Axis In Girls Research Articles

Evaluating the gonads of left-handed children using ultrasonography and comparing the findings with those of right-handed ones.

Lateralization affected gonad size in girls. In boys, gonads were not affected by lateralization. Cerebral lateralization may affect the hypothalamic-pituitary-gonadal axis in girls. • Hand use varies according to which cerebral hemisphere is dominant. Males tend to be more left-handed than females. Brain asymmetry can affect the neuroendocrine axis. • Ultrasonographic gonadal dimensions were examined in left-handed and right-handed children. Cerebral lateralization may affect the hypothalamic-pituitary-gonadal axis in girls.

Analysis of the incidence of central precocious puberty treated with gonadotropin-releasing hormone analogs. Impact of the COVID-19 pandemic

Introduction. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, consultations of girls with idiopathic central precocious puberty (ICPP) increased in several countries, but there were no data from Argentina. This increase may be related to changes in lifestyle and stress levels resulting from the lockdown, which particularly affected the child population. Objectives. 1) To describe the progression of the incidence of ICPP requiring inhibition of the hypothalamic-pituitary-gonadal (HPG) axis in girls between 2010 and 2021 in a cohort from the Metropolitan Area of Buenos Aires. 2) To compare the characteristics of girls diagnosed with ICPP during the pandemic with those of a control group. Methods. Interrupted time-series and case-control study. Results. The annual incidence remained stable between 2010 and 2017. Since 2017, it increased to an average of 59.9% (95% CI: 18.6-115.5) and appears to have accelerated during the pandemic. We found an association between ICPP and requiring inhibitory treatment between June 1st, 2020 and May 31st, 2021 and 2 variables: maternal age at menarche (OR: 0.46, 95% CI: 0.28-0.77) and family history of ICPP (OR: 4.42, 95% CI: 1.16-16.86). Conclusion. We evidenced a significant increase in the incidence of ICPP with requirement of HPG axis inhibition since 2017. Increased exposure to various environmental triggers during the COVID-19 pandemic may have had a greater influence in girls with some genetic predisposition.

Rapid progressive central precocious puberty: diagnostic and predictive value of basal sex hormone levels and pelvic ultrasound.

Objectives Data on the predictive values of parameters included in the diagnostic work-up for precocious puberty (PP) remain limited. We detected the diagnostic value of basal sex hormone levels, pelvic ultrasound parameters and bone age assessment for activation of the hypothalamic-pituitary-gonadal axis in girls with PP, in order to help in the decision to perform GnRH testing. Patients and methods We retrospectively considered 177 girls with PP. According to puberty evolution, the girls were divided into two groups: rapid progressive central precocious puberty (RP-CPP) and non/slowly progressive/transient forms (SP-PP). In all patients we considered Tanner stage, basal luteinizing hormone (LH) and estradiol (E2) values, bone age, and pelvis examination. We assessed the diagnostic value of each variable and identified the number of pathological parameters that best identify patients with RP-CPP. Results Basal LH≥0.2IU/L, E2 level ≥ 50pmol/L, uterine longitudinal diameter ≥3.5cm, transverse uterine diameter ≥1.5cm, endometrial echo and ovarian volume ≥2cm3 were significantly associated with RP-CPP (p≤0.01). The ability to diagnose RP-CPP was enhanced with increasing number of pathological hormonal and instrumental parameters (p<0.001). With more than three parameters detected, sensitivity and specificity reached 58% (95%CI 48-67) and 85% (95%CI 74-92), respectively, with a PPV=86% (95%CI 76-93) and PPN=54% (95%CI 43-54); the area under the ROC curve was 0.71 (95%CI 0.65-0.78). Conclusion Despite the availability of different tests, diagnosing RP-CPP remains difficult. A diagnosis model including at least three hormonal and/or ultrasound parameters may serve as a useful preliminary step in selecting patients who require GnRH testing for early detection of RC-PP.

Treatment with Depot Leuprolide Acetate in Girls with Idiopathic Precocious Puberty: What Parameter should be Used in Deciding on the Initial Dose?

