Questions Addressed and Suggestions
How Does Obesity Affect age Cutoffs for the Evaluation of the Young Girl With Early Breast Development?
In the general approach to evaluating a girl with early breast development, the main goal is to differentiate true GnRH-dependent CPP from benign variants, such as premature thelarche. Progressive CPP can lead to early onset of menses and reduced adult height, and more importantly, it may be a sign of an undiagnosed underlying hypothalamic/pituitary lesion. Therefore, initial evaluation is aimed at identifying those girls who warrant further investigations (such as brain imaging) and pubertal suppression with GnRH analogues (for height preservation and psychosocial concerns).[15,16,34–37]
Several studies have demonstrated that age of breast development is strongly associated with body weight.[1,14–17,37,38] The Pediatric Research in Office Settings (PROS) study was one of the first large studies to show that breast development was occurring at younger ages than the previously used norms, and that younger age of development was correlated with higher BMI Z-scores. Subsequent studies using both inspection and palpation to minimize any impact of lipomastia have yielded similar results and demonstrated a progressive relationship between increased BMI and earlier breast development. In fact, elevated BMI has been reported as the strongest predictor of earlier age of thelarche.[14,17,37]
However, this weight-related decrease in age of breast development is not always associated with evidence of early "true" central puberty. Aksglaede et al compared pubertal development in cohorts of girls from 1991 and 2008. Although mean age of thelarche had declined by a full year in the 2006–2008 cohort, population-based gonadotropin levels had not changed significantly, suggesting that earlier breast development was not necessarily associated with earlier activation of the hypothalamic-pituitary-gonadal (HPG) axis. This lack of uniform HPG axis activation may explain, in part, why the average age of breast development has decreased more substantially than the average age of menarche in recent population studies.[5,39,40]
On the other hand, although less marked, there is a correlation between increasing BMI and declining age of menarche, suggesting that obesity is not only a risk factor for early breast development, but also early central puberty in some cases.[39–43] Those obese girls with early breast development who have initiated true puberty may be at risk of early menarche and compromised adult height. Confirming HPG activation in these cases will inform the counseling and anticipatory guidance provided to the patient and family/caregiver regarding likely progression of pubertal development and allow for consideration of treatment. Furthermore, given the lack of data demonstrating that obesity is an independent predictor of normal central nervous system (CNS) imaging in those with CPP (see "Does Obesity Affect Age Cutoffs for Evaluation With MRI in the Case of CPP?" below), it seems prudent to identify those girls with HPG axis activation so they can be assessed for pathologic/neurogenic causes if warranted.
Suggestion: Age cutoffs for the evaluation of the obese girl with early breast development should not differ substantially from the nonobese girl. These girls should have a complete history and physical examination. If needed, palpation should be carefully performed to distinguish between lipomastia and true breast tissue. Presence of firm glandular tissue under the areolae (Tanner stage 2) or extending beyond (Tanner stage 3+), best palpated with the patient in the supine position indicates thelarche. For those with confirmed thelarche, we recommend evaluation include assessment of the HPG axis to identify those with CPP.
Does Obesity Affect Results of Diagnostic Testing When Performed?
Gonadotropins. GnRH-dependent central precocious puberty is distinguished from other causes of precocity by pubertal levels of LH. A basal LH value of ≥ 0.3 mIU/L is commonly used to diagnose CPP (although cutoff is specific to local assay) and obviates the need for GnRH stimulation testing. Baseline LH levels, however, do lack sensitivity below these thresholds and do not definitively rule out CPP.[44–47] Therefore, GnRH stimulation testing can be performed if clinical presentation/progression continues to suggest CPP. Following administration of GnRH or a GnRHa, a peak LH level outside the normal range for the assay (> 5.0 mIU/L for most assays) indicates an activated HPG axis.[36,48,49]
Given that our goal is to identify those obese children with HPG axis activation, we must consider whether obesity affects the results of diagnostic testing. This question has been addressed in children indirectly through physiologic studies of the effects of BMI on LH levels. For example, Bordini et al compared sleep-related LH levels in prepubertal and pubertal girls with and without obesity and noted that obese pubertal girls had a significantly blunted sleep-related LH rise compared with nonobese girls, including some profiles that overlapped with those of prepubertal girls. Another study showed reduced LH pulse frequency during overnight sampling in prepubertal and early pubertal (Tanner stage 2) obese girls; however, the pulse frequency normalized by Tanner stage 3. These data are interesting and speak to how obesity may influence the HPG axis.
