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Original Article |
Reproductive Endocrine Unit and the National Center for Infertility Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Dr. Corrine K. Welt, Reproductive Endocrine Unit and the National Center for Infertility Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114.
Abstract
Inhibin B is a product of the granulosa cells of growing preantral and antral follicles. Despite the large ovarian volume and increased follicle number typically detected in women with polycystic ovary syndrome (PCOS), previous studies demonstrate that inhibin B is not elevated as would be expected in PCOS, but is inversely correlated with body mass index (BMI). We therefore hypothesized that inhibin B levels in women with PCOS are regulated by a factor related to BMI. Thus, LH, sex steroids, and metabolic parameters were measured in 50 anovulatory PCOS subjects in pools constituted from equal aliquots of serum drawn every 10 min for 4 h and were correlated with inhibin B. Based on the results of these correlative studies, inhibin B regulation by human chorionic gonadotropin (hCG) and insulin was tested directly.
In PCOS subjects, inhibin B correlated inversely with BMI (r = -0.413; P < 0.004) and fasting insulin (r = -0.409; P < 0.004). Inhibin B also correlated directly with pool LH (r = 0.419; P < 0.003), LH pulse amplitude (r = 0.512; P < 0.0001), and SHBG (r = 0.429; P < 0.003). The relationships demonstrated for inhibin B were not demonstrated for inhibin A, nor were they evident in normal subjects.
To determine whether the correlations represent regulation of inhibin B, i.e. stimulation of inhibin B by LH or suppression by insulin, two interventional studies were performed. In the first study hCG (5000 U) was administered to PCOS subjects (n = 15) to mimic the effects of LH. Inhibin B was not increased, but was significantly reduced 24 h after hCG administration (223.8 ± 21.3 vs. 152.4 ± 15.9 pg/ml; P < 0.0005). In the second study, diazoxide (100 mg every 8 h) was administered for 3 d to PCOS subjects (n = 9). Inhibin B increased (85.4 ± 12.4 to 136.6 ± 18.8 pg/ml; P < 0.05) in association with a decrease in the insulin area under the curve (104 ± 29 to 83 ± 22 nmol/liter·min; P < 0.05) induced by diazoxide.
In PCOS subjects, inhibin B demonstrated significant relationships with BMI and factors related to BMI, including LH, insulin, and SHBG. Although LH was associated with inhibin B, hCG administration suppressed inhibin B secretion after 24 h, whereas short-term insulin suppression increased inhibin B. These findings suggest that both increased LH and insulin may account for the relative suppression of inhibin B in patients with PCOS.
POLYCYSTIC OVARY SYNDROME (PCOS) is a common cause of menstrual dysfunction and infertility in reproductive-aged women. The ovaries in women with PCOS are characterized by an increased number of small antral follicles and thecal cell volume. The granulosa cells from these follicles secrete increased amounts of estradiol after FSH stimulation, suggesting that they are not atretic (1). Inhibin A and inhibin B, ovarian proteins that act in an endocrine manner to suppress FSH and locally to enhance follicle development (2), are produced by the granulosa cells of normal and PCOS follicles, and possibly by the theca in PCOS follicles (3, 4, 5). Therefore, it is expected that inhibin A and inhibin B would be increased in PCOS subjects compared with normal women based on the increased ovarian and thecal cell volume, the increased number of small follicles, and the relative suppression of FSH compared with LH. However, the majority of previous studies examining serum inhibin levels in women have failed to demonstrate such an increase, whether using assays with antibodies directed at the 
-subunit of inhibin (6, 7) or specific for dimeric inhibin A (8, 9, 10) or inhibin B (9, 10, 11, 12, 13). Only two small studies found an increase in inhibin A (14) and inhibin B (14, 15) in PCOS; however, these studies did not select patients across the broad range of body mass indexes (BMIs) characteristic of PCOS, perhaps accounting for the differences.
Recent studies suggest that inhibin B levels in PCOS are inversely correlated with BMI (9, 10, 11, 12). We therefore hypothesized that a factor related to BMI is responsible for inhibin B regulation in PCOS. Inhibin B and inhibin A levels in pooled samples collected over 4 h of frequent blood sampling were correlated with gonadotropins, sex steroids, and metabolic parameters in a large, well characterized group of PCOS subjects. Based on the results of this observational study, interventional studies were performed using LH and insulin, which are strongly related to BMI and are commonly abnormal in PCOS. These studies help to dissect the mechanisms of inhibin B regulation in PCOS.
