  • Genes associated with synaptonemal complex formation:
    • SYCE1.
  • Genes associated with cohesin complex formation:
    • SMC1B; and
    • STAG3.
  • Genes associated with follicle growth, formation and maturation:
    • BMP15 (growth);
    • GDF9 (growth);
    • FIGLA (formation); and
    • FSHR (maturation).
• The genes involved in POI relate to complex cellular and reproductive processes, including gonadal differentiation and development, DNA replication and repair, meiosis, oogenesis, folliculogenesis, endocrine signalling and mitochondrial function.
• Women affected by POI as part of a multi-system condition may have an overarching genetic explanation for their syndrome identified. Genotype-phenotype correlation can facilitate targeted genomic testing.
• If karyotyping reveals a Turner syndrome diagnosis, referral to specialist services should follow, as well as specific investigation for the presence of Y chromosome material.
• FMR1 ‘premutations’, associated with the clinical spectrum of Fragile X syndrome, have a long-standing association with POI.
• Expanded genomic testing, including panel-based, single nucleotide polymorphism array and exome sequencing approaches, are currently only performed on a research basis for selected populations of women with POI. Women with a phenotype suggestive of a syndromic cause may also be referred for further genomic testing.

For information about testing, see Presentation: Patient with possible premature ovarian insufficiency.

• Established autosomal recessive inheritance, particularly in meiosis-related DNA repair genes, have been identified in cases of POI.
• Autosomal dominant, autosomal recessive and X-linked inheritance have also been identified.
• As well as monogenic inheritance, exome sequencing studies over the last five years have identified high rates of digenic inheritance (variants in two different genes are involved), oligogenic inheritance (variants in more than two different genes are involved) and polygenic inheritance (variants in many different genes are involved) in cohorts of women with POI. However, functional exploration of these inheritance models is limited.
• Referral to clinical genetics and genomic testing may be considered for family members of women with POI who have a confirmed pathogenic variant. This could inform individualised fertility counselling for these women, who are at possible higher risk of developing POI themselves.

• Diagnosis and management of POI is guided by the European Society of Human Reproduction and Embryology.
• Management of POI is complex and should be delivered via a multidisciplinary team, which may include adult and/or paediatric endocrinology, clinical genetics, specialised fertility services, psychology and dedicated support groups.
• Oestrogen deficiency is usually managed with hormone replacement therapy (HRT), which remains the mainstay of treatment.
• Young women with early-onset POI and pubertal failure or arrest require pubertal induction with exogenous oestrogen and, later, progesterone replacement.
• Options for women wishing to start a family include oocyte donation and adoption.
• Even with optimal HRT, women with POI have an increased incidence of anxiety and depression, highlighting the need for a holistic approach to the management of this condition.
• No genetic therapies to ameliorate, arrest or reverse the POI phenotype are available.

For clinicians

• European Society of Human Reproduction and Embryology: Guideline on the management of premature ovarian insufficiency
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• van Kasteren Y M and Schoemaker J. ‘Premature ovarian failure: A systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy’. Human Reproduction Update 1999: volume 5, issue 5, pages 483–492. DOI: 10.1093/humupd/5.5.483

For patients

• Daisy Network (a charity for women with POI)