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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 4 1365-1369
Copyright © 1999 by The Endocrine Society

Original Studies

Follicle-Stimulating Hormone-Inhibin B Interactions during the Follicular Phase of the Primate Menstrual Cycle Revealed by Gonadotropin-Releasing Hormone Antagonist and Antiestrogen Treatment

H. M. Fraser, N. P. Groome and A. S. McNeilly

Medical Research Council Reproductive Biology Unit (H.M.F., A.S.M.), Centre for Reproductive Biology, Edinburgh EH3 9EW; and School of Biological and Molecular Sciences, Oxford Brookes University (N.P.G.), Oxford OX3 OBP, United Kingdom

Address all correspondence and requests for reprints to: Dr. H. M. Fraser, Medical Research Council Reproductive Biology Unit, Centre for Reproductive Biology, 37 Chalmers Street, Edinburgh EH3 9EW, United Kingdom. E-mail: h.fraser{at}ed-rbu.mrc.ac.uk


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The aim was to determine the pattern of inhibin A and inhibin B secretion during the ovulatory cycle of the macaque and to explore the effects of manipulating follicular phase FSH on inhibin B secretion by: 1) blocking the early follicular phase rise in FSH with GnRH antagonist treatment; 2) administering FSH in GnRH antagonist-treated animals; and 3) preventing the midfollicular phase decline in FSH by a specific antiestrogen.

Treatment with GnRH antagonist, starting on day 25 of the cycle, abolished the early follicular phase rise in FSH and the associated increase in inhibin B. The same treatment, followed by exogenous FSH, restored the secretion of inhibin B. Treatment with antiestrogen, commencing during the midfollicular phase, induced a supraphysiological rise in FSH, followed by a marked stimulation of inhibin B and estradiol secretion. Despite continued antiestrogen treatment, FSH secretion declined before peak values of inhibin B and estradiol were attained, implying a potential endocrine role for inhibin B, in addition to estradiol, in the negative feedback regulation of FSH. These results show that follicular phase FSH is the major stimulus for inhibin B secretion.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE UNDERSTANDING of the endocrine role of inhibin at defined stages of the menstrual cycle has depended heavily on specific assay of changes in serum concentrations of the biologically active dimers, inhibin A and inhibin B (1). The first RIA for inhibin, which was found retrospectively to measure both biologically active inhibin and inactive {alpha}-subunit precursors, indicated that, in women (2) and nonhuman primates (3), immunoreactive inhibin was highest during the luteal phase. This contradicted the classical concept that inhibin was a product of the developing follicle and played a negative feedback role, together with estradiol-17ß, in suppressing FSH secretion during the mid- to late follicular phase. However, with the development of enzyme-linked immunosorbent assays, specific for dimeric inhibin A and inhibin B, it has been demonstrated that, whereas the pattern of inhibin A secretion is in accord with the previous, less specific assay, inhibin B peaks during the follicular phase of the human menstrual cycle, giving support to a negative feedback function during the follicular phase (4).

A better understanding of the physiological relationships between FSH, inhibin B, and estradiol can be achieved by hormone manipulations using specific antagonists. Macaques seem to be suitable models, because the expression of inhibin and activin subunits in their ovaries is similar to that in the human (5, 6, 7, 8). The aim of the present report was to determine the pattern of inhibin A and inhibin B during the cycle of the stump-tailed macaque, a species we have used previously for studies on the endocrine role of inhibin (8, 9). Because this showed that inhibin B was highest during the early follicular phase, as in women, we went on to explore the effects of manipulating the intercycle rise and the midfollicular phase decline in FSH on inhibin B secretion. This was achieved by: 1) blocking the rise with GnRH antagonist treatment; 2) administering exogenous FSH in GnRH antagonist-treated animals; and 3) preventing the midfollicular phase decline in FSH by administering a specific antiestrogen, Faslodex. The latter experiment also addresses the extent of the negative feedback role of estradiol, in relation to inhibin B, at this time.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Adult female stump-tailed macaques (Macaca arctoides), weighing 10–13 kg, were captive-bred and housed in a building designed with an emphasis on environmental enrichment. Groups of 3–6 animals were accommodated in rooms of 11 m2, lit partially by natural light, on which was superimposed artificial lighting in a 12-h light, 12-h dark regimen, with lights on at 0700 h. The rooms contained logs and equipment to encourage exercise, and the floor was covered in wood chippings to provide a facility for foraging for nuts and dried fruit. The animals were fed fresh fruit, morning and afternoon on weekdays, and mornings on weekends, together with SDS Old World primate diet, once daily. The animals moved freely from the room to their home cages via connecting tunnels through a partition wall, for their water supply and sleeping area and for collection of blood samples. Daily vaginal swabs were taken to detect the pattern of menstrual bleeding, and the first day of menstruation was designated day 1 of the cycle. These macaques adapt readily to collection of blood samples by femoral venipunture. All had regular ovulatory menstrual cycles, as determined from menstrual pattern and serum concentrations of estradiol-17ß and progesterone in blood samples obtained three times per week, before treatment.

