Approaches to Identify Factors Associated with Pubertal Timing in Self-Limited Delayed Puberty

Abstract

Introduction: Children with self-limited delayed puberty (DP) (constitutional delay) enter puberty after variable waiting times, and the factors associated with their eventual pubertal timing are not well understood.

Methods: We conducted a retrospective study of 99 girls and 228 boys with self-limited DP at an academic medical center between 2000 and 2015. To define features and potential subtypes of self-limited DP, we performed group-based trajectory modeling on childhood growth and latent-variable factor analysis on clinical characteristics. We then conducted time-to-event analyses to identify associations with pubertal timing.

Results: We identified two distinct growth trajectories in individuals with self-limited DP: one with stable and the other with declining height percentiles. Latent-variable factor analysis identified five factors underlying clinical variation that appear to correspond to genetic height potential, body mass index, childhood growth, parental pubertal delay, and medical issues (attention-deficit/hyperactivity disorder and inhaled glucocorticoid use). We observed correlations between pubertal timing and bone age (p = 0.01), childhood height (p = 0.004), and midparental target height (p < 0.001), but not with parental pubertal delay or with testosterone treatment in boys.

Conclusions: By illustrating the heterogeneity within self-limited DP and identifying factors underlying this heterogeneity, our study suggests that there may be multiple causes of self-limited DP. However, our ability to determine when puberty will eventually occur remains limited. Dissecting self-limited DP into its component subtypes may inform future studies of the mechanisms contributing to pubertal delay as well as studies of the short- and long-term outcomes of self-limited DP.

Keywords: Constitutional delay; Growth trajectory; Self-limited delayed puberty; Testosterone treatment.

Fig. 1.. Patterns of childhood growth from group-based trajectory modeling of height

Group-based trajectory modeling of height Z-score residuals after adjusting for midparental height showed two distinct trajectories, with participants in Group 1 exhibiting a minimal decline in height Z-score residuals and participants in Group 2 exhibiting a more substantial decline in height Z-score residuals over time. Dashed lines indicate standard errors.

Fig. 2.. Representative growth charts by sex and growth pattern

Growth charts of a girl (A) and a boy (B) with stable height percentiles across childhood and of a girl (C) and a boy (D) with declining height percentiles across childhood. Arrows indicate midparental height (MPH).

Fig. 3.. Effect of testosterone treatment on time to pubertal onset in boys with self-limited delayed puberty

Survival analysis of time to pubertal onset comparing (A) all boys treated vs. not treated with testosterone, (B) testosterone-treated vs. a subset of untreated boys matched by age, and (C) boys managed by “early-treating” vs. “late-treating” providers. In the unmatched analysis (A), pubertal onset occurred later in boys treated with testosterone, but this difference was no longer observed after age-matching (B). Similarly, no difference in time to pubertal onset was seen between those managed by “early-treating” vs. “late-treating” providers (C). Gray shading indicates standard errors.