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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 3 1021-1025
Copyright © 2000 by The Endocrine Society

Original Studies

Rapid Maturation of the Reproductive Axis during Perimenarche Independent of Body Composition1

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

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, Pennsylvania 17033. E-mail: rsl1{at}psu.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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 measure 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 thereafter. Estradiol output increased rapidly in the year approaching menarche 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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PERIMENARCHE is as vaguely understood as perimenopause, yet receives less attention (Medline textword search in the database from 1966 to present performed November 1, 1999 revealed 4 references to perimenarche and 153 to perimenopause). The perimenarchal period has not been thoroughly studied in healthy cohorts with regular longitudinal follow-up. The events of perimenarche have been well described in cross-sectional studies (1, 2, 3, 4, 5), but these studies are unable to analyze the progression of the individual over time in relation to developmental milestones. To date, the few longitudinal studies of endocrine maturation in healthy pubertal females have been limited by the lack of integrated hormone measurements, small numbers of subjects, or infrequent and limited follow-up of the longitudinal cohort (6, 7, 8). Such studies have underestimated the rate of pubertal development and have contributed to the concept that gradual maturation of the reproductive axis occurs over a 4- to 6-yr period after menarche (2, 9). We obtained serial 24-h urine specimens and made quantitative measurements of reproductive hormones and body composition to establish their relationship to menarche.

None of the previous studies have correlated accurate 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 menarche and female reproductive ability (10, 11, 12). These studies have two major flaws: 1) they analyzed data collected at a variety of sites from 1929–1950, a time period when the U.S. experienced significant socioeconomic change; and 2) there were no direct measurements of body fat. The researchers calculated the percent body fat from height and weight measurements.

We sought to identify the natural history of menarche in a large, healthy cohort of young women studied at 6-month intervals from premenarche onward. Although we did not directly measure hormone production, the 24-h urine collections offered important advantages when examining the ontogeny of menarche. They are not subject to the fluctuations of hormonal pulsatility that are reflected in single serum samples (13). Quantitative measurements of excreted hormone in 24-h urine specimens are more representative of age-related changes in steroid and gonadotropin production than measurement of an isolated serum sample. Persistent and quantitative increases in the output of these hormones form the basis for female sexual maturity (14).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

All procedures involving human subjects were reviewed and approved 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 anthropometric, endocrine, and bone measurements have been reported (15, 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 positive 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 1Go).


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  		Table 1. Tanner stage, body mass index, and dietary information (mean ± SE) from 2 yr before menarche to 3 yr thereafter

 
The study group represents a Caucasian female adolescent population of European ancestry attending public school in central Pennsylvania. All study participants were seen and examined at 6-month intervals 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 normative 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 supplements 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 technique 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 µg/24 h, whereas the urinary testosterone assay had a between-run precision of 12% at a mean concentration of 24 µg/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.

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 composition 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 parameters over time was examined.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The mean weight at menarche of 47.2 ± 0.8 kg in the cohort is consistent with the U.S. population mean (19) and approaches 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. 1Go), in contrast to the trends found for endocrine parameters (Fig. 2Go), with marked rate changes noted in the year approaching menarche. There were also less pronounced rates of change in both weight and weight adjusted for height (body mass index) in this critical year and throughout the perimenarchal period (Table 1Go) than in the measured hormones. Daily food consumption by this study cohort (Table 1Go), 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 significant changes in dietary intake, as indicated by the amount of kilocalories consumed, or in dietary composition during the perimenarchal period.



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  		Figure 1. Body fat composition as measured by skin fold thickness and DXA. Data are presented as the mean ± SE in relation to menarche. n, The number of women at each time point, shown in parentheses.

 


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  		Figure 2. Twenty-four-hour urinary concentrations of estradiol and FSH (upper figure), and testosterone and LH (lower figure). Data are presented as the mean ± SE in relation to menarche. n, Number of women at each time point, shown in parentheses.

 
We have presented the hormonal data (Fig. 2Go) within the framework of the two-cell, two-gonadotropin hypothesis of estrogen synthesis, which theorizes that LH stimulates ovarian 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. 2Go). The effect of calcium supplementation was also examined on all parameters, 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 menstrual bleeding episodes (Fig. 3Go) that plateau at 1 yr postmenarche. 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%.



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  		Figure 3. Mean number of reported menstrual cycles per yr. Data are presented as the mean ± SE in relation to menarche. n, Number of women at each time point.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Body composition has been noted to change during female adolescence, with an increasing percentage of body fat beginning at the growth spurt through menarche (10, 11, 12). Our findings suggest that there are no significant changes in body composition by either by caliper measurements or DEXA analysis during the perimenarchal period, consistent with the results of a more recent report (8). Body composition assessment by DEXA is generally regarded as on par with hydrostatic weighing, and both techniques provide more accurate information than skinfold or bioimpedance measurements (26, 27). The larger estimate of percent body fat by caliper may reflect the inaccuracy of this method. Another interpretation, based on the progressive convergence of the 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 menarche occurs at the time of maximum deceleration of height growth (28).

