Normal Pubertal Development Research Articles

An evidence based approach for diagnosis of adolescent polycystic ovarian syndrome

Abstract The overlap between normal pubertal development and characteristic features of PCOS may confound an accurate diagnosis of PCOS among adolescent girls. Other disorders associated with irregular menses or hyperandrogenism need to be excluded from diagnostic consideration. Even in the absence of a definitive diagnosis and the lack of an approved therapy for PCOS in adolescence, treatment options that both alleviate the current symptoms and decrease the risk for subsequent associated comorbidities are recommended. Although obesity, insulin resistance, and hyperinsulinemia are common findings in adolescents with hyperandrogenism, these features should not be used to diagnose PCOS among adolescent girls.

P-03-026 Secondary premature ejaculation secondary to hyperthyroidism

This case report represents the ejaculatory dysfunction of a young patient secondary to hyperthyroidism. 29 y/o male constructive worker presenting into office complaining of secondary and global premature ejaculation with IELT less than 1 min on both vaginal penetrations and masturbations for the past 2 years which started gradually and has progressed steadily. He reports occasional spontaneous ejaculation when sexually excited. Sexual desire, penile rigidity and ejaculation volume are all normal. He has been married for 4 years and has a 2 y/o son. Wife is healthy and competent with no sexual difficulties. Patient states increased anxiety at work and during sexual intercourse with concomitant palpitating, excessive sweating, and some diarrhea and weight loss recently. He denies any specific auto arousal pattern or any gender identity disorder. States normal pubertal development. Past history and family history non-contributory. Physical exam was essentially normal with BMI of 24.4 and blood pressure of 135/85. Focused genital examination revealed no penile, testicular abnormalities. CBC, CMP, lipid panel and hormonal tests including thyroid panel ordered. Results came back all normal except for suppressed TSH and elevated free T3 and T4.

Leptin receptor null mice with reexpression of LepR in GnRHR expressing cells display elevated FSH levels but remain in a prepubertal state.

Leptin signals energy sufficiency to the reproductive hypothalamic-pituitary-gonadal (HPG) axis. Studies using genetic models have demonstrated that hypothalamic neurons are major players mediating these effects. Leptin receptor (LepR) is also expressed in the pituitary gland and in the gonads, but the physiological effects of leptin in these sites are still unclear. Female mice with selective deletion of LepR in a subset of gonadotropes show normal pubertal development but impaired fertility. Conditional deletion approaches, however, often result in redundancy or developmental adaptations, which may compromise the assessment of leptin's action in gonadotropes for pubertal maturation. To circumvent these issues, we adopted a complementary genetic approach and assessed if selective reexpression of LepR only in gonadotropes is sufficient to enable puberty and improve fertility of LepR null female mice. We initially assessed the colocalization of gonadotropin-releasing hormone receptor (GnRHR) and LepR in the HPG axis using GnRHR-IRES-Cre (GRIC) and LepR-Cre reporter (tdTomato or enhanced green fluorescent protein) mice. We found that GRIC and leptin-induced phosphorylation of STAT3 are expressed in distinct hypothalamic neurons. Whereas LepR-Cre was observed in theca cells, GRIC expression was rarely found in the ovarian parenchyma. In contrast, a subpopulation of gonadotropes expressed the LepR-Cre reporter gene (tdTomato). We then crossed the GRIC mice with the LepR null reactivable (LepR(loxTB)) mice. These mice showed an increase in FSH levels, but they remained in a prepubertal state. Together with previous findings, our data indicate that leptin-selective action in gonadotropes serves a role in adult reproductive physiology but is not sufficient to allow pubertal maturation in mice.

Steroid Sulfatase Deficiency and Androgen Activation Before and After Puberty.

