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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1939-1943
Copyright © 1997 by The Endocrine Society

Reproductive Endocrinology

Serum {alpha}-Inhibin Levels in Polycystic Ovary Syndrome: Relationship to the Serum Androstenedione Level1

Pascal Pigny, Rachel Desailloud, Christine Cortet-Rudelli, Alain Duhamel, Delphine Deroubaix-Allard, André Racadot and Didier Dewailly

Department of Endocrinology and Diabetology (R.D., C.C.R., D.D.R., D.D.) and Laboratory of Endocrinology (P.P., A.R.), Marc Linquette Clinic, Hospital and University Center, F-59037 Lille; and Faculty of Medicine, Centre d’Etude et de Recherche en Informatique Medicale (A.D.), F-59045 Lille, France

Address all correspondence and requests for reprints to: Prof Didier Dewailly, Service d’Endocrinologie et Diabétologie, Clinique Marc Linquette, Centre Hospitalier et Universitaire, F 59037 Lille Cedex, France.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To date, only one study has demonstrated increased serum inhibin levels in women with polycystic ovary syndrome (PCOS). Moreover, no relationship between serum inhibin and either FSH or androgen levels has been noted. This lack of data could be due to 1) the heterogeneity of PCOS and the small sample size of previous studies, and/or 2) the complexity of circulating inhibin molecular forms, which hinders the precise evaluation of bioactive inhibin. In the present study, {alpha}-inhibin levels were assayed in the serum of 61 healthy women and 72 PCOS patients by means of an {alpha}-{alpha} enzyme-linked immunosorbent assay. Serum {alpha}-inhibin levels together with LH and androstenedione (A) levels were significantly increased in PCOS women (mean ± SD, 1.45 ± 0.55 vs. 0.94 ± 0.36 U/mL in controls; P < 0.001). Moreover, simple and partial regression analysis demonstrated that serum A levels were positively and independently correlated to serum {alpha}-inhibin (r = 0.32; P < 0.01) and LH levels (r = 0.48; P < 0.001) in PCOS. The respective influences of {alpha}-inhibin and LH on A variability were 20% and 80%, as determined by multiple regression analysis. In conclusion, in agreement with recent in vitro data, our in vivo results argue for a role of inhibin in the hyperandrogenism of PCOS together with, but independently from, that of LH. Further studies are needed to determine whether this effect is produced by inhibin A and/or B.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INHIBINS ARE dimeric glycoproteins consisting of an {alpha}-subunit covalently joined by disulfide links to either a ßA-subunit (inhibin A) or a ßB-subunit (inhibin B). Besides these mature bioactive forms, inhibins also exist in the circulation as either unprocessed or partially processed high mol wt forms, and free {alpha}-subunit. The physiological significance of the precursor forms of inhibin remains a matter of debate (1). Inhibins are primarily produced by the gonads and the placenta, and have been initially characterized by their ability to exert a negative feedback on pituitary FSH synthesis and release (2). Moreover, numerous recent studies have emphasized the fact that inhibins may act at the gonadal level as paracrine and/or autocrine factors (3, 4, 5, 6).

First generation inhibin immunoassays used antibodies raised against {alpha}-subunit and measured immunoreactive inhibin levels (or {alpha}-inhibin). Among them, the Monash RIA using antiserum 1989 (7) was the first available and the most widely used assay (8). The lack of specificity of these assays for the bioactive dimeric forms of inhibin may explain why a physiological role for inhibin in FSH release could not be demonstrated in men (9). However, evidence supporting such a role in women has been reported (10). Recently, new two-site inhibin immunoassays have been developed, permitting the measurement of either dimeric inhibin A or inhibin B (11, 12, 13). However, a high degree of assay specificity does not seem to be required for all clinical applications of inhibin measures, as previously suggested (14). For example, {alpha}-inhibin levels may be used as a valuable index of granulosa cell (GC) activity or maturity (15, 16), as the majority of serum immunoreactive inhibin is thought to arise from the GC in nonpregnant women.

