Robert I. McLachlan

Stimulation of Sertoli cell inhibin secretion by the testicular paracrine factor PModS

The testicular paracrine factor PModS is produced by peritubular myoid cells under androgen control and modulates Sertoli cell function and differentiation. The observation that luteinizing hormone (LH) stimulates inhibin production in vivo, but has no effect on isolated Sertoli cells in vitro, suggested an indirect mode of LH action, potentially mediated by PModS. The effects of the testicular paracrine factor PModS and hormones on inhibin secretion by Sertoli cells were investigated to provide insight into the endocrine control of inhibin expression. An inhibin radioimmunoassay was utilized which showed essentially parallel displacement curves with purified bovine follicular fluid inhibin, Sertoli cell conditioned medium and concentrated Sertoli cell secreted proteins. An immunoblot analysis of Sertoli cell secreted proteins with the inhibin antisera consistently detected a 32 kDa protein which is the expected size of the mature of inhibin (alpha beta) and periodically detected a 57 kDa protein which is speculated to be an incomplete processed form of the inhibin precursor (alpha 43 beta). Follicle-stimulating hormone (FSH) was found to stimulate inhibin secretion initially between days 2 and 5 of Sertoli cell culture. Insulin and retinol alone had no significant effect on inhibin secretion; however, together they appeared to enhance the ability of FSH to stimulate inhibin secretion. Testosterone had no effect on inhibin production alone or in combination with other regulatory agents. PModS was found to stimulate inhibin secretion approximately 3-fold, but with a delayed time course of stimulation which did not occur until days 5-7 of Sertoli cell culture. Treatment with a combination of PModS and FSH resulted in an apparent maximal stimulation of inhibin secretion. Both forms of PModS, PModS (A) and PModS (B), were found to have equivalent biological activities in their ability to stimulate inhibin production with an apparent half-maximal effective concentration between 10 and 15 ng/ml. The current study provides evidence for the local testicular control of inhibin production and adds to the complexity of the endocrine control of inhibin expression. The cellular interaction is proposed in which LH acts on Leydig cells to stimulate androgen production which in turn acts on peritubular cells to regulate PModS production which subsequently can act on Sertoli cells to control inhibin production. Testicular control of inhibin production provides a potential short feedback loop for the local regulation of androgen production and an additional regulatory element for the pituitary-gonadal axis.

SERUM INHIBIN LEVELS DURING THE PERIOVULATORY INTERVAL IN NORMAL WOMEN: RELATIONSHIPS WITH SEX STEROID AND GONADOTROPHIN LEVELS

Inhibin is a gonadal glycoprotein believed to be important in the regulation of pituitary FSH secretion and/or to function as a paracrine factor within the ovary and testis. We studied serum levels of inhibin, oestradiol (E2), progesterone (P), FSH and LH during the periovulatory interval in order to determine whether there is differential control of sex steroid and inhibin secretion by the mature follicle and the emerging corpus luteum. Seven normal cyclic women were admitted 3–4 days prior to midcycle and blood samples drawn every 3 h for 5–7 days. Serum E2, P, FSH, LH and inhibin were measured by radioimmunoassay. Data were normalized around the peak LH value (0 h). Serum E2 and inhibin rose in parallel (r = 0.92, P < 0.001) between – 69 and – 18 h, E2 reached a peak of 1296 ± 154 (mean±SEM) pmol/1 at −18 h, then fell to 1050± 139 pmol/1 at 0 h. Serum inhibin, on the other hand, continued to rise to a peak of 837±95U/lat – 6 h, fell to 455±48 U/lat +45 h, then rose again. On average, the peak inhibin level occurred 10.4± 5.1 h after the peak E2 (P < 0.05). Inhibin levels were positively correlated with both serum LH and FSH between – 24 and +24 h (P<0.01). Serum E2 was negatively correlated with LH, FSH and inhibin between – 24 and 0 h (P < 0.01). Serum P levels increased from 1.8 ± 0.3 nmol/1 at – 24 h to 14.3 ± 1.0 nmol/1 at +60 h. Serum inhibin was positively correlated with serum P from −24 to 0 h (P<0.01) and +45 to +60 h (P < 0.01), but was inversely correlated from 0 to +45 h(P< 0.01). We conclude that the maturing follicle secretes both E2 and inhibin in parallel until – 18 h, at which time the process of luteinization is initiated by the onset of the midcycle LH surge, as evidenced by the rise in P. E2 secretion then falls while inhibin secretion rises, indicating different regulation of secretion of these two hormones by the maturing follicle. Furthermore, the close positive correlation between inhibin and gonadotrophin levels around midcycle suggests that FSH and/or LH stimulate inhibin secretion and that the presumed negative feedback effect of inhibin on FSH secretion is overcome at this time. After midcycle, inhibin secretion initially falls, then rises, while P rises progressively. This transient divergence of P and inhibin secretion may occur during the transformation of the preovulatory follicle into the corpus luteum.

Inhibin and the regulation of testicular function. Historical and clinical aspects.

The role of feedback factors in the regulation of testicular function remains enigmatic, with a number of paradoxical observations making it difficult to put forward a satisfying account of the normal physiology and of the disturbances that occur in testicular diseases. This brief review highlights some of the historical aspects of the development and explorationiof the inhibin concept, and examines currently available clinical data in man to underline our continued state of uncertainty as to how the testis is involved in the regulation of its own dual functions of maintaining virility and fertility.

The immunoreactive inhibin secretion pattern in the midluteal phase: relationships with luteinizing hormone and progesterone

With the development of a sensitive radioimmunoassay for inhibin, luteal phase inhibin levels have been noted to parallel progesterone levels and be acutely dependent upon luteinizing hormone (LH) stimulation. To define the midluteal secretory pattern of immunoreactive inhibin and its relationships with LH and progesterone, blood samples were obtained from five normal women every 20 min for a period of 24 h. Individual data series of LH, progesterone and inhibin were analysed for pulsatile secretion using an adaptive‐threshold method. Inhibin levels exhibited a relatively frequent, low‐amplitude pulsatile secretory pattern (14.6 ± 6.9 pulses/24 h (mean ± SE), amplitude = 17% of the mean inhibin level). In contrast, LH levels demonstrated an infrequent high amplitude secretory pattern (6.2 ± 0.7 pulses/24 h, amplitude = 139% of the mean LH level). The average progesterone pulse frequency and amplitude were intermediate to LH and inhibin (9.2 ± 1.2 pulses/24 h, amplitude = 36% of the mean progesterone level). In addition, each individuals hormone data were analysed for coincident pulsatile secretion and cross‐correlations were performed on the data, with one hormone pattern shifted relative to another by 20‐min time intervals. None of the individual inhibin data series showed significant pulse coincidence when compared to the LH or progesterone data series. The cross‐correlation analysis, however, revealed a significant (P < 0.05) relationship in general trends between the inhibin and LH data series, and the inhibin and progesterone data series in three subjects. These findings suggest that (1) inhibin exhibits a relatively frequent low‐amplitude pulsatile secretory pattern in comparison to LH and progesterone in the midluteal phase of the menstrual cycle, and (2) while the secretion of these three hormones is interrelated, there is not a strong coupling between secretory pulses of inhibin and either LH or progesterone pulses.