Context:Steroid sulfatase (STS) cleaves the sulfate moiety off steroid sulfates, including dehydroepiandrosterone (DHEA) sulfate (DHEAS), the inactive sulfate ester of the adrenal androgen precursor DHEA. Deficient DHEA sulfation, the opposite enzymatic reaction to that catalyzed by STS, results in androgen excess by increased conversion of DHEA to active androgens. STS deficiency (STSD) due to deletions or inactivating mutations in the X-linked STS gene manifests with ichthyosis, but androgen synthesis and metabolism in STSD have not been studied in detail yet.Patients and Methods:We carried out a cross-sectional study in 30 males with STSD (age 6–27 y; 13 prepubertal, 5 peripubertal, and 12 postpubertal) and 38 age-, sex-, and Tanner stage-matched healthy controls. Serum and 24-hour urine steroid metabolome analysis was performed by mass spectrometry and genetic analysis of the STS gene by multiplex ligation-dependent probe amplification and Sanger sequencing.Results:Genetic analysis showed STS mutations in all patients, comprising 27 complete gene deletions, 1 intragenic deletion and 2 missense mutations. STSD patients had apparently normal pubertal development. Serum and 24-hour urinary DHEAS were increased in STSD, whereas serum DHEA and testosterone were decreased. However, total 24-hour urinary androgen excretion was similar to controls, with evidence of increased 5α-reductase activity in STSD. Prepubertal healthy controls showed a marked increase in the serum DHEA to DHEAS ratio that was absent in postpubertal controls and in STSD patients of any pubertal stage.Conclusions:In STSD patients, an increased 5α-reductase activity appears to compensate for a reduced rate of androgen generation by enhancing peripheral androgen activation in affected patients. In healthy controls, we discovered a prepubertal surge in the serum DHEA to DHEAS ratio that was absent in STSD, indicative of physiologically up-regulated STS activity before puberty. This may represent a fine tuning mechanism for tissue-specific androgen activation preparing for the major changes in androgen production during puberty.

Acquired Hypogonadotropic Hypogonadism (AHH) in Thalassaemia Major Patients: An Underdiagnosed Condition?

IntroductionIn males, acquired hypogonadotropic hypogonadism (AHH) includes all disorders that damage or alter the function of gonadotropin-releasing hormone (GnRH) neurons and/or pituitary gonadotroph cells. The clinical characteristics of AHH are androgen deficiency and lack, delay or halt of pubertal sexual maturation. AHH lead to decreased libido, impaired erectile function, and strength, a worsened sense of well-being and degraded quality of life (QOL).Patients and methodsWe studied 11 adult men with thalassemia major (TM) aged between 26 to 54 years (mean ± SD: 34.3 ± 8.8 years) with AHH. Twelve age- and sex-matched TM patients with normal pubertal development were used as a control group. All patients were on regular transfusions and iron chelation therapy. Fasting venous blood samples were collected two weeks after transfusion to measure serum concentrations of IGF-1, free thyroxine (FT4), thyrotropin (TSH), cortisol, luteinizing hormone (LH), follicle stimulating hormone (FSH), total testosterone (TT), prolactin and estradiol (E2), glucose, urea, creatinine and electrolytes (including calcium and phosphate). Liver functions and screening for hepatitis C virus seropositivity (HCVab and HCV-RNA) were performed. Iron status was assessed by measuring serum ferritin levels, and evaluation of iron concentrations in the liver (LIC) and heart using MRI- T2*. Bone mineral density was measured at the lumbar spine (L1–L4) for all patients with AHH by dual energy X-ray absorptiometry (DXA) using Hologic QDR 4000 machine.ResultsThe mean basal serum LH and FSH concentrations in AHH patients were 2.4 ± 2.2 IU/L and 1.2 ± 0.9 IU/L respectively; these, values were significantly lower compared to the control group. Semen analysis in 5 patients with AHH showed azoospermia in 3 and oligoasthenozoospermia in 2. The percentage of patients with serum ferritin level >2000 ng/ml (severe iron load) was significantly higher in AHH patients compared to controls, 5/11 (45.4 %) versus1/12 (8.3%), p=0.043. Heart iron concentrations (T2* values) were significantly lower in AHH patients compared to controls (p=0.004). Magnetic resonance imaging in the 3 azoospermic patients revealed volume loss and reduction of pituitary signal intensity. Heart T2* values were significantly reduced in the AHH group vs. the controls (p=0.004). On the other hand, liver iron concentration (mg/g dry weight) was not different between the two groups of TM patients. Using DXA, 63.6 % (7/11) of patients with AHH were osteoporotic, and 36.3 % (4/11) were osteopenic.ConclusionsIn this cohort of thalassemic patients iron overload and chronic liver disease appear to play a role in the development of AHH. Treatment of AHH in TM patients is a vital and dynamic field for improving their health and QOL. Early identification and management of AHH are very crucial to avoid long-term morbidity, including sexual dysfunction and infertility. Therapy aims to restore serum testosterone levels to the mid–normal range. Many exciting opportunities remain for further research and therapeutic development.

