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Pilot study of racial differences and longitudinal changes in inhibin B in the late reproductive years

2002; Elsevier BV; Volume: 77; Issue: 1 Linguagem: Inglês

10.1016/s0015-0282(01)02946-6

1556-5653

Michelle Battistini, Ellen W. Freeman, Jeane Ann Grisso, Mary D. Sammel, Lori Hollander, Beatriz Garcia-Espana,

Genetic and phenotypic traits in livestock

In healthy women 35 to 47 years of age with normal menstrual cycles, we observed statistically significant declines in levels of inhibin B; there was a greater decline in Caucasian women than in African American women.Inhibin B may play an important role in explaining the endocrinology of perimenopause. Several groups, using a variety of study designs, have identified a decline in inhibin B levels in the perimenopause, which appears to correlate with the increase of FSH and may predate changes in E2 (1Soules M.R. Battaglia D.E. Klein N.A. Inhibin and reproductive aging in women.Maturitas. 1998; 30: 193-204Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 2Burger H.G. Cahir N. Robertson D.M. Groome N.P. Dudley E. Green A. et al.Serum inhibins A and B fall differentially as FSH rises in perimenopausal women.Clin Endocrinol. 1998; 48: 809-813Crossref PubMed Scopus (165) Google Scholar, 3Burger H.G. Dudley E.C. Hopper J.L. Groome N. Guthrie J.R. Green A. et al.Prospectively measured levels of serum follicle-stimulating hormone, estradiol, and the dimeric inhibins during the menopausal transition in a population-based cohort of women.J Clin Endocrinol Metab. 1999; 84: 4025-4030Crossref PubMed Scopus (351) Google Scholar, 4Seifer D.B. Scott R.T. Bergh P.A. Abrogast L.K. Friedman C.I. Mack C.K. et al.Women with declining ovarian reserve may demonstrate a decrease in day 3 serum inhibin B before a rise in day 3 follicle-stimulating hormone.Fertil Steril. 1999; 72: 63-65Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 5Reame N.E. Wyman T.L. Phillips D.J. De Kretser D.M. Padmanabhan V. Net increase in stimulatory input resulting from a decrease in inhibin B and an increase in activin A may contribute in part to the rise in follicular phase follicle-stimulating hormone of aging cycling women.J Clin Endocrinol Metab. 1998; 83: 3302-3307Crossref PubMed Scopus (120) Google Scholar, 6Ala-Fossi S.L. Maenpaa J. Blauer M. Aine R. Tuohimaa P. Punnonen R. Inhibin A and B in peri- and postmenopause.Maturitas. 1998; 30: 273-281Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 7Lahlou N. Chabbert-Buffet N. Christin-Maitre S. Le Nestour E. Roger M. Bouchard P. Main inhibitor of follicle stimulating hormone in the luteal-follicular transition inhibin A, oestradiol, or inhibin B?.Human Reprod. 1999; 14: 1190-1193Crossref PubMed Scopus (63) Google Scholar, 8Muttukrishna S. Child T. Lockwood G.M. Groome N.P. Barlow D.H. Ledger W.L. Serum concentrations of dimeric inhibins, activin A, gonadotrophins and ovarian steroids during the menstrual cycle in older women.Human Reprod. 2000; 15: 549-556Crossref PubMed Scopus (75) Google Scholar, 9Eldar-Geva T. Robertson D.M. Cahir N. Groome N. Gabbe M.P. MacLachlan V. et al.Relationship between serum inhibin A and B and ovarian follicle development after a daily fixed dose administration of recombinant follicle-stimulating hormone.J Clin Endocrinol Metab. 2000; 85: 607-613Crossref PubMed Scopus (63) Google Scholar, 10Danforth D.R. Arbogast L.K. Mroueh J. Kim M.H. Kennard E.A. Seifer D.B. et al.Dimeric inhibin a direct marker of ovarian aging.Fertil Steril. 1998; 70: 119-123Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 11Welt C.K. McNicholl D.J. Taylor A.E. Hall J.E. Female reproductive aging is marked by decreased secretion of dimeric inhibin.J Clin Endocrinol Metab. 1999; 84: 105-111Crossref PubMed Scopus (312) Google Scholar, 12Klein N.A. Illingworth P.J. Groome N.P. McNeilly A.S. Battaglia D.E. Soules M.R. Decreased inhibin B secretion is associated with the monotropic rise of FSH in older, ovulatory women a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles.J Clin Endocrinol Metab. 