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The Journal of Clinical Endocrinology & Metabolism 89(10):4910 – 4915
Copyright © 2004 by The Endocrine Society
doi: 10.1210/jc.2003-031731
Origins and Consequences of the Elongation of the
Human Menstrual Cycle during the Menopausal
Transition: The FREEDOM Study
F. MIRO, S. W. PARKER, L. J. ASPINALL, J. COLEY, P. W. PERRY,
AND
J. E. ELLIS
Unipath Ltd. (F.M., J.C., P.W.P., J.E.E.), Bedford, United Kingdom MK44 3UP; Unilever Research Colworth (L.J.A.),
Bedford, United Kingdom MK44 1LQ; and Parkwood Clinic (S.W.P.), Bournemouth, United Kingdom BH7 7DW
The menopausal transition is characterized by the appearance of elongated cycles, which become longer and more frequent as menopause approaches. Several endocrine abnormalities have been attributed to these cycles; however, no
quantitative studies of their causes and consequences exist to
date. This study is based on sequential daily urinary concentrations of FSH, LH, estrone 3-glucuronide (E1G), and pregnanediol 3-glucuronide (PdG) from 34 women with perimenopausal menstrual irregularity (total of 289 cycles). The timing
of ovarian response was determined as the day of E1G take-off
(ETO). Other parameters measured were the mean FSH concentration before ETO (FSHETO) and the midluteal levels of
T
HE VARIATION IN the length of the menstrual cycle
throughout life has been extensively investigated
(1– 6). The most visible event associated with menopausal
transition is the appearance of menstrual irregularity (7, 8).
This irregularity results mostly from the appearance of
longer cycles interspersed with cycles of normal duration
or even shorter. Initially, these cycles are sporadic and not
very extended, but as menopause approaches, both the
frequency and length of the elongated cycles increase (2,
4 – 6, 9, 10).
Due to its complexity, there are substantial difficulties in
investigating the endocrinology of the menopausal transition. A few studies, however, have revealed some important
features. Remarkably, the first half of these cycles is characterized by intervals with a substantial rise in circulating
levels of FSH, with minimal estradiol production or inhibin
(11, 12). Also, during the luteal phase, progesterone levels are
generally lower, and often there is no significant rise.
Studies based on measurements of urinary hormones have
shown results similar to those for serum. These studies have
established the usefulness of analysis of urinary hormones in
the study of the menstrual cycle and have focused attention
on other abnormalities in these elongated cycles, with potentially significant health consequences, such as the existence of an increased estrogen to pregnanediol ratio during
the luteal phase (13–16).
Abbreviations: CV, Coefficient of variation; E1G, estrone 3-glucuronide; ETO, E1G take-off; FSHETO, FSH levels before ETO; PdG, pregnanediol 3-glucuronide.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
PdG, E1G, and LH. There was a strong parallelism between
ETO and cycle length variability. FSHETO levels increased
gradually with ETO. Both ETO and FSHETO were inversely
related to luteal PdG and directly related to E1G. PdG and LH
levels were inversely related. All comparisons were highly
significant (P < 0.0001). We conclude that delayed ovarian
response underlies the elongation of the menstrual cycle in
the menopausal transition, which is likely to be caused by a
temporary lack of ovarian responsiveness to FSH. A progressive decline in luteal PdG with increased E1G occurs in association with these trends. (J Clin Endocrinol Metab 89:
4910 – 4915, 2004)
Although the work performed to date provides important
clues for understanding the endocrinology of the menopausal transition, it is limited to the description of hormonal
patterns in a handful of cycles. To determine general trends
of the origin, consequences, and progression of the menopausal transition, relatively large quantitative studies are
required.
