Elevated Inhibin Research Articles

Serum inhibin A and angiogenic factor levels in pregnancies with previous preeclampsia and/or chronic hypertension: are they useful markers for prediction of subsequent preeclampsia?

Our objective was to determine whether measurement of placenta growth factor (PLGF), inhibin A, or soluble fms-like tyrosine kinase-1 (sFlt-1) at 2 times during pregnancy would usefully predict subsequent preeclampsia (PE) in women at high risk. We analyzed serum obtained at enrollment (12(0/7) to 19(6/7) weeks) and follow-up (24-28 weeks) from 704 patients with previous PE and/or chronic hypertension (CHTN) enrolled in a randomized trial for the prevention of PE. Logistic regression analysis assessed the association of log-transformed markers with subsequent PE; receiver operating characteristic analysis assessed predictive value. One hundred four developed preeclampsia: 27 at 37 weeks or longer and 77 at less than 37 weeks (9 at less than 27 weeks). None of the markers was associated with PE at 37 weeks or longer. Significant associations were observed between PE at less than 37 weeks and reduced PLGF levels at baseline (P = .022) and follow-up (P < .0001) and elevated inhibin A (P < .0001) and sFlt-1 (P = .0002) levels at follow-up; at 75% specificity, sensitivities ranged from 38% to 52%. Using changes in markers from baseline to follow-up, sensitivities were 52-55%. Associations were observed between baseline markers and PE less than 27 weeks (P < or = .0004 for all); sensitivities were 67-89%, but positive predictive values (PPVs) were only 3.4-4.5%. Inhibin A and circulating angiogenic factors levels obtained at 12(0/7) to 19(6/7) weeks have significant associations with onset of PE at less than 27 weeks, as do levels obtained at 24-28 weeks with onset of PE at less than 37 weeks. However, because the corresponding sensitivities and/or PPVs were low, these markers might not be clinically useful to predict PE in women with previous PE and/or CHTN.

709: Identifying the pregnant smoker at high risk for preterm birth

URATO, JULIETTE MADAN, ROBERT QUINN, ANDREA PULKKINEN, SABRINA D. CRAIGO, Tufts University New England Medical Center, Boston, Massachusetts, Foundation for Blood Research, Scarborough, Maine OBJECTIVE: It is well-established that maternal smoking during pregnancy is associated with several pregnancy complications, including preterm birth. Yet, while many women smoke during pregnancy, it is not known which of these will deliver prematurely. Inhibin A levels are known to be elevated in pregnant smokers compared with nonsmokers. Our objective was to determine if Inhibin A levels in pregnant smokers are associated with preterm delivery. STUDY DESIGN: A retrospective cohort study was performed. 7,795 pregnant smokers were identified in a database of 39,421 pregnant women who participated in a statewide serum screening program from 1999 to 2005. Pregnancy outcomes were obtained from the Maine birth records database that was cross-referenced to the serum screening database. Relative risks and 95% confidence intervals for preterm birth were estimated based on Inhibin A level. RESULTS: In the cohort of 7,795 smokers, there were 726 births 37 weeks (9.31%), 201 births 34 weeks (2.58%), and 76 births 30 weeks (0.97%). For pregnant smokers an elevated Inhibin A level was associated with preterm birth (see Table.) An Inhibin A level 2.0 MOM was found in 195 of the 726 pregnant smokers with a preterm birth 37 weeks (26.9%), 64 of the 201 34 weeks (31.8%), and 25 of the 76 30 weeks (32.9%). CONCLUSION: Pregnant smokers with an Inhibin A level 2.0 MOM are at increased risk of preterm birth. Those pregnant smokers with INH A levels 2.5 are at particularly high risk. A significant proportion of the smokers who will deliver prematurely will have an Inhibin A level 2.0 MOM.