The increase in the number of spines on the gonadotropin-releasing hormone neuron across pubertal development in rats.

The onset of puberty is initiated by an increase in the release of the gonadotropin-releasing hormone (GnRH) from GnRH neurons in the hypothalamus. However, the precise mechanism that leads to the activation of GnRH neurons at puberty remains controversial. Spines are small protrusions on the surface of dendrites that normally receive excitatory inputs. In this study, we analyzed the number and morphology of spines on GnRH neurons to investigate changes in synaptic inputs across puberty in rats. For morphological estimation, we measured the diameter of the head (DH) of each spine and classified them into small-type (DH < 0.65μm), large-type (DH > 0.65μm) and giant-type (DH > 0.9μm). The greatest number of spines was observed at the proximal dendrite within 50μm of the soma. At the soma and proximal dendrite, the number of spines was greater in adults than in juveniles in both male and female individuals. Classification of spines revealed that the increase in spine number was due to increases in large- and giant-type spines. To furtherexplore the relationship between spines on GnRH neurons and pubertal development, we next analyzed adult rats neonatally exposed to estradiol benzoate, in which puberty onset and reproductive functionsare disrupted. We found a decrease in the number of all types of spines. These results suggest that GnRH neurons become to receive more and greater excitatory inputs on the soma and proximal dendrites as a result of the changes that occur at puberty and that alteration to spines plays a pivotal role in normal pubertal development.

Educational Needs of Adolescents Regarding Normal Puberty and Menstrual Patterns.

Objective:The study aimed to determine the level of knowledge and the sources of information about normal puberty and menstrual patterns in Turkish schoolgirls from İstanbul.Methods:The study sample was comprised of 922 randomly chosen schoolgirls. A questionnaire survey of knowledge of normal pubertal development and menstrual patterns was conducted.Results:The age of the girls ranged between 10 and 17 years and 82.3% had had menarche. The leading source of pubertal information was the mothers (84.2%). There was no statistically significant relationship between the mothers’ education level and the level of knowledge of the students about pubertal development (p>0.05). The main source for 18% of students was their teacher, but only 6% had a preference for their teacher providing education on this topic. Students who attained menarche preferred education about puberty to be given by health professionals and to both genders at the same setting (p<0.01). A total of 31.5% of students thought that the first symptom of puberty was acne. Half (50.7%) of the students did not know the time period between the beginning of puberty and menarche. The girls who had attained menarche were more knowledgeable about puberty, largely through their own experience.Conclusion:This study shows that schoolgirls have an insufficient level of knowledge about normal puberty. Education programs must be conducted for students and their parents.

Update on Common Childhood Endocrine Disorders

This issue focuses on a number of common childhood endocrine disorders. Dr. Stacy Meyer and her contributing colleagues have done an excellent job putting together a very readable overview of those disorders. The article begins with a topic that is “front and center” on most parents minds when they see their child’s primary clinician: is my child growing normally? Following the formula for estimating genetic linear growth potential (for both boys and girls) and tips on an appropriate physician examination when there are concerns about linear growth, Dr. Meyer reviews the differential diagnosis and treatment of children with short stature—including familial short stature and growth hormone deficiency. This practical approach for primary care clinicians continues throughout the article. Growth is followed by an overview of normal pubertal development, another common parental concern (for teens too!) in primary care. The management of precocious puberty (central and peripheral) and delayed puberty are addressed in this section. Dr. Meyer then reviews conditions that produce euthyroid states in which the efficacy of treatment is controversial—e.g., TSH elevation in obese children. Of course, there are numerous hypothyroid and hyperthyroid diseases of childhood that respond to therapy and Dr. Meyers carefully reviews important aspects of the management of these childhood diseases, including childhood thyroid cancer. As Dr. Meyer and her colleagues note in their conclusion, pediatric endocrinology is evolving with new effective treatment options for children with endocrine disorders. Because the presentation of pediatric endocrine disease can be quite variable the primary care clinician must have an index of suspicion to identify children who will benefit from therapy early in their disease. Within this issue Dr. Meyer and her contributing colleagues have given the primary care clinician the “gift” of a well organized, easily readable compendium of childhood endocrine disorders as well as an overview of normal growth and pubertal development. This issue is a valuable resource for all clinicians who provide primary health care to children and their families.