Thus, we undertook this study with the objective of determining 1) the relevance of the timing in ovarian response
to the elongation of the menstrual cycle during the menopausal transition, 2) whether the changes in ovarian response
are due to insufficient stimulus from the pituitary or temporary impeded responsiveness from the ovary, and 3) the
consequences of the elongation of the cycle to steroid profiles
during the luteal phase. To achieve this, we examined profiles of four major reproductive urinary hormones, FSH, LH,
estrone 3-glucuronide (E1G), and pregnanediol 3-glucuronide (PdG), over several menstrual cycles in 34 women with
perimenopausal menstrual irregularity. The main parameters investigated were the onset of ovarian response during
the follicular phase, the variation in FSH production before
the onset of ovarian response, and midluteal levels of PdG,
E1G, and LH.
Subjects and Methods
Subjects
The data presented here are part of the FREEDOM study, which
included a population of 112 healthy Caucasian women recruited in
response to advertisements. Volunteers were selected by interview and
were assigned to one of four preliminary clinical groups (fertile, premenopausal, perimenopausal, and postmenopausal) on the basis of
menstrual history, vasomotor symptoms, and other symptoms, such as
premenstrual changes. Exclusion criteria were the use of hormonal con-
4910
Miro et al. • Cycle Changes in Menopausal Transition
traception or hormone replacement therapy during the trial or in the 6
months before study entry, pregnancy, breastfeeding, hysterectomy, or
a past history of diagnosed pituitary disorder. Also excluded were
women taking any medication known to interfere with the secretion and
action of reproductive hormones. Each volunteer provided urine samples for a period of 6 –18 months.
The present study is based on data from 34 women with perimenopausal menstrual irregularity, Stages of Reproductive Aging Workshop
stages ⫺2 to ⫺1 (17). Ages ranged from 40 –53 yr, with a median body
mass index of 25.
The study was performed in accordance with current guidelines on
good practice in clinical research and the Declaration of Helsinki. Ethical
approval for the study was obtained from the Unilever Research Laboratory Colworth and the east Dorset local medical research ethical
committees. Informed, written consent was obtained from all volunteers.
Hormonal analyses
Each volunteer provided daily urine samples (first morning void),
which were collected in universal containers with sodium azide as
preservative (0.1%). Volunteers were asked to keep the samples at 4 C
until delivery to the laboratory (on a weekly basis). At arrival, the
specimens were aliquoted and stored at 4 C until analyzed. All samples
were analyzed within 3 months of arrival at the laboratory. Stability
studies carried out in our laboratory show no significant loss of immunoactivity in the samples for any of the hormones measured for at least
1 yr.
Each sample was analyzed for FSH, LH, estrone 3-glucuronide (E1G),
and pregnanediol 3-glucuronide (PdG). The assays were carried out by
immunoassay, using AutoDelfia (Perkin-Elmer Life Sciences, Cambridge, UK) with highly specific in-house developed antibodies and
following in-house established and validated protocols (18).
The sensitivity of the FSH assay was 0.17 IU/liter. The intraassay
coefficients of variation (CVs) were 5.1%, 2.4%, and 1.8% for concentrations of 1.8, 8.2, and 42.9 IU/liter, respectively, whereas the interassay
CVs at the same concentrations were 4.0%, 3.4%, and 2.4%. The sensitivity of the LH assay was 0.09 IU/liter. The intraassay CVs were 6.4%,
3.6%, and 2.0% for concentrations of 2.3, 10.6, and 51.6 IU/liter, respectively, whereas the interassay CVs at the same concentrations were
10.0%, 4.8%, and 1.6%, respectively. The sensitivity of the E1G assay was
0.21 nm. The intraassay CVs were 5.1%, 2.5%, and 2.2% for concentrations of 3.4, 17.1, and 85.4 nm, whereas the interassay CVs were 4.2%,
2.6%, and 2.7%, respectively. The sensitivity of the PdG assay was 0.14
␮m. The intraassay CVs were 15.6%, 7.8%, and 7.7% for concentrations
of 1.6, 8.1, and 40 ␮m, whereas the interassay CVs were 6.6%, 1.6%, and
4.9%, respectively.