1996; 81: 2742-2745Crossref PubMed Scopus (341) Google Scholar).The purpose of this study was to measure longitudinal changes in inhibin B levels in Caucasian and African American women in their late reproductive years before the onset of menstrual cycle irregularities.The subjects (n = 17) were from a National Institutes of Health-funded longitudinal, population-based study of women 35–47 years with regular menstrual cycles. The original sample and study methods have been described in detail (13Grisso J.A. Freeman E.W. Maurin E. Garcia-Espana B. Berlin J.A. Racial differences in menopause information and the experience of hot flashes.J Gen Intern Med. 1999; 14: 98-103Crossref PubMed Scopus (83) Google Scholar, 14Freeman E.W. Sammel M.D. Grisso J.A. Battistini M. Garcia-Espagna B. Hollander L. Hot flashes in the late reproductive years risk factors for African American and Caucasian women.J Women’s Health & Gender-Based Med. 2001; 10: 67-75Crossref PubMed Scopus (143) Google Scholar). Data collection involved in-person interviews and blood samples obtained between days 2 and 6 of the menstrual cycle (mean [SD] 3.9 [1.3 days]). Data collection was repeated eight times over a 2-year period at predetermined intervals, including paired samples at the beginning of two consecutive menses (approximately 1 month apart on four different occasions). The sample selected for this pilot study included eight African American and nine Caucasian women. None of the subjects were obese (body mass index [BMI] >30).Data analysis included comparisons of changes over time of inhibin B by race and by age categories (bivariate analyses). Longitudinal data were analyzed with random intercept linear regression models, which assume that inhibin B levels were correlated equally across assessments within each subject. Standard errors for the geometric mean of inhibin (Fig. 1) were computed using a bootstrap resampling of the data. The number of resamples used was 5,000 (15Davison AC, Hinkley DV. Bootstrap methods and their application. New York: Cambridge University Press, 1997;16–18.Google Scholar). The study was approved by the Institutional Review Board at the University of Pennsylvania.Dimeric inhibin B was measured in serum by Dr. Patric Sluss at the Massachusetts General Hospital using a sensitive, two-site nonisotopic immunoassay (Serotec). The intra- and interassay coefficients were <8% and 30). Data analysis included comparisons of changes over time of inhibin B by race and by age categories (bivariate analyses). Longitudinal data were analyzed with random intercept linear regression models, which assume that inhibin B levels were correlated equally across assessments within each subject. Standard errors for the geometric mean of inhibin (Fig. 1) were computed using a bootstrap resampling of the data. The number of resamples used was 5,000 (15Davison AC, Hinkley DV. Bootstrap methods and their application. New York: Cambridge University Press, 1997;16–18.Google Scholar). The study was approved by the Institutional Review Board at the University of Pennsylvania. Dimeric inhibin B was measured in serum by Dr. Patric Sluss at the Massachusetts General Hospital using a sensitive, two-site nonisotopic immunoassay (Serotec). The intra- and interassay coefficients were <8% and <20%, respectively; the range was 50–500 pg/mL; the sensitivity was 15 pg/mL. The FSH was measured by radioimmunoassay using Coat-A-Count commercial kits (Diagnostic Products, Los Angeles, CA). The interassay and intraassay coefficients of variation from the assayed samples were 7.4% and 11.1%, respectively. Inhibin B levels declined significantly over the 2-year period in the total sample. The rate of change in inhibin B differed markedly by race (P=.002), with Caucasian women experiencing the greater decline (Fig. 1). The difference in the rate of decline by race persisted after adjustment for age and FSH levels at baseline. There also was a trend for a greater decline in inhibin B in women in the older compared with the younger age category, although the results were not statistically significant (P=.06). Inspection of the data showed little change in inhibin B levels in the four subjects aged 35–39 years at baseline and decreasing levels for women 40 years and older at baseline. The FSH levels increased significantly overall (P=.006). However, the actual values of FSH did not reach levels considered to be indicative of perimenopause. Average levels increased (SD) from 7.32 ± 2.4 at baseline to 10.5 ± 7.9 at 26 months. Of note, the rates of change in FSH levels did not differ by baseline values of FSH, age, or race. The results of this study showed that inhibin B levels declined markedly over time in a sample of women with normal menstrual cycles who were aged 35–47 years at baseline. These data may support the hypothesis that inhibin B is the earliest marker of the decline in follicle number across reproductive aging (10Danforth D.R. Arbogast L.K. Mroueh J. Kim M.H. Kennard E.A. Seifer D.B. et al.Dimeric inhibin a direct marker of ovarian aging.Fertil Steril. 