Recurrent Gynandroblastoma of Ovary-A Case Report

Gynandroblastoma is a rare ovarian tumor that is composed of both Sertoli cells and granulosa cells. Only 23 cases have been reported in the literature, and recurrence has never been described. We report the first case of a recurrent gynandroblastoma along with its molecular analysis and immunohistochemical studies. A 49-year-old Gravida 0 woman with a 10-year prior diagnosis of ovarian-mixed stromal tissue tumor (well-differentiated Sertoli cell and granulosa cell tumor) and staging laparotomy, presented now with a retroperitoneal mass and an elevated inhibin level. CT scan was suspicious for recurrence. The patient had no prior adjuvant therapy. The histomorphological features of the recurrent tumor had both Sertoli cell and granulosa cell tumor. The molecular analysis of both primary and recurrent tumor showed minor genetic instability in the 17q12.2 gene locus with no dedifferentiation or progression, which is consistent with a low-grade tumor. The immunohistochemical staining profile showed positivity for CD99, inhibin, calretinin, and vimentin; focal positivity for cytokeratin AE1/AE3 and negative for EMA and melan-A. All the previously mentioned immunostainings support the diagnosis. We report the first case of a recurrent gynandroblastoma 10 years after initial presentation along with its molecular analysis and immunohistochemical studies.

Selective Theca Cell Dysfunction in Autoimmune Oophoritis Results in Multifollicular Development, Decreased Estradiol, and Elevated Inhibin B Levels

We describe the clinical course of three women with presumptive autoimmune oophoritis who developed multiple follicles but very low to undetectable estradiol levels. Multiple follicles developed spontaneously in all subjects and during pulsatile GnRH treatment for ovulation induction in subject 1. The development of multiple dominant follicles was accompanied by LH levels in the postmenopausal range and FSH levels at the upper limit for premenopausal women. Serum inhibin B levels were elevated appropriately in the setting of multifollicular development, but estradiol levels remained low. Measurement of estradiol precursors demonstrated androstenedione and estrone levels below the 95th percentile in normal women. Adrenal cortical antibodies, and antibodies to 21-hydroxylase and P450 side chain cleavage enzymes were identified in all subjects. All subjects met the criteria for premature ovarian failure during follow-up. Subject 1 later developed adrenal failure, whereas subject 3 had adrenal failure at the time of the study. These subjects elucidate the hormonal pattern in autoimmune oophoritis, before the full criteria for premature ovarian failure are met. The elevated inhibin A and B levels, which accompany the development of multiple small and dominant follicles in these women, suppress FSH relative to LH levels, virtually independent of estradiol. These data provide further evidence for an important role of inhibin B and inhibin A in the negative feedback control of FSH. In addition, the normal inhibin A and inhibin B production in the absence of estradiol precursors and estradiol provide insight into the selective dysfunction of the theca cells in autoimmune oophoritis.

Repression of the Inhibin α-Subunit Gene by the Transcription Factor CCAAT/Enhancer-Binding Protein-β

Inhibin is a dimeric peptide hormone produced in ovarian granulosa cells that suppresses FSH synthesis and secretion in the pituitary. Expression of inhibin alpha- and beta-subunit genes in the rodent ovary is positively regulated by FSH and negatively regulated after the preovulatory LH surge. We have investigated the role of the transcription factor CCAAT/enhancer-binding protein-beta (C/EBPbeta) in repressing the inhibin alpha-subunit gene. C/EBPbeta knockout mice fail to appropriately down-regulate inhibin alpha-subunit mRNA levels after treatment with human chorionic gonadotropin, indicating that C/EBPbeta may function to repress inhibin gene expression. The expression and regulation of C/EBPbeta were examined in rodent ovary, and these studies show that C/EBPbeta is expressed in ovary and granulosa cells and is induced in response to human chorionic gonadotropin. Transient cotransfections with an inhibin promoter-luciferase reporter in a mouse granulosa cell line, GRMO2 cells, show that C/EBPbeta is capable of repressing both basal and forskolin-stimulated inhibin gene promoter activities. An upstream binding site for C/EBPbeta in the inhibin alpha-subunit promoter was identified by electrophoretic mobility shift assays, which, when mutated, results in elevated inhibin promoter activity. However, C/EBPbeta also represses shorter promoter constructs lacking this site, and this component of repression is dependent on the more proximal promoter cAMP response element (CRE). Electrophoretic mobility shift assays show that C/EBPbeta effectively competes with CRE-binding protein for binding to this atypical CRE. Thus, there are two distinct mechanisms by which C/EBPbeta represses inhibin alpha-subunit gene expression in ovarian granulosa cells.

