Human Reproduction

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Human Reproduction, Vol. 16, No. 7, 1359-1364, July 2001
© 2001 European Society of Human Reproduction and Embryology

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

Joop S.E. Laven¹, Babek Imani¹, Marinus J.C. Eijkemans², Frank H. de Jong³ and Bart C.J.M. Fauser¹

¹ Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, ² Centre for Clinical Decision Sciences, Department of Public Health and ³ Department of Internal Medicine, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands

	Abstract

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BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

Key words: androgens/gonadotrophins/inhibin B/normogonadotrophic anovulatory infertility/PCOS

	Introduction

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Chronic anovulation constitutes a major proportion of infertile couples (20–25%) (van Santbrink et al., 1997). According to the World Health Organization (WHO) (Rowe et al., 2000), anovulatory patients are classified on the basis of two endocrine parameters, the concentrations of endogenous gonadotrophins and oestrogens. Approximately 80% of patients suffering from chronic anovulation present with serum FSH concentrations within the normal range in combination with some endogenous oestrogen activity. These women are classified as normogonadotrophic normo-oestrogenic anovulatory infertility, more commonly referred to as WHO 2 (Rowe et al., 2000). Since aetiological factors underlying this condition may vary from one patient to another, WHO 2 anovulatory women constitute a notoriously heterogeneous population.

The polycystic ovarian syndrome (PCOS), characterized by chronic anovulation, hyperandrogenaemia and sometimes hyperinsulinaemia (Dunaif, 1999), is the most common cause of normogonadotrophic normo-oestrogenic anovulatory infertility. Certainly, PCOS is part of the WHO 2 group, with a variable reported incidence based on differences in inclusion criteria used (van Santbrink, 1997). A previous National Institute of Health (NIH) consensus workshop concluded, but by no means unanimously, that hyperandrogenaemic chronic anovulation should be considered the hallmark criterion for the diagnosis of PCOS (Dunaif et al., 1992). More recently, it was reported (and agreed by the last NIH consensus workshop) that the occurrence of polycystic ovaries should be added (Dewailly, 2000).

Inhibin is a dimeric non-steroidal glycoprotein hormone that selectively inhibits FSH production and/or release from the pituitary. It consists of two partially homologous sub-units, combined with either ßA (inhibin A) or ßB (inhibin B) (Robertson et al., 1997). Recently, it was reported that inhibin A serum concentrations are high around ovulation and during the mid-luteal phase of the normal menstrual cycle. In contrast, inhibin B seems to be the predominant form secreted by developing small antral follicles during the early follicular phase (Groome et al., 1996). Recent reports on serum and follicular fluid inhibins in PCOS are conflicting. According to some authors, concentrations of total immunoreactive inhibins (Mizunuma et al., 1994), inhibin (Pigny et al., 1997), or inhibin B (Lambert-Messerlian et al., 1994; Anderson et al., 1998; Lockwood et al., 1998) are raised. Others found normal concentrations of total immunoreactive inhibin (Buckler et al., 1988; Pache et al. 1992) or inhibin B (Magoffin and Jakimiuk, 1998).

Since inhibin B selectively inhibits FSH, high inhibin B could be held responsible for an elevated LH/FSH ratio characteristic for some patients (Magoffin and Jakimiuk, 1998). Moreover, inhibin may directly stimulate theca cell androgen biosynthesis (Hillier et al., 1991). Inhibin B concentrations might also represent the extent of ovarian dysfunction in these patients, since an increased number of healthy follicles (Hughesdon, 1982; Pache et al., 1991a) may result in increased serum concentrations. The present cross-sectional study in a large cohort of normogonadotrophic anovulatory infertile patients was conducted to investigate whether inhibin B concentrations were correlated with endocrine and ultrasound findings in WHO 2 and PCOS patients.

