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Original Studies |
Prince Henry’s Institute of Medical Research (H.G.B.), Monash Medical Centre, Victoria 3168, Australia; The Office for Gender and Health (E.C.D., J.R.G., L.D.) and Department of General Practice and Public Health (J.L.H.), The University of Melbourne, Melbourne 3050, Australia; Oxford Brookes University (N.G.), Oxford OX3 OBP, United Kingdom; and Queensland Institute of Medical Research (A.G.), Brisbane 4029, Queensland
Address correspondence and requests for reprints to: Prof. H.G. Burger, Prince Henry’s Institute of Medical Research, Level 4, Block E, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail: henry.burger{at}med.monash.edu.au
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In this study, we present hormonal measurements from an ongoing longitudinal study of a population-based cohort of women aged 45–55 yr and pre- or perimenopausal at baseline, whose experience of the menopausal transition and menopause is being recorded annually (3). Most of the blood samples drawn from cycling women were taken during the early part of the follicular phase. Because the dates of final menses have been identified prospectively, this study provides the first comprehensive description of the concomitant natural history of FSH, E2, and the dimeric INH in relation to final menses.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Date of menopause
At each interview, women were asked to complete a menstrual calendar recording dates of menstrual bleeding between interviews. At each follow-up interview, the menstrual calendar was collected and used to verify the date of her last menstrual period. A woman was deemed to have completed the menopausal transition and to be "postmenopausal" once she had reported absence of menses for 12 or more months. Thus, for this group of women, the date of the final menstrual period (FMP) was defined.
Hormonal assays
Fasting blood samples were drawn between the 4th and 8th days of the menstrual cycle or after 3 months of amenorrhoea. This protocol was achieved in 91% of samples. Serum FSH and E2 were measured as described previously (3). Dimeric INHA and INHB were measured by specific ELISA, as specified by the authors (7, 8). INHA was measured in terms of the First International Standard for INHA (Human Recombinant, 91/624, 30–34k; NIBSC, Potters Bar, UK), expressed in terms of its nominal vial content (5 µg). INHB standard was provided by the author (NG), the sensitivities for INHA and INHB ELISA, as determined from two SD above the mean blank value, were 10 pg/mL and 25 pg/mL, respectively. The between-plate within-assay variations for INHA and INHB ELISA were 6.4% and 7.9% (n = 6), and between-assay variations from eight assays were 12% and 19%, respectively. INH assays were undertaken in Melbourne using the stored serum from the first 5 yr of the study only. Samples below assay sensitivity were given the value of assay sensitivity: INHA = 10 pg/mL (n = 300, 63%); INHB = 25 pg/mL (n = 357, 74%); and E2 = 20 pmol/L (n = 232, 29%).
Study sample
The present study is based on those 150 women who had experienced a natural menopause during the 6 years of follow-up, whose date of FMP was defined, and who provided at least one blood sample during follow-up. Excluded were women who experienced a surgical menopause through hysterectomy, bilateral oophorectomy, endometrial or iatrogenic ablation; and women who took hormone therapy before the cessation of menses. In total, 795 blood samples were taken (average, 5.3 per woman). Two thirds of women contributed a complete set of six blood samples, whereas one third contributed, on average, 3.9 samples due to either dropout from the study or refusal to give blood.
Statistical analysis
The women experienced menopause at varying times in the 6 years
of follow-up. By aligning each measurement from a woman according to
the date of her FMP, we were able to summarize the accumulated hormone
data over a 9-yr time-scale (from 4 yr before through to 5 yr after the
FMP). Geometric means were calculated for the following 6-month
groupings: all samples obtained within 3 months on either side of the
FMP were grouped and referred to as the time 0 samples. Samples
obtained between 3 and 9 months on each side of the FMP were pooled and
referred to as either 6 months before or 6 months after final menses,
respectively. The other samples were pooled and grouped similarly in
6-month intervals, extending to 4 yr before and 5 yr after final
menses. The numbers of samples analyzed at each time point are shown in
Table 1
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The longitudinal data were analyzed as repeated measures ordered
by time (t), either as chronological age or as time relative to FMP,
taking into account any correlation between successive observations
within individuals. Log transformation of FSH and
E2 values was performed before analysis to ensure
that the distributions of the residuals (observed values-fitted values)
were close to normal. Nonlinear mixed effects analyses were used to
model the means of the log-transformed hormone levels, µ, as a
function of time, t (measured in years), according to the equation
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is the approximate time of maximum rate of
change, h1 is the maximum mean,
h is the mean at time of maximum change, and
0 and 1 are
parameters representing rates of change (9, 10, 11). This function was
shown to provide a good description of the changing hormonal levels.
