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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 5 1730-1735
Copyright © 1998 by The Endocrine Society

Original Studies

Mid-Follicular Phase Pulses of Inhibin B Are Absent in Polycystic Ovarian Syndrome and Are Initiated by Successful Laparoscopic Ovarian Diathermy: A Possible Mechanism Regulating Emergence of the Dominant Follicle

Gillian M. Lockwood, S. Muttukrishna, N. P. Groome, D. R. Matthews and W. L. Ledger

Nuffield Department of Obstetrics and Gynaecology, Oxford Radcliffe Hospital (G.M.L., S.M., W.L.L.), Oxford; Diabetes Research Laboratories, Radcliffe Infirmary (D.R.M.), Oxford; School of Biological and Molecular Sciences, Oxford Brookes University, Oxford (N.P.G.)

Address all correspondence and requests for reprints to: Gillian M. Lockwood, Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Maternity Department, Headington, Oxford, United Kingdom OX3 9DU.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The hypothalamic pulse generator of GnRH is recognized to be central to ovulatory function as evidenced by the anovulation of women with hypogonadotrophic hypogonadism due to Kallmann’s syndrome or severe anorexia nervosa. LH is released from the anterior pituitary in pulses, the frequency of which is closely entrained with those of GnRH. In contrast, secretion of FSH is influenced by a number of regulatory molecules, including GnRH, estradiol, inhibin, and activin. The close temporal relationship between changes in levels of inhibin B and FSH in the mid-follicular phase suggests that the release of inhibin B by the preovulatory follicle critically regulates pituitary FSH secretion. Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders affecting ovulation, and abnormal ovarian morphology as detected by ultrasonography remains the most sensitive diagnostic marker for this disorder. The etiology of PCOS is unclear, but its effective treatment by both anti-estrogens and by exogenous FSH suggests that a primary disorder of FSH regulation may be central. To investigate the possible role of inhibin B in the pathology of PCOS, serum inhibin B levels were measured in 10 women with PCOS on cycle day 5 of a spontaneous or progestrogen-provoked bleed and compared with levels on cycle day 5 of 10 women with regular ovulatory cycles. The mean serum inhibin B levels in the PCOS patients were significantly higher at 248 (±43.4) pg/mL compared with normal controls, 126 (±18.6) pg/mL (P < 0.01). Ten women with clomiphene resistant PCOS and 5 normal controls consented to undergo serial blood sampling on cycle day 5. Time Series Analysis using a Fourier Transformation to analyze the power spectrum of the data revealed that in normal women there is a distinct periodicity in inhibin B levels with a clear peak detectable every 60–70 min (P < 0.05), whereas in women with ovulatory dysfunction due to PCOS, no such pattern of regular pulsatility was seen. Four women with PCOS whose anovulation was successfully treated with laparoscopic ovarian diathermy (LOD) underwent repeat venous sampling following LOD. Their serum inhibin B levels fell to the upper limit of the normal range (160± 38.5) pg/mL, and pulsatility was initiated It is possible that inhibin B pulses are being generated directly by the ovary in response to pulses of GnRH in the peripheral circulation, or indirectly in response to FSH pulses arising in the pituitary. The function of inhibin B pulses in the mid-follicular phase of the normal cycle remains to be elucidated, but the absence of the normal pulsatile pattern in women with PCOS, in conjunction with high basal levels of inhibin B arising from the multiple small follicles characteristic of the PCOS ovary, appears to reinforce the development of a large cohort of small, developmentally arrested, and ultimately atretic follicles in these patients. Initiation of normal inhibin B pulsatility by LOD in patients with polycystic ovaries appears to correlate with the post-operative onset of ovular cycles.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