However, these concepts have shown variable translation to clinical studies of early puberty. The available data show that basal, nonstimulated LH values do not differ between obese and nonobese girls with CPP;[52–54] however, other studies have shown that responses to GnRH stimulation testing may be impacted by BMI, with obese girls having significantly lower LH peaks and LH/FSH (follicle-stimulating hormone) ratios than nonobese girls.[53–55] This observation, again, seems to only apply during early stages of puberty (Tanner 2–3), as LH levels after GnRH stimulation in Tanner stage 4–5 showed no correlation with BMI.[52,55] These clinical studies, therefore, raise the possibility of false negative GnRH stimulation tests and missed diagnoses of CPP in obese girls. We note, though, that this possibility is only theoretical, as all girls in these studies who had been diagnosed clinically with CPP also already had stimulated LH values above assay cutoffs for diagnosis of CPP.
Suggestion: Basal LH values remain an effective first-line test for identification of CPP, followed by stimulation testing when warranted. Obesity is associated with lower peak LH responses to GnRH stimulation testing in early puberty. This effect could theoretically lead to false negative tests; thus, it is important to continue to consider CPP if other clinical features are consistent with this diagnosis.
Bone age. Advanced skeletal maturation is among the clinical features used to diagnose CPP, and significant bone age (BA) advancement is typically more suspicious for true CPP than benign entities such as premature thelarche or slowly progressive/intermittent CPP.[34,35] However, advanced BA, along with increased growth velocity, is often observed among obese children even without early puberty, potentially confounding diagnostic/discriminatory utility.[9,36]
Studies have shown a strong correlation between BA standard deviation score (SDS) and BMI SDS even at young ages within the general population.[56–58] In a study of 167 children (age 3–18 years), those with obesity had more advanced BA compared with those without obesity. BA was advanced more than 2 years in 33% of obese children compared with only 1% of nonobese children. Another study also observed the effect of obesity on BA advancement, specifically among preschool children (age 3–6 years).
In the assessment of children with early puberty, significantly (> 2 years) advanced BA typically favors CPP over benign variants, although such advancement can occasionally be seen in girls with both isolated premature thelarche and premature adrenarche.[61,62] In these benign variants, as in the population studies discussed above, higher BMI Z-scores are associated with more advanced BA.[60–62] Thus, perhaps not surprisingly, obesity not only blurs the distinction between bone ages seen among prepubertal vs pubertal children, but it can also confound the distinction of CPP from benign variants of early development.
Suggestion: Advanced BA is common in obese girls and should be used with caution to distinguish CPP from other forms of sexual precocity.
Does Obesity Affect age Cutoffs for Evaluation With MRI in the Case of CPP?
Although most cases of CPP in girls will be idiopathic, the differential diagnosis does include potentially serious and treatable CNS lesions. In a systematic review and meta-analysis, the prevalence of abnormal MRI findings within the overall CPP population was 9% for girls younger than 8 years, with the prevalence in individual studies ranging from 0% to 27%.[8,11,63–65] When stratifying based on age, prevalence was much higher for the girls younger than 6 years compared with those aged 6 to 8 years (19%-25% vs 2%-11%).[66–68] Indeed, younger age is the strongest predictor of CNS pathology, and MRI is routinely recommended in all girls younger than 6 years.[69,70] The benefit of neuroimaging in girls with CPP older than 6 years of age remains controversial, with some studies in support[11,67,71] and other studies against routine MRI.[63,65,70,72,73]
Chalumeau et al aimed to identify clinical features that could predict CNS abnormalities and the need for MRI among a group of 197 children, 11 (5.6%) of whom had CNS findings. Using a BMI Z-score cutoff of > 0.5, they found no significant association (positive or negative) between BMI and risk of CNS abnormalities. Although the number of individuals with CNS findings in this study was small, similar studies have also found no difference in BMI SDS between girls with CPP and normal vs abnormal imaging.[67,71,74] In fact, none of these studies identified any strong clinical or biochemical predictors of CNS abnormalities and therefore continued to recommend routine imaging in girls younger than 8 years. It has been suggested that obesity is a strong enough basis for early puberty that MRI can be deferred, but data from the above studies indicate that presence of obesity does not fully mitigate the risk of underlying pathology when the early puberty is secondary to true CPP.
Suggestion: MRI should be performed for all girls younger than 6 years with CPP, regardless of weight status. For girls aged 6 to 8 years, decision around MRI should be individualized and based on the same factors as in children without obesity, such as medical history, racial/ethnic population group, family history of pubertal timing and neurologic risk factors.
How Does Obesity Impact Consideration of GnRHa Therapy?