A Kiss and a PRomise.

The discovery eleven years ago that deleterious mutations in the gene encoding the kisspeptin receptor (KISS1R) cause a failure of normal pubertal development in humans (1, 2) has propelled an entire field of neuroendocrine research focused on understanding how the ligand for this receptor, kisspeptin, regulates the hypothalamic-pituitary-gonadal axis. Hypothalamic kisspeptin potently stimulates GnRH secretion and the subsequent release of LH and FSH from the pituitary (3,–10). Kisspeptin neurons act as essential relay points to the GnRH neurons, integrating feedback from steroid hormones (7, 11, 12), circadian inputs (13,–17), and metabolic signals (18,–23).

Multiple endocrine glands insufficiency due to langerhans cell histiocytosis (LCH): a case report

LCH is the rare disease involving clonal proliferation of Langerhans cells, abnormal cells deriving from bone marrow and capable of migrating from skin to lymph nodes. The clinical presentation of LCH may occur in multiple organs: bone, skin, lymph nodes or pituitary gland, but clinical presentation of LCH rarely occurs in multiple endocrine systems. We presented a special case who was diagnosed with LCH and presentation of LCH occurred in multiple systems: pituitary gland, thyroid, adrenal gland. A 11 years old girl was hospitalized for lump on the neck. Past history: one year ago, she was diagnosed with autoimmune polyendocrine syndromes and treated with hormone replacement (levothyroxine 3mcg/kg/day, desmopressin 4 mcg/kg/day, hydrocortisone 10 mcg/kg/day). Physical examination showed: she had a swollen lump on her neck, she had a temperature of 38° C. She had no polyuria, no polydipsia. Her height was 141cm (-0.29 SD); her weight was 37 kg; her BMI was 18.5 (50th – 70th) .She had normal growth velocity and normal pubertal development. Laboratory evaluation revealed : WBC : 10.3 × 109 /l ( normal range : 4×10 9 /l – 10 ×109 / l) ; CRP : 105.78 mg/l ( normal range : < 10 mg/l ); serum cortisol at 8 a.m : 16.3 nmol/l ( normal range : 200 – 600 nmol/l ); T3 : 1.8 nmol/l ( normal range : 1 – 3 nmol/l ), T4 : 135.9 nmol/l ( normal range : 50 – 150 nmol/l ), TSH : 0.002 mUI/ml ( normal range : 1 – 5 mUI/ml ); blood osmotic pressure : 279 moms/kg, urinary osmotic pressure : 127 mosm/kg; plasma glucose level and electrolyte were normal. An MRI of brain showed: thickened pituitary stalk. A biopsy of the lump on her neck showed: features of Langerhans Cell; skeletal and long bone radiograph showed no osteolytic lesion. She was treated with hormone replacement and chemotherapy. Written informed consent was obtained from the patient's parent or guardian for publication of this Case report (and any accompanying images). A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Olfactory Agenesis in Kallmann Syndrome (KS).

