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Endocrine Care |
Division of Endocrinology, Department of Medicine, Children’s Hospital (I.L.S., M.R.P.), Boston, Massachusetts 02115; and Reproductive Endocrine Unit, Massachusetts General Hospital (M.R.P.), Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Mark R. Palmert, M.D., Ph.D., Division of Pediatric Endocrinology and Metabolism, Rainbow Babies and Children’s Hospital, University Hospitals Health System, 11100 Euclid Avenue, Cleveland, Ohio 44106. E-mail: . mrp13{at}po.cwru.edu
Abstract
Despite the clinical importance of delayed puberty, the understanding of this condition is hampered by the lack of studies evaluating etiologies and predisposing factors among large case series. We performed a retrospective study of clinical and laboratory data from adolescents (
18 yr of age) with delayed puberty who had been seen in our clinic between 1/96 and 7/99 (n = 232 subjects; 158 males and 74 females). Family histories of pubertal timing among primary relatives were classified as negative, having at least a tendency to pubertal delay (development 
1 SD beyond the mean), or diagnostic of delay (development 2 SD beyond the mean).
The most common cause of delayed puberty was constitutional delay of growth and maturation (CD), which affected 53% of the subjects (63% of males and 30% of females). The remaining subjects could be divided into four categories: those with an underlying condition associated with delayed, but spontaneous, pubertal development [functional hypogonadotropic hypogonadism (FHH)], 19% of subjects; those with permanent hypogonadotropic hypogonadism, 12% of subjects; those with permanent hypergonadotropic hypogonadism, 13% of subjects; and those without clearly classified disorders, 3% of subjects. Like CD, FHH was male predominant, whereas the other categories either affected both genders equally or were predominantly female. In total, 50 different etiologies led to pubertal delay within our case series. Data permitted classification of family histories of pubertal timing among primary relatives in 95 of 122 of the CD and in 25 of 45 of the FHH cases. Analysis revealed at least a tendency to pubertal delay in 77% of the CD and in 64% of the FHH families and a diagnosis of delay in 38% of the CD and 44% of the FHH families. Both parents contributed to the positive family histories. The rates of positive family histories among the CD and FHH groups were approximately twice those seen among the other subjects in our case series. Among all subjects, those with FHH had the most marked growth delay, and girls had the greater bone age delay. Among the boys and at comparable chronological ages, CD and FHH were characterized by greater delays in pubic hair development and bone age than in the other diagnostic groups. Although CD is typically associated with leanness, 22% of our subjects had a BMI SD score at the 85th percentile or above for chronological age. These overweight subjects differed from the rest of the CD group: bone age was less delayed, and height was less affected. Finally, our analysis suggested a possible association between attention deficit disorder with or without hyperactivity and pubertal delay in our CD and FHH subjects.
Our study provides valuable data regarding the variety and frequency of diagnoses that lead to delayed puberty. The results underscore the importance of performing a thorough evaluation and family history in adolescents with delayed puberty. Moreover, the data from our case series provide clues for unraveling the mechanism(s) of idiopathic pubertal delay and lead to the hypothesis that the pubertal delay seen among some subjects with FHH and CD may stem in part from similar underlying physiology.
DELAYED PUBERTY is defined as lack of the initial signs of sexual maturation by an age that is more than 2–2.5 SD above the mean for the population (
13 yr in girls and 14 yr in boys) (1, 2, 3, 4, 5, 6, 7). In most cases delayed puberty is not due to any underlying pathology, but instead represents an extreme end of the normal spectrum of pubertal timing, a developmental pattern referred to as constitutional delay of growth and maturation (CD). Although common, CD is a diagnosis of exclusion, as a wide variety of underlying conditions are known to lead to delayed or absent puberty (discussed in Refs. 8, 9, 10, 11, 12, 13).
Only a few previous studies have attempted to characterize the etiologies and clinical characteristics among large numbers of young adults with delayed puberty (14, 15, 16). Even the most comprehensive of these are limited by not having focused solely on delayed puberty, but instead having included a broad range of reproductive endocrine abnormalities within the case series (14), by including few subjects with constitutional delay (15), or by having focused on a single gender (14). Thus, although there is much anecdotal experience, few data are available regarding the relative frequencies of the various etiologies to help guide the practitioner during the evaluation of an adolescent with delayed puberty.
