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The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A.
Copyright © 2000 by The Endocrine Society

Rapid Maturation of the Reproductive Axis during

Perimenarche Independent of Body Composition*
RICHARD S. LEGRO, HUNG MO LIN, LAURENCE M. DEMERS, AND TOM LLOYD
Departments of Obstetrics and Gynecology (R.S.L.), Health Evaluation Sciences (H.M.L., T.L.), and
Pathology (L.M.D.), College of Medicine and University Hospitals, Pennsylvania State University and
Pennsylvania State Geisinger Health System, Milton S. Hershey Medical Center, Hershey,
Pennsylvania 17033

ABSTRACT
The development of the reproductive axis is thought to be a gradual
process, but our understanding of the complex endocrine changes that
accompany the transition from premenarche to reproductive life in
women has been hampered by the paucity of longitudinal studies. We
studied 112 premenarchal Caucasian females at 6-month intervals
over 4 yr and obtained a detailed reproductive and dietary history. We
quantified reproductive hormones in 24-h urine collections as a mea-
sure of daily output and measured body composition biometrically and
with the use of dual energy x-ray absortiometry scans. The percent
body fat did not change appreciably in the study period (range, 21–
24%) and was unrelated to menarche. Sex steroid and gonadotropin
levels changed exponentially in the year approaching menarche. FSH
levels peaked at menarche and then progressively declined thereaf-
ter. Estradiol output increased rapidly in the year approaching men-
arche and then plateaued thereafter. The frequency of menstrual
bleeding increased rapidly and plateaued at 1 yr postmenarche. At 1
yr, 65% of these adolescent women had established a pattern of 10 or
more menstrual episodes/yr, and by 3 yr postmenarche this figure
exceeded 90%. There were no significant changes in dietary intake of
protein, carbohydrate, or fat in the same period. Menarche occurs as
a result of rapid maturation of the reproductive axis and heralds the
reestablishment of a negative sex steroid feedback loop that parallels
the adult threshold. These events appear to develop independent of
changes in body composition and diet, but may reflect the improved
nutrition and socioeconomic status of the late 20th century. (J Clin
Endocrinol Metab 85: 1021–1025, 2000)

P ERIMENARCHE is as vaguely understood as perimeno-

pause, yet receives less attention (Medline textword
search in the database from 1966 to present performed No-
measurements of body composition with hormonal values.
Reaching a critical body weight with particular emphasis
placed on fat mass has been proposed as necessary for men-
vember 1, 1999 revealed 4 references to perimenarche and arche and female reproductive ability (10 –12). These studies
153 to perimenopause). The perimenarchal period has not have two major flaws: 1) they analyzed data collected at a
been thoroughly studied in healthy cohorts with regular variety of sites from 1929 –1950, a time period when the U.S.
longitudinal follow-up. The events of perimenarche have experienced significant socioeconomic change; and 2) there
been well described in cross-sectional studies (1–5), but these were no direct measurements of body fat. The researchers
studies are unable to analyze the progression of the indi- calculated the percent body fat from height and weight
vidual over time in relation to developmental milestones. To measurements.
date, the few longitudinal studies of endocrine maturation in We sought to identify the natural history of menarche in
healthy pubertal females have been limited by the lack of a large, healthy cohort of young women studied at 6-month
integrated hormone measurements, small numbers of sub- intervals from premenarche onward. Although we did not
jects, or infrequent and limited follow-up of the longitudinal directly measure hormone production, the 24-h urine col-
cohort (6 – 8). Such studies have underestimated the rate of lections offered important advantages when examining the
pubertal development and have contributed to the concept ontogeny of menarche. They are not subject to the fluctua-
that gradual maturation of the reproductive axis occurs over tions of hormonal pulsatility that are reflected in single se-
a 4- to 6-yr period after menarche (2, 9). We obtained serial rum samples (13). Quantitative measurements of excreted
24-h urine specimens and made quantitative measurements hormone in 24-h urine specimens are more representative of
of reproductive hormones and body composition to establish age-related changes in steroid and gonadotropin production
their relationship to menarche. than measurement of an isolated serum sample. Persistent
None of the previous studies have correlated accurate and quantitative increases in the output of these hormones
form the basis for female sexual maturity (14).

