Pubertal Disorders Research Articles

Assessment of impact of nutritional status on pubertal development in adolescent girls of two senior secondary schools of Dehradun and to correct pubertal disorders by adolescent health counseling and adequate pharmacological intervention

Background: Adolescence is a transitional stage of physical and psychological development that occurs during the period from onset of puberty to adulthood. Adolescent nutrition is crucial for proper growth and development and a prerequisite for achieving full development potential. Aims and Objectives: The objectives of the study were as follows: (1) To find out the gross nutritional status in girl students of two senior secondary schools in Dehradun, (2) to assess the level of pubertal development in them, (3) to find out correlation of nutritional status (body mass index, BMI) with pubertal development and physical activity, and (4) to do counseling on adolescent health and pharmacological intervention as needed. Materials and Methods: A cross-sectional observational study was undertaken among 200 adolescent girls of two senior secondary schools of Dehradun. They were of 12-18 year age group studying in class VI to XII. The sample was selected by systematic random sampling Their physical examination (weight & height ) was done to calculate BMI & pubertal assessment was done by means of oral questionnaire and by showing Tanner charts. The corelation between BMI & onset of pubertal events was analyzed statistically by Chi-square test. Results: Body mass index was normal in 44%, low in 52% of students& high in 4%. On assessing pubertal events, menarche has occurred in 74% of students out of which maximum number of students attained menarche at age of 12 years followed by 13 years. Breast changes (thelarche) were present in 74.5% of students and pubic hair was present in 68% of students. A correlation was found between BMI and pubertal events. In girls with low BMI (underweight), menarche was present in 52.94% of cases, breast changes were in 52.94% of cases, regularity of periods in 42.59% of cases in girls with high BMI (overweight/obese), menarche was present in 91.66% of cases, breast changes were in 100% of cases, and regularity of periods in 36.36% of cases. Pallor was present in 37.5% of the total girls. Out of number of girls with normal weight, 80% had regular physical activity and girls with high BMI had very less regular physical activity. Conclusion: The study concluded that underweight, overweight, and anemia were the nutritional problems detected and there was a statistically significant correlation of BMI with onset of pubertal events. Those with low BMI had delayed puberty and those with high BMI had earlier onset of pubertal events. Hence, the need for correction of nutritional disorders with healthy diet, physical exercise, and clinical consultation was considered very crucial to solve the problems of early and delayed puberty. Hence, counseling the girls on adolescent’s health was encouraged in schools including imparting knowledge, nutritional education, and supplementation.

Novel mechanisms for the metabolic control of puberty: implications for pubertal alterations in early-onset obesity and malnutrition.

Puberty is driven by sophisticated neuroendocrine networks that timely activate the brain centers governing the reproductive axis. The timing of puberty is genetically determined; yet, puberty is also sensitive to numerous internal and external cues, among which metabolic/nutritional signals are especially prominent. Compelling epidemiological evidence suggests that alterations of the age of puberty are becoming more frequent; the underlying mechanisms remain largely unknown, but the escalating prevalence of obesity and other metabolic/feeding disorders is possibly a major contributing factor. This phenomenon may have clinical implications, since alterations in pubertal timing have been associated to adverse health outcomes, including higher risk of earlier all-cause mortality. This urges for a better understanding of the neurohormonal basis of normal puberty and its deviations. Compelling evidence has recently documented the master role of hypothalamic neurons producing kisspeptins, encoded by Kiss1, in the neuroendocrine pathways controlling puberty. Kiss1 neurons seemingly participate in transmitting the regulatory actions of metabolic cues on pubertal maturation. Key cellular metabolic sensors, as the mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK) and the fuel-sensing deacetylase, SIRT1, have been recently shown to participate also in the metabolic modulation of puberty. Recently, we have documented that AMPK and SIRT1 operate as major molecular effectors for the metabolic control of Kiss1 neurons and, thereby, puberty onset. Alterations of these molecular pathways may contribute to the perturbation of pubertal timing linked to conditions of metabolic stress in humans, such as subnutrition or obesity and might become druggable targets for better management of pubertal disorders.

Prevalence of growth and endocrine disorders in Malaysian children with transfusion-dependent thalassaemia.