Inhibin‐producing ovarian granulosa cell tumor as a cause of secondary amenorrhea: Case report and review of the literature

We report the case of 31-year-old patient with an inhibin B-secreting granulosa cell tumor of the left ovary who presented with secondary amenorrhea. Preoperative serum hormonal levels were as follows: follicle-stimulating hormone (FSH) 0.3 mIU/mL, luteinizing hormone (LH) 9.81 mIU/mL, estradiol 142.0 pg/mL and inhibin B 2429 pg/mL. Gonadotropin-releasing hormone (GnRH) test revealed no FSH response and a normal LH response. After removal of the tumor, the levels of FSH and inhibin B returned to within the normal range, and regular menses resumed 27 days postoperatively. In premenopausal women, secondary amenorrhea may be the initial manifestation of granulosa cell tumor. A low FSH level coupled with normal levels of E2 and LH, the inhibition of the FSH response to GnRH and an elevated inhibin level suggest the presence of an inhibin-secreting ovarian tumor and also rule out the possibility of isolated FSH deficiency.

Absent biologically relevant associations between serum inhibin B concentrations and characteristics of polycystic ovary syndrome in normogonadotrophic anovulatory infertility.

Dominant follicle selection is disturbed in normogonadotrophic anovulatory infertility [World Health Organization (WHO) 2] and remaining early antral follicles are either healthy or atretic. This study was conducted to investigate whether inhibin B serum concentrations (produced by healthy small antral follicles) represent the extent of ovarian abnormalities in WHO 2 women and patients with polycystic ovarian syndrome (PCOS), constituting a subgroup of WHO 2 patients. Ultrasonographic and endocrine characteristics in 379 WHO 2 patients and 30 normo-ovulatory controls were compared. In the WHO 2 patients, the PCOS subgroup and the controls, inhibin B concentrations were similar. Inhibin B concentrations were weakly but significantly correlated with the total number of ovarian follicles (r = 0.282; P < 0.001), LH (r = 0.347; P < 0.001), and testosterone (r = 0.269; P < 0.001) but not with serum oestradiol concentrations (r = 0.057). Most (71%) patients with elevated inhibin B also presented with increased concentrations of LH and/or hyperandrogenaemia. In a subgroup of 190 subjects, classified as PCOS based on hyperandrogenaemia and polycystic ovaries, elevated inhibin B concentrations were found in 23% of cases. Aforementioned correlations were similar in PCOS as in WHO 2 patients. In conclusion, inhibin B serum concentrations are normal in WHO 2 and PCOS women, suggesting a normal number of healthy early antral follicles despite increased overall follicle numbers in PCOS.

Tumor stroma as the main source of inhibin production in ovarian epithelial tumors.

Elevated serum inhibin levels have been found in ovarian cancer patients; however, the source of the elevated inhibin is uncertain. Previous studies of activin in human ovarian cancer suggest that activin may promote the growth of the tumor. The aims of this study were to examine the source of elevated inhibin from ovarian epithelial tumors (OETs) and to preliminarily investigate the role of the gonadotropin-inhibin/activin relationship in the development of OET. The protein and mRNA expression of alpha and betaA subunits of inhibin/activin were examined by immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR) in 120 OETs, including 30 benign cystadenomas, 30 borderline tumors, and 60 carcinomas. Stromal and epithelial cells were microdissected from 23 OETs to further examine the expression of alpha and betaA subunits by RT-PCR. Dimeric inhibin A and activin A production were measured by using the two-site ELISA from three OET cell lines in culture under treatment of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). betaA subunit was expressed in the epithelial component of 100% of the cystadenomas, in 80% of borderline tumors, and in 75% of the carcinomas, but not in tumor stroma. Inhibin alpha expression was not found in the epithelium of all OETs studied, but focal inhibin alpha immunoreactivity was seen in the tumor stroma (mainly luteinized stromal cells) in the majority of cases. Dimeric activin A was produced by all of the three OET cell lines with a 1.5-1.9-fold increment after FSH stimulation. However, activin A production was not augmented by LH treatment. No inhibin A was produced by the three OET cell lines with or without gonadotropin stimulation. The stroma of OET is the major source in the production of inhibin alpha (monomer). Dimeric inhibin A production may be the result of combined efforts of the tumor stroma (alpha subunit) and epithelium (betaA subunit). Cellular, compartmental expression of inhibin and activin subunits may play a role in the development of OET, although the mechanism remains undefined. The unopposed activin A production stimulated by FSH in OET cell lines suggests that activin production may represent one of the cellular mechanisms of growth promotion by FSH.