Treatments

To investigate the effects of blocking the intercycle rise in FSH, GnRH antagonist treatment was initiated during the late luteal phase (day 25 of the cycle). Immediately before injection, the GnRH antagonist [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,D-(Hci)6,Lys(iPr)8,D-Ala10]GnRH (Antarelix, Europeptides, Argenteuil, France) was dissolved in water containing 5% mannitol, to a concentration of 10 mg/mL. Four macaques were given three daily injections of the GnRH antagonist, administered sc in the thigh, at a dose of 1 mg/kg, as described previously (10). Blood samples were collected daily for 21 days from the start of treatment and 3 times per week thereafter, until the first posttreatment cycle.

To investigate the effects of adding back FSH during GnRH antagonist treatment, four animals commenced treatment with three daily injections of Antarelix on day 25 of the cycle, as described above. Recombinant FSH (Gonal-F, Serono, UK), 7.5 1U per dose, dissolved in sterile water, was administered by sc injection starting at 0900 h, 1 day after initiation of GnRH antagonist treatment and repeated at 1700 h for 5 days. The dose approximates 80 IU in women, equating to a low-dose protocol, and was chosen in an attempt to recreate the physiological profile of endogenous FSH at this time. Blood samples were collected as above.

To examine the effects of blocking estradiol feedback on FSH and inhibin secretion, four macaques in the midfollicular phase of the cycle (day 8) were treated with 0.2 mg/kg Faslodex (ZM182780) (Zeneca Pharmaceuticals, Macclesfield, UK), a steroidal pure antiestrogen (11), dissolved in propylene glycol, once daily for 3 days. Blood samples were collected at 0, 2, 4, 6, 8, and 12 h after the first injection, and daily for the next 10 days.

Assays

Serum inhibin A and inhibin B were measured using the two-site enzyme-linked immunoassays developed for human serum and validated in our laboratory for the macaque, as described previously (12). The assays used 50 µL serum in duplicate and had sensitivities of 4 ng/L for inhibin A and 16 ng/L for inhibin B. Estradiol-17ß and progesterone were measured by RIAs (13), detection limits being 30 pmol/L and 0.7 nmol/L, respectively. Macaque FSH was measured as described (14) using a heterologous RIA with a detection limit of 2 µg/L NICHHD cyn-FSH-RP1, and inter- and intraassay coefficients of variance of 15 and 11%, respectively. LH was measured by RIA, based upon recombinant cynomolgus monkey LH and supplied by the National Hormone and Pituitary Program, NIDDKD. A rabbit antiserum (AFP342994) was used as a final dilution of 1:750,000. Rec-mo LH-RP-1 (AFP-6936H) was used for radioiodination, as instructed, and results were expressed as µg/L of the same preparation. Assay sensitivity was 0.3 µg/L, and inter- and intraassay coefficients of variance were 12 and 7%, respectively. FSH concentrations, after administration of Gonal-F, were measured by a routine human FSH immunoradiometric assay (4), in which macaque FSH is not detected.

To obtain the profile of inhibin A and inhibin B throughout the normal cycle, daily serum samples from eight macaques with normal ovulatory cycles were measured; and the results were plotted, relative to the day of the midcycle LH surge.

Data for hormone concentrations were subjected to one-factor ANOVA for repeated measures. The individual means were further examined using the Newman-Keuls test for pairwise comparisons. Differences were considered significant at a level of P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Serum concentrations of inhibin A were low during the follicular phase of the cycle, rose after the midcycle LH/FSH surge, and reached peak values during the midluteal phase, before declining in a manner similar to progesterone (Fig. 1Go). In contrast, serum concentrations of inhibin B were highest during the early-to-midfollicular phase of the cycle, when estradiol was still low (Fig. 1Go). Peak values were associated with the early follicular phase FSH peak (Fig. 2Go), correlation coefficient (r = 0.549) rising (to R = 0.82) (P < 0.01), when the FSH values were shifted forward by 1 day, implying that FSH was driving the rise in inhibin B.



