Evaluation of metabolic parameters and aortic elasticity in normotensive children with premature adrenarche

Objectives Premature adrenarche may be associated with an intrauterine programmed metabolic syndrome which should be considered as a warning sign for coronary heart disease due to accelerated atherosclerosis, hypertension, type 2 diabetes mellitus (DM), and polycystic ovary syndrome. Methods Seventy-three patients with premature adrenarche were evaluated for metabolic parameters and aortic elasticity to evaluate the susceptibility to atherosclerosis and compared with a control group. The patients were examined in two groups as overweight and nonoverweight, and metabolic and cardiac parameters were also compared among these groups. Strain, distensibility, and stiffness index parameters were used to evaluate aortic elasticity. Results Biochemical parameters and cardiac measurements were not statistically different between patients and controls. They also did not differ between patients with normal weight and overweight groups. Atherogenic index and insulin resistance were closely related and a positive correlation between cholesterol and triglyceride, and ascending aortic stiffness was found. Conclusions The results may suggest that cholesterol and triglyceride-related arterial involvement is more involved in the pathogenesis of arterial stiffness. It can be considered that ‘being overweight’ or ‘having metabolic profile characterized by insulin resistance and dyslipidemia’ are the major coexisting factors influencing the vascular structure, rather than increased androgens and premature adrenarche itself.

PCOS Features and Steroid Profiles Among Young Adult Women with a History of Premature Adrenarche

Context Premature adrenarche (PA) may increase the risk for polycystic ovary syndrome (PCOS). Objective To study features of PCOS in young adult women with a history of PA. Design and participants Thirty PA and forty-two control females were followed from prepuberty to young adulthood (median age 18.1 years). Main outcome measures Ovarian function, the use of contraceptives, and clinical and biochemical indicators of hyperandrogenism. Results We found no differences in the use of hormonal contraceptives (50 vs 50%, PA vs controls, respectively; P > .999), indication for using contraceptives (P = .193), or in the history of oligo- (17 vs 26%, P = .392) and amenorrhea (0 vs 0%, P > .999). Among women not using hormonal contraceptives, those with a history of PA had a higher prevalence of hirsutism (27 vs 0%, P = .023) but not acne (87 vs 67%, P = .252). Steroid profiles were broadly comparable between the groups, but PA women had lower sex hormone-binding globulin (SHBG) concentrations (30.1 vs 62.4 nmol/l, P < .001) resulting in higher free androgen index (3.94 vs 2.14, P < .001). The difference in SHBG levels persisted through BMI adjustment. SHBG correlated negatively with HOMA-IR (r -0.498, P = .003). Anti-Mullerian hormone concentrations were comparable between the groups (39.3 vs. 32.1 pmol/l, P = .619). Conclusions PA was not associated with evident ovarian dysfunction in young adult women. However, women with a history of PA had decreased SHBG levels and thus, increased bioavailability of circulating androgens.

Familial Hyperinsulinism due to HNF4A Deficiency and Benign Premature Adrenarche: A Case Report

Background: Familial Hyperinsulinism due to HNF4A deficiency (FHI-HNF4A) is a form of diazoxide-sensitive, diffuse hyperinsulinism, characterized by transient or persistent hyperinsulinemic hypoglycemia, and a propensity to develop Maturity-Onset Diabetes of the Young type 1 (MODY1). The association between FHI-HNF4A deficiency and benign premature adrenarche (BPA) is unknown. The Case: We report the case of a 5-year-old girl with FHI-HNF4A, controlled on diazoxide, who presented with BPA and Tanner stage III pubic hair associated with body odor and acne. Work-up revealed elevated dehydroepiandrosterone sulfate (DHEAS), elevated free testosterone, and advanced bone age. Insulin levels were elevated in the setting of normal fasting blood glucose. We discuss the possible hormonal underpinnings of hyperandrogenism. Conclusion: Though the underlying pathophysiology of this phenotype is unclear, a possible synergistic mechanism exists between insulin-induced hyperandrogenism and HNF4A deficiency leading to a transient decrease of SHBG and thus increased free testosterone levels. Further investigation is required to determine the association between HNF4A dysfunction and BPA.