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

Inhibin A and pro-alpha C inhibin in Down syndrome and normal pregnancies.

Using two enzyme-linked immunosorbent assays specific for inhibin A and pro-alpha C inhibin, levels of the two proteins were assessed in maternal serum from 43 Down syndrome and 300 chromosomally normal pregnancies at 15-17 weeks' gestation. Compared to the control pregnancies, both inhibin A and pro-alpha C inhibin were significantly elevated in the Down syndrome pregnancies with median levels, expressed as multiples of the normal median, of 1.53 MoM and 1.34 MoM, respectively (P < 0.001 and P = 0.046 compared to controls). Levels of inhibin A and pro-alpha C inhibin were weakly but significantly correlated in both the control and the Down syndrome sera (r = 0.25, P < 0.0001; r = 0.4, P = 0.008, respectively). These data suggest that the mechanism(s) underlying the elevated inhibin levels observed in Down syndrome may affect the regulation of both the inhibin alpha- and beta A-subunits.

The time course of follicle-stimulating hormone suppression by recombinant human inhibin A in the adult male rhesus monkey (Macaca mulatta).

In higher primates, FSH secretion appears to be regulated by a control system consistent with that described by the classical inhibin hypothesis. The purpose of the present experiment was to examine the time course of inhibin's action to suppress FSH secretion in the intact adult male rhesus monkey. To this end, five adult males implanted with indwelling venous catheters and exhibiting typical episodic patterns of LH and testosterone (T) secretion received a 4-day i.v. infusion of recombinant human (rh) inhibin A (832 ng/h x kg) followed, after a 4-week interval, by vehicle infusion of similar duration. Changes in circulating FSH concentrations during the inhibin and vehicle infusions were determined using a sensitive homologous macaque RIA, whereas enzyme-linked immunosorbent assays were employed to track inhibin A, inhibin B, and inhibin pro-alpha-C levels during the experiment. Normal pulsatile activity in the hypothalamic-pituitary-Leydig cell axis was confirmed by monitoring changes in circulating concentrations of LH and T in 12-h windows of sequential blood collection (1200-2400 h; every 20 min) before, during, and after the rh inhibin A and vehicle infusions. Although infusion of rh inhibin A, which led to a 12 ng/ml square wave increment in circulating levels of this inhibin dimer, produced a marked decline in circulating FSH concentrations, significant suppression of the secretion of this gonadotropin was not manifest until 54 h after initiation of the infusion. Despite the marked decline in FSH secretion during the last 24 h of the 4-day infusion of recombinant hormone, circulating inhibin B and pro-alpha-C concentrations were maintained at preinfusion control levels (1 ng/ml). The finding that imposition of an exaggerated circulating inhibin signal led to suppression of FSH secretion in the male monkey only after 2 days of exposure to the hormone indicates that in this species the feedback action of testicular inhibin on FSH secretion is heavily lagged. Moreover, as the decrease in FSH did not lead to changes in native inhibin secretion, it seems reasonable to propose that the FSH-inhibin feedback loop that governs testicular function in higher primates operates with considerable hysteresis at both the pituitary and gonadal levels. The failure of dramatically elevated inhibin A levels to influence the pulsatile secretion of LH in the monkey reinforces the idea that in this species the pituitary action of testicular inhibin is specific for FSH and does not involve modulation of GnRH receptor levels.