Subjects and Methods
PCOS patients
Patients between the ages of 16 and 39 yr (mean ± SD, 28.6 ± 5.7 yr), were diagnosed with PCOS based on the presence of chronic oligomenorrhea (fewer than nine menstrual periods per year) and/or clinical or biochemical evidence of hyperandrogenism (16). Elevated serum androgen and LH levels and PCO morphology were not required to make the diagnosis. Late-onset congenital adrenal hyperplasia was excluded, as previously described (17). All subjects had TSH levels between 0.4–5 IU/ml and PRL levels below 25 µg/liter. Subjects were taking no medication except stable thyroid hormone replacement for a minimum of 2 months before the study, with the exception of one patient with essential hypertension whose ß-blocker was discontinued immediately before the study.
Normal women
Normal women (n = 25) served as a control group for comparison. They were between the ages of 18–42 yr (mean ± SD, 27.8 ± 7.0 yr) and had regular menstrual cycle lengths between 25–35 d. Ovulation was documented in the luteal phase before the study with serum progesterone levels above 19 nmol/liter, with the exception of two subjects who were within 3 d of menses or ovulation and had progesterone levels above 6 nmol/liter. All subjects were healthy, had been taking no medications for at least 3 months before the study, and had normal TSH and PRL levels. All subjects had Ferriman-Gallwey hirsutism scores (18) of 10 or less. All studies were performed between d 1–7 of the early follicular phase, with the onset of menses designated d 1.
Protocol
The study was approved by the institutional review board of the Massachusetts General Hospital, and all subjects gave their written informed consent.
PCOS and normal subjects underwent an extensive evaluation, as previously described (17). Two PCOS and one normal subject have been added to our previous series (17). The evaluation included a detailed history and physical exam, with determination of BMI and assessment of hirsutism by the method of Ferriman and Gallwey (18). Ovarian morphology was assessed by transvaginal ultrasound (Sonolayer L, SAL-778 with transvaginal 5-MHz probe, Toshiba, Tokyo, Japan) with interpretations by a single technologist. Ovarian volume was calculated as length x width x height in centimeters divided by 2. Polycystic ovarian morphology was defined as 10 or more follicles, 2–8 mm, in a peripheral array as viewed in a single plane (19). The size of all follicles 8 mm or greater and the presence of a corpus luteum were recorded.
Each PCOS subject underwent blood sampling via an indwelling catheter every 10 min from 2000–0800 h (12 h). Previous studies have documented the absence of diurnal variation in gonadotropin secretion in these patients (20). In normal subjects, blood sampling was performed from 1600–2400 h, and the subjects were kept awake until sampling was complete to avoid the known effects of sleep on gonadotropin secretion in the early follicular phase (21).
A progesterone level greater than 9 nmol/liter within 7 d of the onset of the study was taken as evidence of presumed recent ovulation in PCOS subjects. Although menses may represent an anovulatory withdrawal bleed, any bleeding within 7 d of the onset of the study was also taken as evidence of possible ovulation to avoid the time frame in which LH might be transiently suppressed in PCOS subjects due to recent ovulation (17). A follicle 11 mm or larger in the presence of an estradiol level of 100 pg/ml or more was taken as evidence of dominant follicle development. Based on these criteria, PCOS subjects with menses or ovulation (n = 9) or evidence of a dominant follicle (n = 4) were excluded from the primary analysis. Therefore, although 63 subjects participated initially, 50 subjects were included in the final analysis. The earliest cycle day on which subjects were studied was d 9 (Table 1
).
