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From the Clinical Research Centers |
Division of Endocrinology, Department of Medicine, Children’s Hospital (M.R.P.), and the Clinical Investigator Training Program, Beth Israel Deaconess Medical Center-Harvard/Massachusetts Institute of Technology Division of Health Sciences and Technology, in collaboration with Pfizer, Inc. (M.R.P.), Boston, Massachusetts 02115; the Reproductive (H.V.M., P.A.B.) and Pediatric Endocrine ( P.A.B.) Units, Massachusetts General Hospital, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Paul A. Boepple, M.D., Reproductive Endocrine Unit, Bartlett Hall Extension 5, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114.
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Abstract |
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We have conducted a study that delineates the initial presentation and 12-yr follow-up of 20 patients who initially presented with unsustained or slowly progressive puberty as young girls. The patients were first seen between 1984–1987. They all underwent extensive clinical and hormonal studies, including frequent blood sampling and pelvic ultrasound to characterize pituitary-gonadal function. Twelve years later, we were able to locate 17 of the patients, and 16 of these agreed to participate in a questionnaire-based follow-up study. Follow-up data about the other patients were gleaned from available medical records as were corroborative data regarding the 16 study participants.
Our results indicate that this form of early puberty is a benign entity. Seventy percent of our patients experienced cessation of their early pubertal development, whereas the remainder reported a slowly progressive course. Those with a slowly progressive course were older than those with an unsustained course [mean age of thelarche, 6.1 vs. 3.4 yr (P < 0.01); age of pubarche, 6.0 vs. 4.0 yr (P = 0.02); age at our evaluation, 7.1 vs. 5.2 yr (P = 0.02)]. They also had more advanced skeletal maturation (bone age, 10.2 vs. 7.3 yr; P = 0.04) at the time of our evaluation. Both groups, however, had similar outcomes with respect to linear growth and young adult reproductive function. On the average, the study patients reached their genetic targets for final height (mean final height, 165.5 ± 2.2 cm; mean genetic target height, 164.0 ± 1.1 cm; P = NS). The average age of menarche was 11.0 ± 0.4 yr. Twenty-three percent of our patients have evidence of anovulatory menstrual cycles, which is comparable to the 28% found in normative studies of similarly aged women. Two of the patients have become pregnant to date. Unsustained or slowly progressive puberty in young girls does not warrant therapy with GnRH agonists. Thus, when evaluating patients with early pubertal development, one should ensure that sexual maturation is continually progressive before initiating potentially unnecessary therapy.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Given the gradual awakening of the GnRH pulse generator, it is not surprising that a spectrum of presentations has been found among girls with premature sexual development. These presentations range from patients with uncomplicated cases of premature thelarche to progressive central precocious puberty (9). Several reports have focussed attention on intermediate positions along this spectrum, employing terms such as slowly progressive puberty and thelarche variant to describe children with early evidence of gonadal activation but slow progression toward complete pubertal development (9, 10, 11). In addition to this spectrum of early sexual development, it is clear that gonadarche does not progress in all patients once it is initiated. A small number of girls with unsustained or transient central precocious puberty have been described in single case reports (12, 13) and in one small series (14).