As the factors that regulate the onset of puberty remain elusive, it is important to characterize naturally occurring variations in pubertal timing as fully as possible. New insights into the control of puberty will probably derive from a more complete understanding of the factors that underlie CD. For example, although CD is known to have a genetic basis, few studies have assessed the frequency or pattern of the familial predisposition within a large number of subjects with CD (15, 16), nor have studies addressed the interesting question of whether a genetic predisposition to later pubertal development underlies the presentation of delayed puberty among some adolescents with systemic disorders.
To provide further data regarding the etiologies and factors predisposing to delayed puberty, we reviewed the records of patients who were seen in the endocrine clinic at Children’s Hospital (Boston, MA) with delayed puberty between January 1996 and July 1999. Here we report the characteristics of those 232 cases.
Subjects and Methods
Subject population
Using endocrine division (17) and hospital-wide databases (18), we identified adolescents (18 yr of age) seen for delayed puberty in the endocrine clinic at Children’s Hospital between January 1996 and July 1999. To capture subjects who might not have been included in these databases, clinic appointment logs were also reviewed. Individual records were then reviewed to establish eligibility. Girls with lack of breast development by age 13 yr and boys with lack of testicular enlargement (testis size <2.5 cm in length or <4 cc in volume) by age 14 yr were included in the case series. All identified subjects (n = 232) were included in the analysis. In a retrospective chart review, it is difficult to fully verify the chief complaints of individual subjects. However, based on available data, the chief complaints of the vast majority of the patients were either pubertal delay or slowed linear growth. In a subset of subjects, gonadal function was being monitored in the context of a known underlying disorder.
Protocol and methods
The record review was approved by the institutional committee on clinical investigation. Data obtained from retrospective review of paper and electronic records included chronological age (CA), bone age (BA), weight (WT), height (HT), body mass index (BMI), Tanner stage (1, 2), testicular size as well as levels of FSH and LH. In addition, diagnostic evaluations for underlying disorders were reviewed, medical histories of concurrent disorders were examined, and parental heights and family history of pubertal delay were obtained from the clinic appointment records.
The endocrine division sends all families of new patients a detailed history questionnaire that includes items regarding medical illnesses as well as timing of puberty among siblings, parents, and grandparents. In addition, the initial visit history and physical examination form used in our clinic includes the completion of a pedigree detailing medical illnesses and timing of puberty among family members. These data were used for classification of family histories of the timing of puberty. Family history among primary relatives and extended family members was classified as having at least a tendency to delayed puberty (development 1 SD beyond the mean; men with pubertal onset after age 13 yr and/or growth spurt after age 15 yr; women with menarche after age 14 yr) or as diagnostic of delayed puberty (development 2 SD beyond the mean; men with pubertal onset after age 14 yr and/or growth spurt after age 16 yr; women with menarche after age 15 yr) (1, 2, 3, 4, 5, 6, 7).
Based upon clinical history and corroborating laboratory data, we classified subjects as having CD when they had no underlying illness or endocrinopathy and their growth rate was consistent with delayed case curves on the longitudinal growth charts used in our endocrine program (L. Bayer and N. Bayley, University of Chicago Press, 1959). Subjects were classified as having functional hypogonadotropic hypogonadism (FHH) if an underlying condition was identified that did not lead to permanent hyper- or hypogonadotropic hypogonadism. Data permitted confirmation of diagnoses through documentation of spontaneous pubertal development in 92% of the boys and 91% of the girls in the CD group and 87% of the boys and 93% of the girls in the FHH group; follow-up data were not available for the remaining subjects. No long-term follow-up data were available to permit evaluation of adult sexual function in any of our subjects. Although the lack of documentation regarding spontaneous puberty in a small subset of the CD and FHH subjects may have introduced an element of diagnostic uncertainty into the study, we chose to include all identified subjects in the analysis 1) because it allowed us to keep the study population intact and 2) because no clinical or laboratory characteristics distinguished those with and without documentation of spontaneous puberty. Moreover, exclusion of those subjects without documentation of spontaneous puberty from the data analysis did not alter the study’s findings.
