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 at least 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:

• disordered menstrual cycles (spontaneous amenorrhea or irregular menstrual cycles) for at least four months;
• elevated follicle stimulating hormone (FSH) concentration >25 IU/L.
  • Note: FSH assessment should be repeated after four to six weeks if there is diagnostic uncertainty. FSH testing for the diagnosis of POI does not have to be timed to a specific day of the menstrual cycle.

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). However, 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, LH, oestradiol
• 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

• In general, over 80% of people with this condition do not currently have an underlying cause of POI identified.
• 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. Often, genetic variants resulting in POI are inherited in an autosomal recessive manner; evidence for the pathogenicity of several autosomal dominant variants at population level is weak. There is also a clear polygenic basis to a proportion of POI, where for these women POI lies at the extreme end of the physiological spectrum of age at natural menopause.
• 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 and/or Clinical Genetics review.
• For information about testing, see Presentation: Patient with possible premature ovarian insufficiency.

• Established autosomal recessive inheritance, particularly in meiosis-related and/or DNA repair genes, have been identified in cases of POI – often within familial and/or consanguineous kindred (for example, MCM8, MCM9).
• Other forms of inheritance (for example, autosomal dominant) have also been identified (for example, NR5A1).
• As referenced above, there is a strong non-Mendelian polygenic component to POI too; those with the top percentiles of polygenic risk have a similar risk of POI as compared to established monogenic causes.
• 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 a possibly higher risk of developing POI themselves.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

• 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 are currently available to ameliorate, arrest or reverse the POI phenotype.

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:

• McGlacken‑Byrne SM, Suntharalingham JP, Ishida M and others. ‘A tiered approach to exome sequencing analysis in early‑onset Primary Ovarian Insufficiency‘. Journal of Clinical Endocrinology and Metabolism 2025: volume 110, issue 11, pages 3,142–3154. DOI: 10.1210/clinem/dgaf124
• Ruth KS, Day FR, Hussain J and others. ‘Genetic insights into biological mechanisms governing human ovarian ageing‘. Nature 2021: issue 596, pages 393–397. DOI: 10.1038/s41586-021-03779-7
• Shekari S, Stankovic S, Gardner EJ and others. ‘Penetrance of pathogenic genetic variants associated with premature ovarian insufficiency‘. Nature Medicine 2023: volume 29, issue 7, pages 1692–1699. DOI: 10.1038/s41591-023-02405-5
• 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)