Received October 1, 1999. Revision received November 8, 1999. Ac-

cepted November 19, 1999.
Address all correspondence and requests for reprints to: Richard S.
Legro, M.D., Department of Obstetrics and Gynecology, Room C3608,
500 University Drive, Milton S. Hershey Medical Center, Hershey, Penn-
sylvania 17033. E-mail: rsl1@psu.edu.
* This work was supported by USPHS Grants RO1-HD-25973 (to T.L.)
and K08-HD-0118 (to R.S.L.), and General Clinical Research Center
Grant MO1-RR-10732 (to Pennsylvania State University).
Subjects and Methods
Subjects
All procedures involving human subjects were reviewed and ap-
proved by the institutional review board for clinical research studies at
the Pennsylvania State University College of Medicine (Hershey, PA).
Details of the recruitment and retention strategies and baseline anthro-
pometric, endocrine, and bone measurements have been reported (15,

1021

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1022 LEGRO ET AL. JCE & M • 2000
Vol 85 • No 3

16). In brief, the entire cohort of the Pennsylvania State Young Women’s
Health Study began in 1990 with 112 premenarchal females, with a mean
age at initiation into the study of 11.9 ⫾ 0.1 yr (mean ⫾ se). The study
originally started as a randomized trial of calcium supplementation to
examine the effects of calcium on bone mass accretion. The initial pos-
itive effect of calcium supplementation on bone accretion in this cohort
disappeared over time as hormonal factors became dominant (17). At the
baseline visit, 48% were randomized to calcium, and this remained
around 50% for each subsequent visit (see also Table 1).
The study group represents a Caucasian female adolescent popula-
tion of European ancestry attending public school in central Pennsyl-
vania. All study participants were seen and examined at 6-month in-
tervals throughout the study. The average relative difference between
actual and target visit dates was 1.5%. The physical characteristics of the
study groups were similar to appropriate age-matched national nor-
mative values (18, 19).
Methods
The date of menarche and the frequency of menstrual bleeding were
based on interviews and questionnaire data. The mean age of menarche
for the cohort was 13.3 ⫾ 0.1 yr. The subjects completed 3-day food
records, including 2 weekdays and 1 weekend day, before each study
visit. Subjects reported all food, drink, and vitamin and mineral sup-
plements that were consumed over the 3 days, estimating serving sizes
using common household measures. Mean daily nutrient intake values
were obtained from a computer nutrient analysis program (Nutritionist
III and IV, N-squared Computing, San Bruno, CA).
Twenty-four-hour urine specimens were obtained from each subject
every 6 months during the 4 yr of the study for measurements of
estradiol, testosterone, LH, and FSH. The urine samples were collected
independently of menstrual bleeding and cycle day (follow-up visits
were scheduled at the completion of the visit for 6 months in the future).
Steroid hormone assays were performed using established RIA tech-
nique that employ ether extraction and Celite chromatography before
the RIA (15). The day to day reproducibility of the urinary estradiol
measurements during this study averaged 12% at a mean concentration
of 4 ␮g/24 h, whereas the urinary testosterone assay had a between-run
precision of 12% at a mean concentration of 24 ␮g/24 h. Intra- and
interassay coefficients of variation for urinary LH and FSH values were
less than 10%. The urinary gonadotropin RIA method used has been
published previously (20) and involves acetone precipitation of the
gonadotropins from the urine sample and reconstitution in assay buffer,
concentrating the sample 80-fold in the process. The low end detection
for this assay was 1.0 mIU/mL.
TABLE 1. Tanner stage, body mass index, and dietary information (mean ⫾
All women were examined for height, weight, and Tanner breast
staging by the same research nurse (Nan Johnson-Rollings, R.N.) at each
visit. The percent body fat was determined at 6-month intervals by dual
energy x-ray absortiometry (DXA) scan, and skinfold measurements
were obtained with calipers at five sites: triceps, subcapsular, umbilicus,
suprailiac, and midthigh (21). Body composition analyses, including
percent body fat, were obtained from the DXA scans performed with a
QDR-2000 instrument (Hologic, Inc., Waltham, MA). As reported by
others (22), our observed coefficient of variation was less than 0.7% for
the day to day quality control scans using the manufacturer’s spine
phantom. All body composition scans were obtained using the pencil
beam mode in the presence of the Hologic, Inc., three-step acrylic/
acrylic-aluminum wedge standard that simulates lean and soft tissue
(23). Body composition analysis was performed using Hologic, Inc.,
software, version 5.71A.
Statistical analysis
Data from women (n ⫽ 7) who were taking contraception hormones
or other medications known to affect sex steroid and gonadotropin
analysis were eliminated from analysis from the point of initiation of
these treatments. Statistical procedures were accomplished using a
range of procedures (SAS Institute, Inc., Cary, NC). Descriptive statistics
and t tests were used to characterize the sample and to make simple
comparisons of interest. For the various endocrine and body composi-
tion parameters obtained every 6 months, starting up to 2 yr before
menarche and up to 3.5 yr postmenarche, the multivariate analyses of
variance was performed using SAS PROC MIXED and accounting for
the time effect. Unlike the usual ANOVA and regression models, this
model accommodates the within- and between-subject variabilities that
are inherent in a longitudinal study. The linearity of the various pa-
rameters over time was examined.
Results
The mean weight at menarche of 47.2 ⫾ 0.8 kg in the cohort
is consistent with the U.S. population mean (19) and ap-
proaches this proposed menarchal weight threshold of
47.8 ⫾ 0.5 kg (11). There were no significant changes in body
composition either as determined by DXA or using skin fold
thickness (Fig. 1), in contrast to the trends found for endo-
crine parameters (Fig. 2), with marked rate changes noted in
the year approaching menarche. There were also less pro-
SE) from 2 yr before menarche to 3 yr thereafter

