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Key Points

  • Disease summary:

    • Infertility is defined as failure to conceive in the setting of regular intercourse within 1 year for women younger than 35 years within 6 months for women older than 35 years. The prevalence of infertility is between 7% and 15%. There are many causes of infertility, with estimates of female factor infertility as an explanation in up to 37% of couples and both male and female factor infertility in 35% of couples. Causes of female infertility include ovulatory disorders, chromosomal abnormalities, endometriosis, pelvic adhesions, tubal blockage and other tubal abnormalities, and hyperprolactinemia. There is growing evidence that genetic abnormalities are present in as many as 10% of infertile females and 15% of infertile males. There is also evidence to suggest that chromosomal abnormalities and single gene mutations contribute to the cause of infertility in a proportion of couples seeking infertility therapy. In 2002 the Italian community of professionals working in reproductive medicine sought to set out guidelines for the appropriate use of genetic testing in infertile couples.

  • Differential diagnosis:

    • Genetic causes of female infertility include ovulatory disorders such as Kallmann syndrome, fragile X syndrome, as well as karyotype abnormalities, and primary ciliary dyskinesia. Infertility can also be noted as a minor manifestation in many other genetic conditions including galactosemia, mucopolysaccharidosis, Prader-Willi, cystic fibrosis, pseudohypoparathyroidism type 1a, progressive external ophthalmoplegia, autoimmune polyglandular syndrome type I, ovarian leukodystrophy, ataxia telangiectasia, Demirhan syndrome, and blepharophimosis-ptosis-epicanthus inversus syndrome.

  • Monogenic forms:

    • In addition to the single gene defects noted earlier, additional rare genetic abnormalities have been identified in infertile women. These include mutations in the follicle-stimulating hormone (FSH), luteinizing-hormone (LH), and gonadotropin-releasing hormone (GnRH) receptors, and mutations in the androgen receptor causing androgen insensitivity syndrome.

  • Family history:

    • A three-generation pedigree for genetic disorders should be obtained from any patient who is undergoing evaluation or treatment for infertility. A family history of males or females with intellectual disability may indicate transmission of fragile X syndrome, and testing for this disorder is indicated.

  • Twin studies:

    • Twin studies have demonstrated a greater concordance between monozygotic than dizygotic twins in reference to age of menopause. The prevalence of premature ovarian failure is three- to fivefold greater in both monozygotic and dizygotic twins. There are reports in the literature of “ovarian discordancy” in monozygotic twins, and also of sister → sister ovarian tissue transplantation in these cases.

  • Genome-wide associations:

    • Genome-wide association studies (GWASs) have been used to elucidate the genetic etiology of premature ovarian failure. Candidate genes have been identified; however, the small size of these studies has limited the statistical power of their results. Array comparative genomic hybridization (a-CGH) analysis is also being researched on cohorts of women with premature ovarian failure for analysis of copy number variants (CNVs) over the genome. A number of potential candidate genes including PTHB1 and ADAMTS19 have been identified in this fashion, although larger follow-up studies are needed to confirm these findings.

Diagnostic Criteria and Clinical Characteristics


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