Examination of FSH and estradiol levels during perimenarche suggests that menarche represents a more distinct physiological event than mere estrogen-stimulated breakthrough 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 are inferential and may reflect the bias of the substances measured. Other putative growth factors in female reproductive development, such as inhibin (29) or leptin (30), may figure prominently in the events we describe. Estradiol levels plateau within 6 months of menarche, suggesting rapid maturation of this aspect of the hypothalamic-pituitary-ovarian axis. The response of the end organ (in this case, breast development by Tanner stage) to increased estradiol production required a longer period to achieve full maturation, but the greatest spurt in breast development occurred in the year following menarche.

The rapid burst in LH production in the 6-month period before menarche suggests that this increase is also pivotal to menarche (proportionally it is the largest of any hormone measured), although it is not followed by an exponential increase in testosterone levels. The plateauing of LH levels after menarche suggests, as with FSH, the beginning of negative sex steroid feedback at the time of menarche on LH levels. There were significant increases in LH levels in the calcium-supplemented group at 1.5 and 2.0 yr postmenarche compared to those in the placebo group, but these differences appeared to be due to a large number of high LH outliers in the calcium-supplemented group. When these were eliminated from analysis there were no significant differences between treatment groups. This larger number of LH outliers in the treatment group suggests the random concentration of several midcycle LH surges. Testosterone increased linearly during perimenarche, suggesting a slightly longer and more complex maturation of this portion of the reproductive axis.

The rapid development of frequent menstrual cycles mirrors the rapid rise in sex steroids. We did not measure cycle intervals or progesterone levels and therefore may only infer the frequency of ovulatory cycles. Frequent menstrual bleeds have not been synonymous with ovulatory cycles in previous studies of the postmenarchal period (2, 9, 31, 32). Cyclicity in sex steroid levels postmenarche is implied by the increasing SEs in these measurements postmenarche compared to their small premenarchal variations as well as by the progressive decrease in the SE of the number of menstrual bleeding episodes. Our collections were obtained by design independent of cycle day (the study was initiated among premenarchal women) and thus reflect quantitative changes over the whole menstrual cycle as these developed in the individual women. Our sample size was large enough to allow for random 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 postmenarche 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 steroids 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 acceleration in the rate of reproductive development may reflect improved socioeconomic status and life style/diet in the late 20th century among this healthy, relatively homogeneous ethnic group of adolescent women. Alternatively, it may have been overlooked in previous studies due to their limitations. Our findings are consistent with a model of saltation and stasis for the maturation of the reproductive axis, a controversial concept in human development (33, 34).

The strength of our study is the regular follow-up of a homogeneous group of young women recruited before menarche, with good study retention and intensive evaluation at each visit. During the 4 yr of this study, 88 (79%) of the original 112 participants remained in the study, a retention rate far exceeding those in previous studies of this type (35). No significant differences were noted between those who dropped out and those who remained in the study in terms of baseline age, height, weight, or bone measurements. As such, this represents a group with a similar ethnicity and environment. One weakness is that these findings may not be extrapolated to all groups of young women in America. Ethnic origin as well as socioeconomic factors figure prominently in the age of menarche as well as the tempo of reproductive development (36, 37). The homogeneity of this study group, exclusively Caucasian women of European descent, may explain the slightly higher age of menarche noted in our cohort compared to that in other ethnic groups.

In summary, our prospective study of a young group of healthy adolescent women suggests that menarche results from a rapid and saltatory maturation of the reproductive axis, independent of changes in body fat. The rapid establishment of frequent menstrual bleeding episodes in our cohort suggests regular ovulatory function at an earlier age than previously estimated. This may hold important implications for adolescent pregnancy and initiation of contraception for perimenarchal women in the next century.


   Acknowledgments
 
We acknowledge the efforts of the research coordinator, Nan Johnson-Rollings, R.N., whose devotion to the study and its subjects was essential to its success; the staff of the General Clinical Research Center at the M. S. Hershey Medical Center for their excellent care of the research subjects; and the Core Endocrine Laboratory of the Department of Pathology for their assay expertise. Additionally, we thank the following reviewers for their careful reading and critique of earlier versions of this manuscript: Robert Rosenfield, M.D., Department of Pediatrics, University of Chicago; and William C. Dodson, M.D., Department of Obstetrics and Gynecology, Richard L. Levine, M.D. Department of Pediatrics, and Melvin Horwith, Department of Medicine, Pennsylvania State University College of Medicine.


   Footnotes
 
1 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). Back

Received October 1, 1999.

Revised November 8, 1999.

Accepted November 19, 1999.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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