Endocrine dysfunction due to iron overload secondary to frequent blood transfusions is a common complication in children with transfusion-dependent thalassaemia (TDT). We ascertained the prevalence of endocrine dysfunction in children with TDT seen in a hospital setting in Malaysia. We reviewed all patients with TDT who had ≥ 8 blood transfusions per year. Patients who had a history of stem cell transplantation, concurrent autoimmune diseases or were newly diagnosed to have TDT were excluded. Standard diagnostic criteria were used in the diagnosis of various endocrine dysfunctions. Of the 82 patients with TDT, 65% had at least one endocrine dysfunction. Short stature was the commonest (40.2%), followed by pubertal disorders (14.6%), hypoparathyroidism (12.3%), vitamin D deficiency (10.1%), hypocortisolism (7.3%), diabetes mellitus (5.2%) and overt hypothyroidism (4.9%). Subclinical hypothyroidism and pre-diabetes mellitus were seen in 13.4% and 8.6% of the patients, respectively. For children aged < 10 years, the prevalence of both thyroid dysfunction and hypoparathyroidism was 9.1%. Two-thirds of children with TDT experienced at least one endocrine dysfunction. Thyroid dysfunction and hypoparathyroidism may be missed if endocrine screening is only performed in children with TDT > 10 years of age. Close monitoring for endocrine dysfunction and hormonal therapy is essential to prevent long-term adverse outcomes.

SUN-265 Performance of Basal and GnRH Analog-Stimulated LH Levels Assessed by an Electrochemiluminescence Assay in Girls with Central Precocious Puberty

Background: The laboratory evaluation of patients with precocious puberty is useful to differentiate central precocious puberty (CPP) from isolated thelarche (IPT) and peripheral precocious puberty (PPP). Ultrasensitive immunoassays, such as electrochemiluminescence (ECLIA), improved sensitivity and specificity of basal and GnRH-stimulated LH levels to establish the differential diagnosis among these conditions. Aim: To establish the diagnostic value of basal and GnRHa-stimulated LH values and basal estradiol assessed by ECLIA in pubertal disorders. Patients and Methods: We included 38 girls with pubertal disorders (28 CPP, 8 IPT, and 2 PPP). Their medical records were systematically revised. Clinical and hormonal data [basal and GnRH analog -stimulated LH levels (2 hs after leuprorrelin 3.75 mg) and basal estradiol] were analyzed. Gonadotropins and estradiol levels were assessed by ECLIA (Roche, Cobas e 6000). The functional sensitivity of the assays was 0.15 IU/L for LH, FSH 0.6 IU/L for FSH and 17 pg/mL for estradiol. Basal gonadotropins and estradiol were also assessed in a control group composed by 16 prepubertal and 19 pubertal girls. The cutoff values for basal and GnRH analog- stimulated LH for diagnosis of CPP was set at < 0.3 IU/L and 8 IU/L, respectively (1). Results: The mean age of girl with CPP, IPT, and PPP at the first clinical visit was 8 ± 0.9yr (5.25- 9.6 yr), 4.25± 2.6 (0.7-7.8 yr), and 5.12±2.9 (3.1 -7.1 yr), respectively. All CPP girls presented breast development ranging from B2 to B5, whereas IPT group B2-B4 and PPP group (B2). Pubarche was presented in 86% of girls with CPP (PH 2- PH 5). Only one girl in IPT group also presented pubarche (PH3), associated to zinc oxide cream use and none in PPP group presented pubarche. The mean basal LH was 3.4 ± 1.6 (<0.1- 8.6 IU/L), 0.15 ± 0.03 (< 0.15-0.2 IU/L), and <0.15 IU/L for CPP, IPT, and PPP, respectively. In CPP group, GnRHa- stimulated LH and basal estradiol levels were 6 ± 2.8 (4-61.4 IU/L) and 21 ± 17 (<17- 90 pg/ml), respectively. The sensitivity and specificity of basal and GnRHa-stimulated LH values for diagnosis of CPP was 64.7 % and 100%, respectively. However, the cutoff of 5 IU/L for GnRHa-stimulated LH improved sensitivity to 87.5% but with lower specificity of 67%. Estradiol was undetectable (<17 pg/ml) in 48% girls with CPP. In the IPT and PPP groups, basal LH <0.3 IU/L was detected in all patients. In the control group, all but one prepubertal girl had basal LH <0.15 IU/L. In addition, basal estradiol > 17 pg/ml was present in two girls from control prepubertal group. In the control pubertal group (B3-B4), mean basal LH was 4.2± 2.3 (<015- 8.8 IU/L) and basal estradiol was 61 ± 34 (<17-135pg/mL). Conclusion: The diagnostic value of basal and GnRH-stimulated LH levels assessed by ECLIA to diagnosis CPP is limited and must be interpreted together with clinical data. Reference: (1) Freire AV et al, Clin Endocrinol (Oxf), 2013.