Data preparation and analyses
When all hormonal measurements were completed, we developed
graphic profiles for all hormones, adjusted, and smoothed. The statistical
approach used to smooth and adjust the profiles was based on the
obtained PdG curve. Briefly, a smooth curve was fitted to ln(PdG), and
the residuals were used to adjust the other hormones. This was achieved
using the SAS/IML Splinec routine with a smoothing parameter of 10
(19). This retrospective approach was found to have equivalent effects
to creatinine adjustment (19a). FSH and LH results are expressed as
international units per liter, E1G as nanograms per milliliter, and PdG
as micrograms per milliliter.
Parameters investigated
Cycle length. Cycle length was considered the length of the interval
between two consecutive menstrual bleeding episodes, with d 1 as the
first day of menstrual bleeding. Spotting was identified from diary
entries; it was sporadic and usually occurring on the days after menstrual bleeding. Midcycle bleeding was distinguished in retrospective
from d 1 bleeding, because it was unrelated to a drop in PdG or E1G
levels. There were 13 episodes of midcycle bleeding, six of them associated with high levels of FSH and low E1G and PdG levels, five in the
presence of increasing E1G levels; there was an episode of bleeding 2 d
after a real menstrual period; and finally, there was a case with 2 d of
bleeding 3 d after an LH peak.
J Clin Endocrinol Metab, October 2004, 89(10):4910 – 4915 4911
Day of E1G take-off (ETO). ETO was used to estimate the timing of the
ovarian response. It indicates the time taken from d 1 of the cycle to
the start of the first sustained rise in E1G and is estimated through the
application of an algorithm, as described previously (18). Briefly, the
algorithm was applied to smoothed-adjusted values of E1G throughout
the menstrual cycle and measured the magnitude of the increase in E1G
for each day in the cycle with a positive slope, excluding the last 10 d
of the cycle.
Mean FSH levels before E1G take-off (FSHETO). This parameter was used
to determine changes in FSH secretion in relation to the onset of the
ovarian response. It is estimated as the mean value of FSH from the first
day of the cycle to ETO.
Midluteal PdG. This was the maximum value of PdG during the cycle.
Because the smoothing process produced symmetrical profiles of luteal
PdG, the maximum PdG values typically occurred at the midluteal
phase. This parameter was used to estimate the ability of the corpus
luteum to produce progesterone.
Midluteal E1G. Midluteal E1G was used to estimate estrogen production
during the luteal phase. It was determined as the value of E1G concomitant to maximum PdG.
Midluteal LH. Midluteal LH was used to estimate the levels of LH during
the luteal phase. It was determined as the value of LH on the day of
maximal PdG.
Statistical analyses
To determine the impact of delayed ETO on cycle elongation, we
divided the cycle into two intervals: 1) from the beginning of the cycle
to ETO, and 2) the rest of the cycle. For each individual, the sd for total
cycle length, ETO, and total length-ETO were calculated. The values
obtained were compared using the Sign test, contrasting the hypothesis
that ETO is the most variable interval in the cycle, and thus: sd (ETO) ⬎
sd (length of cycle ⫺ ETO).
To determine the variation in FSHETO with increasing ETO, the distribution of ETO was divided into four intervals according to quartiles,
and the adjusted mean values of FSHETO for each interval were compared. To take into account subject differences, two-way ANOVA was
used. The same approach was used to determine PdG and E1G variations in relation to ETO (as well as FSHETO), and LH in relation to PdG.
Results
Hormonal profiles from a total of 289 complete menstrual
cycles from 34 women were considered in the analysis. A
number of cycles (8% of the total) had very high basal levels
of E1G (ⱖ20 ng/ml) with considerably reduced FSH levels.
Because of the existing negative feedback between estrogens
and FSH, we excluded these cycles from the analysis of FSH.
Four other cycles were excluded because there was an abundant number of missing samples. Overall, the median number of cycles analyzed per volunteer was nine, and the median and mean length of the cycle were, respectively, 28 and
34.8 d, with a range of 167 d.
