The current observations verify the presence of apoptosis in the human ovary and endometrium. In the ovary apoptosis plays a major role in determining the female reproductive lifespan. The present results show, that the apoptosis-regulating factors Bcl-2 and Bax are expressed in fetal ovary, and their exact function requires further study (I). While the essential role of Bax in inducing oocyte apoptosis has been demonstrated in mice, such observations have to be confirmed in humans due to species-specific differences (Perez et al. 1999, Matikainen et al. 2001a). One of these differences concerns transcription factor p53, which has been shown to be related to the activation of apoptosis in several cell types. P53 is expressed in both human and mouse ovaries, but the mouse bax gene lacks a p53 binding site, while human bax promotor has a consensus binding site (Miyashita & Reed 1995, Tilly et al. 1995, Schmidt et al. 1999, Makrgiannakis et al. 2000,), suggesting that in humans the activation of p53 may lead to increased Bax expression and consequently to the activation of apoptosis. To find out the exact mechanisms of Bcl-2 and Bax in human ovarian apoptosis, more complete documentation of the whole Bcl-2 family is required.
For obvious reasons, functional experiments with human tissue are complicated. Immortalized human cell lines are easily available, but they often have little relevance to actual physiological function. The present work establishes, that apoptosis is the mechanism of corpus luteum regression and suggests that the local estrogen concentration might have a role in the regulation of this event (III). However, functional studies on human CL tissue or luteinized granulosa cells are required to verify this.
Several knockout and transgenic animal models have been used to study ovarian apoptosis. Similarly, it is possible that careful studies on humans with proven genetic mutations that affect their reproductive phenotype will provide more information about the molecular mechanisms behind the regulation of apoptosis. Ultimately, better understanding of ovarian apoptosis may lead to novel methods to control female reproductive functions. By preventing oocyte apoptosis, it could be possible to increase the size of the resting follicle stock, thereby prolonging the reproductive life span and delaying the onset of menopause, which could be of special importance for women at risk of premature ovarian failure. In addition, the prevention of oocyte apoptosis could be important in preventing oocyte loss and sterility caused by environmental insults such as radio- and chemotherapy or industrial toxins that are known to cause oocyte apoptosis (Matikainen et al. 2001a, reviewed in Morita & Tilly 1999).
Defects in apoptosis-regulating pathways play a role in the development of cancer (reviewed in Wyllie 1997a). In endometrial cancer, significant alterations in the rate of apoptosis were observed, which may be due to changed expression of apoptosis-regulating factors (V). Detailed knowledge of the molecular mechanisms of transformation of normal proliferative tissue to cancer will most likely reveal new targets for pharmacological intervention in this event.