Oophorectomy improves pituitary activin inhibitory function preventing lactotroph hyperplasia development.

Among pituitary adenomas, prolactinomas are the most frequently diagnosed (about 50%). Dopamine agonists are generally effective in the treatment of prolactinomas. However, a subset of about 25% of patients does not respond to these agents. The management of drug-resistant prolactinomas remains a challenge for endocrinologists and new inhibitory treatments are needed. Pituitary activins inhibit lactotroph function. Its expression and action were found reduced in animal models of lactotroph hyperplasia (female mice overexpressing the B subunit of the human chorionic gonadotrophin and female mice knockout for dopamine receptor type 2). In these models, an oophorectomy avoids prolactinoma development. Hormonal replacement with oestradiol and/or progesterone is not enough to reach the tumor size observed in transgenic females. We postulated that the loss of gonadal inhibins after an oophorectomy contributes to prevent hyperplasia development. Here, we demonstrated that an oophorectomy at 2 months age recovers the following in adulthood: (i) pituitary activin expression, (ii) activin receptor expression specifically in lactotroph population, (iii) activin biological activity in lactotrophs with a concomitant reduction of Pit-1 expression. To summarize, when an oophorectomy is performed, inhibins are lost and the inhibitory action of pituitary activins on lactotroph population is recovered, helping to prevent lactotroph hyperplasia development. These results emphasize the importance of the inhibitory action of activins on lactotroph function, positioning activins as a good therapeutic target for the treatment of resistant prolactinomas.

Anti-Müllerian hormone and Inhibin B after stem cell transplant in childhood: a comparison of myeloablative, reduced intensity and treosulfan-based chemotherapy regimens.

Serum concentrations of Anti-Müllerian hormone (AMH) and Inhibin B were used to assess potential fertility in survivors of childhood haematopoietic stem cell transplantation (HSCT) after three chemotherapy-conditioning regimens of differing intensity. Of 428 patients transplanted between 1990-2012 for leukaemia and immunodeficiency 121 surviving >1 year after a single HSCT were recruited. Group A had a treosulfan-based regimen (low-toxicity); Group B had fludarabine/melphalan (Flu-Mel) (reduced-intensity) and Group C had busulphan/cyclophosphamide (Bu-Cy) (myelo-ablative). Mean age at HSCT and follow-up and length of follow-up were 3.6, 11.8 and 9.9 years. Mean AMH standard deviation scores (SDS) were significantly higher in Group A (-1.047) and Group B (-1.255) than Group C (-1.543), suggesting less ovarian reserve impairment after treosulfan and Flu-Mel than after Bu-Cy. Mean serum AMH concentration was significantly better with treosulfan (>1.0 µg/l) than with Flu-Mel or Bu-Cy. In males, mean Inhibin B SDS was significantly higher in Group A (-0.506) than in Group B (-2.53) and Group C (-1.23) with the Flu-Mel group suffering greatest impairment. In conclusion, a treosulfan-based regimen confers a more favourable outlook for gonadal reserve than Flu-Mel or Bu-Cy in both sexes. Higher values of Inhibin B after Bu-Cy than after Flu-Mel may reflect recovery over time.

Vaccination with inhibin-α provides effective immunotherapy against testicular stromal cell tumors.

BACKGROUND: Testicular cancer is the most common male neoplasm occurring in men between the ages of 20 and 34. Although germ-line testicular tumors respond favorably to current standard of care, testicular stromal cell (TSC) tumors derived from Sertoli cells or Leydig cells often fail to respond to chemotherapy or radiation therapy and have a 5-year overall survival significantly lower than the more common and more treatable germ line testicular tumors. METHODS: To improve outcomes for TSC cancer, we have developed a therapeutic vaccine targeting inhibin-α, a protein produced by normal Sertoli and Leydig cells of the testes and expressed in the majority of TSC tumors. RESULTS: We found that vaccination against recombinant mouse inhibin-α provides protection and therapy against transplantable I-10 mouse TSC tumors in male BALB/c mice. Similarly, we found that vaccination with the immunodominant p215-234 peptide of inhibin-α (Inα 215-234) inhibits the growth of autochthonous TSC tumors occurring in male SJL.AMH-SV40Tag transgenic mice. The tumor immunity and enhanced overall survival induced by inhibin-α vaccination may be passively transferred into naive male BALB/c recipients with either CD4+ T cells, B220+ B cells, or sera from inhibin-α primed mice. CONCLUSIONS: Considering the lack of any alternative effective treatment for chemo- and radiation-resistant TSC tumors, our results provide for the first time a rational basis for immune-mediated control of these aggressive and lethal variants of testicular cancer.

[Inhibins and Activin A in hypertensive Disorders of Pregnancy and HELLP-Syndrome]. / Inhibine und Aktivin A bei hypertensiven Schwangerschaftserkrankungen und HELLP-Syndrom.