As might be expected from the spectrum of presentations, not all young girls with early puberty warrant therapy with GnRH agonists (15). However, few long term data are available about the natural history of unsustained (12, 13, 14) or slowly progressing (10, 15) early puberty in young girls. During our studies of central precocious puberty (16, 17, 18), we identified a cohort of 20 girls who had clinical features of central precocious puberty but without biochemical evidence of persistent hypothalamic-pituitary-ovarian axis activation. We elected not to treat these girls with a GnRH agonist, but instead recommended careful monitoring in case their sexual maturation resumed at an accelerated pace. Here we report the results of a follow-up study conducted 12 yr after these girls’ initial evaluations that was designed to determine the history of their subsequent pubertal development, their final adult heights, and whether they have any reproductive endocrine abnormalities as young adults.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The diagnosis of early puberty was made based upon the classic
definition: onset of breast development and/or menses before 8 yr of
age. Recent studies have defined the age of onset of secondary sexual
development in girls in the United States to be younger than previously
reported in other populations (19), forcing a reevaluation of the
already arbitrary distinction between precocious puberty and the early
extreme of the normal range. Many of our study patients would be
defined as having precocious puberty regardless of the normative data
employed, but some may fall within the extreme end of the normal range
using the more recent data (see ages of onset in Table 1
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). None of the 20 patients had a
pubertal response to exogenous GnRH; each had a LH increase of less
than 25 IU/L above baseline and a peak FSH greater than or equal to the
peak LH in response to exogenous GnRH. Thus, at that time, these girls
were not considered candidates for long term pituitary-gonadal
suppression with a GnRH agonist. The peak LH level of 25 IU/L was
chosen because of the considerably higher LH responses exhibited by
patients presenting with true central precocious puberty, whose
pubertal patterns of LH secretion were clearly evident with frequent
sampling (16, 17, 18) (Table 2). It should be noted that LH levels measured
by RIA using the Second International Reference Preparation of human
menopausal gonadotropin LH standard differ from those measured by
recently developed immunoassays that employ the WHO Second
International Standard, human pituitary LH 80/522. The RIA levels are
2–3 times higher than the levels obtained with the newer assays. In
fact, GnRH-stimulated LH levels of 5 IU/L have been suggested as
diagnostic of precocious puberty using one modern
immunochemiluminometric assay (8, 20).
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The initial studies were performed at one of three participating institutions [Massachusetts General Hospital (Boston, MA); Children’s Hospital (Boston, MA); and Children’s Medical Center of the University of Virginia (Charlottesville, VA)]. Informed consent was obtained before the start of the original studies and before completing the follow-up questionnaire; each family was explicitly given the opportunity to refuse participation in the follow-up study. Both the initial evaluation and the follow-up study had institutional human research committee approval.
Characterization of gonadotropin secretion was based upon LH and FSH serum levels during frequent blood sampling (every 10–20 min) during the night (2200–0200 h) and day (1000–1400 h) and after the iv administration of 2.5 µg/kg natural sequence GnRH. Nighttime and daytime sampling was extended if permitted by phlebotomy guidelines. Single serum samples were obtained for the measurement of estradiol, dehydroepiandrosterone sulfate (DHEAS), and somatomedin C (Sm-C). Standing height was measured in the morning at least 30 min after the patient’s rising using a wall-mounted stadiometer; the average of three replicates is reported. A left hand and wrist x-ray was obtained during the admission to monitor skeletal maturation. A pelvic ultrasound was performed to assess ovarian size and morphology as well as uterine configuration. Vaginal smears or urinary samples were obtained for calculation of maturation index scores. Three patients (no. 4, 12, and 13) underwent serial 6-month evaluations to characterize their pubertal development more fully.
The study patients were initially referred to us from throughout the
United States, making it impractical to bring them to Boston, MA, for
follow-up evaluations. Thus, the follow-up study was conducted via
questionnaire. The follow-up questionnaire was designed to collect
information regarding growth, pubertal development, and reproductive
milestones. Specifically, it asked for the subject’s height, weight,
medical history, current and past medications (including oral
contraceptives), natural history of early pubertal development, age of
menarche, menstrual cycle length, and presence and severity of acne and
hirsutism. Corroborative information was obtained by review of the
patients’ medical records when available. If needed, families were
recontacted by phone to clarify and confirm follow-up data. For the
patients who could not be located or chose not to complete the
questionnaire, follow-up data were gleaned from the available medical
records (Table 3).