Subjects with hypogonadotropic hypogonadism had known central nervous system disorders and/or documented low levels of gonadotropins (mean ± SD; boys: LH, 0.3 ± 0.4 IU/liter; FSH 0.7 ± 1.0 IU/liter; girls: LH, 0.6 ± 0.6 IU/liter; FSH, 1.3 ± 1.4 IU/liter), whereas subjects with hypergonadotropic hypogonadism had known gonadal failure and/or documented high levels of gonadotropins (boys: LH, 21.4 ± 11.3 IU/liter; FSH, 49.9 ± 27.0 IU/liter; girls: LH 32.3 ± 20.9 IU/liter; FSH 104.2 ± 61.3 IU/liter). Reference ranges for the LH and FSH values are not reported because these assays were performed as part of the clinical evaluations and were not all performed in a single reference laboratory. Too few of the subjects had available sex steroid data to permit meaningful inclusion of these data.
Midparental height was calculated for boys as [(HT of mother + 13 cm) + HT of father]/2 and for girls as [(HT of father - 13 cm) + HT of mother]/2 (19). SD scores for HT, WT, and BMI were calculated using the method and standard curves released by the Centers for Disease Control in 2000 (http://www.cdc.gov/growthcharts/).
Statistical analysis
Data are displayed as the mean ± SD. t tests for independent samples were used to determine significance when comparing clinical characteristics between groups. The Shapiro-Wilks W test was employed to test for normality among the BMI SD scores for CA. Statistical tests were performed using the Complete Statistical System: Statistica (StatSoft, Inc., Tulsa, OK). Statistical significance was attributed to two-tailed P < 0.05.
Results
Our case series consisted of 158 boys (mean age, 15.1 ± 0.9 yr) and 74 girls (mean age, 14.5 ± 1.4 yr). The etiologies of delayed puberty were divided into 5 groups as presented in Fig. 1
and Tables 1–3. Although a male-predominant disorder, CD was the most common diagnosis among both boys and girls. Among the 232 subjects, diagnoses were as follows: 122 with CD (53%), 45 with FHH (19%), 29 with permanent hypogonadotropic hypogonadism (Hypo H) (12%), and 30 with permanent hypergonadotropic hypogonadism (Hyper H) (13%). In 6 subjects, the etiology of delayed puberty was not clearly classifiable (3% of the case series).
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and Table 4. Although quite variable, assessments of nutritional sufficiency and growth impairment revealed that SD scores for HT, WT, and BMI for CA were lower in the FHH group compared with the combined data from the Hypo and Hyper H groups (P = 0.004 for HT, P = 0.001 for WT, and P = 0.0007 for BMI, respectively). Data from the CD group were intermediate. Delayed BAs were seen in all diagnostic categories, but the delay seen among girls was greater than that among boys (mean delay of 2.7 ± 1.6 yr for girls vs. 1.9 ± 1.2 yr for boys; P < 0.0001; Table 4). Among the boys and at comparable chronological ages, CD and FHH were characterized by greater delays in pubic hair development and BA than the other diagnostic groups [mean Tanner stage for pubic hair in CD, 2.0 ± 0.8; in FHH, 1.8 ± 0.8; in the combined Hypo H and Hyper H groups, 2.9 ± 1.3 (P < 0.001 for both CD and FHH vs. the combination of Hypo H and Hyper H); mean BA delay in the combined Hypo H and Hyper H groups, 1.0 ± 1.3 (P < 0.01 for both CD and FHH vs. the combination of Hypo H and Hyper H)].
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, where it is demonstrated that both parents contributed to the positive family histories for boys and girls. Among CD subjects, data permitted classification of family history in 95 of 122 subjects. These histories were positive for at least a tendency to pubertal delay (development 1 SD beyond the mean) in 77% of the cases and for a diagnosis of delay (development 2 SD beyond the mean) in 38%. In many cases, the family history of delay seemed to extend beyond the nuclear family, as illustrated by the examples shown in Fig. 3.