The polycystic ovary syndrome (PCOS) is a heterogeneous entity characterized by insulin resistance, hyperandrogenemia, a high serum LH/FSH ratio and chronic anovulation in the presence of bilateral polycystic ovaries (17, 18, 19). To explain the inappropriately low serum FSH levels found in this syndrome, it has been suggested that polycystic ovaries might secrete higher amounts of inhibin, leading to inhibition of pituitary FSH secretion (20, 21). Furthermore, recent in vitro data indicate that inhibin enhances both basal and LH-induced androgen production by human thecal cells (TC) (22, 23, 24). Some studies have evaluated the hypothesis that the endocrine or paracrine influence of inhibin might be enhanced in PCOS. However, these studies were performed by measuring either {alpha}-inhibin or dimeric inhibin, and generally did not find a difference in serum inhibin levels between control women and PCOS patients (25, 26, 27), with one exception (28). In these studies no relationship between either serum androgen or FSH and inhibin levels in PCOS women was noted. However, these reports included small numbers of women with PCOS (between 5–23). As PCOS is a heterogeneous entity involving several pathophysiological factors, a small sample size could mask such a relationship. Here we report a large scale study evaluating {alpha}-inhibin levels in women with PCOS and in healthy controls using an {alpha}-{alpha} enzyme-linked immunosorbent assay (ELISA) that detected free {alpha}-subunit, inhibin A, and, to a lesser extent, inhibin B (100% and 16.7% cross-reactivities, respectively). This assay has good correlation with the results of the Monash RIA for the determination of inhibin in human follicular fluid (29). We demonstrate that PCOS women have higher serum {alpha}-inhibin levels than controls. Furthermore, we provide for the first time in vivo evidence that serum {alpha}-inhibin, in conjunction with and independently of LH, is linked to the hyperandrogenism of PCOS.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patient population

Controls. The control population is comprised of 61 healthy women [age, 18.1 ± 2.7 yr (mean ± SD); range, 15–27 yr] recruited on the occasion of an annual physical examination carried out at the Centre de Bilan de Santé, Institut Pasteur (Lille, France). The exclusion criteria were a history of menstrual disturbances (i.e. cycle length either <25 days or >35 days), hirsutism, or hormonal treatment during the 3 months before the study. Their body mass indexes (BMIs) ranged from 17–37 kg/m2 (mean ± SD, 22.7 ± 5 kg/m2).

Women with PCOS. Seventy-two women with PCOS were recruited into the study. They were referred to our department for hyperandrogenism and/or ovulation disorder. Patients ranged in age from 14–37 yr (mean ± SD, 23.6 ± 4.8 yr), and BMI ranged from 17–37 kg/m2 (mean ± SD, 25.6 ± 4.9 kg/m2). The diagnosis of PCOS was based on the presence of at least one clinical criterion (hirsutism determined by a modified Ferryman and Galway score >8, menstrual and/or ovulatory disturbances, or minor signs such as acne or seborrhea) associated with either one ultrasonographic criterion and/or one biological criterion. Biological criteria were basal serum LH levels greater than 6 IU/L, testosterone greater than 0.7 ng/mL, and/or androstenedione (A) greater than 2.2 ng/mL, as previously reported (30). The ultrasonographic criterion was an ovarian area more than 5.5 cm2 uni- or bilaterally (31). Pelvic ultrasonographic examination was performed by the abdominal route in all patients and by the vaginal route in sexually active women. Any patient with one or more follicles with a diameter greater than 10 mm was excluded from the study so as not to confound the data with a dominant follicle. No patient had received long term hormonal treatment or oral contraceptives for at least 3 months before the study. One patient with insulin-dependent diabetes mellitus was excluded. Massively obese patients (i.e. BMI >37 kg/m2) were also excluded from this study, as a preliminary report by us (32) showed that they tended to have very low levels of {alpha}-inhibin as well as other endocrine abnormalities independent of PCOS.

Sampling procedure

All controls and PCOS subjects underwent blood sampling in the early follicular phase (i.e. between days 3 and 5 after the last menstrual period). The last mestrual period occurred either spontaneously or after withdrawal of didrogesterone (Duphaston, Roussel Laboratories, Paris, France; 10 mg/day for 7 days) in amenorrheic or oligomenorrheic PCOS women. A total of 30 mL blood were drawn in each fasting subject at 0800 h. Five 5-mL aliquots were collected in tubes for assays of LH, FSH, inhibin, estradiol, and insulin, and one 5-mL aliquot was collected in a tube containing ethylenediamine tetraacetate for the assay of A.

Hormonal immunoassays

{alpha}-Inhibin was measured by a two-site immunoenzymometric assay (Inhibin {alpha}-{alpha} Easia, Medgenix, Fleurus, Belgium), as previously described (33). Both antibodies used in this assay recognized distinct epitopes on the {alpha}-subunit of human inhibin (34). Human inhibin used as a standard was extracted from the follicular fluid of women undergoing hyperstimulation in an in vitro fertilization program. This standard was calibrated against a reference pool of sera from 30 healthy men (33), which was arbitrarily assigned a value of 1 U/mL (1 U of this standard corresponds to 400 pg recombinant 32-kDa inhibin A). The minimal detectable amount of inhibin was 0.1 U/mL. The intra- and interassays coefficients of variation were 6.5% and 8.3%, respectively (33). No cross-reactions were observed with inhibin-related proteins such as activins, follistatin, or TGFß. Inhibin A (WHO reference preparation) and recombinant inhibin B exhibited 100% and 16.7% cross-reactivities in this assay, respectively (29).