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LH, FSH, estradiol, DHEAS, and Sm-C were measured using specific RIAs as previously reported (21, 22, 23, 24). Bone age determinations were made using the Tanner-Whitehouse radius-ulnar-short standards (17, 25). Vaginal maturation index scores were calculated according to the method of Meisels (16, 26). Ovarian volume was calculated using the equation (length x width x height) ÷ 2 (27). Hirsutism was evaluated by the questionnaire, which included general questions about the presence of hirsutism and therapy as well as a self-reported modified Ferriman and Gallwey score (28). Midparental heights were calculated using the equation [(paternal height (cm) - 13) + maternal height (cm)] ÷ 2. Parental heights were obtained from data acquired during the initial evaluations and were confirmed when possible by report in the questionnaire. Final height data for the patients were obtained by self-report. SD scores for height were calculated using National Center for Health Statistics data (29). Predicted heights were calculated using the height SD score for bone age obtained at the initial evaluation and projecting it onto the National Center for Health Statistics adult height data (29).
Statistical snalysis
LH pulses were identified using modified (30) Santen and Bardin (31) criteria. Two-tailed nonparametric tests for independent variables were used to compare data from the 20 girls in this study with data from girls with true idiopathic central precocious puberty and to compare data from the subset of girls in this study who experienced slow progression of their early puberty with data from the subset who experienced no progression. Final heights of the follow-up study participants were compared with their midparental heights using a t test for dependent samples. Statistical tests were performed using the Complete Statistical System: Statistica from StatSoft, Inc. (Tulsa, OK) All data are presented as the mean ± SEM. Statistical significance was attributed to P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Clinical characteristics. The 20 patients with unsustained or
slowly progressive early puberty were enrolled in our study between
1984–1987. All patients had onset of breast development and/or menses
before 8 yr of age They differ from girls with classic premature
thelarche because of the presence of one or more of the following:
menses, pubic hair, accelerated growth velocity, and/or bone age
greater than 2 SD above chronological age. Their initial
historical, clinical, and laboratory data are presented in Tables 1
and 2. For comparative purposes, data available from the study of 96 girls
with idiopathic central precocious puberty are also included. The
clinical characteristics of the study patients differed from those with
true central precocious puberty in several parameters that are indirect
indexes of their exposure to sex steroids, including bone age, breast
development, height velocity, maturation index score, and Sm-C level.
The larger ovarian volumes found in the patients with idiopathic
central precocious puberty provide further evidence that their ovarian
sex steroid production was greater than that in the study patients.
Taken together, these findings indicate that the patients with true
precocious puberty had more advanced precocity than our current study
patients, which is not surprising because the two patient groups were
initially separated based upon their patterns of gonadotropin secretion
as well as their peak LH and FSH responses to exogenous GnRH.
Four of the study patients (no. 1–4) had breast development, advanced bone age, and increased height velocity, but no pubic hair at the time of our physical examination (although two of these patients had a reported history of pubic hair development). These four girls are included in our study cohort because of either progressive breast development (patient 1) or bone age advancement and rapid growth (patients 2–4). It is also possible, however, that these girls could be classified as having the thelarche variant that has been reported previously (11, 32). The other 16 patients had a history of breast development and/or menses along with the presence of pubic hair, a presentation that is consistent with a picture of complete isosexual pubertal development. Five of these patients (patients 16–20) had experienced at least one episode of vaginal bleeding or spotting. Two of the patients (patients 1 and 10) were half-sisters with the same mother.
Skeletal growth and maturation. As a group, the 20 patients with unsustained or slowly progressing early puberty were tall for chronological age (mean SD score, +1.7) but short for bone age (mean SD score, -1.0), a combination of features that would predict a final height below the general population mean of 163.7 ± 6.1 cm (±SD) (29) and below the expectation based on genetics (midparental height SD score, +0.1). This pattern was accentuated among the comparison group with true central precocious puberty, who were similarly tall for chronological age (mean SD score, +2.4) but had more advanced bone ages and were consequently even shorter for bone age (mean SD score, -2.2).