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  		Figure 1. Serum concentrations of inhibin A, inhibin B, estradiol, progesterone, and FSH during the ovulatory cycle of the stump-tailed macaque. Values are means ± SEM of eight cycles, centered around the day of the preovulatory LH surge.

 


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  		Figure 2. Relationship between FSH and inhibin B, during the follicular phase, shown by plotting serum concentrations of inhibin B around the peak of the inter cycle rise in FSH. Values are means ± SEM of eight cycles, as in Fig. 1Go.

 
Treatment with GnRH antagonist, starting on day 25 of the luteal phase, abolished the early-follicular-phase rise in FSH and suppressed serum LH to nondetectable levels (Fig. 3Go). This was associated with a total absence of the normal follicular phase rise in inhibin B and a suppression of serum estradiol concentrations. A high dose of the GnRH antagonist was employed to help ensure that FSH secretion would be suppressed, because FSH is generally less susceptible to GnRH antagonist treatment than LH. This probably results in depot formation and continued slow release of the compound. Subsequently, the normal late follicular phase rise in estradiol, the midcycle LH surge, and ovulation all failed to occur; and inhibin A and inhibin B were maintained at basal levels for 27–36 days. Thereafter, recovery was evident; and entering the data around the time of posttreatment ovulation (which occurred 45 ± 4 days, mean ± SEM, after start of treatment) also provides confirmation of the association between the reinitiation of pituitary gonadotropin secretion and the rise in inhibin B followed by the recovery of the cyclic pattern of estradiol, progesterone, and inhibin A secretion (Fig. 3Go).



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  		Figure 3. Effect of treatment with GnRH antagonist (arrows), beginning on day 25 of the cycle, on serum concentrations of FSH, inhibin B, inhibin A, LH, estradiol, and progesterone in the macaque. Values are means ± SEM for four animals. The shaded area shows SD around control cycles aligned to day 0 being day 25 of the normal cycle.

 
GnRH antagonist treatment, in association with exogenous FSH, resulted in a variable increase in inhibin B, with one animal being restored to the physiological range, two having supraphysiological rises, and the remaining animal having a minimal rise (Fig. 4Go). Calculation of the cumulative serum concentrations of human FSH (achieved during the treatment period in each macaque), plotted against the cumulative inhibin B values obtained over the same period, failed to show a significant correlation. However, when the ages of the animals were taken into account, it was found that the animal showing the least response was the oldest. Removal of the data concerning this animal revealed a significant correlation between the serum FSH concentrations attained and the inhibin B produced. Inhibin A declined to basal levels and was uninfluenced by the exogenous FSH. Estradiol secretion did not change consistently over the treatment period. However, whereas GnRH antagonist treatment alone resulted in estradiol levels falling to less than 100 pmol/L (Fig. 3Go), with exogenous FSH, values associated with the late luteal/early follicular phase range (approximately 200 pmol/L) were observed (Fig. 4Go).



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  		Figure 4. Effect of treatment with GnRH antagonist (arrows), beginning on day 25 of the cycle, followed 1 day later by replacement FSH (shaded area) on serum concentrations of inhibin B, inhibin A, and estradiol in the macaque. Values are means ± SEM for four animals.

 
Treatment with the antiestrogen during the midfollicular phase, when FSH was declining, induced significant increases (P < 0.001) in the secretion of FSH, LH, inhibin B, and estradiol (Fig. 5Go). The rise in serum concentrations of FSH was rapid, being significantly above (P < 0.01) pretreatment values at 8 h after the first injection. LH followed a similar pattern, although the magnitude of the rise was different from that of FSH; whereas the increase in FSH was twice that observed for the early follicular or preovulatory peaks, that of LH was less than half that observed during the preovulatory LH surge (compare Figs. 3Go and 5Go). This gonadotropin rise was followed by a supraphysiological increase in estradiol-17ß and inhibin B, values being significantly elevated by 12 h and reaching a peak on the day after the third injection and, like FSH, they were twice the magnitude of the peak values seen in the normal cycle (Fig. 5Go). It was of interest that the subsequent decline in FSH and LH took place as the treatment with antiestrogen was continuing and the serum concentrations of inhibin B and estradiol were continuing to rise, so that by treatment day 3, FSH and LH concentrations had returned to baseline, whereas the rise in inhibin B and estradiol was maximal. Despite the stimulation of estradiol secretion, an LH surge and progesterone rise indicative of ovulation did not follow. Instead, estradiol and inhibin B secretion declined before rising again to normal preovulatory levels, so that ovulation was delayed by an estimated 5–7 days. Inhibin A secretion was not stimulated by antiestrogen treatment; all samples remained below 20 ng/L (data not shown).



