A variable mix of genetic, epigenetic and environmental factors may result in a “mismatch” sequence of reduced prenatal weight gain (with reduced subcutaneous adipogenesis, and thus a reduced capacity for safe lipid storage) and augmented postnatal weight gain (with augmented lipogenesis, and thus an augmented need for lipid storage). Such a “mismatch” may lead to ectopic lipid accumulation, particularly in the liver and viscera (central obesity), whose endocrine reflection tends to be insulin resistance [1,2].

In prepubertal girls, a lowering of circulating SHBG and adiponectin, and an amplification of adrenarche (high DHEAS levels sometimes eliciting a precocious pubarche) are among the responses to such an ectopic accumulation of lipids. These responses can be viewed as being adaptive since they result in accelerations of body growth and maturation that conceivably represent a concerted feedback mechanism to reduce ectopic adiposity.

If this first mechanism does not suffice to reduce ectopic fat, then girls may develop another acceleration of growth and maturation by activating their gonadotropic axis, conceivably again in a homeostatic attempt to escape from central obesity. This concept can largely explain the worldwide trends towards younger ages of pubertal onset and menarche in girls [3-5].

During the first years post-menarche, both growth- and maturation-accelerating mechanisms lose their homeostatic efficacy on ectopic fat, because body growth is virtually exhausted. If the energy balance remains chronically positive, then the underpinning drive of ectopic adiposity will also remain, and the endocrine responses to this drive will also persist, thus potentially resulting in a full-blown phenotype of adolescent PCOS including LH hypersecretion which, in turn, can drive ovarian androgen excess and oligo-anovulation.

In Barcelona, a  low-dose combination (SPIOMET) of spironolactone (to raise the activity of brown adipose tissue), pioglitazone (to raise adiponectinemia) and metformin (to raise the circulating concentrations of appetite-attenuating GDF15) was recently found to be capable of reducing ectopic fat – without causing a loss of body weight – thereby reversing the entire PCOS phenotype in adolescent girls and young women [6,7]. Marked increments of insulin sensitivity and adiponectinemia were among the effects of SPIOMET treatment. Given the emerging evidence from Córdoba [8] that hypo-adiponectinemia may be a key driver of obesity-induced precocious puberty, it may be worthwhile to explore whether SPIOMET in mini-dose allows young “mismatch” girls to escape from an accelerated maturation (early pubarche, early puberty and/or early menarche) and also from adolescent PCOS.

Perhaps SEEP’s PEG (= SGA) investigators will be the first to test whether mini-dose SPIOMET can slow down the rapid tempo of maturation in young “mismatch” girls with reduced prenatal weight gain (birthweight for gestational age in the lower tertile, thus below -0.44 SD) and augmented postnatal weight gain (BMI for chronological age in the upper tertile, thus above +0.44 SD).

Conflicts of interests

The authors declare no conflicts of interest related to this article.

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