Ovarian dysgenesis

The shared signature is hypergonadotropic hypogonadism: raised follicle-stimulating hormone (FSH) and luteinising hormone concentrations with low oestradiol, together with disordered or absent menstrual cycles. The presentation varies with the residual germ cell pool. At the severe end there is primary amenorrhoea with absent or arrested puberty, small compact or streak ovaries and a hypoplastic uterus; up to 50% of primary amenorrhoea cases have gonadal dysgenesis. At the milder end puberty and menarche proceed normally, with secondary amenorrhoea in adolescence or early adulthood. Oestrogen deficiency raises long-term cardiovascular and skeletal risk.

The estimated prevalence is approximately 1% in women under 40 years of age. A substantial proportion of cases is attributable to identifiable genetic forms, with chromosomal abnormalities frequently identified in presentations with primary amenorrhoea. Ovarian dysgenesis with primary amenorrhoea sits at the rarer, more severe end.

The OMIM database currently lists ten genes associated with ovarian dysgenesis. Sequencing of large cohorts assigns a molecular cause to a minority, more often with primary than secondary amenorrhoea. The genetic forms can be grouped into chromosomal abnormalities, nonsyndromic and syndromic forms. The most common genetic cause is Turner syndrome (45,X karyotype). Nonsyndromic forms include as most common monogenic cause. Syndromic forms include (POI combined with sensorineural hearing loss).

The genetic conditions associated with ovarian dysgenesis follow heterogeneous inheritance patterns. The spectrum includes chromosomal aetiologies (most prominently karyotype 45,X and X-chromosome rearrangements), autosomal recessive single-gene disorders affecting folliculogenesis or meiotic recombination, autosomal dominant entities, X-linked premutation expansions, and rare mitochondrial conditions.

• Panay N, Anderson RA, Bennie A, Cedars M, Davies M, Ee C, et al. Evidence-based guideline: premature ovarian insufficiency. Human Reprod open. 2024;2024(4): hoae065. doi: 10.1093/hropen/hoae065. PMID: .
• Federici S, Rossetti R, Moleri S, Munari EV, Frixou M, Bonomi M, et al. Primary ovarian insufficiency: update on clinical and genetic findings. Front Endocrinol (Lausanne). 2024;15:1464803. doi: 10.3389/fendo.2024.1464803. PMID: .
• Rocca WA, Gazzuola Rocca L, Smith CY, Kapoor E, Faubion SS, Stewart EA. Frequency and type of premature or early menopause in a geographically defined American population. Maturitas. 2023;170:22-30. doi: 10.1016/j.maturitas.2023.01.012. PMID: .
• Ke H, Tang S, Guo T, Hou D, Jiao X, Li S, et al. Landscape of pathogenic mutations in premature ovarian insufficiency. Nature medicine. 2023;29(2):483-492. doi: 10.1038/s41591-022-02194-3. PMID: .