Elongated cycles
All volunteers showed at least one elongated cycle in their
profiles. These cycles were chiefly characterized by an increased duration in the period before ETO, and presented
other particular features too. The difference between this
type of cycle and the normal type is shown in Fig. 1. Cycle
1 is a case of typical duration (28 d), whereas cycle 2 is an
elongated cycle (47 d). ETO occurs considerably later in cycle
2 (d 20 vs. d 7), and FSH reaches much higher levels (FSHETO
is 14.7 IU/liter in cycle 1 and 44.31 IU/liter in cycle 2). During
the luteal phase, maximum values for PdG are lower in cycle
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J Clin Endocrinol Metab, October 2004, 89(10):4910 – 4915
Miro et al. • Cycle Changes in Menopausal Transition
FIG. 2. Distribution of the SD of the length of cycle and the interval
before ETO for each individual. Analysis by the Sign test revealed a
higher contribution of ETO in cycle SD than the complementary half
(P ⬍ 0.0001). The dashed line provides a reference for the hypothetical
situation where SD (length of cycle) ⫽ SD (ETO).
FIG. 1. Effects of the elongation of the menstrual cycle during the
menopausal transition: two menstrual cycles from a woman with
menstrual irregularity. The upper panels show FSH and LH profiles,
the lower panels E1G and PdG. Cycle 1 is a 28-d-long cycle. Cycle 2
is a 47-d-long cycle. Comparatively, the latter cycle shows delayed
E1G rise (ETO), higher FSH befor ETO, lower luteal PdG, and higher
E1G.
2 (7.7 vs. 18.7 ␮g/ml), whereas E1G levels are higher (56.3 vs.
24.4 ng/ml). The mean (⫾sd) cycle length values after ETO
were 20.95 ⫾ 4.34 for typical cycles and 27.95 ⫾ 11 for elongated cycles.
Effect of variation in day of ETO on elongation of the cycle
Application of the Sign test revealed a much higher magnitude of sd for the interval for ETO than for the rest of the
cycle (P ⬍ 0.0001), and indeed, there was a very strong
association between the sd for ETO and the total length of the
cycle (Fig. 2).
Variation in FSH in relation to delay in ovarian response
ETO distribution was divided into quartiles, and the adjusted mean FSHETO values for the intervals were compared.
A simultaneous increase in both variables was found
[F(3,252) ⫽ 47.56; P ⬍ 0.0001; Fig. 3].
Changes in midluteal PdG and E1G in parallel with
delayed ovarian response
The CV values for PdG and E1G were 79 and 49, respectively. To investigate the relationship between delayed ETO
and midluteal levels of PdG and E1G, we applied the same
approach used previously for ETO and FSHETO. In this case,
a gradual decrease in PdG levels in parallel with increasing
ETO was found [F(3, 252) ⫽ 7.05; P ⬍ 0.0001; Fig. 4A]. By
contrast, an increase in E1G was found in association with
ETO [F(3, 252) ⫽ 11.85; P ⬍ 0.0001; Fig. 4B].
Changes in midluteal PdG and E1G in parallel
with FSHETO
To investigate the variation in midluteal PdG and E1G in
relation to increasing FSHETO levels, the same approach as
that for ETO was applied. The results were comparable to
those found for ETO, with an inverse relationship between
FIG. 3. Relationship between increase in E1G take-off time (ETO)
and mean FSH over the same period (FSHETO). ETO distribution was
divided into four intervals according to the quartiles (25%:5, 50%:7,
75%:11.5). Data show adjusted means with SE bars and were analyzed
using two-way ANOVA [F(3,252) ⫽ 47.56, P ⬍ 0.0001]. The asterisk
indicates the first quartile significantly different (P ⬍ 0.05) from the
first.
FSHETO and PdG levels [F(3, 252) ⫽ 8.24; P ⬍ 0.0001] and a
direct one with E1G [F(3, 252) ⫽ 16.67; P ⬍ 0.0001; Fig. 5].
Changes in LH during the midluteal phase in relation
to PdG
To determine the nature of the PdG deficiency observed in
relation to the increased delay in ovarian response, we compared the variations in luteal PdG and LH. When the distribution of midluteal PdG values was divided into four
intervals according to its quartiles, and the adjusted mean
values of LH for each interval were compared, a marked
inverse correlation between both variables was found [F(3,
252) ⫽ 18.76; P ⬍ 0.0001; Fig. 6].