Imbalanced Expression of Inhibin and Activin Subunits in Primary Epithelial Ovarian Cancer

Objectives.Inhibins and activins are related gonadal peptides with opposing biologic actions on gonadotropin regulation, cell differentiation, and proliferation. The previous study of activin in ovarian cancer cell lines suggests that activin may promote growth of ovarian cancer. Elevated serum inhibin levels were also found in ovarian cancer patients; however, the source of elevated inhibin is unknown. This study is designed to examine the expression of inhibin and activin subunits as well as activin receptor in primary ovarian epithelial tumors to explore their role in the process of ovarian epithelial tumorigenesis.Methods.The protein and mRNA expression of α and βA subunits of inhibin/activin as well as of activin receptor mRNA were examined with immunohistochemistry (IHC) and reverse transcription–polymerase chain reaction (RT–PCR) in 112 ovarian carcinomas. Cases included 59 serous, 23 endometrioid, 16 mucinous, 9 clear cell, and 5 undifferentiated carcinomas. We also tested normal ovary and benign and borderline ovarian tumors for comparison. These included 17 ovarian surface epithelial samples, 6 serous and 5 mucinous cystadenomas, and 9 serous and 7 mucinous tumors of low malignant potential. A total of 139 ovarian tumors were analyzed by IHC and a total of 63 ovarian tumor samples were tested by RT–PCR.Results.Inhibin α subunit expression was found in 47% of ovarian surface epithelia and focal α immunoreactivity was seen in tumor stroma, but was not found in the epithelial component of ovarian cystadenomas, tumors of low malignant potential (LMP), or carcinomas. Activin βA subunit was expressed in 93% of surface epithelia, in the epithelial component of all cystadenomas, in 81% of LMP tumors, and in 72% of carcinomas, but not in tumor stroma. Activin expression did not correlate with histologic grades, tumor types, and surgical stages. Activin receptor type I and II mRNA-amplified products were found in virtually all the surface epithelial samples and ovarian tumors.Conclusions.The data suggest that imbalanced expression of inhibin and activin subunits in ovarian surface epithelium may represent an early event which leads to epithelial proliferation. Unopposed βA and activin receptor expression in epithelial compartment of ovarian tumors suggest that activin may be available as autocrine and/or paracrine factors in ovarian epithelial tumors. But exact roles of inhibin and activin in ovarian epithelial tumors remain to be defined.

Serum Inhibin and Disease Status in Women with Ovarian Granulosa Cell Tumors

Objective.To determine if immunoreactive inhibin assayed in serum from women with granulosa cell tumors correlated with tumor burden, reflected response to treatment, or predicted recurrent disease.Study design.Serum samples were collected following bilateral oophorectomy (BSO) with or without other indicated surgery in 15 patients with granulosa cell tumors. Inhibin radioimmunoassay (RIA-Inh) was performed on all samples and results were correlated with tumor burden, disease status, and treatment response.Results.Fifteen patients had serum assayed for inhibin with levels ranging from 0 to 7470 U/liter. In 4 patients with measurable recurrent disease, inhibin levels correlated directly with tumor burden (r2= 0.96). Four patients had serum drawn during clinical remission and in all 4 patients elevated inhibin levels predated recurrence by a median interval of 11.5 months (range 7–20). The remaining 7 were treated for primary disease and were in clinical remission with a median follow-up of 33 months (range 9–53). Four of these 7 patients were surgically staged: 2 were FIGO Stage I and inhibin levels fell to 0 U/liter; 2 patients had metastatic disease (Stage IIc and IIIa) and their inhibin levels were found to be elevated following complete resection. The remaining 3 were not surgically staged, and all had elevated inhibin levels while in clinical remission, suggesting occult disease. Of the 15 total patients, 1 who was treated with chemotherapy for recurrent disease was followed with serial inhibin levels. She showed a complete response to therapy with inhibin levels falling from 975 to 0 U/liter with 15 months follow-up.Conclusions.Serum inhibin levels reflect tumor burden and may be valuable in assessing response to chemotherapy or predicting recurrent disease in women with granulosa cell tumors who have had BSO. Serum inhibin level evaluation should be incorporated into large-group trials of therapy for granulosa cell tumors.