The regression coefficients ß1 and
ß2 represent the linear effects of age and body
mass index (BMI), respectively, when adjusting for time. When both age
and BMI were found to be statistically significant, their interaction
was tested by the addition of the term ß3 (age.
BMI) into the equation. The correlation between repeated measures,
adjusted for time and possibly age and BMI, was estimated as a function
of the absolute time between repeated measures,
tj-tk , where
tj and tk represent the
times of measures, and is a measure of the "tracking" of levels in
an individual about the fitted mean. Tracking refers to the extent to
which individuals above (below) the mean for their age or time relative
to FMP and BMI, remain above (below) the mean as time progresses. The
models were fitted by restricted maximum likelihood using an iterative
procedure, assuming normal error structure (12). Analyses were carried
out in SAS (SAS Institute Inc., Cary, NC) (13), using the macro
NLINMIX. Because a large proportion of the INHA and INHB data were below the level of sensitivity, means only are presented, with the values below the threshold presumed to take the value of the threshold.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Geometric means for FSH, E2, and the dimeric INH
at 6-month intervals around the FMP are shown in Fig. 1. For INHA and INHB assays, the
percentage of samples that fell at or below the level of sensitivity
was calculated and shown in parentheses in Fig. 1b.
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5-fold over 3 yr, from 17.5 (13.5–22.5) at
-11/2 yr, to 48.4 (39.0–60.1) at the time of FMP, and to
100.5 (91.1–110.8) at +11/2 yr.
Mean E2 levels were characterized by large
variability in the premenopausal years, as shown in Fig. 2. Mean E2 levels
were 287(142–581) pmol/L at 4 yr and fell by 60% to 113 (83–155)
pmol/L at the time of the FMP and to 35 (29–41) at +11/2 yr.
Between +2 and +5 years mean E2 levels approached
the sensitivity level for the assay (20 pmol/l).
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50% to 13.5 (11.7–15.4) ng/L at the time of
the FMP, with a minor fall thereafter. The proportion of values
undetectable 6 months after FMP was 68%, and this rose to 94% by 4
years after FMP. Mean levels of INHB were 48.9 (33.1–72.4) ng/L at
21/2 yr before FMP, and fell by 40% to 28.5 (26.4–30.8) at
6 months after FMP. INHB averaged 35.2 (29.5–42.0) ng/L at the time of
the FMP. The majority of INHB samples (83%) were undetectable at 6
months after the FMP, and this rose to 100% by +31/2 yr. Log FSH was negatively correlated with the other hormones: logE2 (r = -0.73), logINHA (r = -0.41), and logINHB (r = -0.36). Log(E2) was positively correlated with logINHA (r = 0.45) and logINHB (r = 0.39); all P < 0.001.
Modeling of FSH and E2
When log(FSH) was modeled as a function of age, the fitted curve
was increasing almost linearly from age 46–54 and then flattened
abruptly to be a constant from about age 56 onward. The effect of BMI
was significant; ßBMI = -0.015, s.e =
0.006, P < 0.01. The model for mean log (FSH)
vs. age is shown in Fig. 2a
, with separate curves drawn for
varying levels of BMI (20, 25, and 30 kg/m2). The
correlation between the residuals were about 0.6 for measures one year
apart, 0.4 for those two years apart, and plateaued at 0.3 for those 3
or more years apart.
Log(FSH) was similarly modeled as a function of time relative to
FMP. The nonlinear equations provided a good fit to the means for years
before and after the FMP. In the best fitting model for log(FSH), BMI
had a significant effect (ßBMI = -0.022,
s.e = 0.004, P < 0.0001), such that the greater
the BMI, the lower the level of serum FSH; age also had a significant
effect (ßage = 0.034, s.e = 0.011,
P < 0.01). The rate of increase in FSH reached a
maximum at approximately -0.85 (s.e = 0.45) yr, or 10 months,
before the FMP. Mean values stabilized by about 2 yr after the FMP. The
best fitting model for mean log(FSH) is shown in Fig. 2, b and c, with
separate curves drawn for varying levels of BMI (20, 25, and 30
kg/m2) and varying ages (45, 50, and 55 yr); the
corresponding parameter estimates are shown in Table 2. The vertical displacement of these
lines illustrates the small (although statistically significant)
effects of BMI and age on mean FSH when compared with the change across
the period under observation and the overall variation. The
correlations between the residuals were modest and significantly
greater than zero; they decreased from 0.4 for measures 1 yr apart, to
0.3 for those 2 yr apart, to 0.2 for those 3 yr apart, and plateaued at
0.2 for those 4 or 5 yr apart.
