Activin Subunits Research Articles

Localization of the activin signal transduction components in normal human ovarian follicles: implications for autocrine and paracrine signaling in the ovary.

The intraovarian function of gonadally produced activin is unclear, and many in vitro studies have suggested a role for activin in follicle development. To identify the follicular developmental stages at which these ligands may be acting, we have used immunohistochemical localization of the ligand subunits, receptor subtypes, and Smad co-activating proteins within the same follicles. The earliest stages of follicle development (primordial to primary) show no immunoreactivity for the activin subunits or their receptors. Oocytes from these early stages contain immunostaining for Smad2 and Smad4, consistent with signaling by other TGF-beta superfamily members. Immunostaining for the activin type II receptor first appears in oocytes and oocyte-associated cumulus cells at the secondary follicle stage. However, activin is not produced in these follicles, suggesting that either the receptors are inactive at this stage or they are used by another protein. Co-localization of activin and inhibin subunits, receptors, and Smads only occurs in granulosa and theca cells of small antral, aromatase-positive follicles as well as granulosa cells of early atretic follicles. In addition, multivariate statistical analysis reveals that the ligands and their cellular signaling complexes are independently regulated. Together, these data strongly suggest that the intraovarian role of activin is limited to a few developmental stages and that other TGF-beta family members may use this cell autonomous signaling machinery in early follicle development.

Serum and tissue expression of activin a in postmenopausal women with breast cancer.

Activins are growth factors involved in the control of cell proliferation and differentiation. Human breast tissues express immunoreactive activin subunits, and activin A is able to inhibit the replication of mammary cells in vitro. The aim of the present study was to evaluate 1) whether breast cancer expresses activin betaA subunit mRNA, 2) whether serum activin A levels are altered in postmenopausal women with breast cancer, and 3) how circulating activin A levels change after tumor removal. Four groups of women (n = 158) were enrolled for the present prospective study: two groups were composed of postmenopausal women with breast cancer (n = 74) or benign lesions (n = 15); the third was a control group composed of healthy postmenopausal women (n = 62); and the fourth group included healthy fertile women (n = 7) undergoing plastic surgery with removal of non-neoplastic mammary tissue. RT-PCR showed that betaA subunit mRNA was expressed in breast carcinoma, fibroadenoma, and normal mammary tissue, and the level of expression was higher in carcinoma than in normal tissue (P < 0.05). Dimeric activin A was detectable in homogenates of breast cancer tissue at concentrations twice as high as in non-neoplastic tissue (P < 0.01). In women with breast cancer, median serum activin A levels were significantly higher than in controls (P < 0.001). The high serum activin A levels in patients with breast cancer were not correlated with the presence of lymph node metastasis, tumor grade, or tumor diameter. After tumor excision, a significant decrease of activin A in the first and second postoperative days was observed (P < 0.01; Friedman's ANOVA). Conversely, activin A levels remained unchanged after plastic surgery in healthy women. The present results suggest that activin A is expressed and secreted in postmenopausal women with breast cancer. The pathophysiological and possible clinical implications of this finding remain to be investigated.

Expression of activin receptors, follistatin and betaglycan by human endometrial stromal cells; consistent with a role for activins during decidualization.

Decidualization of the human endometrium is critical for implantation, but the mechanisms involved are largely unknown. Activin subunits are expressed in endometrium during decidualization. From its known actions in cell differentiation and tissue remodelling, we hypothesized that activin A is involved in the paracrine regulation of decidualization. We examined the expression of activin receptors (ActRs) by semi-quantitative and real-time RT-PCR. mRNA for all ActR subtypes (Ia, Ib, IIa and IIb) was detected in endometrium, with maximal expression in the early secretory phase and in early pregnancy. ActR protein was localized exclusively to stromal and endothelial cells. This expression pattern was confirmed by in-situ hybridization. Activin bioavailability is locally regulated by its binding protein, follistatin, and also by the antagonist, inhibin. Inhibin competition for ActRII binding is enhanced by the binding protein, betaglycan. Follistatin and betaglycan were also detected in the endometrium, localized to stromal and epithelial cells. This co-expression of activin subunits, receptors and binding proteins indicates that stromal cells are capable of responding to activin, and that there is tight local regulation of activin action within the endometrium. As activin production is up-regulated in decidual cells, this provides further evidence for an involvement of activins during stromal cell decidualization.