Kallmann syndrome (KS) is a heterogeneous genetic disorder characterised by isolated gonadotrophic deficiency and anosmia. Defective migration of GnRH neurons along with olfactory neurons results in hypoplasia or agenesis of olfactory bulb and or sulci and gonadotrophin deficiency. We hereby report a young female who presented with features of hypogonadism and anosmia. A 17-year-old female presented to our endocrine clinic with primary amenorrhea. She was born of non-consanguineous marriage and her birth history was unremarkable and developmental mile stones were normal. On questioning, she admitted to the fact that she was not very appreciative of smell from the childhood when compared to other family members. Her stature was at par with her peers and there was neither a history of any chronic illness nor any medication. She had one male elder sibling whose growth and pubertal development were normal according to age. On examination, her height was 162 cm with a mid-parental height of 159 cm. There was no pallor or oedema or thyromegaly. There were no dysmorphic features. Her Tanner staging for breasts was prepubertal (Tanner 1) and pubic hair was also Tanner stage 1. Cardiovascular, respiratory and neurological examinations were within normal limits. Her blood investigations were as follows: TSH – 2 uIU/ml (Normal: 0.8-4), FT4-1.1 ng/dl (Normal: 0.8-1.8), FSH-0.2mIU/ml, LH-0.2mIU/ml, Prolactin-12 ng/ml (Normal<20), morning cortisol -16 μg/dl (Normal: 12-15), Hemoglobin- 13.2 gm/dl, Creatinine- 1.1 mg/dl (Normal: 0.8-1.3). She underwent MRI scanning of the brain [Table/Fig-1] which revealed the absence of olfactory bulb and olfactory sulci [Table/Fig-1]. The MRI brain of a normal subject is shown in [Table/Fig-2] for comparison. Her low gonadotropin levels in the absence of normal pubertal development and imaging features were suggestive of KS, a form of hypogonadotropic hypogonadism. There were no skeletal or renal abnormalities. She was initiated on cyclical oestrogen – progesterone pills with which she developed secondary sexual characters along with menstrual bleeding at one year follow up. [Table/Fig-1]: MRI brain of the patient showing absence of olfactory sulci and bulb [Table/Fig-2]: MRI brain of a normal subject displaying olfactory sulci and bulb KS is a heterogeneous genetic disorder which include hypogonadism and anosmia due to hypoplasia or agenesis of olfactory bulb and sulci along with GnRH deficiency [1]. It is a genetically heterogenous condition, with X-linked, autosomal dominant and recessive modes of inheritance due to mutataions in KAL 1, FGF 8/ FGFR1 and PROK2/PROK2R respectively [2]. The X linked forms may be associated with other phenotypic features. The autosomal forms of KS (A-KS) exhibit no consistent phenotype apart from gonadotropin deficiency and anosmia, although a heterogeneous collection of defects are seen in a minority of cases. The associated defects include cleft palate or other craniofacial and dental defects, unilateral renal agenesis or aplasia; cryptorchidism, micropenis, neural hearing defects and synkinesis or mirror movements of hand [3]. Since GnrH pulsation studies may not be possible at all centres, MRI with 1 mm cut is an important diagnostic tool for diagnosis of KS. Management of these subjects include screening for associated anomalies and monitoring for progressive worsening secondary to organ defects. The goal of the treatment is two folds. First, hormone replacement therapy is needed to induce puberty and to maintain gonadal hormones at near normal physiological levels till fifth decade of life. Secondly, fertility treatment involves administering gonadotrophins to induce ovulation.

Reference values for serum dehydroepiandrosterone-sulphate in healthy children and adolescents with emphasis on the age of adrenarche and pubarche.