Serum insulin levels were measured in duplicate by a RIA (Bi-insulin RIA, Diagnostics Pasteur, Marnes de Coquette, France) using an antipig insulin polyclonal antibody and human [125I]insulin as a tracer. Results are expressed as microinternational units per mL in terms of the WHO 66/304 reference preparation. This RIA displayed a 40% cross-reactivity with human proinsulin. Intra- and interassay coefficients of variation were less than 6% and 9%, respectively.

Serum gonadotropin levels were evaluated by two immunoassays provided by Cis Bio International (France). These immunometric assays used monoclonal antibodies raised against LH and FSH. Results are expressed as milliinternational units per mL in terms of the First International Reference Preparation 68/40 (LH) and the Second International Reference Preparation 78/549 (FSH). Intra- and interassay coefficients of variation were less than 5% for the two immunoassays.

Estradiol concentrations were measured in duplicate in unextracted serum by RIA using kits provided by Biomérieux (France). The detection limit was 12 pg/mL. The intra- and interassays coefficients of variation were 9.8% and 8.7%, respectively.

A was measured by RIA after extraction with ethyl ether using a kit provided by Immunotech (France). The limit of detection was 0.04 ng/mL. The intra- and interassay coefficients of variation were 8.1% and 11.9%, respectively.

Statistical methods

Data are expressed as the mean ± SD. Statistical analysis for differences between the means of two independent groups was performed by Student’s t test. P < 0.05 was considered significant. Significant relations between {alpha}-inhibin and particular variables were evaluated by the Pearson correlation coefficient. Comparisons within different variables were investigated by multiple regression analysis, which included partial correlation coefficients. Data were analyzed with SAS statistical software (SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical and biological data

The principal clinical and biochemical features of the control and PCOS groups are presented in Table 1Go. Higher serum levels of {alpha}-inhibin (Fig. 1Go), LH, and A were observed in women with PCOS than in controls. Age and BMI were also greater in the PCOS group, whereas estradiol and fasting insulin serum levels did not differ. Finally, serum FSH was significantly lower in the PCOS women than in the controls.


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  		Table 1. Clinical and endocrine characteristics of women with PCOS and control subjects

 


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  		Figure 1. Distribution of individual inhibin serum levels according to percentile are shown for PCOS patients (n = 72) and controls (n = 61). Horizontal small bars represent the 10–90th percentile range, and the boxes indicate the 25–75th percentile range. The horizontal lines in the boxes correspond to the geometric mean.

 
Relationships among A, LH, and {alpha}-inhibin

Using simple regression analysis (Table 2Go), we noted that A was the only factor correlated to circulating {alpha}-inhibin levels (r = 0.32; P < 0.01) in PCOS group (Fig. 2Go). As expected, LH and A were also highly correlated among PCOS women (r = 0.48; P < 0.001; Fig. 2Go), but not controls. {alpha}-Inhibin remained correlated to A after controlling for LH by partial regression analysis (r = 0.27; P < 0.05). Likewise, the correlation between A and LH was still significant after controlling for {alpha}-inhibin levels (r = 0.45; P < 0.001). Thus, LH and {alpha}-inhibin appeared to be two independent variables determining the variability of A levels in PCOS women. In a theoretical model in which A would depend exclusively on these two variables, multiple regression analysis (incremental partial sum of squares) indicated that LH and {alpha}-inhibin accounted for 80% and 20% of the variability of A in PCOS, respectively. The results of the correlation matrix were not significantly modified when BMI and insulin were introduced into the model. Likewise, no significant relationship was found between A and fasting insulin in either control or PCOS women. Finally, {alpha}-inhibin did not show a significant correlation with age in either of the two groups.


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  		Table 2. Pearson coefficients of correlation between {alpha}-inhibin and other parameters in the studied population

 


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  		Figure 2. Relationship between A levels and LH concentrations (top; r = 0.48; P < 0.001) and A levels and {alpha}-inhibin levels (bottom; r = 0.32; P < 0.01) in PCOS women (n = 72).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
To date, most of the data obtained in clinical studies investigating the role of inhibin are based on the use of the first generation inhibin immunoassays. Unfortunately, these assays are unable to distinguish between inhibin A and inhibin B, and may also detect unprocessed precursor forms and free {alpha}-subunits (1, 8). Recently, two-site immunoassays have been developed that can specifically measure serum levels of dimeric inhibin A or B with some sensitivity (11, 12). Initial results obtained with these assays indicated that inhibin A and inhibin B displayed different secretory patterns during the menstrual cycle; inhibin A is mainly secreted in the luteal phase and in pregnancy, whereas inhibin B rises in the early follicular phase (11, 12, 13, 35). In men, inhibin B seems to be the form of inhibin that is most important for the physiological control of FSH release (36, 37).