Expression and dimerization of the rat activin subunits betaC and betaE: evidence for the ormation of novel activin dimers.

Activins are cytokines of the transforming growth factor beta family, which plays a central role in the determination of cell fate and the regulation of tissue balance. Family members are composed of two subunits and this dimerization is critical for liganding their cognate receptors and execution of proper functions. In the current study we focused on the localization of activin betaA, betaB, betaC and betaE subunits in the adult rat and analyzed the composition of putative activin beta dimers. By dissecting tissue distribution of various activins, we found that the liver, in particular the hepatocytes, is the major source for activin betaC and betaE transcripts, since other tissues almost failed to express these isoforms. In sharp contrast, the emergence of activin betaA and betaB appeared ubiquitous. Using a highly selective proteome approach, we were able to identify homo- as well as heterodimers of individual activin subunits, indicating a high redundancy of ligand composition. Certainly, this broad potential to homo- and heterodimerize has to be considered in future studies on activin function.

Gonadal malignant germ cell tumors express immunoreactive inhibin/activin subunits.

Inhibin and activin are proteins produced by ovarian granulosa cells and testicular Sertoli cells and are members of the transforming growth factor-beta superfamily. Since increased circulating levels of immunoreactive inhibin were detected in women with malignant ovarian tumors, they were proposed as tumor markers for ovarian carcinoma. Immunohistochemical studies later confirmed the presence of inhibin and activin subunits in granulosa cell tumors and epithelial ovarian cancer, as well as in Sertoli and Leydig cell testicular cancer. However, there is discrepant information on the detection of inhibin and activin in malignant germ cell tumors (MGCT). The aim of the present study was to evaluate the immunohistochemical expression of the inhibin/activin alpha, betaA and betaB subunits in ovarian and testicular MGCT specimens using polyclonal antisera. The ovarian tissue samples were composed of 19 MGCT, including dysgerminoma (n=18) and yolk sac tumor (n=1). The testis specimens included classic seminomas (n=20), embryonal carcinomas (n=7), choriocarcinomas (n=2), and yolk sac tumor (n=1). Ovarian and testicular malignant germ cell tumors expressed positive staining for inhibin/activin alpha, betaA and betaB subunits, with some variations between and within individual tumors: while ovarian dysgerminomas were diffusely positive for alpha, betaA and betaB, testicular tumors expressed alpha and betaB subunits, whereas betaA staining was weak. The present results show positive staining for inhibin/activin subunits in ovarian and testicular MGCT, suggesting a possible role in tumorigenesis with the resultant clinical implication.

Localization of an activin/activin receptor system in the porcine ovary.

The aim of this study was to locate a possible activin/activin receptor system within porcine ovaries containing functional corpora lutea. In situ hybridization was used to assess the gene expression of beta(A)- and beta(B)-activin subunits, and immunohistochemical studies were done to detect activin-A protein and activin receptor type II. mRNA expression of the beta(A)- and beta(B)-activin subunits was found in the granulosa from the unilaminar follicle stage onward, in the developing thecal layer of multilaminar and small antral follicles, in the theca interna of mid-sized antral follicles, in corpora lutea, and in the ovarian surface epithelium. Immunoreactive activin A protein could be detected at the same ovarian sites, but in thecal tissue of small antral follicles only. This protein was also demonstrated at the peripheral zone of oocytes from multilaminar and antral follicles. A positive immunoreaction for activin receptor was found in granulosa cells from multilaminar and older follicles and in oocytes from the earliest stages of follicular development onward. In late multilaminar follicles and in antral follicles, the oolemma was stained. Except for small antral follicles, a positive activin receptor immunoreaction was absent in the follicular theca. Activin receptor immunoreaction was furthermore present in corpora lutea and in the ovarian surface epithelium. It is concluded that, within porcine ovaries containing functional corpora lutea, an activin/activin receptor system is present in all intact follicles, the corpora lutea and the surface epithelium. Within follicles, granulosa and theca cells are the main sites of activin synthesis, while oocytes and granulosa cells are the main activin binding sites.