	Materials and methods

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Patients
The local Medical Ethics Review Committee approved this study and informed consent was obtained from all participants. Three hundred and seventy-nine patients attending our fertility clinic between 1994 and 1999 with: (i) infertility, (ii) oligomenorrhea (interval between periods >35 days) or amenorrhea (absence of vaginal bleeding for at least 6 months), (iii) serum FSH concentrations within normal limits (1–10 IU/l) (van Santbrink et al., 1995; Schipper et al., 1998), (iv) positive withdrawal bleeding after progestagen administration in case of amenorrhea, and (v) between 20 and 40 years of age were included in the present study. Standardized initial screening (clinical, transvaginal ultrasound and fasting blood withdrawal) was performed on a random day between 9 and 11 a.m. as previously described (van Santbrink et al., 1997). A PCOS subgroup of patients exhibited hyperandrogenaemia and an increased ovarian volume. Hyperandrogenaemia was defined as an elevated (>4.5) free androgen index [testosteronex100/sex hormone binding globulin (SHBG)], whereas the ovarian volume was considered increased above 10.8 ml (van Santbrink et al., 1997).

For sonographic imaging, a 6.5 MHz vaginal transducer (model EUB-415; Hitachi Medical Corporation, Tokyo, Japan) was used. The ovaries were localized and scanned as described previously (Pache et al., 1991b). Ovarian volume, stroma echogenicity (arbitrarily scored from 1 to 3 per ovary) as well as the mean follicle number were assessed as described earlier (van Santbrink et al., 1997).

The control group consisted of 30 healthy volunteers selected by advertisement and paid for participation as previously published (Schipper et al., 1998). Inclusion criteria were a regular menstrual cycle (26–30 days), 20–35 years of age, normal body mass index (BMI 18–25 kg/m²) and no previous use of medication or oral contraceptives during at least 3 months prior to the study. Transvaginal ultrasound and blood sampling were performed during the early follicular phase (cycle day 3, 4 or 5).

Hormone assays
Blood samples were obtained by venepuncture and processed within 2 h after withdrawal. Serum was stored at –20°C and assayed for LH, FSH, androstenedione, testosterone, inhibin B, oestradiol and progesterone. Serum LH and FSH concentrations were measured by immunofluorometric assay (Amerlite, Ortho-Clinical Diagnostics, Amersham, UK), while serum oestradiol, progesterone, testosterone, androstenedione and SHBG concentrations were measured by radioimmunoassay (RIA) provided by Diagnostic Products Corp. (DPC, Los Angeles, CA, USA), as described previously (Imani et al., 2000). Intra- and inter-assay coefficients of variation were <5 and 15% for LH, <3 and 8% for FSH, <8 and 11% for androstenedione, <3 and 5% for testosterone, <5 and 7% for oestradiol, <16 and 17% for progesterone, and <4 and 5% for SHBG respectively. Dimeric inhibin B concentrations were assessed using an immuno-enzymometric assay obtained from Serotec (Oxford, Oxon, UK), as described previously (Schipper et al., 1998). The detection limit of the assay, defined as the amount of inhibin equivalent with the signal of the blank +3 SDs of this signal, was 3.4 ng/l. Intra- and inter-assay coefficients of variation for inhibin B were <9 and 15% respectively.

Data analysis
Data are presented as median and range. Due to the non-parametric distribution, groups were compared using the Mann–Whitney rank-sum test. Non-parametric cross correlations and analysis of co-variance was performed using a commercially available software package (Statistics Package for Social Sciences, Chicago, IL, USA). A P value < 0.05 was considered to indicate statistical significance.

	Results

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Normo-ovulatory controls (n = 30) presented with a median age of 29 years (range 20–35 years), median cycle duration of 28 days (range 25–32 days) and median BMI of 21.4 kg/m²(range 18.9–24.2 kg/m²). The upper limit of normal inhibin B was 213 ng/l (95th percentile) and the lower limit (5th percentile) was 22 ng/l (Figure 1). Medians of inhibin B on cycle day 3, 4 and 5 were 103, 130 and 135 pg/l respectively. These values were not statistically different. For further comparisons with WHO 2 patients and PCOS patients, day 3 concentrations of inhibin B in controls were used.

View larger version (25K): [in this window] [in a new window]   Figure 1. Box and whisker plots indicating median inhibin B serum concentrations (solid bars) with 25th and 75th quartiles (lower and upper borders of boxes) and ranges (whiskers) in normogonadotrophic oligoamenorrhoeic infertile [World Health Organization (WHO 2)] and in a subgroup of polycystic ovarian syndrome (PCOS) women during the early follicular phase in regularly cycling controls.