Time table
Yr in relation to menarche ⫺2 (8/22) ⫺1 (30/57) ⫺0.5 (42/75) 0 (42/81) 0.5 (38/80) 1 (43/81) 2 (43/84) 3 (33/68)
(no. Ca2⫹/total no.)
Breast development and
auxological data
Tanner stage 2.2 ⫾ 0.1 2.4 ⫾ 0.1 2.9 ⫾ 0.1 3.1 ⫾ 0.1 3.5 ⫾ 0.1 4.1 ⫾ 0.1 4.6 ⫾ 0.1 4.9 ⫾ 0.0
(22) (58) (78) (88) (87) (85) (84) (68)
Ht (cm) 148.7 ⫾ 1.4 150.2 ⫾ 0.9 153.4 ⫾ 0.8 156.1 ⫾ 0.7 159 ⫾ 0.7 161.4 ⫾ 0.7 163.8 ⫾ 0.7 165.4 ⫾ 0.6
(22) (60) (78) (90) (87) (87) (87) (83)
Wt (kg) 40.2 ⫾ 1.9 40.2 ⫾ 0.9 44.3 ⫾ 0.7 47.2 ⫾ 0.8 49.7 ⫾ 0.8 52.2 ⫾ 0.8 54.3 ⫾ 0.8 56.2 ⫾ 0.8
(22) (60) (78) (90) (87) (87) (87) (83)
BMI (kg/m2) 18.0 ⫾ 0.6 18.5 ⫾ 0.3 18.8 ⫾ 0.2 19.3 ⫾ 0.3 19.6 ⫾ 0.3 20.0 ⫾ 0.3 20.2 ⫾ 0.2 20.5 ⫾ 0.2
(22) (60) (78) (90) (87) (87) (87) (83)
Nutrient intake
Protein (% calories) 15 ⫾ 0.6 14.6 ⫾ 0.3 14.6 ⫾ 0.3 14.8 ⫾ 0.3 15.0 ⫾ 0.3 14.6 ⫾ 0.3 15.5 ⫾ 0.3 15.5 ⫾ 0.3
(21) (60) (78) (88) (87) (85) (87) (80)
Carbohydrate 53.9 ⫾ 1.3 53.3 ⫾ 0.7 53.5 ⫾ 0.7 53.5 ⫾ 0.7 54.0 ⫾ 0.6 54.3 ⫾ 0.7 53.0 ⫾ 0.6 55.4 ⫾ 0.7
(% calories) (21) (60) (78) (88) (87) (85) (87) (80)
Fat (% calories) 31.0 ⫾ 1.1 32.0 ⫾ 0.7 31.8 ⫾ 0.7 31.7 ⫾ 5.2 31.1 ⫾ 0.6 31.2 ⫾ 0.6 31.4 ⫾ 0.6 29.2 ⫾ 0.6
(21) (60) (78) (88) (87) (85) (87) (80)
Cal/kg 47.7 ⫾ 2.5 46.9 ⫾ 1.4 43.7 ⫾ 1.3 43.3 ⫾ 1.3 38.2 ⫾ 1.2 37.3 ⫾ 1.1 36.0 ⫾ 1.0 34 ⫾ 1.0
(21) (60) (78) (88) (87) (85) (87) (80)
The number of women for each observation, both calcium supplemented and total observed (number of Ca2⫹ supplemented/number of total
observations) is located below the mean values.