REGULAR, cyclical mono-ovulation in women is achieved by a complex interaction of hormonal signals that prevent the default to atresia, which is the fate of 99.98% of the approximately 2,000,000 primordial follicles that exist in the ovaries of the new-born female infant (1). Preantral stages of follicular growth occur independently of gonadotropic stimulation (2). However, antrum formation requires stimulation by FSH, acting via its receptor in the granulosa cell surface membrane (3). From puberty, cyclic increases in pituitary FSH secretion rescue a cohort of follicles from atresia according to the threshold concept (4). Although multiple follicles are recruited to begin preovulatory development, as the FSH concentration rises at the beginning of each cycle, usually only one survives to become dominant—the follicle whose granulosa cells are most responsive to FSH. Development of the dominant follicle is characterized by the secretion of increasingly large amounts of estradiol and inhibin B into the circulation. Inhibins are heterodimeric glycoproteins consisting of {alpha}-ßA (inhibin A) and {alpha}-ßB (inhibin B) subunits. Activin A (ßAßA) is homodimer. There is evidence to suggest that the maintenance of dominance is effected by intraovarian paracrine signaling (5), with inhibins and activins acting as important paracrine messengers (6). The development of a sensitive immunoassay that can distinguish the active dimeric inhibins A and B from each other and from the biologically inert monomer pro-{alpha}C (which circulates in great excess in the bloodstream) has revealed inhibin B to be the predominant form of inhibin in small, preovulatory follicles (7). Inhibin B rises from early in the follicular phase to reach a peak coincident with the onset of the mid-follicular phase decline in FSH levels. Studies of inhibin B in hyperstimulated cycles have shown that very high levels (>1000 pg/mL) are generated in the presence of multiple follicles (8), whereas the mid-follicular phase rise in inhibin B in spontaneous cycles originates from the few predominant follicles. In superovulatory cycles, the multiple codominant follicles are presumably responsible for the high levels of inhibin B found, and this observation is consistent with studies showing that small follicles express more ßB mRNA. PCOS is a heterogeneous disorder that may present with a set of severe symptoms such as obesity, hyperandrogenism, menstrual irregularity, and infertility, or with a single finding of polycystic ovarian morphology on pelvic ultrasonography (9). Several studies have estimated the prevalence of polycystic ovaries in women without overt ovulatory dysfunction and have found rates of approximately 20% (10, 11, 12, 13). The size and pattern of cysts described by Adams, et al.(14) as characteristic of polycystic ovaries resembles that of multiple small follicles arrested during maturation before the emergence of a dominant follicle. This feature, combined with the observation that women with PCOS are extremely sensitive to exogenous gonadotropins, led us to investigate whether women with polycystic ovaries showed disordered inhibin B production.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Plasma samples were obtained from ten fertility patients with PCOS with severe oligomenorrhoea (<6 spontaneous menses per year) and hyperandrogenism and who had failed to ovulate in response to a maximal dose of the antiestrogen, clomiphene citrate, of 150 mg daily from day 2–6 of a spontaneous or progesterone-induced bleed (clomiphene-resistant PCOS). Normal control samples were obtained from ten women with regular ovulatory cycles on cycle day 5 following a spontaneous bleed. Ten women with PCOS who were about to undergo laparoscopic ovarian diathermy (LOD) and five healthy volunteers with regular ovulatory cycles also consented to undergo serial blood sampling via a small in-dwelling venous catheter every 10 min for a period of 6 h on cycle day 5 of a spontaneous or progesterone-induced bleed. Five of the PCOS patients had elevated LH levels (>10 IU), and five had levels at the upper limit of the normal range for the mid-follicular phase. Approximately 2 mL blood was obtained with each sample, and the in-dwelling venous catheter was flushed with heparinized saline between samples. Samples were centrifuged, stored at -20 C, and assayed for LH, FSH, and inhibin B. The mean age of the ten women with PCOS who provided a single sample and the (different) ten who underwent serial sampling was 32.1 yr and 29.4 yr, respectively, and their average Body Mass Indices (BMI) were 28 (range 23–32) kg/m2 and 27 (range 24–30) kg/m2, respectively. The mean age of the normal controls was 33.2, and they had an average BMI of 24 (range 22–26) kg/m2.