Ovarian and uterine characteristics. Despite clinical evidence of estrogen effect in all 20 of our study patients, none had a serum estradiol level at the time of evaluation that was above the level of detection of our assay (20 pg/mL). Ultrasonography revealed a prepubertal uterus in 17 of the patients, whereas 3 (patients 10, 15, and 19) had evidence of early pubertal changes. No ovarian cysts/follicles greater than 5–6 mm or any ovarian enlargement was seen in any of our patients except subject 15, who had large ovaries with polycystic changes (33).
Neuroendocrine evaluation. Four of the girls had one or two LH
pulses identified during overnight frequent sampling, but all of these
pulses were of low amplitude, with a mean excursion of 2.2 IU/L. Each
patient in our cohort had a FSH-predominant response to GnRH
administration, which is in contrast to the patients with true
precocious puberty, who had LH-predominant responses (Table 2) along
with clear-cut evidence of pubertal pulsatile LH secretion. A
comparison between the LH secretion profiles in our patients with
unsustained (A) or slowly progressive early puberty (B and C) and those
with true precocious puberty (D) is shown in Fig. 1.
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Description of cohort. We conducted the follow-up study an
average of 12.3 yr (range, 10.1–13.9 yr) after the 20 patients’
initial evaluations for precocious puberty. We were able to locate 17
(85%) of the patients, and 16 (94%) agreed to participate in the
study, with 4 choosing to undergo a phone interview instead of
completing the questionnaire themselves, and 1 patient providing only
final height data. The average length of follow-up in the 16
participants was 12.4 yr (range, 10.3–13.9). For the patients who
could not be located (no. 4, 18, and 19) or who chose not to
participate fully in the questionnaire study (no. 17 and 20), follow-up
information was obtained from available medical records. Corroborative
data regarding the 16 study participants was also obtained from medical
records (see Table 3).
Natural history of early development; final height and age of menarche. Five of our 20 patients (patients 2, 9, 12, 13, and 14) reported that the physical signs of puberty progressed, although slowly. The other 10 girls who returned the survey reported that no further pubertal development occurred until at least age 8 yr, and 2 of them (patients 3 and 5) stated that the pubertal changes regressed. Similarly, none of the patients followed through medical records experienced further pubertal progression, and one (patient 19) experienced regression of her pubertal development. The patient with the most extensive medical records (patient 4) experienced waxing and waning breast development and had not progressed beyond Tanner stage 3 breasts and Tanner stage 2 pubic hair by 8.3 yr of age (she initially had Tanner stage 4 breasts and Tanner stage 1 pubic hair at 4.6 yr of age). She had not yet experienced menarche at the time of her last endocrinology clinic visit at age 8.8 yr, but was beginning to progress further through puberty at that time.
Further evidence that the pace of pubertal development diminished in
our cohort is derived from their final heights and ages of menarche. Of
the five patients who reported slowly progressing pubertal development,
none reached menarche before 9.4 yr of age (range, 9.4–12.3), and each
reached a final height that equaled or exceeded their genetic potential
(Table 3). As a group, the 16 patients who participated in the
questionnaire study had a mean final height SD score of
0.3, slightly exceeding their target midparental height SD
score of 0.1 (P = NS; see Tables 1 and 3 and Fig. 2). The average age of menarche in the 15
patients who completed the questionnaire was 11.0 yr (range, 8.8–13).
The four patients (no. 3, 9, 12, and 15) who experienced menarche
at less than 10 yr of age all achieved their midparental
heights.