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Nine additional subjects between the ages of 24–33 yr (mean ± SD, 24.2 ± 1.7 yr; BMI, 33.6 ± 7.0 kg/m2) and meeting the PCOS criteria outlined above received diazoxide to suppress insulin secretion. Blood was drawn for measurements of inhibin B, gonadotropins, estradiol, testosterone, leptin, and SHBG. Insulin and glucose were then assessed using an oral glucose tolerance test in which blood samples were drawn every 30 min for 2 h after a 75-g glucose load. Subsequently, diazoxide (100 mg every 8 h) was administered for 3 d to lower insulin levels. Baseline blood samples and the oral glucose tolerance test were repeated on d 4. Diazoxide was not tested in normal subjects, as inhibin B typically increases in the early follicular phase as the cohort of growing follicles is recruited (24, 25).
Assays
To assess integrated concentrations of LH and FSH during the frequent sampling studies in PCOS and normal women, a serum pool was created from equal aliquots of each sample across the 8- to 12-h sampling period. Inhibin A, inhibin B, SHBG, leptin, testosterone, and androstenedione were measured in frequent blood samples pooled across matching 4-h periods in PCOS and normal subjects (2000–2400 h). Inhibin A was measured in 11 lean PCOS subjects and 13 obese PCOS subjects with both high (n = 8) and normal (n = 5) LH levels and in 3 obese and 3 lean normal subjects to confirm previously published findings (8).
LH, FSH, estradiol, testosterone, SHBG, and 17-hydroxyprogesterone were measured by RIA as previously described (26, 27, 28, 29). Androstenedione was measured by RIA after extraction from serum (17). Insulin was measured using a two-site monoclonal nonisotopic system (Abbott Laboratories, Abbott Park, IL). Leptin was measured using a RIA (Linco Research, Inc., St. Charles, MO). Inhibin A and inhibin B were determined using commercial ELISA kits (Serotec, Oxford, UK) according to the manufacturer’s directions, as previously described (8, 30). Inhibin A results are reported as international units per milliliter of the WHO International Standard 91/624 (0.15 IU International Standard = 1 pg inhibin A against Serotec calibrators). The limit of detection was 0.6 IU/ml for inhibin A and 15.6 pg/ml for inhibin B, with an intraassay coefficient of variation (CV) of 10% and an interassay CV of less than 20% for both assays.
Data analysis
Pulsatile secretion of LH was determined using a modified version of the Santen and Bardin algorithm, which has recently been validated in an in vivo model (31). A pulse was identified in the frequent sampling series when the peak minus the nadir exceeded 1 IU/liter and 3 times the assay CV determined for the individual study. In addition, each pulse was required to have a second point that met at least one of these two criteria.
Inhibin B and inhibin A levels were log-normalized because they were not normally distributed, and results in PCOS and normal subjects were compared using t tests. Gonadotropin steroid and metabolic parameters were compared in PCOS and normal subjects using Mann-Whitney rank-sum tests. Spearman correlations were used to examine the relationship of inhibin B and inhibin A to gonadotropin, steroid, and metabolic parameters in PCOS and normal subjects. Paired t testing was used to compare inhibin B, steroid levels, SHBG, leptin, and insulin and glucose mean and area under the curve before and after hCG stimulation or diazoxide administration. P < 0.05 was taken as the minimum level of significance for all comparisons with the exception of correlations in which P < 0.004 was used to determine significance due to the number of variables examined.
Results
Characteristics of PCOS and normal women
Despite attempts to recruit obese normal subjects, BMI was higher in PCOS subjects compared with normal women, as were fasting insulin and leptin, whereas SHBG was lower (Table 1
). As previously described (17), the patients with PCOS had higher LH, LH/FSH ratio, LH pulse amplitude, LH pulse frequency, testosterone, androstenedione, and 17-hydroxyprogesterone, but similar FSH and estradiol levels, compared with normal women in the early follicular phase (Table 1). There was no difference in any of the baseline hormonal parameters in the subset of PCOS women in whom inhibin A and B levels were measured after hCG administration compared with the large PCOS group. In the additional PCOS subjects in whom diazoxide was administered, baseline SHBG was lower, and the LH/FSH ratio and fasting insulin level were higher compared with those in the larger PCOS group.