The PCOS patients underwent laparoscopic diathermy (LOD) within 3 months of serial sampling, according to the protocol descibed by Armar et al. (14a). Briefly, at laparoscopy, four diathermy punctures were made in the surface of both ovaries to a depth of 4 mm for a duration of 4 seconds. Following diathermy the treated ovaries were cooled in the pool of Hartmann’s solution, which had been instilled into the pelvis following CO2 insufflation. Following LOD, patients were encouraged to keep a daily temperaure chart to identify ovulation and were invited to attend again for serial sampling on day 5 of their first spontaneous menstruation after LOD or after progesterone provocation of a withdrawal bleed if no spontaneous menstruation had occurred after 6 weeks.

Plasma concentrations of dimeric inhibin B were measured in triplicate 50 µL aliquots using an enzyme immunoassay described in detail elsewhere (7). Minimum detection limit of this assay was 50 pg/mL and the intra and interplate variations were 5 and 7.5% respectively. Plasma concentrations of FSH and LH were measured using Immulite chemiluminescent assay equipment (Diagnostic Products Corporation, Los Angeles, CA). Mean detection limits for FSH and LH were 0.1 and 0.7 IU respectively, and the intra and interplate variation was 5.2 and 6.7% repectively for FSH, and 5.7 and 7.2% respectively for LH. Statistical analysis. Time Series Analysis using Fourier Transforms was performed using a mathematical model and software developed by D.R.M. and described in detail elsewhere (15). Autocorrelations and cross correlations of the data were performed using a data package developed by D.R.M. and based on a model described elsewhere (16).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The plasma level of inhibin B in the PCOS patients sampled on cycle day 5 of a spontaneous or progesterone provoked bleed was significantly higher at 248 ± 43.4 (mean ± sem) pg/mL compared with the normal controls at 126 ±18.6 pg/mL (P < 0.01) (Fig. 1Go). No statistically significant correlation was found between inhibin B levels and FSH levels in either group of subjects. There was no statistically significant correlation between BMI and inhibin B levels.



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  		Figure 1. Comparison of inhibin B levels on day 5 in normal controls (n = 5) and in PCOS patients (n = 10).

 
When the serial measurements of inhibin B were analyzed, the data revealed that in women with normal ovulatory function there is a distinct periodicity with peaks of inhibin B detectable every 60–70 min, whereas in the women with clomiphene resistant PCOS no such pattern of regular pulsatility was found (Fig. 2Go). The peak inhibin B values in the normal controls were approximately twice (range 1.8–2.1) the lowest values for each subject. In the PCOS patients, the peak levels were approximately 50% higher than the lowest values (range 1.4–1.7). Six of the ten women with PCOS required progesterone to induce a withdrawal bleed, and four were sampled during a spontaneous cycle; the pattern of inhibin B secretion did not differ between the two groups.



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  		Figure 2. Serum inhibin B levels (a) in a normal control showing 60–70 min pulses and (b) in a PCOS patient.

 
Time Series analysis using a Fourier transformation to analyse the power spectrum of the data confirmed the presence of a statistically significant periodicity of inhibin B detectable every 60–70 min (P < 0.05) in normal, ovular women that is absent in women with PCOS (Fig. 3Go).



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  		Figure 3. a, Normalized mean serum inhibin B levels in normal controls (n = 5); b, Fourier Transform of data.

 
There was no difference in the pattern of blunted pulsatility of inhibin B secretion in the PCOS patients in either the high or normal LH groups, and so their data is combined. This finding was confirmed by the correlograms plotted for the five normal controls and the (grouped) ten PCOS subjects, which revealed, in the case of the normal controls, a periodicity of inhibin B peak secretion of 60 min (r = 0.189; P < 0.05) that was absent in the PCOS patients (Fig. 4Go). Times Series analysis using a Fourier transformation of the FSH data suggested a pulsatile pattern of secretion in the normal controls with a dominant 60-min period and a subdominant 180-min period (Fig. 5Go). Analysis of the FSH data from the PCOS patients again showed a blunted pattern of secretion, and the Fourier transform did not reach statistical significance at the 5% level. The mean FSH levels in the normal controls and PCOS patients was 3.7 and 3.2 IU/L respectively (not significant).



