Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Premature Ovarian Failure (POF) [N97.0]

OMIM numbers: 311360, 309550 (FMR1), 300247 (BMP15), 136435 (FSHR)

Dr. rer. nat. Annett Wagner, Dr. med. Dagmar Wahl

Scientific Background

Premature ovarian failure (menopause under the age of 40) affects 1-2% of the female population and leads to infertility as well as deficiency in sex hormones. Like women with natural menopause usually occurring approximately at the age of 50, patients with POF exhibit an increased risk for disorders such as osteoporosis. Biochemically, there are unproportionally higher FSH levels than LH levels (hypergonadotropic ovarian failure). The causes are genetic in 20-25% of all cases, approximately 10-15% are caused by auto immune responses, 30-40% of all cases are iatrogenic and 40-60% idiopathic. Different genes on the X chromosome contribute to the functioning of the ovaries. POF occurs in 4-5% of all women suffering from the Ullrich-Turner syndrome who did not exhibit primary amenorrhea as well as in partial X chromosome monosomy. Premutations (56-200 CGG repeats) in the FMR1 (Fragile X mental retardation 1) gene are currently the most frequent cause for a premature ovarian failure. Approximately 20% of all carriers of premutations develop POF.

Premutations are found in 0.8-7.5% of all women with sporadic POF. In women with familial POF, the frequency of premutations is up to 13%. If there is a desire for children, genetic counseling is indicated, since there is an increased risk for children with fragile X syndrome as well as a risk for menopause before realization of the desire for children. In another candidate gene, BMP15 (Human Bone Morphogenetic Protein-15, region Xp11.2), a relevant mutation could be detected in 2% of all women suffering from POF. The gene contains two exons and encodes for an oocyte-specific growth and differentiation factor which stimulates the follicular development and the growth of the granulosa cells.

Moreover, mutations in the FSHR gene (follicle-stimulating hormone receptor gene) could be detected in patients with premature ovarian failure. This gene is located on chromosome 2p21-p16 and consists of 10 exons. The receptor must be intact for a normal development of the gonads, production of germ cells and sexual maturation.