Inhibin B and inhibin A levels in PCOS and normal women
A broad range of inhibin B levels was demonstrated in both normal and PCOS subjects, with levels in the PCOS subjects exhibiting a nonnormal distribution. Importantly, samples derived from 4-h pools of frequent blood samples revealed no difference in inhibin B between PCOS and normal subjects in the early follicular phase [median (range), 94.2 pg/ml (15.6–466.4) vs. 75.2 pg/ml (28.4–139.5); P = 0.24; Fig. 1]. There was also no difference in inhibin A levels between PCOS and normal subjects [1.76 mIU/ml (1.0–5.9) vs. 1.63 mIU/ml (1.0–4.4); P = 0.78; Fig. 1]. The absence of a difference in inhibin B and inhibin A between PCOS and controls was evident despite a greater number of follicles and a larger ovarian volume in PCOS (Table 1). Inhibin B and inhibin A were not significantly correlated with cycle day, ovarian volume, or number of follicles 8 mm or larger in PCOS or normal subjects.
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In patients with PCOS, there was a striking inverse relationship between inhibin B and BMI (Table 1). BMI correlated inversely with LH pool (r = -0.646; P < 0.001), LH pulse amplitude (r = -0.646; P < 0.001), and SHBG (r = -0.617; P < 0.001) and positively with fasting insulin (r = 0.510; P < 0.001) and leptin (r = 0.755; P < 0.001). Thus, these factors were also compared with inhibin B along with sex steroids and ovarian parameters.
Each of the variables that correlated with BMI also correlated with inhibin B levels in PCOS subjects. There was a positive correlation between inhibin B and pool LH, which was entirely accounted for by LH pulse amplitude, as there was no relationship with LH pulse frequency (Table 1). Inhibin B also correlated positively with SHBG and inversely with fasting insulin (Table 1). These relationships were not demonstrated in normal subjects, nor were they demonstrated for inhibin A. Neither inhibin B nor inhibin A was significantly correlated with androgens or estradiol in PCOS or normal subjects.
Inhibin B response to hCG in PCOS
To determine whether the positive correlation between inhibin B and LH in PCOS subjects was due to stimulation of inhibin B by LH, hCG, which binds to the LH receptor, was administered to subjects with PCOS. Administration of hCG was associated with an increase in 17-hydroxyprogesterone (4.2 ± 0.6 vs. 7.6 ± 1.2 nmol/liter, baseline vs. peak; P < 0.009) and estradiol (347.3 ± 27.5 vs. 519.1 ± 60.6 pmol/liter; P < 0.003) as previously described (29). However, inhibin B was significantly decreased after hCG administration in PCOS subjects (223.8 ± 21.3 vs. 152.4 ± 15.9 pg/ml; P < 0.0005; Fig. 2). There was no change in testosterone (6.43 ± 0.76 vs. 6.79 ± 0.94 nmol/liter) or androstenedione (15.0 ± 2.4 vs. 16.8 ± 1.7 nmol/liter). Although normal subjects exhibited an increase in 17-hydroxyprogesterone (1.8 ± 0.3 vs. 3.6 ± 0.6 nmol/liter; P < 0.004) after hCG stimulation, there was no change in estradiol (291.8 ± 26.4 vs. 410.4 ± 51.0 pmol/liter), testosterone (2.72 ± 0.13 vs. 2.64 ± 0.31 nmol/liter), androstenedione (7.7 ± 1.4 vs. 7.3 ± 0.7 nmol/liter), or inhibin B (154.2 ± 60.1 vs. 115.2 ± 21.9 pg/ml).
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To determine whether the negative correlation between inhibin B and insulin in PCOS subjects represents suppression of inhibin B secretion by elevated serum insulin levels, diazoxide was administered to subjects with PCOS. As expected, 3 d of diazoxide treatment resulted in a decrease in the insulin area under the curve (104 ± 29 to 83 ± 22 nmol/liter·min; P < 0.05) and an increase in the glucose area under the curve (1070 ± 94 to 1280 ± 142 mmol/liter·min; P < 0.05). The decrease in insulin was associated with a significant increase in inhibin B secretion (85.4 ± 12.4 to 136.6 ± 18.8 pg/ml; P < 0.05; Fig. 3). The single subject in whom inhibin B did not increase was the only one with a BMI less than 25 kg/m2 (21 kg/m2). She also had the lowest fasting insulin (37 pmol/liter) and no evidence of insulin resistance on physical or laboratory exams.