Discussion
Menstrual irregularity is the hallmark of the menopausal
transition (7, 8). Underlying this irregularity is the appearance of elongated cycles, which, as menopause approaches,
become more prevalent and more protracted (2, 4, 6, 8, 9). In
addition, these cycles appear to have unusual hormonal features (11–16). To determine the causes and implications of the
elongation of the menstrual cycle, we have carried out an
extensive quantitative study based on the hormonal profiles
of 289 menstrual cycles from 34 women in the menopausal
transition.
A prominent feature of the perimenopausal elongated cy-
Miro et al. • Cycle Changes in Menopausal Transition
J Clin Endocrinol Metab, October 2004, 89(10):4910 – 4915 4913
FIG. 4. Relationship between increase in ETO time and
midluteal levels of PdG (A) and E1G (B). ETO distribution
was divided into four interval according to the quartiles
(25%:5, 50%:7, 75%:11.5). Data show adjusted means with
SE bars and were analyzed using two-way ANOVA [for A,
F(3,252) ⫽ 7.05, P ⬍ 0.0001; for B, F(3,252) ⫽ 11.85, P ⬍
0.0001]. The asterisk indicates the first quartile significantly different (P ⬍ 0.05) from the first.
FIG. 5. Relationship between increase in FSHETO and midluteal levels of PdG (A) and E1G (B). FSHETO distribution
was divided into four intervals, according to the quartiles
(25%:6.3, 50%:10.6, 75%:19.6). Data show adjusted means
with SE bars and were analyzed using two-way ANOVA [for
A, F(3,252) ⫽ 8.24, P ⬍ 0.0001; for B, F(3,252) ⫽ 16.67, P ⬍
0.0001]. The asterisk indicates the first quartile significantly different (P ⬍ 0.05) from the first.
FIG. 6. Midluteal LH levels in relation to PdG (A) and E1G
(B). Distributions of luteal levels of PdG and E1G were
divided into four intervals according to the quartiles. Data
show adjusted means with SE bars and were analyzed using
two-way ANOVA [A, F(3,252) ⫽ 18.76, P ⬍ 0.0001; B,
F(3,252) ⫽ 17.9, P ⬍ 0.0001]. The asterisk indicates the first
quartile significantly different (P ⬍ 0.05) from the first.
cle is the existence of a lag phase in ovarian response during
the follicular phase. This feature has been described as a
prolonged hypoestrogenic phase at the beginning of the cycle
(13) or as the inactive phase of the cycle (20). To determine
the significance of this lag phase in the elongation of the
menstrual cycle, we defined the variable ETO to measure the
onset of ovarian response. The marked parallelism found
between the variability in ETO and total cycle length indicates that elongation of the menstrual cycle is fundamentally
the result of the delay in ovarian response.
A delayed ovarian response has two major causes: inadequate FSH stimulus from the pituitary, and ovarian refractoriness to FSH. Due to the nature of the pituitary-ovary
interaction, the absence of an ovarian response to FSH results
in a progressive increase in FSH; indeed, after ovariectomy,
FSH levels rise gradually over several days until reaching a
maximal value (21). Our results indicate an association between longer ETO and higher FSH levels, which is consistent
with a temporary lack of responsiveness to FSH. Elevated
FSH during the follicular phase of the elongated cycles has
been widely reported (11–13, 16, 22–25).
The origin of this temporary refractoriness of the ovary is
as yet unknown. Possible causes include an increase in the
rate of follicular atresia or a slower rate of follicular growth.
Several investigators have concluded that the human ovary
undergoes a process of accelerated follicular depletion toward the end of the fourth decade of life (26 –28). Equally, in
vitro fertilization results show a steep decline in the rate of
success at this age (29), and histological studies have described increased atresia of primordial and primary follicles
in the ovaries of women approaching the menopause (30).