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. The effect of BMI was not significant
(ßBMI = 0.004, s.e = 0.008,
P = 0.6). The correlation between the residuals were
about 0.4 for measures 1 yr apart, 0.2 for those 2 yr apart, and
plateaued at 0.1 for those 3 or more years apart.
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, and corresponding parameter estimates are shown in Table 2.
There was an independent age effect (ßage =
-0.085, s.e = 0.016, P < 0.0001), but no
independent BMI effect (ßBMI = 0.007, s.e
= 0.007, P = 0.3). The maximum rate of change was
estimated to occur at about the time of FMP. Again the three separate
fitted curves are drawn at varying ages (45, 50, and 55 yr),
illustrating a strong age effect. The correlations between the
residuals were weak, being 0.2 for measures 1 yr apart, 0.1 for those 2
yr apart, and negligible for those 3 or more years apart. Calculations were made of the specificity and sensitivity of FSH and E2 measurements as markers of menopausal status. This was done by calculating for the overall data set, the level of serum FSH and of serum E2 at the intersection of their fitted longitudinal curves with the date of final menses (107.9 IU/L and 88.5 pmol/L, respectively. The specificity was the percentage of premenopausal women whose values were below this level for FSH, above for E2, and the sensitivity was the percentage of postmenopausal women above this level for FSH, below for E2. The sensitivity of FSH and E2 was 85% and 84%, respectively, and the specificity was 76% and 67%, respectively.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We demonstrated that analysis as a function of age gives a misleading
impression. For example, although the average FSH level increases
exponentially from age 46 to 54, this is not the experience of a
typical woman. As shown in Fig. 2, the FSH profile will depend strongly
on the timing of the woman’s last menstrual period and, to a lesser
extent, on her age and BMI. Similar comments apply to
E2.
Our analysis has shown that the level of tracking with age is moderately strong for FSH and less for E2. The correlation between log (FSH) levels 1 yr apart was about 0.6. Even log(FSH) measures taken 5 yr apart were correlated, after adjusting for age. These correlations are reduced somewhat by adjusting instead for time since FMP, indicating that much of the tracking of hormone levels with age as a woman passes through the menopausal transition, is explained by the actual timing of her FMP. Similarly for E2, the age-adjusted and time since FMP-adjusted values were correlated over time. Also, the estimated effect of BMI on mean FSH levels was greater, and measured with more precision, once the time scale was adjusted for the FMP.
The variability in serum E2 levels is likely to be due to a substantial extent to the variability both within and between subjects, in the day of the follicular phase on which the single blood samples were obtained (between days 4 and 8). Whereas in young women of reproductive age levels of serum E2 are generally stable during this part of the follicular phase, the latter is known to shorten as menopause approaches. It is, thus, likely that samples particularly those taken after days 5 or 6, may reflect the rising levels of E2 as midcycle approaches in such older women. The logistics of the study made it impossible to confine sampling to days 3 or 4 of the cycle which might have been expected to lessen the degree of variability.
Although changes at the level of the hypothalamo-pituitary axis have been described in relation to and after the menopause (14, 15), the marked decline in follicle number (2) suggests that the major explanation for the hormonal changes lies within the ovary. Because both the sex steroids and the INH are products of the granulosa cells lining ovarian follicles, the disappearance of follicles from the ovary would be expected to be manifest in declining abilities to secrete the steroids and the INH, as, indeed, is evident in the present study.
As had been found in previous studies (4, 5), serum FSH levels rise progressively before final menses and continue to rise for the first 2 to 4 years after the menopause itself. Average levels of estradiol in the early follicular phase are maintained (albeit rather erratically) as women approach the final menses, and it is only in the year or so before final menses that levels fall substantially. Recent studies have suggested that estrogen levels may be, if anything, higher in women during the start of the menopausal transition than in their earlier reproductive years (16, 17).