The antibodies in our inhibin ELISA recognize both bioactive dimeric inhibins and free {alpha}-subunit, which are both produced and released by GC under the control of FSH (38, 39, 40). However, we estimate that this lack of assay specificity does not hinder our results, since we used this assay as an index of GC function and responsiveness to FSH. With our assay, we were able to demonstrate that serum {alpha}-inhibin levels are increased in PCOS women, whereas most of the previous studies have failed to demonstrate such a relationship, regardless of the type of inhibin assay (25, 26, 27). Only Mizunuma et al. reported a significantly higher {alpha}-inhibin level in a series of 23 women with PCOS (28). There may be various explanations for the discrepancies between our data and those of others. Firstly, patient populations differed from one study to another because of different selection criteria. Secondly, the small size of the populations could have masked a difference. Hence, the large size of our patient and control populations allowed us to use more powerful statistical tests. Finally, inhibin immunoassays differ in their specificity (1, 29), making comparisons between the results of different studies difficult. The increase in {alpha}-inhibin levels that we observed suggested that the GC of polycystic ovaries are functionally active (41). This agrees with the findings of other studies that the follicles in polycystic ovaries are not simply atretic, but contain steroidogenically active GC when tested in vitro (42). It is also in agreement with the hypothesis that the follicles of anovulatory polycystic ovaries exhibit premature maturational arrest (42, 43), a developmental stage at which inhibin synthesis is increased (39).

This is the first report demonstrating in vivo that {alpha}-inhibin is positively related to A levels in PCOS women. This raises the possibility that part of the circulating inhibin in PCOS patients originates from the TC, which in PCOS patients are hyperplastic and secrete increased amounts of A in response to the high levels of LH. Jaatinen et al. (44) and Roberts et al. (45) effectively demonstrated in vitro, using in situ hybridization, that both GC and TC of normal and polycystic ovaries express inhibin subunit messenger ribonucleic acid. Moreover, {alpha}-subunit messenger ribonucleic acid levels were higher in TC compared to GC of polycystic ovaries, in contrast to the normal ovary (45, 46). Accordingly, the serum levels of inhibin B in PCOS patients were significantly and positively correlated to the LH level in a recent study (47). However, the paradoxical decrease in this peptide 24 h after hCG injection (47) brings into question whether circulating inhibin in some way reflects TC secretory activity, in parallel with A.

In our study, the relationship between {alpha}-inhibin and A was noted to be independent of LH, whereas no clear association was found between {alpha}-inhibin and LH. Consequently, we would favor the hypothesis that {alpha}-inhibin exerts a positive effect on A secretion through either a paracrine (from GC) or autocrine (from TC) action independent of and in addition to stimulation by LH (Fig. 3Go). In our series, the influences of {alpha}-inhibin and LH were estimated to be 20% and 80%, respectively, as determined by multiple regression analysis. Such a conclusion was not unexpected in view of in vitro studies showing that inhibin enhanced both insulin- and LH-stimulated A production in cultured human TC (22, 23). It has been previously proposed that abnormalities of the activin/inhibin paracrine or autocrine system may be involved in the hyperandrogenism of PCOS (45, 48).



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  		Figure 3. Schematic diagram of the putative mechanisms leading to hyperandrogenemia in PCOS women. LH is the main modulator of androgen excess in the syndrome by its actions on TC. Inhibin is produced by the GC under FSH stimulation and by the TC, contributing to androgen overproduction. Insulin, particularly hyperinsulinism, may accentuate the hyperandrogenemia either directly or by enhancing LH action on TC.

 
Surprisingly, insulin appeared to not have a role in our theoretical multiple regression analysis model. The lack of correlation between fasting insulin and A in our series disagrees with previous reports (49, 50). Nonetheless, it should be noted that fasting insulin may not provide an accurate estimate of hyperinsulinism. Thus, in a recent report, Morales et al. (51) demonstrated a correlation between the 24-h mean insulin concentration and A levels in obese subjects (both controls and PCOS).

In conclusion, our in vivo data agree with the in vitro models noting that LH is the major factor involved in the control of ovarian androgen production by the TC of polycystic ovaries (48). However, inhibin seems to play a small, but significant, regulatory role in the TC synthesis of A, acting in either a paracrine and/or autocrine fashion. Further studies are needed to determine whether this effect is exerted by inhibin A, inhibin B, or both.


   Acknowledgments
 
We thank Prof. R. Azziz for his help in editing the manuscript, and Mrs. S. Derudder for her assistance in collecting the blood samples. We also thank Mrs. Y. Descamps for her excellent technical assistance, and Mrs. M. Cuvelier for typing the manuscript.


   Footnotes
 
1 This work was supported by grants from the Delegation of Research of CHU (Lille, France) and the Direction Régionale des Etudes Doctorales, University of Lille II. Back

Received November 5, 1996.

Revised February 13, 1997.

Accepted March 6, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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