The ovary in women is not the major source of circulating Activin-A but is for Inhibin-B.

Objective: Inhibins and Activins are major modulators of FSH, having opposite effects on its secretion. Besides the ovary, where it was originally characterized, inhibin and activin subunits are also produced in other sites including the pituitary. This study assessed the relative contribution of ovarian Inhibin-B (predominant form during the follicular phase) and Activin-A to the circulating pool in women.

The contribution of inhibins and activins to malignant prostate disease

The normal human prostate expresses inhibin and activin subunits. In prostate cancer, the inhibin α subunit gene is down regulated and this is associated with loss of heterozygosity (LOH) at the gene locus and methylation of the promoter. These data support the hypothesis that the inhibin α subunit is tumor suppressive in the prostate. The pluripotent effects of activins and the similarities to transforming growth factor β (TFGβ) suggest a role for activins in progression to malignancy, whereby, the normal growth inhibitory action of activin A observed on benign cells is lost with the acquisition of activin resistance in prostate cancer cells. The mechanisms of rendering tumor cells resistant to activin A may include: alteration in activin binding protein (follistatin) synthesis and/or dimerisation with activin β C to form novel activin dimers. The contribution of the activin signalling cascade to malignancy requires further evaluation to identify the synergies and differences to other members of the TGFβ superfamily.

Follistatin production by skin fibroblasts and its regulation by dexamethasone

Activin and follistatin (FS) appear to play a role in the development of the skin and its appendages, in the inflammatory process, angiogenesis, and in wound healing. Although there is information on the expression of activin subunits and receptors in fibroblasts and keratinocytes, there are no reports on the regulation of FS expression in these cells. In the present study we analyzed the splicing variants of FS mRNAs in fibroblasts from genital and nongenital skin by RT-PCR and northern analysis, and examined the induction of FS mRNA and protein by hormones and growth factors in skin fibroblasts from human and nonhuman primates. FS mRNA was highly expressed in all fibroblast strains with similar expression regardless of donor species (human or monkey), donor age (neonate or adult), or the organ from which the fibroblast strains were established (skin or pituitary, genital or non-genital skin). Moreover, the band density corresponding to FS-288 was <5–10% of the value for FS-315 in skin fibroblasts as in all other tissues examined. Fibroblast FS mRNA and protein production were biphasically regulated by dexamethasone: low concentrations (0.01 and 0.1 nM) increased whereas higher concentrations (>1 nM) suppressed FS expression. On the other hand, androgens, activin and PACAP38 were without effect. These data establish cultured skin fibroblasts as a model to study FS gene expression in humans, and support a role for follistatin in the normal immune response and in the anti-inflammatory actions of glucocorticoids.

Inhibin Subunits mRNA Expression Level in Human Placenta from Normal and Down's Syndrome Pregnancies

In order to study the mechanisms leading to increased inhibin A and activin A in maternal serum with advancing gestation and increased inhibin A in Down's syndrome pregnancy, the mRNA expression level of inhibin and activin subunits was quantitatively studied in human placenta using Northern blot and semiquantitative RT-PCR analysis. The corresponding protein level was also determined by specific ELISAs for inhibin A, inhibin B, activin A and inhibin pro αC in placental extracts. Normal placenta (n=27) showed a slight significant increase in α and βA subunit mRNA levels in term pregnancy, with no change of the corresponding protein level. Placenta from Down's syndrome pregnancies (n=6) did not differ from controls in either mRNA expression or corresponding protein levels. In conclusion, there is a dissociation between inhibin and activin subunit mRNA levels and the corresponding protein levels in maternal serum, and Down's syndrome inhibin A increase is not explained by mRNA expression upregulation. In an additional study, ovarian cortex tissue from term pregnancies (n=3) were examined. Only the α subunit mRNA was expressed, at a higher level than in the placenta, suggesting that ovary could be a source of inhibin pro αC during pregnancy.

