July 2002, Vol. 8, No. 1

Basic Research 
Illuminating the Role of Inhibins and Activins in Fertility

All currently available hormonal contraceptives for women reduce fertility by influencing levels of the steroid hormones estrogen and progesterone. Altering the levels of these hormones, however, can cause unpleasant side effects in some cases. Population Council molecular endocrinologist Daniel Bernard is conducting basic research that may one day lead to a contraceptive for women that leaves estrogen and progesterone levels largely unaffected, theoretically resulting in fewer side effects. His research concerns two types of protein hormones that play a role in women’s fertility: inhibins and activins. 

Interplay of hormones
Successful reproduction is dependent upon the coordinated regulation and actions of hormones created in the brain, the pituitary gland, and the ovary and testis. In women, for example, various hormones stimulate the maturation of egg-containing follicles in the ovaries. They also trigger ovulation and prepare the uterus for the implantation of fertilized eggs. Feedback loops, in which levels of one hormone influence the production of other hormones, control this monthly cycle. 

One vital hormone involved in female fertility is follicle-stimulating hormone (FSH). The anterior pituitary gland releases FSH, which then travels to the ovary via the bloodstream. In the ovary, FSH binds to molecular receptors on the surface of cells. The binding of a protein or hormone to a receptor can be thought of as a key entering a lock. When the FSH “key” binds with its receptor “lock,” it stimulates the growth of follicles. 

Women who cannot produce FSH or its molecular receptors are infertile because their egg-containing follicles are unable to mature. Drugs that block the action of FSH would be likely to produce reversible infertility in women. (FSH does not appear to be necessary for reproduction in men.) 

Many hormones regulate the production of FSH. Bernard, however, is most interested in pursuing inhibins, which are produced in the ovary and testis, and activins, which appear to affect FSH through their local production within the pituitary gland. As their names suggest, inhibins hinder and activins stimulate the production and release of FSH from the pituitary. Moreover, these hormones selectively influence FSH production and do not directly affect either estrogen or progesterone production.

Investigation into inhibins may also shed light on some diseases. Research has shown that abnormal inhibin production may contribute to the halt in follicle development seen in polycystic ovary syndrome, a disease that can cause infertility and other complications. And women with a rare form of ovarian cancer frequently have abnormal blood levels of inhibin. Both inhibin and activin are part of a larger family of proteins that seem to act as tumor suppressors. 

Gaps in knowledge 
While much has been learned about how activins affect their target cells, there are still gaps in knowledge. Bernard and his colleagues aim to elucidate the cascade of actions generated within cells after the activin “key” binds to one of its “locks,” a receptor known as ActRII. This sequence prompts the production of FSH. 

The lab also seeks to clarify the mechanisms of action used by inhibins. One way that  inhibin hampers the production of FSH is by binding to ActRII, thus blocking activin from binding. Research has shown that alone, inhibin binds only weakly to ActRII. When certain other proteins are present, however, inhibin can bind strongly to the receptor. 

One of these proteins is known as betaglycan. When inhibins interact with betaglycan and bind to ActRII receptors, they do not appear to set off a cascade of signals within the cell. Rather, they seem to work simply by disrupting activin action. As when the wrong key is put in a lock, the lock will not open and the inserted key prevents the correct key from entering. 

Bernard and his team are investigating the possibility that inhibin–receptor binding sets off an unknown process within cells. They are also searching for proteins in the pituitary gland that are similar to betaglycan and for receptors that may be specific to inhibin—in other words a lock that inhibin can open. 

Recently, Bernard and his colleagues discovered and began to characterize a protein, which they named InhBP/p120, that seems to exert some influence over inhibin activity. They showed that InhBP/p120 can form a complex with a different activin receptor, this one called ALK4. When inhibins are added, activin-stimulated gene activity stops almost entirely.

 “Learning how inhibins and activins regulate FSH is critical to understanding the processes governing normal reproduction,” says Bernard. “Understanding these processes may reveal targets for contraceptives, and may also give us insights into some forms of infertility and certain cancers, as well.”

Sources
Bernard, Daniel J., Stacey C. Chapman, and Teresa K. Woodruff. 2001. “Mechanisms of inhibin signal transduction,” Recent Progress in Hormone Research 56: 417–450. 

Bernard, Daniel J., Stacey C. Chapman, and Teresa K. Woodruff. 2002. “Minireview: Inhibin binding protein (InhBP/p120), betaglycan, and the continuing search for the inhibin receptor,” Molecular Endocrinology 16(2): 207–212.

(Return to issue contents)