Johannes D. Veldhuis, MD

Disclosures

March 15, 2000

In This Article

The Aging Human Ovary

Females have a finite nonrenewable complement of oocytes. Hence, control of oocyte depletion is a critical determinant of the human female reproductive life span. A maximal oocyte population of 7 million is estimated to exist at 20 weeks gestation. Two million persist until birth, and there are 400,000 at the onset of puberty. Only approximately 400 oocytes are actually ovulated during a woman's reproductive years. Understanding the mechanisms that regulate the attrition of oocytes is critical for developing strategies that extend the reproductive life span, intervene in premature ovarian failure, and preserve threatened gonadal function in patients undergoing cancer chemotherapy.

Studies using selective transgenic mouse-knockout models have established important roles in germ cell/follicular preservation for sphingomyelinase, ceramide, Bcl-2, the proapoptotic protein Bax, and other apoptosis-modulating substances. For example, Bax promotes the atresia of primordial follicles, and hence knocking out Bax markedly extends the ovarian reproductive life span in mice and prolongs endogenous estrogen secretion by Graafian follicles.

Developing a molecular strategy that promotes follicular protection may limit premature menopause resulting from cytotoxic chemotherapy (eg, adriamycin, doxorubicin, x-rays, cyclophosphamide). On the other hand, gonadotropins and GH/IGF-I rescue more mature follicles by opposing granulosa-cell (not oocyte) death. Transforming growth-factor beta and Müllerian inhibiting substance are proapoptotic -- that is, they promote oocyte death.[2]

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