Localization of activin beta(A)-, beta(B)-, and beta(C)-subunits in humanprostate and evidence for formation of new activin heterodimers of beta(C)-subunit.

Activin ligands are formed by dimerization of activin ss(A)- and/or ss(B)-subunits to produce activins A, AB, or B. These ligands are members of the transforming growth factor-ss superfamily and act as growth and differentiation factors in many cells and tissues. New additions to this family include activin ss(C)-, ss(D)-, and ss(E)-subunits. The aim of this investigation was to examine the localization of and dimerization among activin subunits; the results demonstrate that activin ss(C) can form dimers with activin ss(A) and ss(B) in vitro, but not with the inhibin alpha-subunit. Using a specific antibody, activin ss(C) protein was localized to human liver and prostate and colocalized with ss(A)- and ss(B)-subunits to specific cell types in benign and malignant prostate tissues. Activin C did not alter DNA synthesis of the prostate tumor cell line, LNCaP, or the liver tumor cell line, HepG2, in vitro when added alone or with activin A. Therefore, the capacity to form novel activin heterodimers (but not inhibin C) resides in the human liver and prostate. Activin A, AB, and B have diverse actions in many tissues, including liver and prostate, but there is no known biological activity for activin C. Thus, the evidence of formation of activin AC or BC heterodimers may have significant implications in the regulation of levels and/or biological activity of other activins in these tissues.

Hepatocyte growth factor induces branching tubulogenesis in MDCK cells by modulating the activin-follistatin system

The activin-follistatin system is expressed in tubular cells of the kidney. The present study was conducted to examine the role of the activin-follistatin system in tubulogenesis using Madin-Darby canine kidney (MDCK) cells as a model system. Tubulogenesis was assessed using MDCK cells cultured in collagen gel. The effect of recombinant human activin A on tubulogenesis was examined. Blockade of the action of endogenous activin was achieved by either adding follistatin or transfection of dominant-negative mutant of the type II activin receptor. The production of activin A was examined by Northern blotting, in situ hybridization, and Western blotting. MDCK cells expressed mRNA for the betaA subunit of activin. These cells formed spherical cysts when cultured in collagen gel. Hepatocyte growth factor (HGF) added to the spherical cysts induced branching tubulogenesis. When activin A was added together with HGF, activin A blocked the branching tubulogenesis induced by HGF, and the activin-treated cells were scattered. Conversely, follistatin, an antagonist of activin A, induced branching tubulogenesis qualitatively similar to that induced by HGF. Adenovirus vector-mediated transfer of the gene encoding truncated type II activin receptor, which acts as a dominant negative mutant, also induced branching tubulogenesis. Finally, HGF markedly inhibited the production of activin A in MDCK cells cultured in collagen gel. Activin A produced in MDCK cells tonically inhibits branching tubulogenesis, and HGF induced branching tubulogenesis mainly by blocking the production of activin A.

Activin A and activin receptors in the human thyroid: a link to the female predominance of goiter?

Activin A belongs to the TGF-beta family of growth factors involved in control of tissue formation by growth inhibition and to a family of hormones involved in human reproduction. Serum levels of dimeric activin A display a sexual dimorphism with significantly higher circulating hormone concentrations in men than in women after menopause. Since goiter is far more frequent in women than in men, we investigated the role of this sex-related growth factor in the human thyroid. Primary cultures were obtained from 3 patients with goiter, and 4 with recurrent goiter. Activin A significantly inhibited the proliferation of human thyroid follicular epithelial cells in vitro in concentrations between 0.5 and 50 ng/ml and was almost as potent as TGFbeta-1. Analysis in native tissues from 12 normal thyroids, 16 goiters, and 5 Graves thyroids demonstrated mRNA expression of the activin subunit betaA, TGFbeta-receptor type I and II, activin receptors type I receptors alk2 and alk4, and activin type II receptors actRII and actRIIb. Isoform analysis of the major functional type I activin receptor alk4 revealed the full-length transcript SKR2-1 and transcripts for the partially truncated proteins SKR2-2 and SKR2-3 in normal thyroids and goiters. Semi-quantitative RT-PCR revealed a significant 2.5-fold decrease of mRNA for alk4-1 type I activin receptors in goiter as compared to normal thyroid (p < 0.05), whereas expression of the type II receptor actRII was unchanged. These data identify a novel growth inhibitory pathway by activin in the human thyroid. Down-regulation of activin receptor type lb in goiter hints towards end-organ changes which could contribute to deficient growth inhibition. These data provide a mechanistic model how the sexually dimorphic hormone activin A may protect males from goitrogenesis.

