Evidence of Cardiovascular Morbidity Clinical Trial
Official title:
Biochemical and Radiological Indicators of Cardiovascular Morbidity in Children With Premature Pubarche
Children with premature pubarche will have radiological and radial artery tonometry evidence of cardiovascular morbidity at diagnosis when compared to matched controls.
Premature pubarche (PP), also called premature adrenarche (PA), is the early appearance of
pubic hair before the age of 8 in girls and before 9 in boys. It had been shown that PP
results from excess adrenal androgens. The terms PP and PA are used synonymously and differ
from premature (precocious) puberty, the early activation of hypothalamic-pituitary gonadal
axis. The incidence of PP is almost tenfold higher in girls than in boys. PP in the absence
of congenital adrenal hyperplasia, virilizing ovarian or adrenal tumors has been regarded in
the past as a benign phenomenon that may be associated with transient acceleration of growth
and bone maturation and was not thought to have an adverse effect on the onset and
progression of puberty and on final height in most patients. However, recent evidence
suggests that hyperinsulinemia and obesity are common features in prepubertal and pubertal
girls with a history of PP. Peri- and post-pubertal girls with PP exhibit an increase in
incidence of hirsutism and polycystic ovary syndrome (PCOS). PCOS, a common hyperandrogenic
disorder of women, is characterized by functional ovarian hyperandrogenism (FOH). FOH is
defined as a 17-hydroxyprogesterone and/or androstenedione level >2 SD above that of the
mean for control subjects after subcutaneous gonadotropin-releasing hormone agonist (GnRHa)
stimulation during dexamethasone suppression of the adrenal glands. An increased risk of
ovulatory dysfunction and FOH in adolescence detectable 3 years after menarche has also been
reported in children diagnosed with PP. Serum triglyceride levels in premature adrenarche
patients are higher when compared to controls throughout all stages of pubertal development.
Boys with PP show reduced insulin sensitivity, independent of obesity, as observed in girls
with PP. In Hispanic and Caribbean girls studies have shown prenatal influence on the
development of PP. The lowest birth weights are found in this group of girls with PP who
also have pronounced hyperinsulinism. Also, the presence of dyslipidemia in girls with PP
depends on weight gain after birth. It has been shown that prepubertal girls are inherently
more insulin resistant than boys which has been suggested to be related to the intrinsic
difference in sex linked genes. Early metformin therapy prevents progression from PP to PCOS
in a high risk group of former low birth weight girls, supporting the key role of insulin
resistance in the ontogeny of PCOS.
Early intervention in PP can be initiated before marked obesity, diabetes, hypertension and
increased cardiovascular morbidity related to insulin resistance become associated with
endothelial dysfunction and abnormal vascular structure. Any intervention to decrease
cardiovascular morbidity and mortality related to obesity and insulin resistance optimally
begins in childhood. The short term goal of this proposal is to collect non-invasive
evidence of cardiovascular disease morbidity risk factors at the time of PP diagnosis and to
determine how they progress. Symptomatic endpoints used in most adult intervention trials,
i.e. cardiac events and death, are not applicable in the setting of childhood disease.
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