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The frequency of the BMI SD scores among our CD subjects did not follow a normal distribution (P = 0.001) and was suggestive of a bimodal pattern. Indeed, a subset of the subjects (n = 25 males and 2 females; 22% of the CD group) were overweight (BMI SD score for CA, 85th percentile; see Fig. 4) (20, 21, 22). Data permitted confirmation of the diagnosis of CD through documentation of spontaneous pubertal development in 82% of the overweight subjects; follow-up data were not available for the remaining 18%. The overweight CD subjects differed from the rest of the CD group in that BAs were less delayed (mean delay, 1.4 ± 1.1 vs. 2.1 ± 1.1 yr; P = 0.005) and heights were less affected (HT SD score for CA, -1.1 ± 1.1 vs. -2.1 ± 0.9; P < 0.00001). The diminished BA delay meant that the obese subjects had BAs more advanced than might have been expected for their pubertal status (mean BA of 13.6 ± 1.0 yr at CA 15.0 ± 0.6 yr for obese vs. mean BA of 12.7 ± 1.3 yr at CA 14.9 ± 1.0 yr for nonobese subjects).
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Discussion
We have performed an extensive review of a large case series of adolescents with delayed puberty who were evaluated at a tertiary care center. Because our primary focus was to further understanding of the factors that lead to delayed puberty (and through this to gain further insights into the mechanisms that regulate the timing of puberty in humans), we did not include individuals who began puberty within the normal window and had subsequent abnormal progression. We acknowledge that certain diagnoses might be underrepresented in our case series because our institution has other specialized programs where subjects with disorders such as anorexia nervosa or Turner’s syndrome may receive care. In addition, we did not include subjects within our own clinic population whose diagnoses (e.g. Turner’s syndrome) were made perinatally or in midchildhood and whose cases did not involve presentation with delayed puberty. Although we have many subjects with CD, this entity may be underrepresented because many such adolescents with uncomplicated courses may be managed in the community, and we only included those individuals with CD who met our criteria for pubertal delay. Conversely, due to affiliation with Dana Farber Cancer Institute, there may be an overrepresentation of subjects with pubertal delay stemming from cancer or its treatment. Nonetheless, we believe our study provides extremely valuable data regarding the etiologies of and the predisposing factors for pubertal delay.
Although CD and FHH display significant male predominance in our series, this may relate in part to referral bias. Although there may be differential effects of testosterone vs. estrogen deficiency, the possibility of referral bias is supported by our findings that girls have greater BA delays and tend to have greater growth deficits, suggesting that girls may have been more severely affected than boys when referred. We doubt that the tendency for greater growth deficits among girls stems from undiagnosed nutritional deficiencies, as their BMI SD scores are relatively preserved for both CA and BA. The male predominance seen in CD and FHH differs from the other categories of delayed puberty, which either affect both genders equally or may even be female predominant. Thus, despite the potential confounding introduced by referral practices, the male predominance seen among the subjects with CD and FHH is striking and may well represent a clue to the etiology of these conditions. Male predominance is also seen in congenital idiopathic hypogonadotropic hypogonadism (24), raising the possibility that understanding the etiology of that disorder may provide insight into CD and vice versa.
A genetic predisposition to delayed pubertal development was common among the CD and FHH groups with both parents contributing to the positive family histories. Unfortunately, this important historical information cannot be obtained except through recall, and this inevitably introduces an element of inaccuracy into the data. However, even recalled information is valuable, because studies suggest that even decades after the event, 75–90% of women remember age of menarche and 50% of men remember the timing of their pubertal growth spurt within a year (25, 26, 27). Because we noted that many family members experienced pubertal development significantly later than average, but not necessarily late enough to meet diagnostic criteria for delayed puberty, we classified family histories as being consistent either with at least a tendency to or diagnostic of delayed puberty. Thirty to 50% of the CD and FHH subjects had a positive family history for the diagnosis of delay, but this percentage increased to 56–79% when criteria for delay were relaxed. This finding may also represent a clue to the etiology of delayed puberty among the CD and FHH groups and suggests either variable penetrance or leads to hypotheses such as delay worsening through the combined contribution from each parent or through a genetic mechanism that becomes more profound in subsequent generations.
