Endocrine Development

Delayed puberty (DP) in boys is the lack of sexual maturation at a chronological age of 14 years. Several conditions induce DP and they can be classified into reversible and irreversible causes. The most common cause of DP is constitutional delay of puberty (CDP; 63%), followed by DPs due to functional hypogonadotropic hypogonadism (HH; 20%), congenital isolated HH (9%) and hypergonadotropic hypogonadism (7%). A correct diagnosis, although often difficult, is pivotal for choosing the most adequate therapy. In CDP boys, expectant management can be an option...

The histrelin implant has emerged as a therapeutic option for the treatment of central precocious puberty that has been favorably received by patients and providers. Inserted subcutaneously, the 50-mg implant provides continuous release of the potent gonadotropin-releasing hormone analog (GnRHa) histrelin. Profound suppression of the hypothalamic-pituitary-gonadal (HPG) axis occurs within 1 month of its placement resulting in pubertal arrest, attenuation of skeletal advancement and a progressive increase in predicted adult height...

Since the first use of cortisone in patients around 65 years ago, the use of synthetic glucocorticoids has made a crucial impact on the treatment of several diseases in medicine. Although significant reductions in morbidity and mortality have occurred in patients suffering from cortisol deficiency, conventional hydrocortisone replacement treatment is still inadequate. A major limitation is that it fails to replace cortisol in a physiological manner. Cortisol has a distinct circadian rhythm and acts as a secondary messenger synchronizing the central to peripheral clocks, hence playing a key role in biological processes and the circadian timing system...

A major hallmark of classical congenital adrenal hyperplasia (CAH) is genital ambiguity noted at birth in affected females, which leads to psychological and psychosexual issues in adult life. Attempts to correct genital ambiguity through surgical intervention have been partially successful. Fetal hyperandrogenemia and genital ambiguity have been shown to be preventable by prenatal administration of low-dose dexamethasone initiated before the 9th week of gestation. In 7 of 8 at-risk pregnancies, the unaffected fetus is unnecessarily exposed to dexamethasone for weeks until the diagnosis of classical CAH is ruled out by invasive procedures...

Nonalcoholic fatty liver disease (NAFLD) is one of the most important causes of chronic liver disease in children and adults. Recently, therapeutic supplementation with docosahexaenoic acid (DHA) showed an anti-inflammatory and insulin-sensitizing effect in children with NAFLD. The anti-inflammatory effects of DHA depend on its ability to alter phospholipid composition of the cell membrane, to disrupt lipid rafts and to hamper the transcriptional activity of nuclear factor-x03BA;B that controls the expression of proinflammatory cytokines...

Obesity is a complex and retractable disease for which effective and durable treatments are elusive. Successful treatment of severe obesity with lifestyle modification therapy alone is highly unlikely, particularly for adolescents. Pharmacotherapy, if appropriately prescribed, can be an effective tool to use in conjunction with lifestyle modification therapy to achieve better weight loss outcomes. Only a few obesity medications have been evaluated in children and adolescents with results suggesting modest efficacy...

The first islet transplantation in diabetes mellitus was performed more than 20 years ago. Since then, clinical results have progressively improved. Nowadays, islet transplantation can be considered a real therapeutic option after pancreatectomy for painful chronic pancreatitis (autotransplantation) and in selected adult patients affected by type 1 diabetes mellitus (allotransplantation). Better results are mainly due to the advances in the standardization of islet isolation and purification procedures as well as in the pharmacological treatment of recipients...

In the past decade, the field of type 1 diabetes was characterized by the efforts to integrate technology into the daily management of diabetes. Automated insulin delivery systems have emerged followed by the improvements in technology of pumps and sensors and automated close-loop systems that were developed around the world for overnight as well as for day and night use. Initially, these closed-loop systems were tested clinically in research centers, then at diabetes camps or hotels, and recently at patients' homes...

The period of adolescence is not only marked by important growth and pubertal events, but is also characterized by important psychosocial changes driven by a search for autonomy and the construction of one's identity. It can thus be easily understood that puberty disorders interfere heavily with these process, requiring from the endocrinologist not only medical knowledge, but also a great deal of emotional and psychological skills. They must progressively move from an educational approach that heavily involves the parents to one of shared information and decision making that places the young patient at the center of the therapeutic process...

There are many etiologies of peripheral precocious puberty (PPP) with diverse manifestations resulting from exposure to androgens, estrogens, or both. The clinical presentation depends on the underlying process and may be acute or gradual. The primary goals of therapy are to halt pubertal development and restore sex steroids to prepubertal values. Attenuation of linear growth velocity and rate of skeletal maturation in order to maximize height potential are additional considerations for many patients. McCune-Albright syndrome (MAS) and familial male-limited precocious puberty (FMPP) represent rare causes of PPP that arise from activating mutations in GNAS1 and the LH receptor gene, respectively...