Adrenarche is a component of normal pubertal development. Recent decades have witnessed changes in the timing and tempo of puberty in different populations. We aimed to obtain normative data on dehydroepiandrosterone-sulphate (DHEA-S) secretion in healthy children and to evaluate the age of adrenarche, pubarche and the DHEA-S levels at which pubarche starts in both sexes. Serum DHEA-S concentrations were measured in 531 healthy (291 female) Turkish children aged 1 month-18 years by an automated chemiluminescence method. Pubic hair development was evaluated. DHEA-S concentrations >108·4 nmol/l (40 μg/dl) were regarded as adrenarche. Age-related normative data were constructed. Age at adrenarche and pubarche and the DHEA-S levels at pubarche were estimated using ROC analyses. Serum DHEA-S levels were high in the first 6 months of life then declined below 108·4 nmol/l (40 μg/dl) with a cut-off age of 0·46 years for girls and 0·61 years for boys with 98% and 96% statistical sensitivity. Stable minimum levels were observed for the following 5 years. The cut-off age for DHEA-S levels rising above 108·4 nmol/l (40 μg/dl) was 8·0 and 7·0 years for girls for boys, respectively. DHEA-S levels at transition from Tanner stage P1 to P2 was 90·5 nmol/l (33·4 μg/dl) in girls and 118 nmol/l (43·6 μg/dl) in boys. Median (CI) DHEA-S levels were 170·7(94·8-336) and 244(119·2-357·7) nmo/l [63(35-124) and 90(44-132) μg/dl] in girls and boys, respectively, with Tanner stage P2 pubic hair. We established reference data of serum DHEA-S levels in a large group of children. Currently, adrenarche (DHEA-S>108·4 nmol/l) starts 1 year earlier in boys but higher DHEA-S levels are needed for transition from P1 to P2 in boys.

Kisspeptin cell-specific PI3K signaling regulates hypothalamic kisspeptin expression and participates in the regulation of female fertility.

Hypothalamic kisspeptin neurons integrate and translate cues from the internal and external environments that regulate gonadotropin-releasing hormone (GnRH) secretion and maintain fertility in mammals. However, the intracellular signaling pathways utilized to translate such information into changes in kisspeptin expression, release, and ultimately activation of the kisspeptin-receptive GnRH network have not yet been identified. PI3K is an important signaling node common to many peripheral factors known to regulate kisspeptin expression and GnRH release. We investigated whether PI3K signaling regulates hypothalamic kisspeptin expression, pubertal development, and adult fertility in mice. We generated mice with a kisspeptin cell-specific deletion of the PI3K catalytic subunits p110α and p110β (kiss-p110α/β-KO). Using in situ hybridization, we examined Kiss1 mRNA expression in gonad-intact, gonadectomized (Gdx), and Gdx + steroid-replaced mice. Kiss1 cell number in the anteroventral periventricular hypothalamus (AVPV) was significantly reduced in intact females but not in males. In contrast, compared with WT and regardless of steroid hormone status, Kiss1 cell number was lower in the arcuate (ARC) of kiss-p110α/β-KO males, but it was unaffected in females. Both intact Kiss-p110α/β-KO males and females had reduced ARC kisspeptin-immunoreactive (IR) fibers compared with WT animals. Adult kiss-p110α/β-KO males had significantly lower circulating luteinizing hormone (LH) levels, whereas pubertal development and fertility were unaffected in males. Kiss-p110α/β-KO females exhibited a reduction in fertility despite normal pubertal development, LH levels, and estrous cyclicity. Our data show that PI3K signaling is important for the regulation of hypothalamic kisspeptin expression and contributes to normal fertility in females.

Crohn disease and ulcerative colitis in children: An update for 2014

Crohn disease (CD) and ulcerative colitis (UC), the two main types of inflammatory bowel disease (IBD), have become increasingly common in Australasian children and adolescents in recent years. Furthermore, CD and UC are seen more often in younger children. These conditions are typically more extensive in children and tend to follow more severe disease courses than in adults. Although many children may present with typical symptoms (such as abdominal pain or bloody diarrhoea), others have atypical features (including oral ulceration, short stature or skin manifestations). In addition, many children with IBD will have altered growth or nutrition, which may compromise normal linear growth and pubertal development. Early identification and full assessment of children presenting with possible IBD are essential to avoid consequences of diagnostic delay and to optimise short- and long-term outcomes. Management of IBD encompasses various options and should be undertaken within a team-based, child and family-focused, multidisciplinary setting.