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were tested and found to be similar in the two groups, including final
heights (mean, 164.9 vs. 165.8 cm in the progressors and
nonprogressors, respectively; P = NS), midparental
heights (mean, 164.7 vs. 164.4 cm; P = NS),
and age of menarche (mean, 10.7 vs. 11.1 yr;
P = NS). Three of the patients who progressed did not
have evidence of pulsatile LH secretion during their frequent sampling
studies; conversely, two of the patients with LH pulses detected
initially did not experience pubertal progression. Current reproductive function. Most of the patients who completed the questionnaire have regular menstrual periods, with cycle lengths between 25–35 days. Only one of the young women has attempted reproduction (patient 9), and she has carried a healthy child to term. Patient 13 has had two unintended pregnancies, and she has had one elective abortion and one miscarriage. However, three of our patients probably do manifest chronic anovulation 3 yr or more postmenarche. Two (patients 3 and 15) reported irregular cycles without an underlying pattern, and one (patient 6) has repeated cycles that are longer than 35 days. One of these women (patient 15) is taking oral contraceptive pills to regulate her menstrual periods. It is intriguing to note that she is also the patient who had large ovaries with polycystic changes on initial ultrasound and that she reports having acne that is severe enough to require prescription medication. She may well have the polycystic ovarian syndrome that was evident at 8 yr of age.
Other evidence of hyperandrogenism in adulthood is difficult to discern in a questionnaire study. Six of our patients report having some degree of acne, although only 2 have used prescription topical medications. None of the 15 respondents reports hirsutism that required medical attention.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Our results indicate that this form of early puberty is a benign entity. Although it is difficult to be certain that unsustained and slowly progressive early pubertal development are indeed distinct entities, our patients do demonstrate two different maturational courses. Seventy percent of our patients experienced cessation of their early pubertal development, whereas the remainder experienced a slowly progressive course. On the average, our patients achieved their genetic targets for final adult height, probably because low level or unsustained estradiol production allowed linear growth without leading to premature epiphyseal fusion. Similar results have been reported in two studies that included patients with slowly progressive early puberty (35, 36). The average age of menarche (11.0 yr) in our cohort is lower than the recently published norms for girls in the United States (19), but is within 2 SD of the mean for both white girls (12.88 ± 1.20 yr) and African-American girls (12.16 ± 1.21 yr). Twenty-three percent of our patients do have evidence of anovulatory menstrual cycles, as indicated by irregular patterns and average cycle length over 35 days. This figure is no higher, however, than the 28% found among normal women who are 5–8 yr from menarche (37). Evidence of normal fertility is derived from one of the young women in this study having attempted reproduction with a successful outcome and another having had two unintended pregnancies.
The diagnostic label for patients such as ours is not clear. Several girls with sexual precocity have been reported whose clinical characteristics fell shy of complete central precocious puberty but who manifested marked systemic estrogen effects, such as isolated premature menarche (38, 39) and exaggerated or variant thelarche (11, 32, 40). Most of our patients, however, do not fit within such designations because their physical findings are not limited to estrogen effects but instead include sexual hair (and frequently a history of apocrine odor), signifying androgen effects as well. Similarly, the findings in premature pubarche are typically limited to androgen effects (41). It is true that some patients with premature thelarche progress to true central precocious puberty (32, 42), but our patients are not similar to those patients either. Thus, given the findings of both estrogen and androgen effects in most of our cohort along with the lack of progressive precocity in the majority, we believe that our patients best fit into the category of slowly progressing or unsustained isosexual early puberty (10, 12, 13, 14).
A limited number of such patients have been described before. Fontoura et al. have reported a small group of patients with slowly progressing early puberty (10). Their cohort included some patients with regression of their pubertal changes and others with recurrent and spontaneously reversible spurts of breast development (10). Some of our patients, most notably patient 4, also experienced waxing and waning of breast development, and three (no. 3, 5, and 19) experienced regression of their pubertal findings. All of the patients described by Fontoura et al. (10) had evidence of estrogen and androgen effects, but reports of unsustained, documented central precocity have also included girls without pubic hair development (12, 13).
The underlying etiology of patients with slowly progressive or unsustained early puberty is not well defined (10, 12, 13, 14), and all cases may not be due to a single cause. Indeed, if they are distinct entities, the two courses may represent different underlying biological processes. As two of our patients (no. 1 and 10) are sisters, it is possible that a subset of cases have a genetic etiology. We cannot determine definitively whether the early pubertal development seen in our patients stems from central activation of the hypothalamic-pituitary-ovarian axis (12, 13) or from a cryptogenic peripheral etiology (14). We believe, however, that transient central activation is the more likely cause because no evidence of adrenal or ovarian pathology was found in our patients.