Depot gonadotropin-releasing hormone (GnRH) analogs represent the first-line therapy in sexual precocity due to central precocious puberty. GnRH analogs desensitize the pituitary and account for the suppression of luteinizing hormone and follicle-stimulating hormone leading to a decrease of sex steroid levels. The conventional indications are central puberty starting before the age of 8 years in girls and 9 years in boys. These indications can be extended to difficult conditions with poor adult height prognosis or marked psychosocial impact...

The overall goal of pubertal sex hormone replacement therapy (HRT) in girls is not only about development of secondary sexual characteristics, but also to establish an adult endocrine and metabolic milieu, as well as adult cognitive function. Estradiol (E2) is the first choice for HRT compared to ethinyl estradiol (EE2). E2 is the most potent endogenous estrogen in the circulation, with established levels during spontaneous puberty. Transdermal E2, compared to oral administration, is the first choice to start pubertal HRT...

Male delayed puberty is common, affecting up to 3% of the population. Management of patients with pubertal delay is dependent on the underlying cause. The main differential diagnoses of delayed puberty in males include constitutional delay of growth and puberty (CDGP), idiopathic hypogonadotropic hypogonadism and hypergonadotropic hypogonadism. Treatment of isolated CDGP involves expectant observation or short courses of low-dose sex steroid supplementation. More complex and involved management is required in males with hypogonadism to achieve both development of secondary sexual characteristics and to maximise the potential for fertility...

The aim of this chapter is to revise some common views on changes in pubertal timing. This revision is based on recent epidemiological findings on the clinical indicators of pubertal timing and data on environmental factor effects and underlying mechanisms. A current advancement in timing of female puberty is usually emphasized. It appears, however, that timing is also changing in males. Moreover, the changes are towards earliness for initial pubertal stages and towards lateness for final stages in both sexes...

Caloric-protein malnutrition can slow growth and cause pubertal delay. This chapter focuses on endocrine abnormalities and pubertal alterations in patients with eating disorders, childhood obesity, the female athlete triad and children cancer survivors. Patients with anorexia nervosa (AN) exhibit multiple endocrine abnormalities, including isolated hypogonadotropic hypogonadism. The delay in pubertal development and reduction in growth seen in AN patients may be a direct result of malnutrition. Appropriate psychiatric, nutritional and hormonal therapy is necessary...

Sexual maturation is closely tied to growth and body weight gain, suggesting that regulative metabolic pathways are shared between somatic and pubertal development. The pre- and postnatal environment affects both growth and pubertal development, indicating that common pathways are affected by the environment. Intrauterine and early infantile developmental phases are characterized by high plasticity and thereby susceptibility to factors that affect metabolic function as well as related reproductive function throughout life...

Recent studies have documented earlier pubertal maturation in both girls and boys. Several factors have been proposed to account for earlier maturation. Epidemiologic studies have indicated that genetic factors are the most important influence contributing to the variability in the onset of puberty. Studies have also noted the association of elevated BMI with earlier puberty in girls, although the relationship between BMI and onset of puberty in boys is less consistent. The relationship of BMI and onset of puberty may be mediated by several factors, including leptin and kisspeptin, changes in bioavailable sex hormones, and environmental exposures...

Puberty is a fascinating developmental transition that gates the attainment of reproductive capacity and culminates the somatic and sexual maturation of the organism. Rather than a circumscribed phenomenon, puberty is the endpoint of a long-lasting developmental continuum, which initiates in utero. Besides important genetic determinants, the tempo of puberty is influenced by numerous endogenous and exogenous factors that, acting at different levels of the developing hypothalamic-pituitary-gonadal (HPG) axis along the maturational continuum indicated above, can influence puberty onset...

Reproductive function depends on the activity of the gonadotropic axis, which is controlled by a hypothalamic neural network whose main function is to regulate the secretion of gonadotropin-releasing hormone (GnRH). This endocrine network is not mature at birth, and several phases of activation-inactivation of the gonadotropic axis are necessary for its normal development. The postnatal maturation of the GnRH network lies under the control of a neurodevelopmental program that starts in fetal life and ends at puberty...

Precocious puberty has been classically defined as the onset of sexual secondary characteristics in girls younger than 8 years and in boys younger than 9 years. The discovery of potential factors which trigger human puberty is one of the central mysteries of reproductive biology. Several approaches, including mutational analysis of candidate genes, large-scale genome-wide association studies, and (more recently) whole-exome sequencing, have been performed in attempt to identify novel genetic factors that modulate the human hypothalamic-pituitary-gonadal axis, resulting in premature sexual development...