Premature ovarian failure (POF), also known as primary ovarian insufficiency, is typically defined as amenorrhea with elevated follicle-stimulating hormone levels occurring prior to age 40 years. “Early menopause,” the cessation of ovarian function in the early 40s, probably represents a continuum of ovarian dysfunction lying between formal POF and normal menopause around age 50.

POF has many causes, including infection, endocrine abnormalities, autoimmune disease, and various treatments for cancer. Each of these conditions has some degree of genetic contribution to disease development. In addition, multiple etiologies of POF are primarily due to an underlying genetic abnormality. Some of these are individually rare gene mutations that most internists are unlikely to encounter in practice. Two particular genetic causes of this condition are common enough to merit consideration in primary care practice.

Sex Chromosome Abnormalities

Turner syndrome, which results from the lack of a second sex chromosome (45, X karyotype), is a well-known cause of POF. Although classic Turner syndrome is unlikely to escape diagnosis early in life, some women have mosaic disease, with only a portion of the cells in their body carrying the abnormality. These women may have only subtle outward clinical features, such as slightly short stature or mildly reduced secondary sex characteristics. Establishing the correct diagnosis enables these women to be screened for other significant manifestations of Turner syndrome, such as aortic abnormalities.

Most guidelines include a karyotype as a routine part of the diagnostic workup for POF. Depending on degree of suspicion, it may be appropriate to perform chromosome analysis on both a blood sample and a tissue sample in order to detect low-level mosaicism.

Another possible karyotype finding could be deletion or rearrangement of an X chromosome. Unlike Turner syndrome, these structural X chromosome abnormalities may be inherited, and thus have implications for the woman’s parents, siblings, and/or children.

Rarely, women with secondary amenorrhea due to POF are found to have Y chromosome material in some or all of their cells. This confers increased risk of gonadal cancer, and should prompt consideration of surgical gonadectomy.

Fragile X Syndrome

Fragile X sydrome is the most common inherited cause of mental retardation in boys. The genetics of fragile X syndrome is complex, resulting from large expansions of a trinucleotide (3 base-pair) repeat within the FMR1 gene on the X chromosome. This trinucleotide repeat is present in up to 40-50 copies in normal versions of the gene. When amplified to 200 or more copies, it results in the typical manifestations of fragile X syndrome (most often in affected boys, but occasionally in girls).

The intermediate range of 50-200 trinucleotide repeats is called a premutation, because it increases the risk of further expansion and full-blown fragile X syndrome in future generations. Women who carry a premutation in one of their two copies of the FMR1 gene have a 13%-26% risk of developing POF. Looked at the other way, a fragile X premutation is found in up to 7.5% of women with isolated (sporadic) POF, and in up to 13% of women with familial POF (Fertil. Steril. 2007;87:456-65).

Thus, genetic testing of the FMR1 gene should also be part of the standard workup for POF. Women found to carry a premutation should be advised that their sons and other male relatives – primarily nephews related through sisters and grandsons related through daughters – are at risk for fragile X syndrome. In addition, their female relatives are also at risk for POF if they carry the premutation.

Collectively, genetic contributions to POF are significant enough that a positive family history is found in approximately 15% of cases. Additional features to seek in the family history include autoimmune disease and evidence of sex chromosome abnormalities or fragile X syndrome.

Family history data can be useful in at least two ways. When evaluating a woman with secondary amenorrhea, a positive family history may help to inform the differential diagnosis. Of potentially greater importance is the recognition of a family history of POF in a young, healthy woman. Even if a specific cause of the POF cannot be identified, knowledge of her increased risk for early menopause could be invaluable for anticipatory guidance and family planning.

Additional information about fragile X syndrome is available at www.genetests.org. For more information about premature ovarian failure, see N. Engl. J. Med. 2009;360:606-14; Obstet. Gynecol. 2009;113:1355-63.

Dr. Levy contributes to the “Genetics in Your Practice” column, which regularly appears in Internal Medicine News, an Elsevier publication. He is an assistant professor in the Division of General Internal Medicine and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

卵巢早衰（POF），又称为原发性卵巢功能不全，通常定义为妇女在40岁以前闭经，且伴有促卵泡激素水平升高。“提早绝经”，即40岁出头卵巢功能就提前终止，这一情形很可能是指介于正式POF与50岁左右正常绝经之间的卵巢功能不全。