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.

Analysis of follicular fluid hormone concentrations and granulosa cell mRNA levels for the inhibin-activin-follistatin system: relation to oocyte and embryo characteristics

Objective: To explore the potential roles of inhibin, activin, and follistatin in human oocyte development by quantifying their intrafollicular biosynthesis. Design: Prospective, nonrandomized study. Setting: An IVF unit and academic research laboratory. Patient(s): Thirty one patients undergoing IVF. Intervention(s): Human menopausal gonadotropins or human FSH (or both) were administered. Single-follicle aspirates (n = 110) were collected for analysis. Main Outcome Measure(s): Concentrations of dimeric, total and pro-αC inhibin forms; activin A; follistatin; estradiol; and progesterone were measured in follicular fluids. Granulosa-cell mRNA was analyzed for α, βA, and βB inhibin and activin subunits; follistatin; activin receptors; and β-actin. Hormone concentrations and mRNA levels were correlated with oocytes or embryos from the same follicles. Result(s): Levels of progesterone and follistatin were significantly greater in follicles containing MI or MII oocytes than in those containing GV oocytes. Inhibin α-subunit mRNA levels were significantly higher in follicles containing maturing oocytes, the highest-quality oocytes, and oocytes that were subsequently fertilized. In contrast, inhibin α-subunit mRNA levels were significantly lower in follicles from which higher-quality embryos were obtained. Conclusion(s): Inhibin α-subunit biosynthesis is associated with normal oocyte and follicle maturation, but excessive α-inhibin is associated with poor embryo quality. None of the hormones analyzed were associated with oocyte or embryo quality.

Role of activins in the male reproductive tract.

The search for gonadal proteins that regulate pituitary FSH led to the isolation of inhibins and activins. As members of the transforming growth factor beta (TGFbeta) superfamily of growth and differentiation factors, these proteins have been shown subsequently to affect a range of tissues and systems beyond their role in reproduction. Studies on the expression and synthesis of activins in the male reproductive tract have localized these proteins in the testis, epididymis and prostate. In general, activins regulate cell proliferation and, consequently, the expression and localization of activin subunit mRNAs and proteins within these organs must be discrete. Activin ligand bioactivity is dependent on the presence of the appropriate receptors and signalling systems, but activin ligand formation or access to receptors is regulated by the formation of inhibins or by activin-binding proteins such as follistatin. This review examines the evidence that the capacity to synthesize activins and to regulate activin bioactivity resides in the cells of the male reproductive tract. It is concluded that activins exert their effects through local (autocrine or paracrine) mechanisms, rather than through endocrine systems. The interplay between the inhibins or follistatins provides a degree of regulation of activin bioactivity before ligand signalling events. The challenge for the future is to determine whether there is any difference between the action of individual activin ligands or whether these proteins are functionally redundant, indicating that compensatory mechanisms are essential for male reproductive tract function.

Differential regulation of activin A for hepatocyte growth and fibronectin synthesis in rat liver injury

