Reduced quality and accelerated follicle loss with female reproductive aging - does decline in theca dehydroepiandrosterone (DHEA) underlie the problem?

Abstract

Infertility, spontaneous abortion and conception of trisomic offspring increase exponentially with age in mammals but in women there is an apparent acceleration in the rate from about age 37. The problems mostly commonly occur when the ovarian pool of follicles is depleted to a critical level with age but are also found in low follicular reserve of other etiologies. Since recent clinical studies have indicated that dehydroepiandrosterone (DHEA) supplementation may reverse the problem of oocyte quality, this review of the literature was undertaken in an attempt to find an explanation of why this is effective? In affected ovaries, oxygenation of follicular fluid is low, ultrastructural disturbances especially of mitochondria, occur in granulosa cells and oocytes, and considerable disturbances of meiosis occur. There is, however, no evidence to date that primordial follicles are compromised. In females with normal fertility, pre-antral ovarian theca cells respond to stimulation by inhibin B to provide androgen-based support for the developing follicle. With depletion of follicle numbers, inhibin B is reduced with consequent reduction in theca DHEA. Theca cells are the sole ovarian site of synthesis of DHEA, which is both a precursor of androstenedione and an essential ligand for peroxisome proliferator-activated receptor alpha (PPARα), the key promoter of genes affecting fatty acid metabolism and fat transport and genes critical to mitochondrial function. As well as inducing a plethora of deleterious changes in follicular cytoplasmic structure and function, the omega 9 palmitate/oleate ratio is increased by lowered activity of PPARα. This provides conditions for increased ceramide synthesis and follicular loss through ceramide-induced apoptosis is accelerated. In humans critical theca DHEA synthesis occurs at about 70 days prior to ovulation thus effective supplementation needs to be undertaken about four months prior to intended conception; timing which is also suggested by successful interventions to date. In humans and primates that undergo adrenarche, the adrenal zona reticularis (ZR) is the major site of DHEA production, however this is also reduced with age. Concomitant loss in function of the ZR might account for the acceleration in the rate of aging seen in humans in the late thirties' age group.

Figure 1

Graph of the frequency of spontaneous abortion by age, amongst pregnancies monitored in a group of normal women who had no interventions and were studied prospectively from the time they attempted to conceive in a study known as the PALS: Pregnancy and Lifestyle Study.

Figure 2

The model (left and above dotted line) shows the response of the pre-antral theca to inhibin B, which results in production of DHEA and PPARα in follicles from about 200 μm. It is proposed that reduced levels of PPARα primarily account for both the decline in follicle number and the loss of oocyte quality that ultimately leads to errors of cell division and arrested development. The defects that occur in cytoplasmic organelles, especially mitochondria, are largely responsible for decline in follicle quality. These can be attributed to key changes in fat metabolism and transport and mitochondrial function that are directly caused by dysfunction of PPARα secondary to low DHEA. These same changes also lead to increased production of ceramide, apoptosis and hence accelerated decline in the size of the follicle pool. The area to the right of the dotted line indicates that in humans and those primates where the adrenal ZR produces an alternative source of DHEA, that age related loss of ZR cells accelerates the rate of aging in the late thirties age group.