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Discussion
The results in this large, well characterized group of anovulatory PCOS subjects confirm the inverse relationship between inhibin B and BMI that has previously been described in PCOS (9, 10, 11, 12). They further demonstrate that serum inhibin B levels in PCOS subjects exhibit strong correlations with factors related to BMI, including LH, insulin, and SHBG. Finally, direct manipulation of LH and insulin begin to elucidate the mechanisms of inhibin B regulation in PCOS.
The concept that BMI may play a role in inhibin B regulation is not surprising. Although obesity is not a necessary feature of PCOS (32, 33), a large number of women with PCOS are obese (34, 35), and weight loss increases the rate of spontaneous ovulation in these women (36, 37). Therefore, as inhibin B serves as a marker of small antral follicle growth (23, 38), the suppression of inhibin B with increased BMI suggests that granulosa cell or follicular production of inhibin B and possibly follicle health are decreased with obesity. This may be true even in regularly cycling obese women, because obesity itself is associated with anovulation (39, 40), and an inverse relationship has been demonstrated between inhibin B and BMI in normal women (10), although was not seen in the current study using a smaller number of controls. In this study and others, however, BMI is tightly correlated with LH (17), SHBG (35), fasting insulin, and leptin in PCOS. Thus, a factor related to BMI is likely to be directly responsible for inhibin B regulation. To determine whether these associated factors were causative, LH and insulin were manipulated. BMI and SHBG cannot be changed without altering other hormonal parameters.
Despite the positive correlation of LH and inhibin B secretion in PCOS subjects, hCG administration decreased, rather than increased, inhibin B levels, demonstrating that there is no cause and effect relationship between acute hCG (LH) stimulation and inhibin B secretion. It is unlikely that the timing of the post-hCG sample resulted in a failure to observe inhibin B stimulation, as the peak or plateau of dimeric inhibin secretion after FSH stimulation occurs at approximately 24 h (23). These findings are also consistent with the inability of LH to stimulate inhibin B secretion in vivo in normal subjects (23) and in vitro in PCO and normal ovaries (38). Indeed, it is possible that LH, like hCG in this experimental situation, decreases inhibin B expression and/or secretion. In the rodent, inhibin B decreases on the day of the proestrous LH surge (41). In the human, there is little inhibin ßB-subunit expression in the luteinized granulosa cells retrieved 36 h after hCG stimulation (42), and hCG decreases the already low inhibin B secretion from these cells (43). The decreased inhibin B in the current study may be secondary to a decrease in FSH resulting from an increase in estradiol stimulated by hCG. However, FSH levels were not measured to confirm this hypothesis. Thus, these studies suggest that rather than stimulate inhibin B, the elevated LH levels characteristic of women with PCOS would be expected to suppress the expression and secretion of inhibin B.
On the other hand, suppression of insulin resulted in increased inhibin B in the absence of changes in LH, FSH, BMI, SHBG, and leptin, demonstrating that insulin negatively regulates inhibin B. This finding is specific for inhibin B, as elevated insulin levels during an iv glucose tolerance test had no effect on total inhibin levels in PCOS, as measured using an assay directed against the inhibin -subunit (7). The absence of an insulin effect on inhibin B secretion in in vitro studies using human granulosa cells from small antral follicles (38) argues against direct inhibin B suppression by insulin. However, insulin may suppress inhibin B indirectly by inhibiting follicle and granulosa cell proliferation. The spontaneous follicular growth and ovulation that occur with insulin-lowering agents support this hypothesis (44, 45). Thus, these findings suggest that in PCOS, lowering insulin acutely results in release from inhibition of follicular growth, as indicated by increased inhibin B. They also suggest that the inverse relationship between BMI and inhibin B may be causally linked to the increased insulin levels observed in women with increased BMI.
The decrease in insulin was accompanied by decreased testosterone, as seen previously (46), and was consistent with in vitro studies suggesting a stimulatory effect of insulin on androgen secretion (47, 48, 49). It is unlikely that testosterone has a direct effect on inhibin B, as there was no correlation between inhibin B and testosterone in this or other studies (9, 11, 12). In addition, testosterone facilitates, rather than inhibits, FSH-stimulated inhibin secretion in vitro (50, 51). There is evidence that androgen excess suppresses follicle growth in PCOS (52, 53, 54). Therefore, we cannot rule out the possibility that decreased testosterone stimulated inhibin B indirectly by facilitating follicle growth.