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 MATURATION DURING PERIMENARCHE 1023

nounced rates of change in both weight and weight adjusted

for height (body mass index) in this critical year and through-
out the perimenarchal period (Table 1) than in the measured
hormones. Daily food consumption by this study cohort
(Table 1), whether examined by food group or by specific
nutrient intake, was similar to that determined in a national
survey of white, female adolescents (24). There were no sig-
nificant changes in dietary intake, as indicated by the amount
of kilocalories consumed, or in dietary composition during
the perimenarchal period.
We have presented the hormonal data (Fig. 2) within the
framework of the two-cell, two-gonadotropin hypothesis of
estrogen synthesis, which theorizes that LH stimulates ovar-
ian thecal cell androgen production, which, in turn, undergo
aromatization to estrogens in the granulosa cell under FSH
stimulation (25). Estradiol, LH, and FSH values displayed
exponential changes in the perimenarchal period, whereas
testosterone showed linear changes (Fig. 2). The effect of
calcium supplementation was also examined on all param-
eters, and no differences were noted, except for LH levels at
1 and 1.5 yr postmenarche. Testing for nonlinear curves over
the study period was significant for estradiol (⫺0.57 t2; P ⬍
0.0001), LH (⫺0.93 t2; P ⬍ 0.0001), and FSH (⫹2.49 t3; P ⬍
0.05). These endocrine events culminate in frequent men-
strual bleeding episodes (Fig. 3) that plateau at 1 yr post-
menarche. By 1 yr, 65% of these adolescent women had
established a pattern of 10 or more menstrual episodes/yr,
and by 3 yr postmenarche this figure exceeded 90%.

Discussion
Body composition has been noted to change during female
adolescence, with an increasing percentage of body fat be- FIG. 2. Twenty-four-hour urinary concentrations of estradiol and
ginning at the growth spurt through menarche (10 –12). Our FSH (upper figure), and testosterone and LH (lower figure). Data are
findings suggest that there are no significant changes in body presented as the mean ⫾ SE in relation to menarche. n, Number of
composition by either by caliper measurements or DEXA women at each time point, shown in parentheses.
analysis during the perimenarchal period, consistent with
the results of a more recent report (8). Body composition surements (26, 27). The larger estimate of percent body fat by
assessment by DEXA is generally regarded as on par with caliper may reflect the inaccuracy of this method. Another
hydrostatic weighing, and both techniques provide more interpretation, based on the progressive convergence of the
accurate information than skinfold or bioimpedance mea- two measurements postmenarche may be a developmental
central redistribution of body fat. Linear changes in height
and weight were noted over the course of the study. These
findings suggest that menarche is unrelated to changes in the
rate of height or growth, including the observation that men-
arche occurs at the time of maximum deceleration of height
growth (28).
Examination of FSH and estradiol levels during perimen-
arche suggests that menarche represents a more distinct
physiological event than mere estrogen-stimulated break-
through bleeding. The progressive suppression of daily FSH
levels postmenarche coupled with the rapid rise in estradiol
implies an abrupt transition point in reproductive maturity
at menarche. At premenarche, the curves suggest a positive
sex steroid feedback on FSH, followed postmenarche by the
rapid development of negative sex steroid feedback on FSH.
This implies a resetting of the gonadostat at the point of
menarche, this time at an adult level. These interpretations
FIG. 1. Body fat composition as measured by skin fold thickness and
are inferential and may reflect the bias of the substances
DXA. Data are presented as the mean ⫾ SE in relation to menarche. measured. Other putative growth factors in female repro-
n, The number of women at each time point, shown in parentheses. ductive development, such as inhibin (29) or leptin (30), may

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1024 LEGRO ET AL. JCE & M • 2000
Vol 85 • No 3