 
Clinical, endocrine and ultrasound parameters of WHO 2 and PCOS subgroup are depicted in Table I. The distribution of individual inhibin B serum concentrations in WHO 2, PCOS and controls is depicted in Figure 1. Correlations between serum inhibin B concentrations and clinical, endocrine and ultrasound parameters in the WHO 2 and PCOS individuals are depicted in Table II as well as in Figures 2 and 3. Co-variance analysis revealed that the interrelationship between inhibin B, FSH, age, and mean follicle number was predominantly determined by the serum FSH concentration. Similarly, co-variance analysis revealed that the interrelationship between inhibin B, LH, testosterone, and androstenedione was mainly determined through the serum LH concentration (data not shown).

View this table: [in this window] [in a new window]   Table I. Clinical, endocrine and ultrasound characteristics (median and range) in 379 patients with normogonadotrophic anovulatory infertility [World Health Organization (WHO 2)] and separately in the subgroup of 190 polycystic ovarian syndrome (PCOS) patients

 

View this table: [in this window] [in a new window]   Table II. Correlations between inhibin B serum concentrations and clinical, endocrine and ultrasound parameters in 379 patients with normogonadotrophic anovulatory infertility (WHO 2), and separately in the subgroup of 190 PCOS patients

 

View larger version (24K): [in this window] [in a new window]   Figure 2. Correlations between inhibin B serum concentrations and mean follicle number (upper panel) and serum oestradiol concentrations (lower panel) in 379 normogonadotrophic oligoamenorrhoeic infertile patients (open and closed dots and continuous line) and in a subgroup of 190 PCOS (closed dots and dotted line) women. Spearman's correlation coefficients and corresponding P values are depicted.

 

View larger version (24K): [in this window] [in a new window]   Figure 3. Correlations between inhibin B serum concentrations and serum LH (upper panel) and serum Testosterone concentrations (lower panel) in 379 normogonadotrophic oligoamenorrhoeic infertile patients (open and closed dots and continuous line) and in a subgroup of 190 PCOS (closed dots and dotted line) women. Spearman's correlation coefficients and corresponding P values are depicted.

 
In WHO 2 patients polycystic ovaries on ultrasound examination (defined as a mean ovarian volume 10.8 ml and/or a mean follicle number per ovary 10) (van Santbrink et al., 1997) was observed in 67% of all patients. Elevated LH and/or testosterone was found in 54%, whereas an elevated inhibin B concentration was found in 15% of all WHO 2 patients. A total of 71% of WHO 2 individuals with elevated inhibin B also presented with increased concentrations of LH and/or increased testosterone. Similarly, 43% of all WHO 2 patients showed elevated serum concentrations of LH and/or testosterone in combination with polycystic ovaries on ultrasound. In PCOS patients, elevated serum LH concentrations were found in 58% of all individuals whereas elevated serum inhibin B concentrations were found in only 23% of all cases. An elevated testosterone plasma concentration was observed in 35% of PCOS patients.

	Discussion

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The data presented here in 379 normogonadotrophic oligomenorrheic patients indicate that overall inhibin B serum concentrations are elevated neither in the total group of WHO 2 women nor in the subgroup of PCOS patients. `High' inhibin B concentrations reported in previous studies (Anderson et al., 1998; Lockwood et al., 1998) were well within the normal range of regularly cycling women in the current study. This discrepancy in absolute values might be due to modifications in the assay that may affect absolute concentrations (N.P.Groome, personal communication). In one study (Lockwood et al., 1998), inhibin B concentrations were assessed on day 5 of the menstrual cycle in contrast to the current study, in which they were measured on day 3. However, inhibin B shows only modest changes at the beginning of the cycle (Groome et al., 1996). In the current series, inhibin B serum concentrations were similar on day 3 compared to days 4 or 5 (data not shown). Moreover, differences in inhibin B concentrations in control subjects (Anderson et al., 1998) might be due to the smaller number of regularly cycling women (n = 10 and 5 respectively) compared with the current study (n = 30). Finally, inhibin B is secreted in a pulsatile fashion (Lockwood et al., 1998) which may affect the accuracy of single blood withdrawal. Besides, one study (Lockwood et al., 1998) included only clomiphene-resistant women, which might represent a different subset of patients.