1998; 70: 119-123Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 11Welt C.K. McNicholl D.J. Taylor A.E. Hall J.E. Female reproductive aging is marked by decreased secretion of dimeric inhibin.J Clin Endocrinol Metab. 1999; 84: 105-111Crossref PubMed Scopus (312) Google Scholar, 12Klein N.A. Illingworth P.J. Groome N.P. McNeilly A.S. Battaglia D.E. Soules M.R. Decreased inhibin B secretion is associated with the monotropic rise of FSH in older, ovulatory women a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles.J Clin Endocrinol Metab. 1996; 81: 2742-2745Crossref PubMed Scopus (341) Google Scholar). To the best of our knowledge, this represents the first comparison of hormonal changes by race among women in the late reproductive years. The significant racial difference in the rate of decline of inhibin B remained after adjusting for age and FSH levels. Further longitudinal follow-up will be essential to evaluate whether the patterns of change persist. If so, it could mean that African American women may respond better to IVF than Caucasian women because of a greater follicle number. Inhibin B levels have been shown to be correlated with success in achieving pregnancy in women with infertility (4Seifer D.B. Scott R.T. Bergh P.A. Abrogast L.K. Friedman C.I. Mack C.K. et al.Women with declining ovarian reserve may demonstrate a decrease in day 3 serum inhibin B before a rise in day 3 follicle-stimulating hormone.Fertil Steril. 1999; 72: 63-65Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). Although FSH levels increased over time, the magnitude of the increase would not be considered clinically significant. This finding adds to the growing evidence that the traditional clinical evaluation of a single FSH level to assess a woman’s menopausal status may be inadequate to reflect the dynamic process of ovarian aging (16Rubinow D.R. Schmidt P.J. Roca C.A. Hormone measures in reproductive endocrine-related mood disorders diagnostic issues.Psychopharm Bull. 1998; 34: 289-290PubMed Google Scholar, 17Schmidt P.J. Gindoff P.R. Baron D.A. Rubinow D.R. Basal and stimulated gonadotropin levels in the perimenopause.Am J Obstet Gyn. 1996; 175: 643-650Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). There are several limitations to this pilot study design. The sample size was small and the power of the study was not sufficient to detect subtle changes in subgroups defined by age. Nonetheless, the study size was adequate to demonstrate statistically significant differences in inhibin B and FSH levels over time and a marked difference in inhibin B levels by race. This sample was restricted to women who were not overweight and thus, the results cannot be generalized to obese women. Unique aspects of this study include the standardized and precise timing of obtaining blood samples within days 2–6 of the menstrual cycle, the multiple determinations of hormone assessments over time, and the population-based recruitment of healthy women without fertility problems or other potential sources of bias. In summary, in a population sample of women in their late reproductive years, we observed a significant decline in levels in inhibin B. The rate of decline in inhibin B differed markedly by race, with a greater decline in Caucasian compared with African American women. Further longitudinal study of this cohort will determine whether the decrease in inhibin B levels is correlated with the length of time to cessation of menses and whether different racial patterns in ovarian aging are maintained in the perimenopause transition. The authors dedicate this manuscript to the memory of Dr. Michelle Battistini.