These data confirm the absence of a difference in inhibin A and inhibin B levels compared with early follicular phase levels in normal cycling women (8, 9, 10, 11, 12, 13). The data also demonstrate that inhibin B was not inversely related to FSH, providing further support that alterations in dimeric inhibin secretion are not responsible for the relative suppression of FSH compared with LH in PCOS. The difference between the current study and studies that demonstrated an increase in inhibin A (14) or inhibin B (14, 15) probably relates to the criteria for selection of PCOS subjects, as it is now apparent that both BMI and follicular development influence inhibin A and/or B levels. In the current study all PCOS subjects were documented anovulatory to avoid the possible increase in FSH, and subsequently inhibin B (25), after release from luteal phase negative feedback. Further, subjects with a dominant follicle were excluded from the current study as in previous studies (9, 10, 55) because both inhibin A and inhibin B levels increase with recruitment of the dominant follicle (24, 30). Most importantly, PCOS subjects in the current study exhibited a broad range of BMIs and had a higher BMI, on the average, than those in recent studies, which demonstrated increased inhibin A and inhibin B (14, 15). A preponderance of lean subjects would have explained higher inhibin B levels in the previous studies.
No differences were observed in inhibin A and inhibin B levels in PCOS compared with normal subjects despite an increase in the number of follicles 8 mm or larger observed by ultrasound in PCOS. Serum dimeric inhibin levels reflect the integrated output of all small antral follicles present in the ovary (23, 38). Therefore, the equivalent inhibin B levels in PCOS and normal subjects taken together with the greater number of follicles on ultrasound in PCOS suggest a relative deficiency in dimeric inhibin secretion per follicle in PCOS. As inhibin has the ability to enhance small follicle growth (56), decreased inhibin secretion in individual PCOS follicles may be responsible for their arrested development. Granulosa cell inhibin -subunit expression is lower in granulosa cells from PCOS subjects compared with normal (5, 57). Follicular fluid inhibin A and inhibin B levels (57) are also lower in follicles of PCOS subjects compared with size-matched follicles from normal subjects, although no differences were demonstrated when PCOS and normal follicles with a high androstenedione/estradiol ratio were compared (58). Finally, follicular fluid inhibin levels are lower in PCOS compared with normal subjects treated with exogenous gonadotropins (59). The lower dimeric inhibin protein could be explained by a smaller number of granulosa cells in PCOS follicles (60), consistent with insulin suppression of folliculogenesis. In addition, data from the current study suggest that the elevated LH levels characteristic of women with PCOS may also suppress inhibin B expression and secretion.
In summary, inhibin B demonstrated significant relationships with BMI and factors related to BMI, including LH, insulin, and SHBG. Despite the positive correlation between LH and inhibin B, LH suppresses, rather than stimulates, inhibin B secretion, suggesting that the observed correlation is confounded by other variables. The negative correlation between insulin and inhibin B and the results of insulin suppression indicate that insulin inhibits inhibin B secretion, probably via suppression of folliculogenesis. Thus, both LH and insulin may play a role in the relative suppression of inhibin B levels in PCOS subjects.
Acknowledgments
We thank Patrick Sluss, Ph.D., and the members of the Reproductive Endocrine Unit Laboratory for their help in assay performance. We thank Kristi Stanton, B.A., for her work on the diazoxide protocol. We acknowledge Judith Adams, D.M.U., for her expertise in performing and interpreting the ultrasounds, and the nurses at the General Clinical Research Center for their conscientious patient care.
Footnotes
This work was supported by NIH Grants U54-HD-29164 and M01-RR-1066.
Abbreviations: BMI, Body mass index; CV, coefficient of variation; hCG, human chorionic gonadotropin; PCOS, polycystic ovary syndrome.
Received April 5, 2002.
Accepted September 4, 2002.
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). Samples from the same individual are connected by a line. The mean inhibin B level in the whole group are indicated (•). **, P < 0.0005.