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  		Figure 4. Autocorrelation - Inhibin B in normal controls. *P < 0.05.

 


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  		Figure 5. Normalized FSH pulses in normal controls (n = 5) and Fourier transform.

 
Cross-correlation analysis of FSH with inhibin B for the normal controls indicated that pulses of inhibin B follow pulses of FSH but with a 50-min lag time (i.e. an increase in FSH is followed 50 min later by a detectable pulse of inhibin B). (Fig. 6Go).



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  		Figure 6. Cross-correlation - FSH with Inhibin B *P < 0.05.

 
There was a statistically significant correlation between LH levels and inhibin B levels in the PCOS patients (r = 0.67; P < 0.001). Time series analysis of the LH data demonstrated regular pulses every 90 min in the normal controls (P < 0.05) (Fig. 7Go).



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  		Figure 7. Normalized mean serum LH levels in PCOS patients (n = 10) and in normal controls (n = 5), and Fourier transform of data.

 
The PCOS patients had higher basal secretion of LH, but the LH pulses in the PCOS patients were less discrete, and the Fourier transform did not reach statistical significance .

Two of the ten patients who underwent LOD conceived following the procedure without experiencing a menstrual period and had healthy singleton pregnancies. A further four experienced ovulation as a result of the LOD as indicated by biphasic temperature charts, an elevation of serum progesterone, and the onset of regular menses. The remaining four patients required further progesterone to induce a withdrawal bleed, but three of the four became responsive to low dose clomiphene citrate (50 mg, day 2–6 of the cycle). All eight patients who failed to conceive immediately after the LOD underwent repeat serial sampling on day 5 of a spontaneous or progesterone provoked bleed, and their gonadotropin and inhibin B levels were compared with their pre-LOD values (Fig. 8Go).



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  		Figure 8. Mean inhibin B and LH levels in PCOS patients before and after LOD inhibin B in pg/mL LH in IU/L. *, Became spontaneously ovular after LOD.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study we have demonstrated that inhibin B secretion by women with anovular PCOS is different both quantitively and qualitatively from that found in women with regular ovulatory cycles. We have shown that the secretion of inhibin B during the mid-follicular phase peak, when it is conjectured that it may be playing a physiologically important role in suppressing FSH secretion, is pulsatile with a regular periodicity of 60–70 min in women who ovulate. We found that women with clomiphene-resistant PCOS secrete high levels of inhibin B (in this study 68% higher than normal controls on average), but their pattern of secretion lacks the regular pulsatility found in the normal controls. Following successful LOD we have demonstrated that women with PCOS who start to have ovular cycles have reduced levels of inhibin B secreted in a pulsatile manner. We have shown that both normal and PCOS patients have pulses of LH and FSH detectable at this point in the cycle, but the PCOS patients’ pattern of pulsatility is blunted and less regular than that seen in the normal controls. Using statistical models derived from Time Series Analysis, we have demonstrated an association between changes in inhibin B levels and FSH in normal, ovulating women.

In early and mid-follicular phases of the ovulation cycle, pulse frequency of the hypothalamic pulse generator is approximately every 90 min. As estrogen levels rise the pulse frequency of GnRH increases to every 60 min before the LH surge. Frequency modulation of pulsatile hormone secretion represents a more sensitive and responsive link between the pituitary and the ovary than is offered by a resetting of the absolute level of FSH in the circulation. Changes in circulating blood volume resulting from physiological alterations in fluid balance will cause fluctuations in hormone levels, whereas pulse frequency will not be affected. Sequential binding to and detachment from hormone receptors allows induction of second messengers within the cell, with subsequent time for receptor reconfiguration and messenger resynthesis before the next pulse, whereas constant exposure to high levels of hormones such as GnRH results in receptor down-regulation and resultant ablation of end-organ response. Pulsatile release of inhibin B from the granulosa cells of the developing predominant follicle may reflect a modifying influence attenuating pituitary FSH release in response to pulses of GnRH, or it could be a response (direct or indirect) to changes in FSH and/or LH levels. It was an unexpected finding that FSH and LH had a different pulse periodicity at this phase of the cycle and that the pulse frequency of inhibin B more closely matched that of FSH (60 mins) than LH (90 mins). This latter was similar to the known frequency of GnRH pulses at this critical stage of the cycle when FSH is being suppressed both by inhibin and by the alternative (or cocompetent mechanism) of rising estradiol levels. If the initial suppression of rising FSH is predominantly mediated by inhibin B, then the time-lag implicit in this long feed-back loop would allow for the initial intercycle rise in FSH followed by a fall, and we therefore speculate that the critical suppressive control of rising FSH could be mediated by changes in the pulsatility pattern of inhibin B.

