Clinical Information

Inhibins are heterodimeric protein hormones secreted by granulosa cells of the ovary and Sertoli cells of the testis. They selectively suppress secretion of pituitary follicle stimulating hormone (FSH) and have local paracrine actions in the gonads. The inhibins consist of a dimer of 2 homologous subunits, an alpha subunit and either a beta A or beta B subunit, to form inhibin A and inhibin B, respectively.

In female individuals, inhibin A is primarily produced by the dominant follicle and corpus luteum; whereas inhibin B is predominantly produced by small developing follicles. Serum inhibin A and B levels fluctuate during the menstrual cycle. Inhibin A is low in the early follicular phase and rises at ovulation to maximum levels in the midluteal phase. In contrast, inhibin B levels increase early in the follicular phase to reach a peak coincident with the onset of the mid-follicular phase decline in FSH levels. Inhibin B levels decrease in the late follicular phase. There is a short-lived peak of the hormone 2 days after the midcycle luteinizing hormone (LH) peak. Inhibin B levels remain low during the luteal phase of the cycle. The timing of the inhibin B rise suggests that it plays a role in regulation of folliculogenesis via negative feedback on the production of FSH. At menopause, with the depletion of ovarian follicles, serum inhibin A and B decrease to very low or undetectable levels.

Ovarian cancer is classified into 3 types: epithelial (80%), germ cell tumors (10%-15%), and stromal sex-cord tumors (5%-10%). Epithelial ovarian tumors are further subdivided into serous (70%), mucinous (10%-15%), and endometrioid (10%-15%) types. Granulosa cell tumors represent the majority of the stromal sex cord tumors.

Elevations of serum inhibin A and B are detected in some patients with granulosa cell tumors. Inhibin A elevations have been reported in approximately 70% of granulosa cell tumors. In these patients, inhibin A levels tend to show a 6-fold to 7-fold increase over the reference range value. Inhibin B elevations have been reported in 89% to 100% of patients with granulosa cell tumors. In these patients, inhibin B levels tend to be elevated about 60-fold over the reference range value. The frequency of elevated levels varies amongst studies, likely due to the different specificities of the antibodies used in the immunoassays. Inhibin A and B also appear to be suitable serum markers for epithelial tumors of the mucinous type, with about 20% of cases having elevated inhibin A levels and 55% to 60% of cases having elevated inhibin B levels. In contrast, inhibin is not a very good marker in nonmucinous epithelial tumors. At best, total inhibin is elevated in 15% to 35% of nonmucinous epithelial ovarian cancer cases.

Inhibin seems to be a complementary to cancer antigen 125 (CA 125) as an ovarian cancer marker. CA 125 is not as good of a tumor marker for mucinous and granulosa ovarian cell tumors. Inhibin shows a better performance in those 2 types of ovarian cancer.

The majority of studies for inhibin A and B as ovarian cancer markers have been limited to postmenopausal women where the levels for both proteins are normally very low. Inhibin levels vary in relation to the menstrual cycle and, therefore, are difficult to interpret in premenopausal women.

Inhibin B has also been used as a marker of ovarian reserve. Every female is born with a specific number of follicles containing oocytes, a number that steadily and naturally declines with age. The number of follicles remaining in the ovary at any time is called the ovarian reserve. As ovarian reserve diminishes, it is increasingly more difficult for the hormones used for in vitro fertilization (IVF) to stimulate follicle development and, thus, the likelihood of successful oocyte retrieval, fertilization, and embryo transfer decreases, all leading to a lower chance of conceiving. As part of an infertility evaluation, attempts are made to estimate a woman's ovarian reserve. Tests to assess ovarian reserve include the following: day 3 FSH, day 3 inhibin B, and anti-mullerian hormone levels. The amount of inhibin B measured in serum during the early follicular phase of the menstrual cycle (day 3) directly reflects the number of follicles in the ovary. Therefore, the higher the inhibin B, the more ovarian follicles present. The level of inhibin B that predicts a poor response to IVF treatment has not been established with this assay.

In male patients, inhibin B levels are higher in those with apparently normal fertility than in those with infertility and abnormal spermatogenesis. Serum inhibin B, when used in combination with FSH, is a more sensitive marker of spermatogenesis than FSH alone. However, the optimal level of inhibin B to assess male infertility has not been established.