Is inhibin a serum marker for ovarian cancer

Research endocrinologists are well aware of inhibin and the family of proteins of which it is a part. Inhibin was discovered almost 70 years ago as a product of the gonads that selectively inhibited the secretion of folliclestimulating hormone (FSH) at the level of the pituitary gland. We now know that inhibin is present in at least two biologically active forms (inhibin A and B) as well as in a variety of a subunit precursor forms and has been implicated not only in endocrine functions, but also as a possible local growth regulator in a variety of tissues. In clinical endocrinology, inhibin B appears to be a useful tool in assessing ovarian reserve and the potential for success in assisted reproduction. Research endocrinologists may not be aware, however, of the developing use of circulating inhibin levels as a diagnostic aid in clinical areas outside endocrinology. For example, in the area of prenatal genetic diagnosis, the measurement of inhibin A has been shown to be useful in maternal serum screening for Down’s syndrome pregnancy in the second trimester. In the area of gynecologic oncology, exemplified by the study of Ala-Fossi and colleagues (1) in this issue of the European Journal of Endocrinology, various forms of inhibin are being tested and applied as possible serum markers of ovarian cancer. Inhibin looked promising as a new ovarian cancer marker in the early 1990s when Healy et al. (2) showed that serum levels were elevated in 29% of 143 postmenopausal women with confirmed ovarian cancer. The inhibin antibody (Monash No. 1989) used for the radioimmunoassay in that study was directed exclusively to the a subunit (3) and detected a combination of biochemical forms otherwise known as total inhibin, that included dimeric inhibin A and B as well as a subunits (4). With the advent of more specific inhibin assays, recent studies have been aimed at determining which form (total inhibin, inhibin A, inhibin B, or the a inhibin subunit precursor as measured by the pro-aC assay) might be the best marker of disease. The most coherent and convincing data that serum inhibin levels are useful as a marker of ovarian cancer come from studies of granulosa cell tumors. All forms of inhibin are elevated in the serum of patients with granulosa cell tumors relative to healthy women of the same age (2, 5). This finding has a sound pathophysiological basis since the granulosa cell is the primary origin of inhibin synthesis. There have been subtle differences in the frequency of elevated levels depending on the biochemical form(s) measured: 100% for total inhibin, 89–100% for inhibin B, 90% for pro-aC, and 71–77% for inhibin A (2, 5, 6). Nevertheless it is clear that both a subunit and dimeric forms of inhibin are secreted in abundance in granulosa cell tumors, with total inhibin, a combination of all forms, most reliably increased. There is a consensus that a inhibin is a better serum marker than dimeric inhibin for all cases of epithelial ovarian tumors, and this is further supported by the study of Ala-Fossi et al. (1) in the present issue of this Journal. Inhibin appears to be a suitable serum marker for epithelial tumors of the mucinous type with about 70–80% of patients having elevated total inhibin (2, 5, 7), 55–60% having elevated inhibin B or pro-aC, and 20% having elevated inhibin A levels (5). In contrast, inhibin is not a very good marker in non-mucinous epithelial tumors. While mucinous tumors characteristically include benign ovarian type stroma which is believed to be a source of inhibin (8), most serous, clear cell and endometrioid carcinomas typically lack such ovarian stroma. At best, total inhibin is elevated in 15–35% and pro-aC is elevated in <15%–30% of non-mucinous epithelial ovarian cancer cases (2, 5, 9). The specificity of the inhibin markers for ovarian cancer has yet to be addressed sufficiently in the literature. Few previous studies have examined cases of non-ovarian cancers or benign disease and the published results suggest rather poor specificity of the inhibin markers. The total inhibin elevation has ranged from 7 to 41% in non-ovarian cancers (2, 5) and 28% in benign gynecologic disease (2, 7). In agreement, Ala-fossi et al. (1) found no difference in pro-aC levels in malignant versus benign ovarian disease. Therefore, inhibin’s utility appears to be limited to monitoring of patients with known ovarian cancer. For granulosa cell tumors, inhibin has been shown to decrease after surgery and to increase with disease recurrence (2, 10). In fact, some patients have a documented rise in inhibin 11 months preceding recurrence of granulosa cell ovarian cancer (11). Neither inhibin A nor inhibin B levels were elevated in granulosa cell tumor patients in remission (6). However, it remains to be investigated whether a European Journal of Endocrinology (2000) 142 331–333 ISSN 0804-4643