Inhibin as a marker for ovarian cancer

Inhibin is a polypeptide hormone produced by the granulosa cells of the ovary, and is present in body fluids as dimers of various sizes each comprising an alpha- and beta-subunit. Free forms of the alpha-subunit also circulate, and the presently available radioimmunoassay (Monash assay) cannot distinguish these from biologically active dimeric inhibin. Recently we described a new two-site enzyme immunoassay able for the first time to measure the levels of dimeric inhibin throughout the human menstrual cycle. The sensitivity limit of this assay is 2 pg ml-1 in human serum with cross-reactivity against activin of 0.05%. The normal range of inhibin in post-menopausal women is < 5 pg ml-1, in pre-menopausal women 2-80 pg ml-1 (2-10 pg ml-1 in the follicular phase, 40-80 pg ml-1 in the luteal phase). This assay was used to determine inhibin levels in sera from 15 (five pre-menopausal and ten post-menopausal) patients with granulosa cell tumours of the ovary. It was raised in a pre-menopausal patient preoperatively (261 pg ml-1), in six post-menopausal patients (32, 43, 54, 66, 24 and 58 pg ml-1) and one pre-menopausal patient with recurrent tumour, (237 pg ml-1), all confirmed clinically. Inhibin was normal in six patients in remission. Oestradiol levels were normal in all patients. Serial levels of inhibin predicted recurrence before overt clinical relapse in two patients. In 29 patients with malignant epithelial ovarian tumours inhibin levels were modestly elevated in nine and normal in the rest. Three patients with endometrioid histology, two with undifferentiated tumours, three with mucinous adenocarcinoma and one with clear cell carcinoma had elevated inhibin levels. Functional inhibin is secreted by all granulosa cell tumours of the ovary studied and can be used as a tumour marker to determine response to therapy and predict recurrence and is superior to oestradiol. A more detailed analysis of the levels of inhibin, and its subunits in epithelial ovarian cancer is needed to identify the molecular forms of the immunoreactive material before optimised assays can be applied to this more common tumour.

Clinical and pathophysiological aspects of inhibin

Inhibin is a peptide hormone normally produced by the ovary. We have previously reported that serum inhibin concentrations are elevated in patients with granulosa cell tumours of the ovary. The aim of this study was to measure serum inhibin in a prospective, consecutive series of 200 patients admitted for suspected ovarian cancer. The serum inhibin radioimmunoassay had a sensitivity of 77 mu/l. The median effective dose was 640 mu/l, while within- and between-assay coefficients of variation in the region of maximal assay precision were 4.3% and 4.3%, respectively. The average effective doses (10 and 90%) in 35 consecutive assays were 211 and 1908 mu/l, respectively. We designated a serum inhibin concentration of > or = 130 mu/l as pathological in castrate or functionally agonadal women. Serum inhibin concentrations were elevated in 12 of 13 post-menopausal patients with mucinous cystadenocarcinoma of the ovary. By contrast, elevated serum inhibin values were found in only nine of 65 women with non-mucinous epithelial ovarian cancers. All patients showed a fall in serum inhibin levels to below 130 mu/l by 1 week after surgery. In post-menopausal women (n = 54) with proven ovarian cancer, serum inhibin concentrations correlated negatively with serum FSH and the clinical stage of their disease (P < 0.05). By contrast, serum inhibin correlated positively with serum oestradiol and progesterone (P < 0.001) but there was no correlation between serum inhibition and serum CA-125 values. We conclude that serum inhibin concentrations are typically elevated in patients proven to have mucinous cystadenocarcinoma of the ovary.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated inhibin concentration in the follicular fluid of dairy cows with chronic cystic ovarian disease

This study compared serum and follicular fluid inhibin and gonadotropin profiles between chronic cystic ovarian diseased (CCOD) and normal cyclic dairy cows. Blood samples and follicular fluid were collected from CCOD cows (n=15) and cyclic cows in the follicular phase of the estrous cycle (control, n=6) and analyzed for inhibin, follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations. There was a significant increase in inhibin and a decrease in FSH and LH concentrations in the follicular fluid of CCOD cows compared with those of cyclic cows (P < 0.05). Mean serum inhibin, FSH and LH concentrations between CCOD and cyclic cows were not differnt (P > 0.05), however, there was a tendency for serum inhibin to be higher and FSH to be lower in CCOD cows compared to cyclic animals (P < 0.1). The FSH pulse frequency also was lower in CCOD cows than in cyclic cows (P < 0.05). These data suggest that increased production of inhibin from cystic follicles of CCOD cows alters pituitary FSH secretion and subsequently reduces the concentration of FSH in follicular fluid. As a result, decreased FSH stimulation at the ovarian level could ultimately lead to the reduction in follicular LH and FSH receptor concentrations, resulting in abnormal follicular steroidogenesis in CCOD dairy cows.