We hypothesize that our patients lie partially along the path from
quiescence to a fully mature pattern of GnRH and gonadotropin secretion
(1, 2, 3, 4, 5, 6, 7, 8). That low level gonadotropin secretion was occurring in our
patients is supported by their ovarian volumes, which frequently exceed
the prepubertal norm of 1 mL or less (26, 43) and provide evidence of
gonadotropin effects, while falling below the gonadal size documented
in patients with true central precocious puberty. Low level
gonadotropin secretion may well have been present but hovering at the
detection limit of the LH assay available at the time. Future studies
will be needed to determine whether similar patients have more abundant
evidence of gonadotropin secretion using the supersensitive
gonadotropin assays that are available today (3, 4, 5, 6, 7, 8, 19). As shown in
Fig. 1C, one patient (no. 13) with a slowly progressive course had no
LH pulses during her initial study, three low amplitude pulse during
the second evaluation (mean excursion, 3.1 IU/L), and then only one low
amplitude pulse during the third study (excursion, 3.0 IU/L). These
data suggest that low level, perhaps intermittent, pulsatile LH
secretion was occurring and was accompanied by progressive ovarian
enlargement and pubertal development in this patient. Patient 12’s
initial study shows a single low level pulse; 6 months later during her
second evaluation, noticeably increased LH secretion was observed. She,
too, had a slowly progressive pubertal course. We believe that the low
level LH pulsatility may have been intermittent in some cases and
transient in others. Recall that some of the patients with no
documented initial pulsatility experienced slowly progressive early
puberty (such as patient 13), whereas others with initially detected
pulsatility did not progress.
It is important to interpret our results in light of the recently published data about the normal timing of pubertal maturation in American girls (19). According to these data, 27.2% of African-American girls and 6.7% of white girls show some secondary sexual characteristics by age 7 yr (19). Our patients were initially referred to us between 1984–1987 because of appropriate concern that they had precocious puberty. Many of them, even with the recent data about the timing of sexual maturation in girls (19), had ages of onset that warrant the diagnosis of precocious puberty. However, the new population data indicate that others, especially the slow progressors (who were older than the nonprogressors at the time of onset and evaluation) may represent an extreme end of the normal spectrum of pubertal initiation. Our data and those of others (35, 36) indicate that girls who develop within the early portion of the normal age range achieve expected adult heights if their puberty progresses slowly despite significant bone age advancement and reduced height SD score for bone age (-1.0 in our cohort).
It is also interesting to note that 35% of our cohort is African-American. Although our sample size is too small to discern significant population differences, this finding is consistent with data showing that African-American girls enter puberty approximately 1–1.5 yr earlier than white girls and experience menarche about 8.5 months earlier (19). Race data are not available from the previous studies of transient early puberty (10, 12, 13, 14), so it will be important to determine in future studies whether unsustained or slowly progressing early sexual maturation, like earlier normal pubertal development, is more common among African-American girls.
From among the spectrum of presentations of early pubertal maturation in girls (9, 10, 11, 12, 13, 14, 15), physical examination and growth data often identify the patients with mild development who do not warrant extensive evaluation or therapy with GnRH agonists. Cases such as ours point out, however, that even when patients have the clinical characteristics of complete isosexual precocity, they still may not warrant therapeutic intervention. Girls with a LH-predominant response to exogenous GnRH are probably good candidates for therapy depending upon their age and adult height potential (9, 15). We would recommend, however, that one consider monitoring patients with a FSH-predominant response and less marked bone age advancement for at least 6 months to ensure that their early development is progressive before the initiation of therapy.
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Acknowledgments |
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Footnotes |
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Received August 28, 1998.
Revised October 15, 1998.
Accepted October 25, 1998.
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References |
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