The clinical and biochemical heterogeneity of PCOS is reflected in the range of neuroendocrine disturbances associated with the syndrome. An increased serum LH concentration is common and occurs primarily as a result of an increase in the amplitude of pulsatile LH, as we found in our PCOS patient group. The literature gives somewhat conflicting accounts of the derangement of LH pulses in PCOS. Kazer et al. (16a) found that the LH pulse frequency of women with PCOS was similar to that of women studied in the early or mid-follicular phase and concluded that elevated LH levels seen in PCOS patients are due to increasd LH pulse amplitude. Waldstreicher et al., (16b) by contrast, found that pulse frequency as well as pulse amplitude are increased in women with PCOS when compared with normal controls. Currently, it remains uncertain as to whether the observed changes in gonadotropins seen in PCOS are a primary abnormality or occur secondary to alterations in peripheral steroid levels. Evidence for the abnormality being caused by increased frequency of GnRH pulses comes from the discordant changes in gonadotrophin secretion that may be induced by rapid frequency exogenous GnRH stimulation in patients with hypogonadotropic hypogonadism. However, if inappropriate gonadotropin secretion is a secondary phenomenon, then manipulation of peripheral steroid levels by ovarian diathermy or induced ovulation may correct the disturbance of gonadotropin secretion, which is a consequence of changes in ovarian steroid feedback signals.

If PCOS is interpreted as a disease of inappropriately low FSH secretion (17) then we can explain the characteristic hormone profile of low/normal FSH in conjunction with elevated LH as a response to elevated inhibin B secretion as suggested by pituitary cell culture studies in sheep (18) and rats (19) which demonstrate that FSH but not LH secretion is suppressed in vitro by inhibin. The "elevated inhibin B" hypothesis therefore, whether it represents an initiation of, or a response to, pituitary-ovarian dysfunction offers a unifying neuroendocrine explanation for the aetiology of PCOS as required by Soule (20) who suggests that most abnormalities in PCOS are more clearly explained as secondary to chronic anovulation rather than of primary pathological import. This present study provides evidence that the ovary in PCOS may well be considered as the prime source of the pathology as the absence of normal inhibin B pulsatility in anovular patients with PCOS, notwithstanding the high ambient levels of inhibin B found in these patients, results in the persistence of a large cohort of small follicles that secrete high levels of inhibin B and perpetuate the ‘vicious cycle’ of inadequate follicular development and dysovulation.

The high levels of inhibin B found in patients with PCOS corresponds well with inhibin B having a possible role as a marker of ovarian reserve (21), as the exaggerated response of the polycystic ovary to exogenous gonadotropins, even after pituitary desensitization with GnRH agonists, is a well-recognized hazard of ART programs involving superovulation. However, just as single hormone estimations are unreliable in representing the hormone status of an individual in relation to LH, so the highly pulsatile nature of inhibin B secretion in normal subjects in the mid-follicular phase and the reduced variability in the presence of elevated background levels of inhibin B in patients with PCOS would require several samples to be taken to ensure a reliable estimation of ovarian reserve was obtained. Further studies are needed, both to explore the patterns of inhibin pulsatility at other stages of the cycle and in other pathological conditions, and to investigate the results of pulsatile exposure to FSH in in vitro systems. However, the present study would seem to offer a possible mechanism by which autoregulation of the hypothathalamo-pituitary-ovarian axis takes place.