Exaggerated Premature Adrenarche in Boys: Comparative Study of a Therapeutic Intervention With the Aromatase Inhibitor Anastrozole Versus Morning Low Dose Hydrocortisone

Background: In boys, idiopathic premature adrenarche (IPA) is defined as the appearance of pubic or axillary hair/odor before the age of 9 yrs, not due to pathology of the adrenal glands. Exaggerated Adrenarche (EXAD), occurring in 10-15% of children with IPA, is characterized by an elevated >10 DHEA/Δ4 ratio (theoretically indicating reduced 3-β-HSD activity) and accelerated bone age (BA) maturation, continuously increasing the projecting distance from the target height (TH) curve, beyond the one observed in the pattern of Constitutional Advancement of Growth (CAG), eventually leading to short stature (SS). It is traditionally successfully treated with a morning (6-8 am) low dose of hydrocortisone (8 mg/m2) in order to reduce the androgens produced and delay BA progression, similarly to the standard treatment of non-classical (late-onset) CAH. Third generation aromatase inhibitors (AI) have been shown to delay BA by inhibiting the peripheral aromatization of androgens and are being widely used off-label to treat short SS in boys. Aims: To evaluate the effectiveness of the AI anastrozole in delaying BA in boys with EXAD. Methods: 39 boys with advanced BA and a predicted adult height (PAH) <170cm and > -1SDS from TH) were included. Group-A (n=28) received anastrozole 1mg x 1 p.o. and group-B (n=11) low dose (8 mg/m2) hydrocortisone at 6-8 am for at least 3 yrs. All measurements were made on the same height meter by the same examiner. The two groups did not differ in terms of age at intervention onset: 8.6 in group A vs 8.74 yrs in group B, TH: 175.7 vs 175.7 cm, PAH: 168.4 vs 167.8 cm and BA advancement: +2.3 yrs in group A vs +2.4 yrs in group B. A 6-month follow-up included clinical examination, BA assessment, and laboratory tests (general blood, lipid chart, LH, FSH, TESTO, E2, E1, and complete calcium metabolism). Lumbar spine DEXA scan and X-Ray was performed on an annual basis. Results: Both groups had a statistically significant gain in PAH after 3yrs of treatment: Group A +10.3 cm (1.53 SD), p<0.001, and group B +7.1 cm (1.06 SD), p=0.007. Thus, group A exceeded their TH by +3cm (0.45 SDS) and group B reached -0.8cm (-0.11 SDS) from their TH, p=0.03. The reduction of BA advancement was statistically significant in both groups (p<0.05), with superiority of the anastrozole-treated group: at 3yrs in group A BA advancement was +0.48 yrs, and at group B +1.24 yrs (p<0.001). No clinical adverse events or abnormal tests were noted in any of the groups. Bone density and vertebral morphology was not affected within or between groups. Conclusions: Aromatase Inhibitors may have a place in managing exaggerated adrenarche in boys, showing superiority to traditional low-dose hydrocortisone in improving predicted adult height and delaying bone age maturation, but notably by overcoming quality of life and compliance issues associated with hydrocortisone therapy (mandatory 6-8 am).

Normal and Premature Adrenarche

Adrenarche is the maturational increase in adrenal androgen production that normally begins in early childhood. It results from changes in the secretory response to ACTH that are best indexed by dehydroepiandrosterone sulfate (DHEAS) rise. These changes are related to the development of the zona reticularis (ZR) and its unique gene/enzyme expression pattern of low 3ß-hydroxysteroid dehydrogenase type 2 with high cytochrome b5A, sulfotransferase 2A1, and 17ß-hydroxysteroid dehydrogenase type 5. Recently 11-ketotestosterone was identified as an important bioactive adrenarchal androgen. Birth weight, body growth, obesity, and prolactin are related to ZR development. Adrenarchal androgens normally contribute to the onset of sexual pubic hair (pubarche) and sebaceous and apocrine gland development. Premature adrenarche causes ≥90% of premature pubarche. Its cause is unknown. Affected children have a significantly increased growth rate with proportionate bone age advancement that typically does not compromise growth potential. Serum DHEAS and testosterone levels increase to levels normal for early female puberty. It is associated with mildly increased risks for obesity, insulin resistance, and possibly mood disorder and polycystic ovary syndrome. Five-10% of premature pubarche is due to virilizing disorders, which are usually characterized by more rapid advancement of pubarche and compromise of adult height potential than premature adrenarche. Most cases are due to nonclassic congenital adrenal hyperplasia. Algorithms are presented for the differential diagnosis of premature pubarche.This review highlights recent advances in molecular genetic and developmental biologic understanding of ZR development and insights into adrenarche emanating from mass spectrometric steroid assays.