distribution of visits throughout the menstrual cycle and for

meaningful inferences about quantitative production and
relationships between hormones. Attempting to normalize
the collections to a specific point in the menstrual cycle
would not have been possible with a premenarchal cohort,
and the concept of frequent anovulatory cycles postmen-
arche would have prevented accurate cycle timing (there is
no midfollicular or midluteal phase in anovulatory cycles).
Such a strategy would also have reduced the power of our
study to determine the quantitative production of sex ste-
roids and gonadotropins across the breadth of the menstrual
cycle.
The rapid establishment of frequent menstrual bleeding
observed in our longitudinal cohort is consistent with rapid
exponential changes in estradiol and gonadotropins. This
FIG. 3. Mean number of reported menstrual cycles per yr. Data are acceleration in the rate of reproductive development may
presented as the mean ⫾ SE in relation to menarche. n, Number of reflect improved socioeconomic status and life style/diet in
women at each time point.
the late 20th century among this healthy, relatively homo-
geneous ethnic group of adolescent women. Alternatively, it
figure prominently in the events we describe. Estradiol levels may have been overlooked in previous studies due to their
plateau within 6 months of menarche, suggesting rapid mat- limitations. Our findings are consistent with a model of sal-
uration of this aspect of the hypothalamic-pituitary-ovarian tation and stasis for the maturation of the reproductive axis,
axis. The response of the end organ (in this case, breast a controversial concept in human development (33, 34).
development by Tanner stage) to increased estradiol pro- The strength of our study is the regular follow-up of a
duction required a longer period to achieve full maturation, homogeneous group of young women recruited before men-
but the greatest spurt in breast development occurred in the arche, with good study retention and intensive evaluation at
year following menarche. each visit. During the 4 yr of this study, 88 (79%) of the
The rapid burst in LH production in the 6-month period original 112 participants remained in the study, a retention
before menarche suggests that this increase is also pivotal to rate far exceeding those in previous studies of this type (35).
menarche (proportionally it is the largest of any hormone No significant differences were noted between those who
measured), although it is not followed by an exponential dropped out and those who remained in the study in terms
increase in testosterone levels. The plateauing of LH levels of baseline age, height, weight, or bone measurements. As
after menarche suggests, as with FSH, the beginning of neg- such, this represents a group with a similar ethnicity and
ative sex steroid feedback at the time of menarche on LH environment. One weakness is that these findings may not
levels. There were significant increases in LH levels in the be extrapolated to all groups of young women in America.
calcium-supplemented group at 1.5 and 2.0 yr postmenarche Ethnic origin as well as socioeconomic factors figure prom-
compared to those in the placebo group, but these differences inently in the age of menarche as well as the tempo of re-
appeared to be due to a large number of high LH outliers in productive development (36, 37). The homogeneity of this
the calcium-supplemented group. When these were elimi- study group, exclusively Caucasian women of European de-
nated from analysis there were no significant differences scent, may explain the slightly higher age of menarche noted
between treatment groups. This larger number of LH outliers in our cohort compared to that in other ethnic groups.
in the treatment group suggests the random concentration of In summary, our prospective study of a young group of
several midcycle LH surges. Testosterone increased linearly healthy adolescent women suggests that menarche results
during perimenarche, suggesting a slightly longer and more from a rapid and saltatory maturation of the reproductive
complex maturation of this portion of the reproductive axis. axis, independent of changes in body fat. The rapid estab-
The rapid development of frequent menstrual cycles mir- lishment of frequent menstrual bleeding episodes in our
rors the rapid rise in sex steroids. We did not measure cycle cohort suggests regular ovulatory function at an earlier age
intervals or progesterone levels and therefore may only infer than previously estimated. This may hold important impli-
the frequency of ovulatory cycles. Frequent menstrual bleeds cations for adolescent pregnancy and initiation of contra-
have not been synonymous with ovulatory cycles in previous ception for perimenarchal women in the next century.
studies of the postmenarchal period (2, 9, 31, 32). Cyclicity in
sex steroid levels postmenarche is implied by the increasing Acknowledgments
ses in these measurements postmenarche compared to their
We acknowledge the efforts of the research coordinator, Nan John-
small premenarchal variations as well as by the progressive son-Rollings, R.N., whose devotion to the study and its subjects was
decrease in the se of the number of menstrual bleeding ep- essential to its success; the staff of the General Clinical Research Center
isodes. Our collections were obtained by design independent at the M. S. Hershey Medical Center for their excellent care of the
of cycle day (the study was initiated among premenarchal research subjects; and the Core Endocrine Laboratory of the Department
of Pathology for their assay expertise. Additionally, we thank the fol-
women) and thus reflect quantitative changes over the whole lowing reviewers for their careful reading and critique of earlier versions
menstrual cycle as these developed in the individual women. of this manuscript: Robert Rosenfield, M.D., Department of Pediatrics,
Our sample size was large enough to allow for random University of Chicago; and William C. Dodson, M.D., Department of

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 MATURATION DURING PERIMENARCHE
Obstetrics and Gynecology, Richard L. Levine, M.D. Department of
Pediatrics, and Melvin Horwith, Department of Medicine, Pennsylvania
State University College of Medicine.
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