OR08-3 The Role Of Neuronal Plasticity In The Timing Of Puberty Onset: Insights From A Mkrn3 Deficient Mouse Model.

Makorin ring finger protein 3 (MKRN3) was identified as a regulator of puberty initiation with the report of loss-of-function mutations in association with central precocious puberty (CPP). MKRN3 is a maternally imprinted gene located on chromosome 15q11.2 in humans. In juvenile mice, Mkrn3 is highly expressed in the preoptic area and the arcuate nucleus of the hypothalamus, with a decrease in expression before puberty initiation. Together, these findings suggest an inhibitory role of MKRN3 on GnRH secretion during the prepubertal quiescent period. MKRN3 contains a RING finger motif and several zinc finger motifs, suggesting E3 ubiquitin ligase and RNA binding activities, respectively. To date, the mechanisms of action of MKRN3 in puberty initiation remain unknown. In this study, we used a Mkrn3 deficient mouse model to identify hypothalamic targets of MKRN3’s inhibitory effects. By Western blot and immunohistochemistry, we confirmed that Mkrn3 protein was undetectable in Mkrn3+/- mice (which inherited the mutant allele from their father), but present in wildtype (Mkrn3+/+) mice. Mkrn3 deletion was associated with accelerated puberty onset in female mice and a trend towards early puberty onset in male mice, as shown by an advanced day of female first estrus and a trend towards earlier age of male preputial separation in Mkrn3 deficient (Mkrn3+/-) compared to Mkrn3+/+animals. Hypothalamic mRNA levels of Gnrh1, Kiss1, Tac2 and Tac1, regulators of pubertal initiation, were measured by RT-qPCR in females at different ages across postnatal development (postnatal day (PND)10, PND15, PND20 and PND25). No significant difference was found in Gnrh1 and Kiss1 expression in the preoptic area, nor in Kiss1, Tac2 and Tac1 expression in the arcuate nucleus, between Mkrn3+/+ and Mkrn3+/- mice, at any of the postnatal day ages tested. Thus, to further investigate possible targets of MKRN3 action using an unbiased approach, we compared the transcriptome (via RNA-sequencing) and proteome (via Tandem Mass Tagging (TMT) method) of the arcuate nucleus of Mkrn3+/+ and Mkrn3+/- female mice at PND15. These analyses revealed differences in gene or protein expression between Mkrn3+/+ and Mkrn3+/- animals in factors involved in extracellular matrix organization, cell adhesion, and axon guidance pathways, which together control neuronal development and synaptic plasticity. These findings suggest that Mkrn3 may be important as a postnatal/prepubertal regulator of hypothalamic neuronal plasticity in mice. In humans, puberty has been shown to be a critical time window of neuronal plasticity. Thus, understanding the involvement of MKRN3 in these processes will provide new insights into pubertal disorders such as CPP and delayed puberty, and may lead to the development of new treatment strategies.

SUN-251 Tanner Stage Adjustment of CDC Height Curves and Potential Clinical Applications

