The role of steroids in follicular growth

Abstract

The steroidogenic pathway within the ovary gives rise to progestins, androgens and oestrogens, all of which act via specific nuclear receptors to regulate reproductive function and maintain fertility. The role of progestins in follicular growth and development is limited, its action confined largely to ovulation, although direct effects on granulosa cell function have been reported. Consistent with these findings, progesterone receptor knockout mice are infertile because they cannot ovulate. Androgens have been shown to promote early follicular growth, but also to impede follicular development by stimulating atresia and apoptosis. The inability of androgens to transduce a signal in mice lacking androgen receptors culminates in reduced fertility. Oestrogens are known to exert effects on granulosa cell growth and differentiation in association with gonadotrophins. Studies with oestrogen receptor knockouts and oestrogen depleted mice have shown us that oestrogen is essential for folliculogenesis beyond the antral stage and is necessary to maintain the female phenotype of ovarian somatic cells. In summary, the action of steroids within the ovary is based on the developmental status of the follicle. In the absence of any single sex steroid, ovarian function and subsequently fertility, are compromised.

Figure 1

Steroid biosynthesis by the ovary. In the theca, under the influence of LH, cholesterol is converted to pregnenolone and metabolised through a series of substrates ending in androgen production. The two-cell, two-gonadotrophin model comes into play with androgens produced by the theca cells transported to the granulosa cells where they are aromatised to oestrogens.

Figure 2

The structure of nuclear hormone receptors. These receptors are composed of 5 structure-function domains labelled A-F (Mangelsdorf et al., 1995) The N-terminal region contains domains A/B, the DNA binding domain (DBD) contains domain C, the hinge region contains domain D and the ligand binding domain (LBD) at the C-terminal end contains domains E/F. Transactivation domains AF1 and AF2 are found in the N-terminal region and the LBD, respectively (White & Parker 1998).