Received August 7, 1997.

Accepted January 13, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Gosden RG. 1985 Biology of menopause. London: Academic Press.
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  19. Waldstreicher J, Santoro NF, Hall JE, Filicori M, Crowley Jr WF. 1988 Hyperfunction of the hypothalamic pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotoph desensitization. J Clin Endocrinol Metab. 66:165–172.[Abstract/Free Full Text]
  20. Yen SSC, Vela P, Rankin J. 1970 Inappropriate secretion of FSH and LH in polycystic ovarian disease. J Clin Endocrinol. 30:435–442.[Abstract/Free Full Text]
  21. Muttikrishna S, Knight PG. 1991 Inverse effects of activin and inhibin on the secretion and synthesis of FSH and LH by ovine pituitary cells in vitro. J Mol Endocrinol. 6:171–178.[Abstract/Free Full Text]
  22. Dahl KD, Campen CA, McGuinness DM, Vale W. 1992 Differential regulation in the release of bioactive vs. immunoactive gonadotropins from cultured rat pituitary cells by inhibin and androgens. J Androl. 13:526–533.[Abstract/Free Full Text]
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M. F. M. Mitwally and R. F. Casper
Aromatase Inhibition Reduces the Dose of Gonadotropin Required for Controlled Ovarian Hyperstimulation
Reproductive Sciences, September 1, 2004; 11(6): 406 - 415.
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 J. Clin. Endocrinol. Metab.Home page
C. K. Welt, A. E. Taylor, K. A. Martin, and J. E. Hall
Serum Inhibin B in Polycystic Ovary Syndrome: Regulation by Insulin and Luteinizing Hormone
J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5559 - 5565.
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C. Welt, Y. Sidis, H. Keutmann, and A. Schneyer
Activins, Inhibins, and Follistatins: From Endocrinology to Signaling. A Paradigm for the New Millennium
Experimental Biology and Medicine, October 1, 2002; 227(9): 724 - 752.
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 Hum ReprodHome page
C. H. Gravholt, R. W. Naeraa, A.-M. Andersson, J. S. Christiansen, and N. E. Skakkebaek
Inhibin A and B in adolescents and young adults with Turner's syndrome and no sign of spontaneous puberty
Hum. Reprod., August 1, 2002; 17(8): 2049 - 2053.
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J. S.E. Laven, B. Imani, M. J.C. Eijkemans, F. H. de Jong, and B. C.J.M. Fauser
Absent biologically relevant associations between serum inhibin B concentrations and characteristics of polycystic ovary syndrome in normogonadotrophic anovulatory infertility
Hum. Reprod., July 1, 2001; 16(7): 1359 - 1364.
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R. J. Norman, C. R. Milner, N. P. Groome, and D. M. Robertson
Circulating follistatin concentrations are higher and activin concentrations are lower in polycystic ovarian syndrome
Hum. Reprod., April 1, 2001; 16(4): 668 - 672.
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C. K. Welt and A. L. Schneyer
Differential Regulation of Inhibin B and Inhibin A by Follicle-Stimulating Hormone and Local Growth Factors in Human Granulosa Cells from Small Antral Follicles
J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 330 - 336.
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M. W. Elting, T. J.M. Korsen, L. T.M. Rekers-Mombarg, and J. Schoemaker
Women with polycystic ovary syndrome gain regular menstrual cycles when ageing
Hum. Reprod., January 1, 2000; 15(1): 24 - 28.
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H.M. Buckler, W.R. Robertson, A. Anderson, M. Vickers, and A. Lambert
Ovulation induction with low dose alternate day recombinant follicle stimulating hormone (Puregon)
Hum. Reprod., December 1, 1999; 14(12): 2969 - 2973.
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H. M. Fraser, N. P. Groome, and A. S. McNeilly
Follicle-Stimulating Hormone-Inhibin B Interactions during the Follicular Phase of the Primate Menstrual Cycle Revealed by Gonadotropin-Releasing Hormone Antagonist and Antiestrogen Treatment
J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1365 - 1369.
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