The Unique Role of 11-Oxygenated C19 Steroids in Both Premature Adrenarche and Premature Pubarche

<b><i>Introduction:</i></b> Recent studies have shown 11-oxygenated androgens (11oAs) are the dominant androgens in premature adrenarche (PA). Our objective was to compare 11oAs and conventional androgens in a well-defined cohort of children with PA or premature pubarche (PP) and correlate these androgens with metabolic markers. <b><i>Methods:</i></b> A prospective cross-sectional study was conducted at a university hospital. Fasting early morning serum steroids (including 11oAs) and metabolic biomarkers were compared and their correlations determined in children ages 3–8 years (F) or 3–9 years (M) with PA or PP (5 M and 15 F) and healthy controls (3 M and 8 F). <b><i>Results:</i></b> There were no differences between PA, PP, and controls or between PA and PP subgroups for sex, BMI z-score, or criteria for childhood metabolic syndrome. Dehydroepiandrosterone sulfate (DHEAS) was elevated only in the PA subgroup, as defined. 11oAs were elevated versus controls in PA and PP although no differences in 11oAs were noted between PA and PP. Within the case cohort, there was high correlation of T and A4 with 11-ketotestosterone and 11β-hydroxyandrostenedione. While lipids did not differ, median insulin and HOMA-IR were higher but not statistically different in PA and PP. <b><i>Conclusions:</i></b> PA and PP differ only by DHEAS and not by 11oAs or insulin sensitivity, consistent with 11oAs – rather than DHEAS – mediating the phenotypic changes of pubarche. Case correlations suggest association of 11oAs with T and A4. These data are the first to report the early morning steroid profiles including 11oAs in a well-defined group of PA, PP, and healthy children.

Premature Adrenarche and its Association with Cardiovascular Risk in Females

Early activation of the adrenal zona reticularis, leading to adrenal androgen secretion, mainly dehydroepiandrosterone sulfate (DHEAS), is called premature adrenarche (PA). The fact that adrenal hyperandrogenism in females has been linked to a cluster of cardiovascular (CV) risk factors, even in prepubertal children, warrants investigation. Controversial results have been obtained in this field, probably due to genetic, constitutional, and environmental factors or differences in the characteristics of participants. In an attempt to understand, in depth, the impact of PA as a potential activator of CV risk, we critically present available data stratified according to pubertal status. It seems that prepubertally, CV risk is increased in these girls, but is somewhat attenuated during their second decade of life. Furthermore, different entities associated with PA, such as polycystic ovary syndrome, non-classical congenital adrenal hyperplasia, heterozygosity of CYP21A2 mutations, and the impact of DHEAS on CV risk, are reviewed. At present, firm and definitive conclusions cannot be drawn. However, it may be speculated that girls with a history of PA display a hyperandrogenic hormonal milieu that may lead to increased CV risk. Accordingly, appropriate long-term follow-up and early intervention employing a patient-oriented approach are recommended.

Role of Body Weight in the Onset and the Progression of Idiopathic Premature Pubarche

<b><i>Background:</i></b> The term premature pubarche (PP) refers to the appearance of pubic hair before age 8 in girls and before age 9 in boys. Although idiopathic PP (often associated with premature adrenarche) is considered an extreme variation from the norm, it may be an initial sign of persistent hyperandrogenism. Factors contributing to PP onset and progression have not been identified to date. <b><i>Aims:</i></b> The objectives of this study are to describe a group of Italian children with PP, to identify potential factors for its onset, and to define its clinical and biochemical progression. <b><i>Methods:</i></b> We retrospectively enrolled all infants born between 2001 and 2014 with PP. Children with advanced bone age (BA) underwent functional tests to determine the cause of PP. Hormonal analysis and BA determination were performed annually during a 4-year follow-up period. <b><i>Results:</i></b> A total of 334 children with PP were identified: idiopathic PP (92.5%, associated with premature adrenarche in some cases); related to precocious puberty (6.6%); late-onset 21-hydroxylase deficiency (0.9%). Low birth weight was associated with premature adrenal activation. Body mass index (BMI) was the only factor that influenced the progression of BA during follow-up. <b><i>Conclusions:</i></b> Low birth weight is a predisposing factor for premature adrenal activation. The increase in BMI in patients with idiopathic PP during the 4-years of follow-up was responsible for BA acceleration. We recommend prevention of excessive weight gain in children with PP and strict adherence to follow-up in order to prevent serious metabolic consequences.