Bone age and Prediction of Adult Height Outcomes. As discussed above, BA may have limited discriminatory value in the diagnosis of CPP in obese girls; however, it remains an important tool for predicting height outcomes, which may impact counseling and treatment decisions.[9,36] BA advancement can be significant in obese girls, which raises concern around the possibility of compromised adult height.[60,61] However, differences in prepubertal growth between obese and nonobese children may mitigate this risk. Studies show that although children with obesity early on in life already show BA advancement, this is often associated with early growth acceleration and tall stature for chronological age. This increased height gain in childhood is then followed by earlier slowing of linear growth—a pattern that results in adult height approximating calculated mid-parental height (MPH).[38,75–78]
In the setting of CPP and early puberty, some[79,80] but not all[81–84] studies have reported that obese girls display more exaggerated BA advancement compared with nonobese girls. In one study by Park et al, in which BA was similarly advanced (2 years) in obese and nonobese girls, predicted adult height (PAH) was significantly lower than MPH in the nonobese group, while PAH and MPH were not significantly different in the obese group. This suggests that not all BA advancement in obese girls will lead to compromised predicted height, again, likely due to the differences in prepubertal growth patterns. Both groups of girls were treated in this study and use of GnRHa was associated with increased PAH at the end of treatment in both the obese and nonobese girls. As studies evaluating height outcomes in obese girls with untreated CPP are lacking, it is not clear what PAH/near adult height the obese girls would have attained without intervention. It is possible that obese girls without concerning PAHs may not warrant therapy. Regardless, this study implies that BA led to accurate prediction of adult height in the obese girls, and that these heights were then increased by GnRHa therapy. Studies are limited, but no data suggest that use of BA for height prediction in obese children is less accurate than in nonobese children. Thus, it is likely that BA may still be used to determine PAH in obese girls and that those with compromised PAH may benefit from consideration of GnRHa therapy.
Suggestion: Despite significant BA advancement in obese girls with CPP, PAH may be preserved due to early accelerated growth. BA can be used to predict adult height in obese girls with CPP, and the resulting PAH can be used to inform counseling around GnRHa treatment.
Effectiveness of GnRHa Therapy. GnRH analogues have been the standard of care in the treatment of CPP since the 1980s. They act by providing a continuous source of GnRH stimulation to the pituitary gonadotrophs leading to their desensitization and subsequent suppression of LH, follicle-stimulating hormone, and sex steroid production. The use of these agents prevents further pubertal development and ideally slows BA advancement, thereby extending the period of growth and preserving/increasing adult height.[36,86]
In our context, it is important to consider if obesity affects the degree of GnRHa-induced pituitary-gonadal suppression and whether GnRHa therapy is as effective in obese as nonobese girls. The answer to the first of these 2 questions appears to be no. Sinthuprasith et al directly compared suppression of gonadotropins during GnRHa treatment among obese and nonobese children and demonstrated that all subjects in both groups displayed mean peak-stimulated LH levels of < 4 IU/L. Similar dosing of either leuprolide or triptorelin was used in obese and nonobese children.
In terms of height outcomes, available data indicate that use of GnRHa in obese girls with precocious puberty can slow BA advancement and allow them to achieve adult heights within their expected mid-parental target ranges, as is observed among nonobese girls.[82–84,87,88] Kim et al directly compared the effect of GnRHa therapy in obese children (N = 74) with that in nonobese children (N = 108). BA advancement decreased similarly in both groups in response to therapy. Both groups also showed significant improvement in PAH and height SDS for BA while on therapy, attaining near adult heights comparable to their MPH. As noted above, Park et al also found that obese children improved their PAH while on GnRHa therapy and reached near final heights exceeding their MPH.
Suggestion: GnRH analogues are effective in increasing/preserving adult height in obese children with CPP.
Does GnRHa Therapy Worsen Obesity?
The safety and efficacy of GnRH analogues is well-established,[36,86] but the long-term impact on body weight has been the interest of much research. A small number of studies have reported increases[88,90–93] or decreases in BMI SDS associated with use of GnRHa to treat girls with CPP. However, the majority of studies have shown no significant change,[95,96] or transient increases[81,87,97–99] during treatment that decrease after termination of therapy. These studies and others have been reviewed by 2 different writing groups[36,86] with the overall conclusion being that BMI SDS before treatment and BMI after treatment at near adult height are not significantly different from each other;[94,100–102] that is, GnRHa therapy is not associated with long-term worsening of obesity among girls with CPP.
It is noted that many girls with CPP are obese at the start of therapy. Thus, even if GnRHa use is not associated with increases in BMI SDS, there is a need for counseling and intervention regarding healthy diet and lifestyle for many children with CPP and their families. Given data indicating that some nonobese girls may also experience a transient increase in BMI SDS with initiation of GnRHa therapy, the need for lifestyle counseling may also be relevant to nonobese children with CPP to help ensure any increases do not persist posttreatment.[81,84,89,95,101–104] Long-term studies of treated girls with CPP provide reassurance that treatment is not associated with increased risk of obesity or poor metabolic outcomes.[95,104] Lazar et al, for example, followed a historical cohort of former CPP girls into the third to fifth decades of life and found that the mean BMI and BMI distribution of both treated and untreated girls with CPP were similar to the normal population.
Suggestion: Obesity should not be a barrier to GnRHa treatment among girls with CPP.
J Endo Soc. 2022;6(1) © 2022 Endocrine Society