Background: The CDC height charts based upon chronological age (CA-Height) don’t account for the different growth patterns that can be seen in variations of puberty, pubertal disorders or ethnic difference in pubertal timing. Adjustment for differences in timing of puberty between race-ethnicity groups affects estimated prevalence of shortness and tallness. Differences in timing of puberty between race-ethnicity groups affects estimated prevalence of shortness and tallness of attained height that remains uncaptured with CA-Height. Methods: Pooled Tanner staging and anthropometric data for 12,316 children age 8-18 years from three US cross-sectional nationally representative surveys from 1966 through 1994; namely: The National Health Examination Surveys (NHES cycle III); the Hispanic Health and Nutrition Examination Surveys (HHANES 1982-1984) and finally, the 3rd National Health and Nutrition Examination Surveys (NHANES III 1988-1994) was analyzed. Tanner-stage height-for-age (TSA-Height) semi-parametric models were used to develop TSA-Height curves accounted for maturation stage and calendar age. Models had additive splines that enabled age smoothing in the estimation of specialized TSA-Height reference charts. Results: TSA-Height charts as generic race-ethnic neutral and stratified by gender were generated and plotted against the CDC CA-Height curves to account for the differences between these models. We provide clinical examples of the utility of these curves in children with variations in pubertal timing and during treatment for pubertal disorders. We also provide the race-ethnicity specific TSA-Height charts stratified by gender for non-Hispanic White and Black, and for Hispanic American. Conclusions: We have used an expanded set of cross-sectional growth and puberty survey data to model the impact of pubertal timing on attained height. These new specialized TSA-Height charts provide a much-needed tool for clinicians to assess and manage linear growth potential for US children over the course of pubertal progression and could have implications on public health assessment.

Gonadotropin-dependent pubertal disorders are common in patients with virilizing adrenocortical tumors in childhood.

ObjectiveTo investigate the impact of early exposure to androgen excess on gonadotropin-dependent puberty (GDP) and final height (FH) of patients with androgen-secreting adrenocortical tumors (ACT) in childhood.MethodsRetrospective cohort study. Occurrence of GDP and achievement of FH were evaluated. Central precocious puberty (CPP) and early fast puberty (EFP) were considered pubertal disorders. Patients with normal puberty and pubertal disorders were compared.ResultsThe study included 63 patients (44F), followed in a single institution from 1975 until 2017. At diagnosis of ACT, median age was 25.8 months; duration of signs, 6 months; stature SDS, 0.5 (−3.6 to 3.9) and bone age advancement, 14.7 months (−27.9 to 85.4). To date, 37 patients developed GDP: 26 had normal puberty; one, precocious thelarche; seven, CPP and three, EFP. GnRHa effectively treated CPP/EFP. Tall stature and older age at diagnosis of ACT were associated with risk of CPP alone (RR 4.17 (95% CI 1.17–14.80)) and CPP/EFP (RR 3.0 (95% CI 1.04–8.65)). Recurrence/metastasis during follow-up were associated with risk of CPP alone (RR 4.17 (95% CI 1.17–14.80)) and CPP/EFP (RR 3.0 (95% CI 1.12–8.02)). Among the 19 patients that reached FH, stature SDS dropped from 1.4 to −0.02 since diagnosis of ACT (P = 0.01). Seventeen achieved normal FH. There was no difference in FH SDS between patients with normal puberty and pubertal disorders (P = 0.75).ConclusionsGonadotropin-dependent pubertal disorders are common in patients with androgen-secreting ACT in childhood. FH is usually not impaired. The study reinforces the importance of close follow-up after surgery to identify and treat consequences of early exposure to androgen excess.

Pattern of Paediatric Endocrine Disorders According to ICD-10 Classification in a Tertiary Centre in Southern Nigeria

Aim: To describe the spectrum of various endocrine disorders seen in children and adolescents in Port Harcourt over the period 2013-2017 using modified European Society of Paediatric endocrinology ICD -10 classification.&#x0D; Study Design: Descriptive, Cross sectional study.&#x0D; Place and Duration: Paediatric endocrinology Unit, Department of Paediatrics, University of Port Harcourt Teaching Hospital. Study was done with data from January 2013 to August 2017.&#x0D; Methods: A retrospective review of 178 patients with various endocrine diseases was reported. Data on biodata, clinical presentations and investigations with diagnosis were retrieved from the clinic and ward records and endocrine unit registers.&#x0D; Results: A total of 178 patients were seen with various endocrine disorders over the study period accounting for 4.5% of Paediatric specialist clinic consultations. There were 89(50.0%) females and 80(44.9%) males. Nine (5.1%) had genital ambiguity. The ages of patients ranged from 12days to 17years with a mean age of 6.9 ± 5.1years. The commonest endocrine disorders were pubertal disorders, diabetes mellitus, thyroid disorders and calcium phosphate metabolism and bone disorders in 34(17%), 27(14%) 23(12%), 22(11%) and 22(11%) respectively. Twenty two (11%) of the patients had obesity and 10(5%) had syndromes with endocrine features. Other disorders seen were sex development and gender disorders, testicular/male reproductive tract disorders, growth disorders (short stature) ovarian/female reproductive tract disorders, pituitary/ hypothalamic disorders and adrenal disorders in 17(9%), 17(9%) 10(5%),7(4%), 5(2.5%) and 3(1.5%) respectively. Type 1 DM remained the commonest type of DM. Most of the patients were of the middle social class (social class III). Challenges to management included high cost of investigations and drugs, high rate of loss to follow up.&#x0D; Conclusion: Pubertal disorders, type 1 Diabetes mellitus, thyroid disorders, calcium and phosphate metabolism and bone disorders and obesity were the commonest cases in our review. Most investigations were available in private laboratories with high cost of investigation leading to loss to follow up and continuation of care.