OBJECTIVE: Are serum concentrations of the ovarian glycoproteins inhibin A, inhibin B, pro-alpha-C and activin A different in normotensive, chronical hypertensive or pregancies complicated by preeclampsia or HELLP-syndrome? What are the clinical consequences? METHODS: Serum concentrations of inhibin A, inhibin B, pro-alpha-C, and activin A of 99 women (37 normotensive patients, 23 patients with chronical hypertension, 25 women with preeclampsia and 14 patients with HELLP-syndrome) at different stages of pregnancy were determined by high specific ELISAS. RESULTS: During pregnancy serum levels of all parameters increased continually and fell rapidly within parturition. Activin A and inhibin B levels showed significant higher serum concentrations in patients with preeclampsia and - even more pronounced - in patients with HELLP-syndrome. Normotensive and chronically hypertensive patients were not different. CONCLUSION: Activin A and inhibin A appear to be viable candidates as laboratory parameters for detection of pregnancy induced hypertension. Maybe furthermore both parameters will allow the discrimination between chronic hypertension and hypertension induced by pregnancy.

Oestradiol feedback stimulation of androgen biosynthesis by human theca cells.

This study analysed the effect of oestradiol on basal and LH-stimulated production of androstenedione and progesterone by human theca cells in monolayer culture. Incubations were carried out for either 2 days (seven experiments) or 4 days (four experiments), in the presence or absence of luteinizing hormone (LH), oestradiol (10(-9)-10(-6) M) or inhibin. Medium collected at 48 and 96 h was stored until radioimmunoassay for steroid content. Theca pooled from small follicles (<10 mm) was used in all but two experiments; in these, ovaries were obtained from ovulatory women in the mid-follicular phase of their cycle and theca from small and large follicles was pooled. Oestradiol inhibited progesterone production in a dose-dependent manner in all experiments, irrespective of follicle size, ovulatory status and ovarian morphology, with maximum effect at 10(-6) M. At this dose, oestradiol had no effect on androstenedione production by theca from four anovulatory women with polycystic ovaries but produced a significant augmentation of both basal and LH-stimulated androstenedione production in theca from five of the seven ovulatory women, with maximal response in theca from the two pre-ovulatory subjects. During the 48-96 h period of incubation, oestradiol augmented androstenedione production in all four experiments and had a greater stimulatory effect than the physiological dose of inhibin (10 ng/ml). This is the first report of oestradiol regulating human theca cell steroidogenesis in a dose-dependent manner.

Human prostatic inhibin suppresses tumor growth and inhibits clonogenic cell survival of a model prostatic adenocarcinoma, the Dunning R3327G rat tumor.

Prostatic inhibin (PI) is a M(r) 10,700 protein found in human seminal plasma and is secreted by the prostate. Recognition of alteration of PI levels in prostatic diseases prompted us to investigate its effect on an animal prostatic adenocarcinoma model, the Dunning R3327G rat tumor. PI not only inhibited in vitro growth of tumor cells but also suppressed tumor growth in vivo. A dose-dependent inhibition of both the clonogenic cell growth and rate of proliferation (DNA synthesis) was observed in tumor cell cultures incubated with purified PI. These inhibitory activities were similar in both androgen-dependent and androgen-independent Dunning tumor cell lines. A functional decapeptide of PI was also found to inhibit Dunning tumor cell colonies in a dose-dependent manner. Daily injection of purified PI into tumor-bearing rats suppressed the tumor growth. A 58% reduction in tumor weight and a 2-fold reduction in tumor growth rate were observed over a 15-day treatment period. Continued treatment with PI significantly suppressed the tumor growth rate by nearly 3-fold. These findings clearly demonstrate a potential application of PI for treating human prostatic adenocarcinoma.

Effect of prostatic inhibin peptide (PIP) on prostate cancer cell growth in vitro and in vivo.

Prostatic inhibin peptide (PIP), is a 94 amino acid protein which is secreted by the prostate gland in an androgen-independent manner. Previously, it has been demonstrated that PIP appears to inhibit follicle-stimulating-hormone (FSH) secretion by the pituitary and prostate glands. In vitro, the Dunning R3327 rat prostate cancer cell line MAT-LyLu (MLL) cells and the human prostate cancer cell line PC-3, are stimulated to grow in response to exogenous FSH and these effects are blocked by PIP. In vivo, PIP inhibits the growth of the highly metastatic MLL prostate cancer cell line. A comparison of hormone levels in control and PIP-treated rats demonstrates a significant inhibition of FSH in treated animals. It appears that, in vivo, PIP may inhibit prostate cancer growth by inhibiting FSH. PIP may represent a novel hormonal treatment for prostate cancer.