Dominant follicle selection is disturbed in polycystic ovaries, resulting in an increased number of follicles per ovary and presumably a variable number of healthy early antral follicles (Fauser, 1994). Because inhibin B is produced predominantly by healthy small follicles it has been postulated that inhibin B concentrations are increased in at least some PCOS patients. Elevated concentrations of inhibin B could be established in two preliminary reports (Anderson et al., 1998; Lockwood et al., 1998) in 9 and 10 PCOS patients respectively. In contrast, in the present study, inhibin B concentrations in PCOS patients were similar compared with WHO 2 and control patients.

It has also been postulated that most of the inhibin B produced in the ovary during the follicular phase originates from the dominant follicle due to the observed major difference in the amount produced by large antral follicles (with androstenedione/oestradiol ratios 4) compared with remain- ing cohort follicles with androstenedione/oestradiol ratios >4 (Magoffin and Jakimiuk, 1998). Follicular fluid oestradiol, androstenedione and total immunoreactive inhibin concentrations as well as androstenedione/oestradiol ratios were similar in PCOS patients compared to controls (Pache et al., 1992). More recently, inhibin B concentrations in these 4–8 mm follicles from polycystic ovaries were also found to be similar to size-matched normal follicles (Magoffin and Jakimiuk, 1998). Increased inhibin secretion by polycystic ovaries could augment LH-stimulated androgen production by theca cells (Hillier et al., 1991). Recent observations in PCOS patients supporting this concept include elevated inhibin concentrations, which were correlated with increased circulating concentrations of androstenedione (Pigny et al., 1997). It was not possible to demonstrate a consistent and strong correlation between inhibin B and LH, testosterone or its precursors in the current study. It therefore appears that alterations in inhibin B concentrations do not play an important local role in vivo in LH-induced androgen production in these patients.

If serum inhibin B concentrations represent the extent of ovarian dysfunction in PCOS, one would expect a good correlation between inhibin B and endocrine hallmarks associated with ovarian abnormalities in these patients, such as elevated serum LH or androgen concentrations. Although ultrasound parameters are weakly correlated with inhibin B, serum oestradiol concentrations were not. In fact, serum oestradiol concentrations were fairly constant at different inhibin B concentrations. The observed lack of a strong, consistent relationship between inhibin B and endocrine markers of PCOS may suggest that inhibin B does not represent the magnitude of ovarian dysfunction in these patients. These results are consistent with recent observations from our group indicating that inhibin B serum concentrations do not predict ovarian responsiveness to ovulation induction (Imani et al., 2000).

It has been postulated that if inhibin is prematurely produced in excessive amounts relative to the developmental stage of the follicle, FSH secretion by the pituitary might become suppressed and concomitantly follicle development could be retarded (Magoffin and Jakimiuk, 1998). If this is true, inhibin B concentrations should be negatively correlated with serum FSH. Based on the observed weak positive correlation between serum inhibin B and FSH concentrations, the current data do not support this concept. The present study supports the contention that FSH is the primary drive of inhibin B synthesis, in line with recent observations during pubertal development (Crofton et al., 1997). Since inhibin B concentrations in PCOS patients (produced by small arrested follicles) are similar to control concentrations, one might speculate that inhibin B exerts limited negative feedback on pituitary FSH production at the beginning of the cycle. Moreover, intra-follicular inhibin B concentrations in PCOS do not significantly decrease with increasing follicle diameters also indicating that FSH is the primary drive of the feedback (Lambert-Messerlian et al., 1997).

In conclusion, inhibin B serum concentrations are normal in most normogonadotrophic anovulatory infertile women, including PCOS, suggesting a normal number of healthy early antral follicles despite increased overall follicle numbers in PCOS. Serum inhibin B assays cannot be recommended for routine screening in normogonadotrophic anovulatory infertility.

	Notes

 
⁴To whom correspondence should be addressed at: Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus University Medical Centre Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.E-mail: laven{at}gyna.azr.nl

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Submitted on December 7, 2000; accepted on March 19, 2001.

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