337 Elevated Maternal Serum Inhibin in Preeclamptic Pregnancies with Intrauterine Growth Retardation

337 Elevated Maternal Serum Inhibin in Preeclamptic Pregnancies with Intrauterine Growth Retardation

Elevated serum inhibin levels and suppressed luteinizing hormone surge in young patients stimulated with gonadotropins.

The physiological role of inhibin and its relation to other sex hormones (estradiol, progesterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH)) has been investigated during gonadotropin-stimulated cycles of 38 in vitro fertilization-embryo transfer/gamete intrafallopian transfer (IVF-ET/GIFT) patients. Human menopausal gonadotropin (hMG) was given from day 3 of the cycle until 1 day before ovulation induction with human chorionic gonadotropin (hCG). Blood samples were taken twice daily and hormone measurements performed by radioimmunoassay or enzyme immunoassay. Patients were divided into two groups: Group A comprised patients < 35 years of age (n = 20) and Group B included patients > or = 35 years of age (n = 18). The pregnancy rate was significantly higher in Group A. During the follicular phase, serum inhibin level rose gradually in both groups but the values were higher in Group A (significantly between days -2 and 0). During the early luteal phase serum inhibin concentrations were similar in both groups. Estradiol pattern did not differ in the two groups. Estradiol pattern did not differ in the two groups. Whilst serum estradiol level did not increase significantly after day 0, serum inhibin concentration reached its peak value 1 day later, on day +1. Serum progesterone was higher in Group A between days +1 and +4 (significantly on days +1, +3 and +4). Serum FSH increased slowly in both groups and did not correlate with serum inhibin concentration. Basal LH concentrations were similar between days -6 and -2 in both groups. Around the time of ovulation induction (day -1, 0 and +1) serum LH was lower in Group A (significantly on day 0).(ABSTRACT TRUNCATED AT 250 WORDS)

Elevation of follicular phase inhibin and luteinizing hormone levels in mothers of dizygotic twins suggests nonovarian control of human multiple ovulation

To determine whether multiple ovulation in mothers of spontaneous dizygotic (DZ) twins is because of higher hypothalamic stimulation or is in response to lower serum levels of ovarian inhibin. Serum hormone levels were measured at five times throughout the cycle in a sample of eight mothers of DZ twins and paired controls. On day 12, ovarian ultrasonography was performed. Blood samples were collected in participants' homes except on day 12 when they were collected at the ultrasonography clinic. Human volunteers who had at least one set of spontaneous DZ twins were paired with controls matched for age and parity. None. Serum inhibin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) levels on approximate cycle days 1,2,8,12, and 21. Serum inhibin levels were elevated throughout the cycle (significantly on day 1) in mothers of DZ twins. Also elevated were early follicular FSH levels, LH levels throughout the follicular phase (significantly on days 1,2, and 8), and early to midfollicular E2 (significantly on day 8) in DZ mothers, indicative overall of greater follicular activity. It is concluded (1) that the primary cause of multiple ovulation in humans is not a decrease in inhibin secretion from the ovary; (2) the increased secretion of FSH and LH may be caused by elevated secretion of, or sensitivity to gonadotropin-releasing hormone; and (3) the elevated inhibin and E2 levels are a response to increased gonadotropin release.

Follicular fluid inhibin activity and steroid levels in ovarian tissue obtained at autopsy from human infants from 18 to 200 days of age

The ovaries of 25 human infants from 18 to 200 days of age were obtained at autopsy, and their follicular fluid was subjected to measurement of inhibin activity, estrogen, progesterone, androstenedione, and testosterone. Significant inhibin activity was present in all samples of follicular fluid (charcoal-treated) (138 +/- 19 U/10 microliter follicular fluid; 10,545 +/- 2758 U/ovary). There was a tendency for greater inhibin activity, follicular volume, and estrogen in infants from 18 to 59 days than in older infants. There was a significant positive correlation between follicular fluid volume, estrogen, and androstenedione, compared with follicular fluid inhibin content per ovary. It is possible that elevated serum follicle-stimulating hormone and luteinizing hormone observed early in life stimulates follicle growth, inhibin, and estrogen production. As a result of elevated inhibin and estrogen, the gonadotropins may be inhibited, which may cause a decline in follicular activity after 4 to 6 months.