Random urinary gonadotropins as a useful initial test for girls with central precocious puberty.

Recent evidence indicates that urinary gonadotropins may be an alternative method for detecting pubertal disorders. The aim of this study was to evaluate the associations of first morning voided (FMV) and random urinary gonadotropins with the pubertal response to a gonadotropin-releasing hormone (GnRH) stimulation test to determine whether random urinary gonadotropins can be used as an alternative method for evaluating central precocious puberty (CPP). In total, 100 girls aged 6.0-8.9 years were enrolled. The subjects were divided into two groups according to their pubertal response to the GnRH stimulation test: a positive group (n = 68) and a negative group (n = 32). Random urinary luteinizing hormone (LH), follicle-stimulating hormone (FSH), and the LH:FSH ratio were significantly positively correlated with FMV urinary LH (r = 0.411, p < 0.001), FMV urinary FSH (r = 0.494, p < 0.001), and the FMV urinary LH:FSH ratio (r = 0.519, p < 0.001). The optimal cutoff values from receiver operating characteristic (ROC) curve analyses were determined to be 0.20 IU/L for random urinary LH (area under the curve (AUC) of 0.812, p < 0.001), 3.03 IU/L for random urinary FSH (AUC of 0.670, p = 0.004) and 0.08 for the random urinary LH:FSH ratio (AUC of 0.784, p < 0.001). No differences were observed between FMV and random urinary LH (p = 0.827), between FMV and random urinary FSH (p = 0.650), or between the FMV and random urinary LH:FSH ratio (p = 0.688) in ROC curve analyses with DeLong's test. Based on our findings, random urinary gonadotropins may be applicable in clinical practice as a useful initial test for girls with CPP.

Disorders of Puberty: Pharmacotherapeutic Strategies for Management.

During puberty, with activation of the hypothalamic pituitary axis that has been quiescent since the neonatal period, linear growth accelerates, secondary sexual characteristics develop, and adult fertility potential and bone mass are achieved, together with psychosocial and emotional maturation.Disordered pubertal onset and progress, either early or late, presents frequently for endocrine care. Where a disorder is found, due either to a central hypothalamic pituitary cause or to primary gonadal failure, pharmacotherapeutic interventions are required to alter the trajectory of disturbed pubertal onset or progress and for maintenance of adolescent and adult sex hormone status. This paper describes pharmacologic interventions used for pubertal disorders but is not intended to address the diagnostic cascade in detail.

Editorial introductions

Editorial introductions

Endocrinopathies in celiac disease: When the endocrinologist sees what is invisible to the gastroenterologist.

Celiac disease (CD) is a systemic, immune mediated and genetically determined small intestinal disorder characterized by intolerance to dietary gluten that generally presents with gastrointestinal symptoms in young children and extra-intestinal manifestations. Furthermore, there is close association between CD and endocrine diseases, including diabetes, autoimmune thyroid diseases, growth and pubertal disorders, etc. probably due to the presence of a common genetic predisposition. The present review aims to highlight and give more insight to the endocrine changes in CD, especially when there are few or no gastrointestinal symptoms and to emphasize on screening opportunities in some endocrine diseases. (www.actabiomedica.it)

Risk factors for pubertal and menstrual function developmental disorders in teenage girls living in the Altai Territory: possibilities of prevention

Risk factors for pubertal and menstrual function developmental disorders in teenage girls living in the Altai Territory: possibilities of prevention

Puberty from bench to clinic: Lessons for clinical management of pubertal disorders

Puberty from bench to clinic: Lessons for clinical management of pubertal disorders

Hypogonadism in male thalassemia major patients: pathophysiology, diagnosis and treatment.