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mentary evaluation, the patient was diagnosed with an ovarian dysgerminoma. The patient underwent neo-adjuvant chemotherapy and bilateral gonadectomy. The karyotype of blood sample and tumour was 46, XY and the study of molecular changes in SRY gene showed a micro deletion in Yp11.23 that is responsible for a codifying sequence deletion of the gene. The patient has initiated hormonal therapy with estradiol at 15 (adding a progesterone formulation after breast development was completed), and she has achieved an adult sexual development and the mid-parental height. Nowadays the patient is 23 years-old and maintains follow up in endocrinology and oncological outpatient clinic. Conclusion: The present case emphasizes the importance of a multidisciplinary approach in Swyer Syndrome, not only for preventing gonadal malignancy, but also for getting a normal pubertal development.

Associations between early alcohol and tobacco use and prolonged time to puberty in boys.

Previous research has demonstrated a relationship between prepubertal alcohol and tobacco use and delayed pubertal characteristics in girls. Although, laboratory research indicates that alcohol and tobacco use inhibits sexual maturation in male rats, human research in this area is lacking. To address this question among boys, we conducted a study to explore the association between early use of alcohol and tobacco and time to development of secondary sexual characteristics. The study population included 3199 boys interviewed between the ages of 11 and 21. Participants reported the ages at which they first experienced body hair growth, deepening of the voice and facial hair growth. Early alcohol and tobacco use were defined as first use preceding the age of pubertal development among those reporting regular consumption patterns. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazard models. Early alcohol use was associated with longer time to body hair growth (HR 0.77; 95% CI 0.69-0.87), voice changes (HR 0.72; 95% CI 0.64-0.82) and facial hair growth (HR 0.77; 95% CI 0.68-0.86), after adjusting for tobacco use and age at interview. Tobacco use was not independently associated with the puberty indicators after controlling for alcohol use and age at interview. Our findings are consistent with the hypothesis that alcohol may inhibit puberty onset in boys, an association that has been previously observed among young girls. Thus, alcohol may be an exposure deserving more scrutiny as a disruptor to normal pubertal development.

Epidermal Growth Factor Receptor (EGFR) Signaling Is a Key Mediator of Hormone-Induced Leukocyte Infiltration in the Pubertal Female Mammary Gland

It is well documented that macrophages and eosinophils play important roles in normal murine pubertal mammary gland development. Although it is accepted that estrogen (E) and progesterone (P) are key players in mammary gland development, the roles these hormones might play in regulating the actions of leukocytes in that process is an understudied area. We show here that P and E, respectively, induce unique, but overlapping, sets of proinflammatory and angiogenic cytokines and chemokines, in the pubertal female BALB/c mammary gland, as well as induce infiltration of macrophages and eosinophils to the mammary periepithelium. This extends earlier studies showing P induction of proinflammatory products in pubertal and adult mammary epithelial organoids and P-induced in vivo infiltration of leukocytes to the adult mammary periepithelium. Importantly, epidermal growth factor receptor-signaling, which is likely mediated by amphiregulin (Areg), a downstream mediator of E and P, is both necessary and sufficient for both E- and P-induced recruitment of macrophages and eosinophils to the pubertal mammary periepithelium. We further show that receptor activator of nuclear factor κB ligand (RANKL), although not sufficient of itself to cause macrophage and eosinophil recruitment, contributes to an optimal response to P. The potency of Areg is highlighted by the fact that it is sufficient to induce macrophage and eosinophil recruitment at levels equivalent to that induced by either E or P. Our finding of a dominant role for Areg in hormonally induced leukocyte recruitment to the pubertal mammary gland parallels its dominance in regulating ductal outgrowth and its role in P-induced proliferation in the pubertal gland.

What do we know about metabolic syndrome in adolescents with PCOS?