Although the two groups may partially overlap, it is interesting to note that subjects in both the CD and FHH categories tend to be male and have a positive family history of delayed pubertal development. On the average, the boys in these two groups also share a greater degree of pubic hair and BA delay than the other diagnostic groups, perhaps indicative of a relatively delayed adrenarche among these subjects (12). These similar characteristics raise the possibility that among some subjects with FHH the physiology underlying pubertal delay is in part similar to that underlying CD. It is also possible that the underlying conditions we identified among the FHH group are more likely to lead to delayed puberty among a predisposed subset. Prospective studies are needed to explore further the significance of positive family histories to the etiology of delayed puberty within the FHH subjects.
Adolescents with CD are typically relatively lean, and this is true for the majority of our case series. The finding of overweight subjects among our CD group may not be surprising given the increasing rates of obesity in the general population (28, 29). On the other hand, if leanness is an etiological component of CD, then it is surprising that we and others observed that subsets of CD subjects are obese (29, 30, 31). Although it is possible that leptin modulates female reproductive endocrine function more finely (a hypothesis that is consistent with obesity being less prevalent among our female subjects), obese subjects with CD argue somewhat against leptin acting as a trigger for pubertal development (32, 33). This is because it is likely that our subjects have the relatively high leptin levels typically associated with increased fat mass (34), and none of our subjects has the morbid obesity that has been associated with leptin deficiency or leptin receptor dysfunction (35, 36, 37). It has been hypothesized that excessive leptin levels may inhibit the hypothalamic-pituitary-gonadal axis (reviewed in Ref. 38), but this too seems unlikely in our moderately obese subjects, although it remains a possibility given the lack of leptin data in our case series. We must also consider whether the pubertal delay seen among our overweight subjects stems from a different etiology than seen in classic CD subjects. However, none of them was diagnosed with a syndrome known to be associated with hypogonadism (such as Prader-Willi syndrome), and the vast majority subsequently demonstrated spontaneous pubertal development.
We wish to be cautious in interpreting the possible association between ADD/ADHD and delayed puberty. The diagnoses of ADD/ADHD were obtained through chart review, rates may be elevated among individuals who receive care at tertiary centers, and behavior undertaken to compensate for delayed puberty and/or short stature may have led to falsely high diagnostic rates. Moreover, association certainly does not prove causality. Nonetheless, we wonder whether this possible association provides a clue to the underlying physiology of pubertal delay seen in the CD and FHH groups. In this regard, it is interesting that a study of a small case series of obese patients with idiopathic pubertal delay also found a high rate of accompanying behavior abnormalities (30). In addition, another group reported that ADD/ADHD leads to growth deficits unrelated to the use of psychotropic medications (39). Prospective studies will help determine the significance of the observed association and indicate whether a link exists between the underlying mechanism of ADD/ADHD and the factors that control the onset of puberty.
In summary, our data indicate that although CD is the most common cause of delayed puberty, a thorough evaluation for underlying illnesses and familial predisposition is certainly warranted. We hope that the insights derived from our study of etiologies, gender predominance, and genetic predisposition will prompt further research and eventual understanding of idiopathic pubertal delay. This condition clearly has a genetic component, and new advances in genetic research may provide tools to aid our understanding of the factors that regulate the timing of puberty (40).
Acknowledgments
We thank Dr. Paul A. Boepple for helpful discussion regarding study design and data interpretation as well as critical review of the manuscript. We also thank Dr. Daniel Nigrin for help with identification of research subjects through database queries.
Footnotes
This work was supported by NIH Grant K23-RR-15544 (to M.P.) and Lawson Wilkins Genentech Clinical Scholar Award (to M.P.).
Abbreviations: ADD, Attention deficit disorder; ADHD, attention deficit hyperactivity disorder; BA, bone age; BMI, body mass index; CA, chronological age; CD, constitutional delay of growth and maturation; FHH, functional hypogonadotropic hypogonadism; HT, height; Hyper H, hypergonadotropic hypogonadism; Hypo H, hypogonadotropic hypogonadism; WT, weight.
Received September 7, 2001.
Accepted January 4, 2002.
References
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