Failure of pubertal growth, delay or absence of sexual development, infertility and sexual dysfunction due to hypogonadism and defective spermatogenesis are frequent and well recognized disturbances among male patients with transfusion dependent (TD) thalassaemia major (β-thal). These problems are attributed mainly to the damage caused by chronic anaemia and the deposition of excess iron in the pituitary gland and testicles. This is a short review of male pubertal disorders in patients with β-thal written by pediatric endocrinologists and haematologists with an interest and active involvement, in the diagnosis and management of these complications in this group of patients. A vigilant clinical evaluation of growth and puberty, as well as an appropriate hormonal evaluation in poly-transfused (TD β-thal) patients is strongly recommended for early detection and treatment of endocrine dysfunction. Of crucial importance also, is the implementation of an efficient chelation regime from early life, to prevent severe iron load and permanent damage to the endocrine glands, particularly those responsible for gonadal function. (www.actabiomedica.it)

Discovery of GnIH and Its Role in Hypothyroidism-Induced Delayed Puberty

It is known that hypothyroidism delays puberty in mammals. Interaction between the hypothalamo-pituitary-thyroid (HPT) and hypothalamo-pituitary-gonadal (HPG) axes may be important processes in delayed puberty. Gonadotropin-inhibitory hormone (GnIH) is a newly discovered hypothalamic neuropeptide that inhibits gonadotropin synthesis and release in quail. It now appears that GnIH is conserved across various mammals and primates, including humans, and inhibits reproduction. We have further demonstrated that GnIH is involved in pubertal delay induced by thyroid dysfunction in female mice. Hypothyroidism delays pubertal onset with the increase in hypothalamic GnIH expression and the decrease in circulating gonadotropin and estradiol levels. Thyroid status regulates GnIH expression by epigenetic modification of the GnIH promoter region. Furthermore, knockout of GnIH gene abolishes the effect of hypothyroidism on delayed pubertal onset. Accordingly, it is considered that GnIH is a mediator of pubertal disorder induced by thyroid dysfunction. This is a novel function of GnIH that interacts between the HPT-HPG axes in pubertal onset delay. This mini-review summarizes the structure, expression, and function of GnIH and highlights the action of GnIH in pubertal disorder induced by thyroid dysfunction.

PATTERN OF PAEDIATRIC ENDOCRINE DISORDERS AS SEEN AT A TERTIARY HEALTH FACILITY IN SOKOTO OVER A 4 -YEAR PERIOD

In most developing countries, data on the pattern of Paediatric Endocrine Disorders is lacking. To describe the pattern of Paediatric Endocrine Disorders as seen in Usmanu Danfodiyo University teaching Hospital (UDUTH), Sokoto, Nigeria, from January 2013 to December 2016. The case files of children seen at the paediatric endocrine/metabolic clinic and those admitted into the wards at UDUTH, Sokoto, from January 2013 to December 2016 were audited retrospectively. Information obtained included age at presentation, gender, principal complaints, final diagnosis and outcome. A total of 37 children presented with various endocrine disorders during the 4 - year- period under review. There were 20(54.1%) males, 15(40.5%) females, and 2(5.4%) patients with genital ambiguity. Patient's age ranged from 3weeks to 15years with a mean age and standard deviation (SD) of 6.9(5.2) years. Majority, 17(46%) of the patients were Adolescents. The endocrine disorders were thyroid disorders- 12(32.4%), diabetes Mellitus 9(24.3%), disorders of energy balance 4(10.8%), disorders of calcium and bone metabolism 4 (10.8%) and pubertal disorders 3(8.1%). Five (13.5%) patients were admitted, four were diabetics, three of which were discharged and 1(2.7%) died. Fifteen (40.5%) patients were lost to follow up in the endocrine clinic. Thyroid disorders, Diabetes Mellitus, Disorders of energy balance, Calcium and bone metabolism and pubertal disorders were the five leading groups of childhood endocrine disorders encountered in our clinical practice in UDUTH, Sokoto.

Gene expression profiling of puberty-associated genes reveals abundant tissue and sex-specific changes across postnatal development.