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy of reproductive-aged women that manifests itself with a variety of features. For this reason, three different diagnostic criteria have been introduced. For adults, the National Institutes of Health Conference (NIH) criteria, which consists of hyperandrogenism and oligo-anovulation, is the most widely used. Symptoms of PCOS usually start with puberty and may overlap with normal pubertal development. Hormonal fluctuations during this period make the diagnosis of PCOS more difficult. Until now, there is no validated diagnostic criteria for PCOS in adolescents. Although menstrual disorders and cosmetic problems are the most common complaints of adolescents with PCOS, patients should also be evaluated for the potential risk for insulin resistance, obesity, subclinical atherosclerosis, diabetes, metabolic syndrome and cardiovascular disease. Obesity is the most prominent predictor of metabolic syndrome. As the incidence of obesity is increasing both in childhood and adolescence, governments will be faced with a social and economic burden in the future. Adolescents with PCOS are more obese than normal adolescents and have an increased risk of metabolic syndrome. It is suggested that abdominal adiposity increases the risk of metabolic syndrome by inducing various cytokine secretions. Although there is no consensus on metabolic syndrome criteria in the adolescent period, International Diabetes Federation (IDF) criteria may be used for children older than 10 years. Various clinical and metabolic markers are investigated for the prediction of metabolic syndrome in the literature. Waist circumference, serum triglycerides and androgens are the suspected predictors of metabolic syndrome. The prevention of abdominal adiposity and the early diagnosis of PCOS in adolescence should be the main target for the prevention of metabolic syndrome. Clinicians should investigate adolescents with PCOS for metabolic and cardiovascular risks and take preventive action. A Mediterranean diet, low in fat and high in fruits and vegetables, along with moderate-intensity exercise and smoking cessation are the recommended interventions for especially obese adolescents with PCOS. Metformin may be the treatment of choice when lifestyle modifications are ineffective.

Long-Term Effects of Peripubertal Binge EtOH Exposure on Hippocampal microRNA Expression in the Rat

Adolescent binge alcohol abuse induces long-term changes in gene expression, which impacts the physiological stress response and memory formation, two functions mediated in part by the ventral (VH) and dorsal (DH) hippocampus. microRNAs (miRs) are small RNAs that play an important role in gene regulation and are potential mediators of long-term changes in gene expression. Two genes important for regulating hippocampal functions include brain-derived neurotrophic factor (BDNF) and sirtuin-1 (SIRT1), which we identified as putative gene targets of miR-10a-5p, miR-26a, miR-103, miR-495. The purpose of this study was to quantify miR-10a-5p, miR-26a, miR-103, miR-495 expression levels in the dorsal and ventral hippocampus of male Wistar rats during normal pubertal development and then assess the effects of repeated binge-EtOH exposure. In addition, we measured the effects of binge EtOH-exposure on hippocampal Drosha and Dicer mRNA levels, as well as the putative miR target genes, BDNF and SIRT1. Overall, mid/peri-pubertal binge EtOH exposure altered the normal expression patterns of all miRs tested in an age- and brain region-dependent manner and this effect persisted for up to 30 days post-EtOH exposure. Moreover, our data revealed that mid/peri-pubertal binge EtOH exposure significantly affected miR biosynthetic processing enzymes, Drosha and Dicer. Finally, EtOH-induced significant changes in the expression of a subset of miRs, which correlated with changes in the expression of their predicted target genes. Taken together, these data demonstrate that EtOH exposure during pubertal development has long-term effects on miRNA expression in the rat hippocampus.

Nutrition and pubertal development.

Nutrition is one of the most important factors affecting pubertal development. Puberty entails a progressive nonlinear process starting from prepubescent to full sexual maturity through the interaction and cooperation of biological, physical, and psychological changes. Consuming an adequate and balanced healthy diet during all phases of growth (infancy, childhood and puberty) appears necessary both for proper growth and normal pubertal development. Girls begin puberty at an earlier age compared to past decades. Excessive eating of many processed, high-fat foods, may be the cause of this phenomenon. Overweight or obese children are more likely to enter puberty early. Some evidence suggests that obesity can accelerate the onset of puberty in girls and may delay the onset of puberty in boys. Moreover, the progression of puberty is affected by nutrition. On the other hand, puberty triggers a growth spurt, which increases nutritional needs including macro and micronutrients. Increased caloric, protein, iron, calcium, zinc and folate needs have to be provided during this critical period of rapid growth. Severe primary or secondary malnutrition also can delay the onset and progression of puberty. The higher incidence of anorexia nervosa and bulimia in adolescents imposes a nutritional risk on pubertal development. Moreover, many environmental endocrine disruptors (EDs) have been identified that can significantly impair the normal course of puberty. This mini-review sums up some important findings in this important complex that link nutrition and pubertal development.