Childhood Adiposity and Adolescent Sex Steroids in the Exploring Perinatal Outcomes Among Children Study

Catherine Kim; Kylie K. Harrall; Deborah H. Glueck; Daniel Shumer; Dana Dabelea

Disclosures

Clin Endocrinol. 2019;91(4):525-533. 

In This Article

Discussion

In a cohort of children who had not yet completed their pubertal transition, we found that, among boys, more rapid growth in fat depots predicted greater risk for low testosterone concentrations roughly 6 years later. These associations were independent of other factors known to affect testosterone production, including LH, insulin, leptin and hepatic fat. These associations were also independent of baseline quantities of fat. These findings suggest that the speed of fat accumulation, a modifiable exposure, is an important determinant of future androgen profiles in boys. We did not observe relationships between fat depot and hormone profiles in girls, suggesting that neither VAT nor SAT are independent determinants of sex steroids in healthy girls without precocious puberty.

Although adolescence represents a time of relatively rapid accumulations in adipose tissue and changes in sex steroids, few reports have examined whether the associations observed in adults are also present in healthy children as they accumulate fat and transition through puberty.

It has long been recognized that greater body weight and body mass index in adult men is inversely related to testosterone concentrations, particularly higher fat mass.[17] Fewer studies have been able to examine whether changes in fat mass over time lead to changes in sex steroids, although these reports also suggest that the loss or accumulation of fat can influence sex steroids. In one secondary analysis of a randomized trial of weight loss, we found that reductions in VAT and SAT resulted in increases in testosterone among overweight adult men.[18] In two other observational cohorts, men with the greatest weight gains had the greatest declines in testosterone over time.[19,20] Prepubertal obese boys tend to have higher testosterone than nonobese boys[21,22] as well as earlier timing of puberty,[23] but obese pubertal boys have lower testosterone levels than nonobese pubertal boys.[24,25]

Our findings build upon this literature in several respects. First, we note that the rapidity of accumulation of fat is important for boys, with more rapid accumulations increasing risk of low testosterone in later adolescence. This represents a potentially modifiable exposure for children who are obese. Visceral adipose tissue growth, as opposed to growth of other tissues, is difficult to assess using metrics that are easily accessible to the practicing clinician. However, lower energy intake from fat and higher levels of aerobic physical activity predict fat deposition in adolescents.[26,27] Thus, for the practicing paediatrician, the emphasis on these healthy behaviours with the intention of limiting harmful fat accumulation can, in turn, influence sex hormone profiles. Preventing rapid gains in fat could ameliorate downstream effects on sex hormones. This implies that slowing the rate of such fat accumulation will affect androgen levels in adolescence, which in turn may impact future cardiovascular risk.[28]

Second, we were able to quantify fat depots precisely through the use of MRI as opposed to anthropometric measures, which may not represent adiposity in specific compartments. In contrast, we did not find associations between fat mass and hormone levels in girls. Previous studies have noted that girls have testosterone levels directly correlated with degree of obesity,[2,3,29] particularly VAT.[29] Our results may have differed from these previous reports for several reasons. We conducted a longitudinal examination of the association between fat and future testosterone, and it is possible that fat mass in girls has relatively little effect, compared with other factors that are also rapidly changing during the pubertal transition.[3] These factors include LH and fasting insulin, which are related to testosterone levels, even after adjustment for adiposity and age.[3] In addition, we examined the relationship between specific fat depots rather than overall body mass, and it is possible that the associations previously observed between body mass and hormone levels reflect other fat compartments than VAT and SAT.

Finally, studies have focused upon the relationship between obesity and puberty timing, rather than sex steroid levels or specific fat measures per se. Puberty is a complex transition of which sex hormones are only a single dimension, and thus it is possible that a stronger relationship exists between obesity and puberty than between VAT, SAT and future sex steroid concentrations in girls.

Among boys, the associations between rate of fat mass accumulation and low testosterone later in adolescence remained significant after controlling for several potential mediators or confounders of the relationship between fat and testosterone, namely insulin,[30] leptin,[31] LH[31] and hepatic fat fraction.[32] In contrast, the relationships of baseline VAT and baseline SAT with future testosterone were no longer significant after adjustment for these factors, consistent with prior studies suggesting a potential mediating role of these factors. This suggests that rapid accumulations in fat affect sex steroid production through other pathways. Although speculative, such pathways could include gut hormones such as ghrelin, which may have inhibitory effects upon the reproductive axis.[33] Other potential pathways include other adipokines that may affect sex steroid production through direct effects on the gonads or through hypothalamic-pituitary pathways.[33] Although the majority of circulating androgens in boys originate in the testes, small amounts of the adrenal androgen dehydroepiandrosterone are converted to androstenedione and then to testosterone. The lack of association between VAT and SAT with DHEA suggests that these particular fat depots did not have a large impact on adrenal androgen production. However, it is possible that adrenal androgen production may have influenced deposition of fat and possibly gonadal testosterone production.[34] Finally, despite the fact that the associations between fat mass accumulation and lower testosterone persist after controlling for LH, the interpretation of this is complicated by the fact that testosterone and LH function in a feedback loop. Normal LH concentrations in a male with hypogonadism may actually signify an LH level that is inappropriately low. Therefore, the finding that fat accumulation and low testosterone are associated while controlling for LH may inappropriately minimize the role of obesity in affecting the hypothalamic-pituitary-testicular axis and its healthy functioning.

The strengths of this report include a relatively large, diverse longitudinal cohort which characterized adiposity using MRI at 2 points in time along with sex hormone measures and possible mediators. We also used a novel and powerful method of analysis[16] that allowed us to meaningfully interpret sex hormone levels below the level of detection, while avoiding potential bias due to imputation or extrapolation of data. However, there are several limitations. We examined multiple sex steroids, and we performed multiple comparisons. Thus, some of the observed associations may have been due to chance and need to be replicated. The optimal method of estimating bioavailable testosterone and oestradiol in lieu of direct measurements is controversial due to possible changes in binding affinity with age and population characteristics. Thus, we did not measure free fractions of sex steroids and sex hormone binding globulin, and it is possible that use of these measures might yield a different pattern of results. We considered this issue carefully in constructing the analysis plan, which rests on the probability of absence of detectable testosterone. Since total testosterone exists in equilibrium with free testosterone, the lack of detectable total testosterone likely indicates low levels of free testosterone, regardless of SHBG levels. If we had examined level of testosterone as the outcome with a conventional survival analysis, we agree the lack of SHBG would be a significant limitation. We did adjust for hepatic fat fraction, which is an indicator of fatty liver and correlated with sex hormone binding globulin, and adjustment did not alter the pattern of results. Body composition may have bidirectional associations with sex hormones,[18] and it is possible that changes in sex hormones influenced body fat deposition. To examine whether this is the case, we would need to examine whether sex hormone changes predicted VAT and SAT at visit 2, after adjustment for baseline VAT and SAT, which we plan to examine in the future.

We conclude that the rate of fat accumulation in children may influence their hormone profiles in later puberty, and specifically that more rapid fat accumulation in boys appears to be associated with subsequent risk of low testosterone. These associations do not seem to occur via insulin levels, hepatic fat, LH or leptin. Future studies should explore the potential role of other adipokines or gut peptides upon sex steroid production, and whether sex steroid profiles in children alter risk of future adiposity and sex hormone disorders in adults. In order to determine whether the impact of VAT upon sex steroid profile persists when participants have completed puberty, another assessment of the cohort is planned when participants are approximately 22 years of age. Until that assessment, it is not known whether the impact of obesity upon sex steroid profiles is limited to the late-pubertal stage.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....