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  		Figure 5. Effect of treatment with antiestrogen (arrows), beginning on day 8 of the follicular phase, on serum concentrations of FSH, inhibin B, LH, and estradiol in the macaque. Values are means ± SEM for four animals.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study shows that the patterns of inhibin A and inhibin B secretion in serum of the stump-tailed macaque are broadly similar to those observed in the human, with maximal secretion of inhibin A occurring during the luteal phase and inhibin B being secreted in highest levels during the early to midfollicular phase. The temporal relationship between the early follicular phase rise in FSH and the peak values of inhibin B during the normal cycle of the human (4, 15, 16) and the stump-tailed macaque imply that this FSH rise drives inhibin B secretion. This relationship was supported by the changes in inhibin B secretion after the hormone manipulations performed. GnRH antagonist, administered during the late luteal phase, blocked the early follicular phase rise in FSH; and subsequently, the normal rise in inhibin B failed to occur. The sequence of changes on reinitiation of pituitary-ovarian function also supported the relationship between FSH and inhibin B.

Further evidence for the relationship between an elevation in follicular phase FSH secretion and a stimulation of inhibin B was provided by the demonstration that exogenous FSH, administered during GnRH antagonist treatment, resulted in a stimulation of inhibin B secretion, albeit at a variable magnitude between animals (17). The animal with the lowest response was the oldest of the group, and the follicles may have required a higher level of stimulation. Finally, the treatment with the antiestrogen showed that high concentrations of FSH can stimulate a marked increase in inhibin B in the mid- to late-follicular phase ovary, a time when inhibin B concentrations are normally beginning to decrease.

With respect to the source of the changes in inhibin B, we know that the inhibin/activin ß-subunit is highly expressed in the granulosa cells of developing follicles in the stump-tailed macaque, as in all primate species reported (5, 6, 7, 8, 17). However, for synthesis of the inhibin B dimer, the production of the {alpha}-subunit within the follicle is essential, and it is therefore {alpha}-subunit production that is likely to be the rate-limiting step for dimeric inhibin production (5, 6, 7). GnRH antagonist treatment does not have acute suppressive effects upon inhibin/activin ß-subunit messenger RNA (mRNA) in the primate ovary (18). Thus, the varying patterns of inhibin B secretion, observed after the hormone manipulations described, are likely to reflect the numbers of follicles expressing the {alpha}-subunit.

Although it is concluded from the results that the follicular phase rise in serum concentrations of inhibin B is dependent upon FSH secretion and that increasing the output of FSH leads to supraphysiological rises in inhibin B, the extent of the endocrine role of inhibin B during the follicular phase of the primate menstrual cycle is not yet clear (1). Administration of recombinant inhibin A, during the early follicular phase in the stump-tailed macaque, failed to suppress serum FSH concentrations (9). Treatment of rhesus monkeys, with a dose of inhibin that far exceeded physiological concentrations, did induce a reduction in FSH (18), giving support to the concept of a potential role in the negative feedback regulation of FSH. The potential of inhibin B to exert a negative feedback on FSH secretion may be implied from our observation that FSH subsequently declined during the antiestrogen treatment period, at a time when inhibin B and estradiol concentrations were at their peak. Assuming complete blockade of the estrogen receptor, it may be suggested that the decline in FSH is a result of negative feedback of inhibin B, although other explanations are possible. The negative feedback role of estradiol during the mid- to late follicular phase of the menstrual cycle is well established and is exemplified by the marked increase in FSH after competitive blockade of the estradiol receptor observed in the present study. On the basis of the temporal relationships between FSH, inhibin B, and estradiol during the early to midfollicular phase, it has been implied that inhibin B exerts a negative feedback effect on the rise in FSH before estradiol (4). Further studies, using hormone manipulations, should be useful in resolving this question.


   Acknowledgments
 
We thank K. Morris and staff for animal management; F. Pitt and I. Swanston for performance and monitoring of assays; E. Pinner for graphics; National Hormone and Pituitary Program, NIDDKD, and Dr. A. F. Parlow for materials for LH assay; Drs. A. E. Wakeling and M. Dukes (Zeneca Pharmaceuticals) for the gift of Faslodex and for helpful discussions; and Dr. R. Deghenghi (Europeptides) for the gift of Antarelix.

Received July 31, 1998.

Revised December 22, 1998.

