Areas of Uncertainty and Future Directions
For all the questions discussed above, additional direct evidence would allow conclusions and suggestions to be strengthened; the currently available literature leaves room for areas of uncertainty and future study. Perhaps the most pertinent unresolved issue is whether the answers to the questions posed above differ for obese males with CPP. Overall, data do suggest a secular trend toward earlier age of testicular enlargement in boys; however, this effect has not been seen in all studies and its magnitude is smaller than that observed in girls.[19–21] Obesity is likely a contributor to earlier puberty in boys, but here too, the effect is smaller and less consistent than that seen in girls,[22–24,37] with some reports of boys with the highest BMI cohorts even experiencing delayed pubertal onset.[19,105] Given these data, we would not advocate for changing age cutoffs or initial evaluations for obese compared to nonobese boys with CPP. Data around the other questions posed here are quite limited and demonstrate the need for more research regarding boys with CPP. One paper did assess the effect of obesity on basal and stimulated LH values. As in girls, there was an observed effect in boys, in this case with both basal and stimulated LH values being lower in obese compared with nonobese boys, again, raising the theoretical concern of possible false negative results. Another paper also examined the effect of GnRHa therapy on BMI in boys with CPP and did not note any significant change over the course of therapy. Without more robust data, there is no reason to suggest answers to the questions posed in this review differ for boys compared to girls.
Regarding the mechanism for BA advancement in obesity, dehydroepiandrosterone sulfate (DHEAS) may play a role as higher DHEAS levels are often found in obese children. Increased adrenal androgen production, with subsequent aromatization to estrogens, may be a key driver of bone maturation and as such, a strong predictor of BA advancement.[60,61,108,109] Therefore, some have recommended measuring DHEAS as an additional part of assessment for accelerated growth and BA advancement in obese individuals with early puberty. While this consideration is mechanistically interesting, it is unclear how the results would impact clinical care.
Another management-related area for future research is whether weight loss could have a role in slowing the rate of pubertal progression among children with CPP. This possibility has not been addressed directly, but BMI trajectory during childhood appears to influence pubertal timing. In a study of 160 obese prepubertal children followed for 1 year in a lifestyle program, girls who had a BMI reduction were less likely to have pubertal onset within the follow-up period. Another study showed that children whose BMI decreased during childhood achieved peak height velocity at older ages, suggesting later onset of puberty. A corollary to these data is the need for studies designed to assess whether lifestyle interventions and weight management in obese children with CPP could impact progression of puberty once it has started.
Finally, understanding of the genetic regulation of pubertal timing is expanding, both from the perspective of quantitative traits and disease-causing mutations. To date, several monogenic causes of CPP have been identified, resulting in identification of the etiology of an increasing number of cases of previously classified as "idiopathic". Researchers have investigated the inter-relationship among obesity, CPP, and some of these genetic causes. Obesity has not been shown to be associated (positively or negatively) with MKRN3 mutations, the most common monogenic cause of CPP.[113,114] However, obesity is a common finding among children with DLK1 mutations.[115–118] Although genetic testing is not currently standard in clinical practice, future research may help establish yield and cost-effectiveness in the workup of CPP, and particularly in the presence of obesity (especially central obesity) and other syndromic features.
J Endo Soc. 2022;6(1) © 2022 Endocrine Society