Perspective: Genetic causes of human reproductive disease

John C. Achermann, Gokhan Ozisik, Joshua J. Meeks, J. Larry Jameson

Research output: Contribution to journalReview articlepeer-review

57 Scopus citations


The genetic mutations described in patients with reproductive disorders have provided important insight into the transcription factors, receptors, and hormones that regulate the HPG axis in humans. These mutations can affect development and function of the HPG axis at many levels. Laboratory investigations and associated features can help to focus on a gene of interest in some cases, but it is likely that these reports represent the most severely affected individuals; less severe loss of function mutations may be manifest as milder clinical phenotypes (e.g. DAX1, LH receptor). Thus, the true prevalence of these genetic abnormalities in patients with reproductive dysfunction or infertility is not known. A major challenge in this field is that mutations lead to infertility, thereby limiting the investigator's ability to use traditional genetic linkage and association studies to identify candidate genes. However, the human genome project is starting to have a major impact on strategies used to identify genetic mutations. The density of polymorphic markers, such as single nucleotide polymorphisms, is increasing rapidly, allowing better gene mapping. In addition, easy access to the structure of genes known to be involved in reproductive disorders is allowing high-throughput screening of candidate genes. A large number of genes involved in reproduction are being identified in transgenic and gene knockout mice. As these phenotypes are characterized more thoroughly, it may be possible to better predict candidate genes in humans based on characteristic hormonal and histologic features of particular mutations. Gene microarrays have the potential to provide gene expression fingerprints associated with specific types of genetic disorders. Finally, it is important to translate advances in genetics into improved clinical management. In addition to genetic counseling, it may be possible to direct selected patients to various forms of assisted reproduction such as intracytoplasmic sperm injection for spermatogenic defects or in vitro fertilization for ovulatory dysfunction. The paradigm of using reproductive physiology and pathophysiology to develop new treatments has a track record of success. In a relatively short period of time, our understanding of the physiologic role of gonadotropins has been used to create recombinant gonadotropins, which are now commonly used to facilitate reproduction. By analogy, the discovery of additional key regulators of gonadal development and gametogenesis may provide additional therapeutic tools for enhancing reproductive function.

Original languageEnglish (US)
Pages (from-to)2447-2454
Number of pages8
JournalJournal of clinical endocrinology and metabolism
Issue number6
StatePublished - 2002

ASJC Scopus subject areas

  • Biochemistry, medical
  • Endocrinology
  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology, Diabetes and Metabolism


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