The timing of human puberty is highly variable, sexually dimorphic, and associated with adverse health outcomes. Over 20 genes carrying rare mutations have been identified in known pubertal disorders, many of which encode critical components of the hypothalamic-pituitary-gonadal (HPG) axis. Recent genome-wide association studies (GWAS) have identified more than 100 candidate genes at loci associated with age at menarche or voice breaking in males. We know little about the spatial, temporal or postnatal expression patterns of the majority of these puberty-associated genes. Using a high-throughput and sensitive microfluidic quantitative PCR strategy, we profiled the gene expression patterns of the mouse orthologs of 178 puberty-associated genes in male and female mouse HPG axis tissues, the pineal gland, and the liver at five postnatal ages spanning the pubertal transition. The most dynamic gene expression changes were observed prior to puberty in all tissues. We detected known and novel tissue-enhanced gene expression patterns, with the hypothalamus expressing the largest number of the puberty-associated genes. Notably, over 40 puberty-associated genes in the pituitary gland showed sex-biased gene expression, most of which occurred peri-puberty. These sex-biased genes included the orthologs of candidate genes at GWAS loci that show sex-discordant effects on pubertal timing. Our findings provide new insight into the expression of puberty-associated genes and support the possibility that the pituitary plays a role in determining sex differences in the timing of puberty.

Involvement of gonadotropin-inhibitory hormone in pubertal disorders induced by thyroid status

Thyroid disorders cause abnormal puberty, indicating interactions between the hypothalamus-pituitary-thyroid (HPT) and hypothalamus-pituitary-gonadal (HPG) axes, which are important in pubertal development. The hypothalamic gonadotropin-inhibitory hormone (GnIH) was shown to be decreased in the early prepubertal stage, suggesting the role of GnIH on pubertal onset. Here, we investigated whether thyroid dysfunction affects pubertal onset in female mice via GnIH regulation. Hypothyroidism showed delayed pubertal onset with increased GnIH expression and reduced pituitary-gonadal activity. Remarkably, knockout of GnIH prevented the effect of hypothyroidism to delay the pubertal onset, resulting in indistinguishable pubertal timing in GnIH-knockout female mice between control and hypothyroidism-induced group, indicating that increased GnIH expression induced by hypothyroidism may lead to delayed puberty. In contrast, hyperthyroidism led to a decrease in GnIH expression, however pubertal onset was normal, implying further reduction of the inhibitory GnIH had little effect on the phenotypical change. Critically, thyroid hormone suppressed GnIH expression in hypothalamic explants and GnIH neurons expressed thyroid hormone receptors to convey the thyroid status. Moreover, the thyroid status highly regulated the chromatin modifications of GnIH promoter, H3acetylation and H3K9tri-methylation. These findings indicate a novel function of GnIH to mediate HPT-HPG interactions that contribute to proper pubertal development.

Menstrual Disorders from Puberty to Early Adult Age: A Cross-Sectional Survey

Introduction: A female encounters various menstrual disorders from puberty to menopause. We evaluated menstrual disturbances in post-menarche age and young adult age.Aim: To know the prevalence and impact of menstrual abnormalities at early adolescent and young adult age and to evaluate course of disorders identified at early adolescent age.Materials and Methods: A cross-sectional survey was carried out through self-administered questionnaire on 367 consented students at Melaka Manipal Medical College at Manipal, during December 2015- April 2016. Data were analysed by Statistical Package for the Social Sciences (SPSS) 16.0 software.Results: Prevalence and pattern of menstrual disorders at early adolescent and at young adult age were noted. The mean age of menarche was 12.1 ±1.1 years.Menorrhagia was the most frequent (14.7% and 11.7%) and polymenorrhea (7.6 % and 6%) was least frequent menstrual disorder at adolescent age and young adult age respectively. Resolution of pubertal menstrual disorders was observed in all disorders, but noticed highest in oligomenorrhea (91%), (p-value <0.05). Prevalence of menstrual related disorder like dysmenorrhea was 88.7% at adolescent age and 67.6% at the young adult age. It was statistically significant reduction. Hindrance in academic performance and social behavior was noted more at young adult age, which was in 23.9% and 46.7% respectively (p-value <0.05).Conclusion: The most prevalent menstrual abnormality was menorrhagia at the early adolescent and the young adult age. Associated the most prevalent menstrual related symptoms were dysmenorrhea at early adolescent age, and premenstrual symptom at the young adult age. The study demonstrates the natural course (decreasing prevalence) of all menstrual disorders from early adolescent to young adult age.