Background/Aims: Both hepatocyte growth and production of extracellular matrix such as fibronectin are essential for liver regeneration. Although activin A is reported to inhibit DNA replication in rat hepatocytes, the role of activin A for liver regeneration after acute injury has not been fully assessed. This study investigated the mechanism by which hepatocyte growth is regulated by activin A during liver regeneration and the effects of activin A on extracellular matrix production. Methods: The mRNA for βA subunit of activin A and activin receptors in hepatocytes and hepatic stellate cells after CCl 4 administration were studied by Northern blotting. Binding of 125I-activin A was tested in these cells. Effects of activin A were examined by DNA, collagen and fibronectin synthesis. Results: βA mRNA was expressed in quiescent hepatocytes, and this expression peaked 12 h after CCl 4 administration. Activin receptor mRNAs and cross-linked ligand/receptor complexes were expressed in hepatocytes and hepatic stellate cells. However, these levels decreased specifically in hepatocytes at 24 h and had normalized by 72 h. The down-regulation of activin receptor was also observed after partial hepatectomy. Antiproliferative response to activin A decreased in hepatocytes at 24 h. Activin A stimulated production of fibronectin by hepatic stellate cells, but the synthesis of collagen was only slightly elevated in hepatic stellate cells following activin stimulation. Conclusions: The down-regulation of activin receptors in hepatocytes may be partly responsible for these cells becoming responsive to mitogenic stimuli. The increase of activin A at the early stage of liver injury has the potential to contribute to the regulation of fibronectin production in hepatic stellate cells.

Human mammary gland and breast carcinoma contain immunoreactive inhibin/activin subunits: evidence for a secretion into cystic fluid.

Inhibins and activins are members of the transforming growth factor beta superfamily and are known to modulate the growth and differentiation of several cell types. The present study investigated the localization of inhibin and activin subunits in human normal and pathological breast tissues. A cross-sectional study comparing the expression of inhibin/activin subunits alpha, betaA and betaB in surgical specimens from women undergoing reductive mammoplasty (classified, according to the phase of the menstrual cycle, as follicular, luteal, or postmenopausal), and patients submitted to lumpectomy for fibrocystic disease, benign (intraductal papilloma, adenomyoepithelioma, and hamartoma) or malignant breast neoplams (intraductal, intralobular, and invasive carcinoma). Immunohistochemistry was used to localize inhibin alpha and activin betaA and betaB subunits in the cytoplasm of epithelial cells of mammary glands. Dimeric activin A, inhibin A and inhibin B were measured by specific two-site enzyme immunoassay in the cystic fluid collected from patients with fibrocystic disease. An intense staining for the alpha inhibin subunit and a mild staining for betaA and betaB subunits were present in samples obtained from normal breast tissue regardless of menstrual cycle phase, and in fibrocystic disease and benign neoplasms. Carcinoma cells stained weakly to moderately for alpha subunit and were negative for betaA and betaB subunits. Fibrocystic disease was associated with absence of betaA subunit expression in normal epithelial cells and intense staining for all subunits in the apocrine cells. Immunoreactive inhibin A, inhibin B, and activin A were also present in cystic fluid, suggesting a local secretion of these proteins. These data suggest a local expression and secretion of inhibin and activin in human normal, fibrocystic disease and neoplastic breast tissues. The low expression of these proteins may facilitate abnormal cell proliferation in breast carcinoma.

O-229. Immunohistochemical localization of inhibin and activin subunits in normal and polycystic ovaries

O-229. Immunohistochemical localization of inhibin and activin subunits in normal and polycystic ovaries

Immunohistochemical localization of inhibin and activin subunits in human epithelial ovarian tumors

Objective: Our purpose was to examine the cellular localization of inhibin and activin subunits in human epithelial ovarian tumors. Study Design: We examined the immunohistochemical localization of the α, βA, and βB subunits of inhibin in human mucinous and serous ovarian tumors including adenoma, cystic tumor with borderline malignancy, and adenocarcinoma. Results: Immunostaining specific for the α, βA, and βB subunits of inhibin was observed in the tumor cells of the mucinous adenoma and the cystic tumor with borderline malignancy. We observed negative immunostaining specific for the α subunit and positive staining specific for the βA and βB subunits in the tumor cells of the mucinous adenocarcinoma. We did not observe any staining for the α subunit of inhibin in the serous tumors including benign adenoma, cystic tumor with borderline malignancy, and adenocarcinoma. However, positive staining results for the βA and βB subunits were observed in the serous tumor cells. Conclusion: Our results suggest that inhibins and activins might be secreted by the mucinous adenoma and the cystic tumor with borderline malignancy and that activins might be secreted by the mucinous adenocarcinoma and the serous tumors including benign adenoma, cystic tumor with borderline malignancy, and adenocarcinoma. (Am J Obstet Gynecol 1999;180:316-22.)