Accepted January 4, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Hayes FJ, Hall JE, Boepple PA, Crowley WFJ. 1998 Differential control of gonadotropin secretion in the human: endocrine role of inhibin. J Clin Endocrinol Metab. 83:1835–1841.[Free Full Text]
  2. McLachlan RI, Robertson DM, Healy DL, Burger HG, de Kretser DM. 1987 Circulating immunoreactive inhibin levels during the normal human menstrual cycle. J Clin Endocrinol Metab. 65:954–961.[Abstract]
  3. Fraser HM, Robertson DM, De Kretser DM. 1989 Immunoreactive inhibin concentrations in serum throughout the menstrual cycle of the macaque: suppression of inhibin during the luteal phase after treatment with an LHRH antagonist. J Endocrinol. 121:R9–R12.
  4. Groome NP, Illingworth PJ, O’Brien M, et al. 1996 Measurement of dimeric inhibin B throughout the human menstrual cycle. J Clin Endocrinol Metab. 81:1401–1405.[Abstract]
  5. Schwall RH, Mason AJ, Wilcox JS, Bassett SG, Zeleznik AJ. 1990 Localization of inhibin/activin subunit mRNAs within the primate ovary. Mol Endocrinol. 4:75–79.[Abstract]
  6. Fraser HM, Lunn SF, Cowen GM, Saunders PTK. 1993 Localization of inhibin/activin subunit messenger RNAs during the luteal phase in the primate ovary. J Mol Endocrinol. 10:245–257.[Abstract]
  7. Roberts VJ, Barth S, ElRoeiy A, Yen SSC. 1993 Expression of inhibin/activin subunits and follistatin messenger ribonucleic acids and proteins in ovarian follicles and the corpus luteum during the human menstrual cycle. J Clin Endocrinol Metab. 77:1402–1410.[Abstract]
  8. Fraser HM, Lunn SF. 1993 Does inhibin have an endocrine function during the menstrual cycle? Trends Endocrinol Metab. 4:187–194.
  9. Fraser HM, Tsonis CG. 1994 Manipulation of inhibin during the luteal-follicular phase transition of the primate menstrual cycle fails to affect FSH secretion. J Endocrinol. 142:181–186.[Abstract]
  10. Fraser HM, Lunn SF, Morris KD, Deghenghi R. 1997 Initiation of high-dose gonadotrophin-releasing hormone antagonist treatment during the late follicular phase in the macaque abolishes luteal function irrespective of effects upon the luteinizing hormone surge. Hum Reprod. 12:430–435.
  11. Dukes M, Waterton JC, Wakeling AE. 1993 Antiuterotrophic effects of the pure antioestrogen ICI 182,780 in adult female monkeys (Macaca-nemestrina) - quantitative magnetic resonance imaging. J Endocrinol. 138:203–210.[Abstract]
  12. Mann DR, Akinbami MA, Wallen K, et al. 1997 Inhibin-B in the male rhesus monkey: impact of neonatal gonadotropin-releasing hormone antagonist treatment and sexual development. J Clin Endocrinol Metab. 82:1928–1933.[Abstract/Free Full Text]
  13. Fraser HM, Sandow J. 1985 Suppression of follicular maturation by infusion of a luteinizing hormone-releasing hormone agonist starting during the late luteal phase in the stump-tailed macaque monkey. J Clin Endocrinol Metab. 60:579–584.[Abstract]
  14. Fraser HM, McNeilly AS, Abbott M, Steiner RA. 1986 Effect of LHRH immunoneutralization on follicular development, the LH surge and luteal function in the stump-tailed macaque monkey (Macaca arctoides). J Reprod Fertil. 76:299–309.[Abstract]
  15. Welt CK, Martin KA, Taylor AE, et al. 1997 Frequency modulation of follicle-stimulating hormone (FSH) during the luteal-follicular transition: evidence for FSH control of inhibin B in normal women. J Clin Endocrinol Metab. 82:2645–2652.[Abstract/Free Full Text]
  16. Lockwood GM, Muttukrishna S, Groome NP, Ledger WL. 1998 Midfollicular 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. J Clin Endocrinol Metab. 83:1730–1735.[Abstract/Free Full Text]
  17. Fraser HM, Lunn SF, Whitelaw PF, Hillier SG. 1995 Induced luteal regression: differential effects on follicular and luteal inhibin/activin subunit mRNAs in the marmoset monkey. J Endocrinol. 144:201–208.[Abstract]
  18. Molskness TA, Woodruff TK, Hess DL, Dahl KD, Stouffer RL. 1996 Recombinant human inhibin-A administered early in the menstrual cycle alters concurrent pituitary and follicular, plus subsequent luteal, function in rhesus monkeys. J Clin Endocrinol Metab. 81:4002–4006.[Abstract/Free Full Text]



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