No previous studies have reported changes in the dimeric INH in relation to the menopause in a longitudinal study design. Two recent cross-sectional studies (18, 19) have described INHA, INHB, and FSH levels in younger and older cycling women and shown inverse relationships, particularly between INHB and FSH. Nevertheless, neither study examined the menopausal transition. Our study has shown that mean levels of both INHA and INHB fall substantially before the final menses, the major falls in INHA being observed in the last 18 months before final menses and INHB over a somewhat longer period. Current interpretations of the sources of INHA and INHB are in accord with the concept that INHA is primarily a secretory product of the dominant follicle and the corpus luteum and INHB of small antral follicles in the recruited cohort (8). INHB levels may be regarded as indicating the size of that recruited cohort. Whether it is falling levels of INHB, which account for the progressive though small rise in FSH with increasing age in regularly cycling women, is the subject of a current study in our laboratories. Preliminary evidence for this possibility has been obtained in a study where serum INHB levels were significantly lower in a group of older regularly cycling women selected to have raised early follicular phase serum FSH levels, in comparison with a control group of young women with levels of serum FSH in the normal young range (20), and more recent evidence was cited above (18, 19).
Previous investigations of levels of mRNA for the INH subunits are
consistent with the above interpretations (21). Thus, 
subunit is
found in both the dominant follicle and in other members of the
recruited cohort. ßA subunit levels are confined largely to the
granulosa cells of the dominant follicle and are subsequently
demonstrable in the corpus luteum, whereas ßB levels are
characteristically found in antral follicles, but not in the granulosa
cells of the dominant follicle.
On the basis of these findings and interpretations, we postulate that the falling levels of INHA as final menses approaches are due to the fact that a progressively larger proportion of menstrual cycles at this time are anovulatory, with failure of development of the dominant follicle. Hence, it is hypothesized that it is only those women who continue to ovulate close to the time of final menses who would be contributing significant INHA levels to the population mean. In contrast, it is hypothesized that the steeply declining follicle numbers would be contributing to the falling INHB levels, and the observation that a higher percentage of INHB measurements are undetectable compared with INHA would be consistent with the probability that a substantial number of women have few, if any, follicles remaining at the time of final menses.
It should be emphasized that the present study provides no data about the prevalence of anovulatory cycles in the population studied. For the reasons of wishing to keep at a minimum the invasive aspects of our prospective longitudinal study of the menopausal transition, and also for consideration of feasibility and cost, data to substantiate the presence or otherwise of ovulation were not collected.
In summary, this study confirms previous observations that there is no
clear-cut biological marker of the menopause or FMP. Levels of FSH rise
progressively at the time when final menses are experienced, whereas
levels of E2 and the dimeric INH fall. The
falling concentrations both of E2 and of the INH
are likely to contribute to the rising levels of FSH. The substantial
individual variation, as evidenced by Figs. 2 and 3, and the modest to
weak tracking of individual levels, provides further strong evidence to
support the previous proposals that the interpretation of isolated
hormonal measurements in women during the menopausal transition cannot
be used reliably to define their reproductive status on an individual
basis.
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Acknowledgments |
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Footnotes |
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Received March 8, 1999.
Revised July 22, 1999.
Accepted July 30, 1999.
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References |
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J. F. Randolph Jr., M. Sowers, I. V. Bondarenko, S. D. Harlow, J. L. Luborsky, and R. J. Little Change in Estradiol and Follicle-Stimulating Hormone across the Early Menopausal Transition: Effects of Ethnicity and Age J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1555 - 1561. [Abstract] [Full Text] [PDF]
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K. Halmesmaki, R. Hurskainen, A. Tiitinen, J. Teperi, S. Grenman, A. Kivela, E. Kujansuu, M. Yliskoski, and J. Paavonen A randomized controlled trial of hysterectomy or levonorgestrel-releasing intrauterine system in the treatment of menorrhagia--effect on FSH levels and menopausal symptoms Hum. Reprod., February 1, 2004; 19(2): 378 - 382. [Abstract] [Full Text] [PDF]
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N. Santoro, B. Isaac, G. Neal-Perry, T. Adel, L. Weingart, A. Nussbaum, S. Thakur, H. Jinnai, N. Khosla, and D. Barad Impaired Folliculogenesis and Ovulation in Older Reproductive Aged Women J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5502 - 5509. [Abstract] [Full Text] [PDF]
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