Does gonadotropin-releasing hormone analog therapy for central precocious puberty in girls affect the body mass index?

Precocious puberty in girls is defined as menarche before the age of 9.5 years. Conventional age cutoff for precocity in girls has been 8 years for thelarche, but considering a progressive decline in the age of thelarche being observed in most parts of the world (in one large meta-analysis globally, 3 months per decade from 1977 to 2013),^[1] a need to change the age of diagnosis of precocity was considered. This decline in age of thelarche is not linked to an earlier age of menarche, but rather may be associated with a slower progression to menarche.^[2] The goal of treating precocity is to prevent further progression of puberty, delay menarche, and preserve adult height.

Gonadotropin-releasing hormone (GnRH) analogs have been used to treat girls with precocity and girls with early normal puberty since the 1980s, to stop the pubertal progression, both for psychosocial reasons as well as to potentially gain some additional inches of height. Sustained high levels of GnRH analogs desensitize the gonadotropes to hypothalamic GnRH drive, causing hypothalamic–pituitary–gonadal axis suppression. This will halt or significantly retard the pubertal progression which gives the girl some more time to grow, even though at a reduced velocity compared to the pre-treatment stage, but without excessive increase (ideally no increase) in bone age (BA), and is likely to add some height in these girls having pubertal onset significantly earlier than the normal age range.

From the perspective of the readers regarding the magnitude of the benefit, a meta-analysis of controlled prospective studies showed that with GnRH analog therapy, there was a 0.63 standard deviation score (SDS) (95% confidence interval [CI] 0.17–1.08) increase in the adult height as compared to pre-treatment height prediction.^[1] The gain in height achieved depends on the age of starting therapy and BA advancement. The younger the girl, with a less advanced BA better the adult height.

GnRH analogs are generally safe and well-tolerated,^[3] but there are reports of increased body mass index (BMI) during GnRH analog therapy. Some studies indicate an increase in BMI,^[4-6] and others have conflicting results.^[7,8]

The current study by Hulse et al. addresses a relevant concern of a possible increase in BMI during GnRH analog therapy.^[9] The authors in their retrospective analysis of 80 girls treated in urban clinics used the conventional cutoff of 8 years for the definition of precocity, but they did not mention the distribution below and above 6–7 years or tempo of puberty, which are important parameters for treatment decisions and height prognosis. They followed up the children with auxology, Tanner staging, BA, and hormonal evaluation. An international consensus in the recent past suggested that clinical efficacy of such treatment can be interpreted by a slowing of growth velocity (GV), regression, or no progression of clinical signs of puberty, a progressive reduction of BA to chronological age (CA) ratio (BA/CA), and finally an increase in the predicted adult height/adult height.^[3]

Authors stopped treatment at CA of 10.5–11.5 years with concurrent BA of 12 years, which is appropriate as most of their peers will be pubertal by that time and height benefit plateaus with treatment beyond this stage. In this study, nearly 61% (49/80) of the girls were overweight or obese, which reflects population trends, more so in urban settings. Other than population trends, a contributing factor to the overrepresentation of overweight/obese girls in this cohort may be the fact that girls with excess adiposity are prone to precocious or early normal pubertal development.^[10]

The authors showed an increase in BMI through almost the entire treatment period. This increase was statistically significant at 1 year and at the end of the treatment, and relatively stabilized during the 2^nd and 3^rd years of treatment. Other studies in the recent past also showed this trend, though not unequivocally.

A recent retrospective Indian study of 179 girls with precocious puberty showed an increase in BMI from 0.4 (0.9) to 0.7 (0.9) SDS over ~2.8 years of therapy. Still, when BMI after treatment was compared to BMI at final adult height in the eligible 58 girls, there was a significant downward trend.^[4] Another study on 32 girls with a mean duration of 2.1 years showed a decline in BMI during therapy, i.e., from 0.5 ± 0.9 to 0.4 ± 0.9 SDS. The authors suggested that regular physical activity might have benefited the girls.^[7]

A recent meta-analysis of 46 studies, including 3606 girls, suggested an increase in BMI during the early treatment phase, which stabilized later, and there was no change in BMI at the end of treatment. Subgroup meta-analysis in this study suggested that girls with higher BMI were less affected by the increase in BMI compared to those with normal BMI.^[11] This increase in BMI may be explained by:

1. These girls are a subset with higher adiposity compared to the general population and tend to remain on their trajectory at least in the initial part of treatment

2. Slowing of GV may be reflected by higher BMI in the initial part of the treatment

3. Pubertal gain of adiposity may be more prominent in these girls, reflecting a subset of the general population in a more advanced stage of puberty, and this difference fades off as other girls in the population advance into normal puberty, eliminating this significant difference.^[12]

The growth velocity of children on GnRH analog therapy for central precocity progressively declines till about 18 months into treatment, and by 2 years of therapy, girls usually grow with a prepubertal growth velocity. Deceleration of velocity below normal for the age is usually not seen. Growth velocity below the normal prepubertal range can compromise height. This phenomenon is usually seen in girls with early and rapidly progressive normal puberty. Some experts have advocated the concomitant use of growth hormone to improve final adult height, but it has not shown good results.^[13] Authors also showed a statistically significant decrease in GV, but that is expected during the early part of the treatment. Hence, the success of the treatment should be interpreted with ΔBA/CA along with decelerated GV. Furthermore, the authors excluded girls with suboptimal pubertal suppression, making interpretation of the GV of the representative population difficult.