Although this increase in follicular demise apparently involves early stages, it might disrupt the sequence of follicular
development, resulting in the delay in recruitment observed
in the elongated cycles.
A deficiency in luteal progesterone (or PdG) in perimenopausal elongated cycles has been noticed in a large number
of studies (12–14, 16, 31, 32). We found a gradual decline in
PdG levels with increasing ETO. Although we detected an
overall inverse relationship between FSH and PdG, there was
no clear gradual pattern allowing the inference of a causal
effect for elevated FSH in the reduction of PdG. Future work
is required to establish the origin of the reduction in PdG.
The reduction in PdG resembles luteal deficiency. Clinically, there are two recognized origins for this condition:
hypothalamic and ovarian (33–36). We observed an inverse
relationship between PdG and LH consequent with an ovarian origin for the luteal defect (33, 34). The occurrence of high
luteal LH levels during the perimenopause has been described previously (14). It remains to be determined whether
the cause of the reduced PdG is reduced cell number, deficient cell differentiation, or reduced LH responsiveness.
In contrast to PdG, midluteal E1G levels increase as ETO
gets longer and FSH higher. This was expected, because
4914
J Clin Endocrinol Metab, October 2004, 89(10):4910 – 4915
abundant research has described increased circulating (37)
and excreted (13, 16, 38, 39) luteal estrogen levels in perimenopausal elongated cycles. Because of the disparity with
PdG and the lack of an inverse relationship between luteal
LH and E1G, the excess estrogens seem to have a source
different from the corpus luteum. We found a very robust
relationship between increasing FSH and E1G. The elevated
FSH might exert a hyperstimulating effect, disturbing the
normal process of follicular development. Multicystic follicular growth with hyperestrogenism has been related to exogenous ovarian hyperstimulation (40) and FSH-secreting
adenomas (41). Moreover, multicystic follicular growth with
high concentration of estrogens (37) and persistence of follicles during the luteal phase (25) have been described in
perimenopausal women.
Additional research is required to better characterize as
well as determine the precise causes of the hormonal abnormalities in these elongated cycles. Studies designed to partially suppress FSH levels before the onset of ETO might be
useful in determining the contribution of this gonadotropin.
Equally, detailed ultrasound follow-up should provide firsthand information on follicular growth dynamics for comparison with the hormonal findings. Finally, measurement of
other hormonal markers of follicular recruitment and development, in particular inhibin B (42, 43), should bring more
accurate information on the onset of the ovarian response.
The possible relationship between perimenopausal hyperestrogenism (further aggravated by reduced progesterone) and morbidity is a matter of concern among some researchers (16, 7, 39, 44, 45). Naturally elevated estrogen levels
have been associated with thickening (46) and even cystic
glandular hyperplasia of the endometrium (37, 38). Given the
characteristics of the elongated cycles, it is paramount to
determine the real impact on health of this hormonal imbalance, particularly because nearly 47% of women experience
at least 5 yr of menopausal transition (10).
In summary, the menstrual irregularity occurring during
the menopausal transition is characterized by the occurrence
of elongated cycles. Our study indicates that this elongation
is mostly the result of a delay in the onset of ovarian response
and suggests that this delay is due to a temporary lack of
ovarian responsiveness to FSH. Concomitant with the increase in the delay in ovarian response is a clear tendency
toward reduced luteal levels of PdG and increased estrogen
levels. A link between increased and elevated FSH appears
likely; however, the origin of the reduced PdG is less clear.
Acknowledgments
Received October 2, 2003. Accepted July 3, 2004.
Address all correspondence and requests for reprints to: Dr. F. Miro,
Unipath Ltd., Priory Business Park, Bedford, United Kingdom MK44
3UP. E-mail: [email protected].
This work was presented in part at the 85th Annual Meeting of The
Endocrine Society, Philadelphia, PA, June 19, 2003, and the 17th International Federation of Gynecology and Obstetrics World Congress of
Gynecology and Obstetrics, Santiago, Chile, November 2, 2003.
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