Longitudinal Investigation of Pubertal Milestones and Hormones as a Function of Body Fat in Girls

Abstract

Context: Epidemiologic studies have demonstrated that overweight/obese girls (OW/OB) undergo thelarche and menarche earlier than normal weight girls (NW). There have been no longitudinal studies to specifically investigate how body weight/fat affects both clinical and biochemical pubertal markers in girls.

Objective: To investigate the effect of total body fat on reproductive hormones and on the maturation of estrogen-sensitive tissues during puberty in girls.

Methods: Ninety girls (36 OW/OB, 54 NW), aged 8.2 to 14.7 years, completed 2.8 ± 1.7 study visits over 4 years. Visits included dual-energy x-ray absorptiometry to calculate total body fat (TBF), Tanner staging, breast ultrasound for morphological staging (BMORPH; A-E), pelvic ultrasound, hormone tests, and assessment of menarchal status. The effect of TBF on pubertal markers was determined using a mixed, multistate, or Cox proportional hazards model, controlling for baseline BMORPH.

Results: NW were older than OW/OB (11.3 vs 10.2 years, P < .01) at baseline and had more advanced BMORPH (P < .01). Luteinizing hormone, estradiol, and ovarian and uterine volumes increased with time with no effect of TBF. There was a time × TBF interaction for follicle-stimulating hormone, inhibin B, estrone, total and free testosterone, and androstenedione: Levels were initially similar, but after 1 year, levels increased in girls with higher TBF, plateaued in girls with midrange TBF, and decreased in girls with lower TBF. Girls with higher TBF progressed through BMORPH stage D more slowly but achieved menarche earlier than girls with lower TBF.

Conclusion: In late puberty, girls with higher TBF demonstrate differences in standard hormonal and clinical markers of puberty. Investigation of the underlying causes and clinical consequences of these differences in girls with higher TBF deserves further study.

Trial registration: ClinicalTrials.gov NCT02583646.

Keywords: adolescent; body fat; neuroendocrine; obesity; puberty.

Published by Oxford University Press on behalf of the Endocrine Society 2021.

Figures

Figure 1.

Protocol schema. Maturation of breast morphology from stage C to E is shown for a representative participant who was studied at 6 visits from age 9.9 years (premenarche) to 12.3 years (7 months post menarche). Solid black lines indicate hypothetical transition points between breast morphological stages, black dotted lines indicate study visits, and the red dotted line indicates menarche. The study procedures completed at each visit are denoted by an “X” below the graph. DXA, dual energy x-ray absorptiometry.

Figure 2.

Ultrasound-based breast morphological staging system used in the current studies. The current staging system includes an additional stage, stage D/E, beyond that in Bruni et al (19), Mann et al (20), and Carlson et al (10).

Figure 3.

Diagram of multistate model of transitions among breast morphological stages A to E.

Figure 4.

Higher total body fat percentage (TBF) is associated with slower progression out of breast stage D. This figure displays the number of transitions between breast morphological stages (BMORPH) C, D, D/E, and E as a function of TBF. BMORPH stages A and B are excluded because of low sample size. The y-axis shows the median number of transitions occurring over 100 person-years, based on 5000 simulations, as previously described (26). The x-axis shows mean TBFs. Transitions for mean TBFs of 14% to 54% are connected by a solid black line to aid visualization. Error bars indicate 95% CI based on percentiles of the simulated values. As highlighted by the black box and arrow, for an individual in breast stage D, a higher mean TBF is associated with a higher probability of remaining in stage D (second column) and a lower probability of transitioning to stages D/E (third column) or E (fourth column) after 1 year. Mean TBF has no effect on the probability of regressing to stage C (first column). See Supplementary material for additional details.

Figure 5.

Temporal change in A, gonadotrophins, sex steroids, inhibin B, the modified vaginal maturation index (mVMI) and B, end-organ measures of estrogen or follicle-stimulating hormone (FSH) effects as a function of percentage total body fat (TBF). The x-axis reflects time since first study visit (V1). Models were adjusted for breast morphological stage at V1 and time of blood draw (am/pm). For models using square-root or natural log transformations, estimates were back-transformed for visualization purposes. aEffect of time, P < .005. bTime × TBF interaction, P < .05. cTime × time × TBF interaction, P < .05. Max, maximum.

Figure 6.

Survival curves of age at menarche in girls with percentage total body fat (TBF) of 20%, 30%, or 40% demonstrating that menarche occurred earlier in girls with higher TBF. Shaded areas indicate the 95% CI.