Inhibins: The “New” Reproductive Hormones

This issue of Seminars in Reproductive Medicine is devoted to inhibins, dimeric glycoproteins belonging to the transforming growth factor β superfamily. After a long history from the first suggestion that "inhibin" might be a hormone, it is now recognized to circulate in distinct forms (inhibin A and B) and to have separate physiological functions and mechanisms of regulation in various reproductive tissues. The purpose of this issue is to present the basic physiology as well as to discuss the developing clinical and physiologic roles for the inhibin family of proteins, including activin and follistatin.

It was over 70 years ago that McCullagh observed that administration of an organic solvent extract of testicular tissue was unable to reverse completely the histological changes in the gonadotrope cells of the pituitary gland after castration in male rats.[1] A water-soluble extract of the testes, containing a putative hormone called inhibin, was needed to restore pituitary histology to normal. This observation was followed by several decades of inactivity until advances in biochemical and molecular testing allowed the purification and cloning of the inhibin family of molecules. Significant advancement in our understanding of inhibin later ensued with the development of specific and sensitive immunoassays by Dr. Nigel Groome and colleagues.[2] [3] The fascinating history of the arduous journey from suggestion to realization of inhibin is reviewed in this issue by Dr. Alan Schneyer.[4]

Because inhibin is an important component in feedback regulation of follicle-stimulating hormone (FSH) and involved in gonadal function, its role in normal and pathophysiological reproductive conditions could be expected. Inhibin is relevant to gonadal development from the time of birth, with serum levels rising at puberty, as do other classic reproductive peptide and steroid hormones. The pattern of inhibin secretion from the developing gonad and its relationship with other reproductive hormones are essential for a complete understanding of the initiation of puberty and errors in this process, a topic covered in careful detail by Drs. Lahlou and Roger.[5]

One of the most interesting details of inhibin physiology has been the sexual dichotomy in circulating forms. Inhibin B is found in male serum, but in the female, granulosa cells of the ovary produce both inhibin A and inhibin B under differential regulation. The functions of inhibin in the normal male and its relationship to testes function are discussed by Drs. O’Conner and deKretser,[6] and Dr. Welt presents the control and actions of inhibin A and B during the normal menstrual cycle.[7] Inhibin A is a product of the corpus luteum and fetoplacental unit, suggesting a likely role in the maintenance of maternal and fetal health during pregnancy. The role of inhibin in normal and high-risk pregnancies is addressed by Dr. Muttukrishna.[8]

The clinical utility of specific inhibin A and B immunoassays has been demonstrated in several situations. The use of inhibin B in several areas of infertility is now common, as it is valuable in women as an index of ovarian reserve. Monitoring of serum inhibin B also is useful in assessment of male fertility. Dr. Lockwood summarizes the potential diagnostic roles for inhibin A and inhibin B in assessing fertility status.[9] Aging has profound implications for fertility, and here again, inhibin provides useful insight into the pathophysiological processes involved. The topic of the patterns of secretion and roles of inhibin in the normal aging process is described by Drs. Hurwitz and Santoro.[10] Baseline information on the changes of inhibin during the perimenopausal transition will be an interesting new area of clinical significance.

Inhibin has been used clinically as a marker of granulosa cell tumor since the mid-1980s, after the development of the first inhibin radioimmunoassay. Inhibin is more sensitive following granulosa cell tumors than the more general marker of ovarian cancer, CA-125. Preliminary studies of the role of inhibin in detecting prostate and other cancers have recently been published. In this issue, Robertson and McNeilage review the subject of inhibins as biomarkers for reproductive cancers.[11] Inhibin has also performed effectively as a clinical serum marker for assessing risk of Down syndrome in the second trimester of pregnancy. This topic and the association of maternal serum inhibin A levels with other fetal anomalies are discussed by Drs. Lambert-Messerlian and Canick.[12]

Despite progress in the field of inhibin, many questions prevail. Studies in animal models not only initiated the field of inhibin research but also continue to enlighten investigators, especially with experimental designs that would not be possible in human subjects. Animal studies are important for breeders, with the potential to allow better control of fertility. Drs. Drummond, Findlay, and Ireland[13] bring together the extensive body of literature on inhibin’s role in rodents and ruminant animal models. One particularly elusive question has been the mechanism of action of inhibin. The paracrine and endocrine mechanisms of inhibin and activin action in the regulation of pituitary gonadotropin synthesis and secretion are eloquently described by Drs. Gregory and Kaiser.[14] In addition, Drs. Cook, Thompson, Jardetzky, and Woodruff bring us up to date with the latest news regarding the intricate mechanisms of inhibin action via newly identified receptors/binding proteins.[15]

The physiology and clinical applications of many reproductive hormones, such as luteinizing hormone, FSH, estradiol, and progesterone, are now very familiar to basic scientists and clinicians alike. The importance of the inhibin family as an essential component of the hypothalamic-pituitary-gonadal axis has now emerged. The future of reproductive endocrinology lies in a broadening of our understanding of inhibin, activin, and follistatin and application of this knowledge to diagnostic testing and therapies. We hope this issue serves as a timely review and window to the future of the “new” reproductive hormone, inhibin.

REFERENCES

• 1 McCullagh D R. Dual endocrine activity of the testes.  Science. 1932;  76 19-20
• 2 Groome N P, Illingworth P J, O’Brien M et al.. Detection of dimeric inhibin throughout the human menstrual cycle by two-site enzyme immunoassay.  Clin Endocrinol (Oxf). 1994;  40 717-723
• 3 Evans L W, Groome N P. Development of immunoassays for inhibin, activin and follistatin. In: Muttukrishna S, Ledger W Inhibin, Activin and Follistatin in Human Reproductive Physiology. London; Imperial College Press 2001: 11-60
• 4 Schneyer A. Inhibins: a historical perspective.  Semin Reprod Med. 2004;  22 161-164
• 5 Lahlou N, Roger M. Inhibin B in pubertal development and pubertal disorders.  Semin Reprod Med. 2004;  22 165-176
• 6 O’Connor A E, de Kretser D M. Inhibins in normal male physiology.  Semin Reprod Med. 2004;  22 177-186
• 7 Welt C K. Regulation and function of inhibins in the normal menstrual cycle.  Semin Reprod Med. 2004;  22 187-194
• 8 Muttukrishna S. Role of inhibin in normal and high-risk pregnancy.  Semin Reprod Med. 2004;  22 227-234
• 9 Lockwood G. The diagnostic value of inhibin in infertility evaluation.  Semin Reprod Med. 2004;  22 195-208
• 10 Hurwitz J M, Santoro N. Inhibins, activins, and follistatin in the aging female and male.  Semin Reprod Med. 2004;  22 209-218
• 11 Robertson D M, McNeilage J. Inhibins as biomarkers for reproductive cancers.  Semin Reprod Med. 2004;  22 219-226
• 12 Lambert-Messerlian G M, Canick J A. Clinical application of inhibin A measurement: prenatal screening for Down syndrome.  Semin Reprod Med. 2004;  22 235-242
• 13 Drummond A E, Findlay J K, Ireland J J. Animal models of inhibin action.  Semin Reprod Med. 2004;  22 243-252
• 14 Gregory S J, Kaiser U B. Regulation of gonadotropins by inhibin and activin.  Semin Reprod Med. 2004;  22 253-268
• 15 Cook R W, Thompson T B, Jardetsky T S, Woodruff T K. Molecular biology of inhibin action.  Semin Reprod Med. 2004;  22 269-276