Objective:Doses of gonadotropin releasing hormone (GnRH) analogues used to treat idiopathic central precocious puberty (iCPP) vary among clinicians. Study aims were to evaluate the efficacy of a monthly 3.75 mg dose of leuprolide acetate (LA) to suppress the hypothalamo-pituitary-gonadal (HPG) axis in girls with iCPP and to determine factors that may have an impact on the supressing dose.Methods:Study subjects were 220 girls receiving LA for iCPP. LA was started at a dose of 3.75 mg/28 days. Suppression was assessed using the GnRH test at the third month. To assess clinical suppression signs and symptoms of puberty were also evaluated. The dose of LA was increased to 7.5 mg/28 days in those who had a peak luteinising hormone (LH) ≥2 IU/L and in whom adequate clinical suppression of puberty was absent. Receiver operating characteristic curves were used to determine thresholds for clinical and hormonal factors affecting the suppressing dose of LA. Logistic regression analyses were used to investigate thresholds which might differentiate between those requiring high dose for suppression and those in whom lower dose LA was adequate.Results:Peak stimulated LH <2 IU/L was achieved in 88.6% with a dose of LA of 3.75 mg (0.11±0.03 mg/kg). Significant variables for differentiating the two doses were body weight (Wt) of 36.2 kg and/or body mass index (BMI)-standard deviation scores (SDS) of 1.64 (p<0.001). Multiple logistic regressions showed that Wt and BMI-SDS values above thresholds indicated requirement of LA at a dose of 7.5 mg/28 days (p<0.001).Conclusion:Monthly injections of 3.75 mg LA is an effective treatment in the majority of girls with iCPP. However, a higher initial dose may be preferred in patients with a Wt ≥36 kg or BMI-SDS ≥1.6 for effective suppression of the HPG axis.

Evaluation of basal sex hormone levels for activation of the hypothalamic-pituitary-gonadal axis.

This study aimed to identify the predictive value of basal sex hormone levels for activation of the hypothalamic-pituitary-gonadal (HPG) axis in girls. Gonadotropin-releasing hormone (GnRH) stimulation tests were performed and evaluated in a total of 1750 girls with development of secondary sex characteristics. Correlation analyses were conducted between basal sex hormones and peak luteinizing hormone (LH) levels ≥5 IU/L during the GnRH stimulation test. Receiver operating characteristic (ROC) curves for basal levels of LH, follicle-stimulating hormone (FSH), LH/FSH, and estradiol (E2) before the GnRH stimulation test were plotted. The area under the curve (AUC) and 95% confidence intervals (CIs) were measured for each curve. The maximum AUC value was observed for basal LH levels (0.77, 95% CI: 0.74-0.79), followed by basal FSH levels (0.73, 95% CI: 0.70-0.75), the basal LH/FSH ratio (0.68, 95% CI: 0.65-0.71), and basal E2 levels (0.61, 95% CI: 0.59-0.64). The appropriate cutoff value of basal LH levels associated with a positive response of the GnRH stimulation test was 0.35 IU/L, with a sensitivity of 63.96% and specificity of 76.3% from the ROC curves when Youden's index showed the maximum value. When 100% of patients had peak LH levels ≥5 IU/L, basal LH values were >2.72 IU/L, but the specificity was only 5.45%. Increased basal LH levels are a significant predictor of a positive response during the GnRH stimulation test for assessing activation of the HPG axis in most girls with early pubertal signs.

Hypothalomo-pituitary-gonadal axis in girls with type 1 diabetes mellitus menstrual disorders and ovarian dysfunction

Type 1 diabetes mellitus (DM) has negative effect on the development and functioning of the reproductive system in young girls. The time of onset of type 1 DM (especially in the puberty period), duration of the disease, and poor compensation of disturbed carbohydrate metabolism are supposed to be the most probable causes of delayed pubertal development exerting negative effect on the age of menarche and increasing the frequency of menstrual problems (largely oligo- and amenorrhea). Despite a wealth of relevant investigations, the cause of reproductive dysfunction remains unknown even though negative effect of type 1 DM on different components of the hypothalamo-pituitary-ovarian axis has been fairly well documented. The pathogenetic mechanisms of reproductive disorders may consist of suppression of pulsed production of gonadotropin releasing hormone (GnRH) due to enhanced central dopaminergic and opiate activities, decreased concentration of insulin receptors on GnRH-synthesizing neurones, and changes of serum leptin level in the affected girls. In patients with type 1 DM, hypothalamic effects on the pituitary may be supplemented by the direct action of products of free radical oxidative activity leading to a decrease in the production of trophic hormones. Also considered, is primary ovarian origin of menstrual disturbances in girls with type 1 DM. Of great importance are studies concerning autoantibodies against different ovarian structures, variations in concentrations of insulin-like growth factor-1 (IGF-1) and hormone ghrelin.

Link Between Body Fat and the Timing of Puberty

Several recent studies suggest that the timing of the onset of puberty in girls has become earlier over the past 30 years, and there is strong evidence that the increasing rates of obesity in children over the same time period is a major factor. This article reviews studies from the United States that examined the age of menarche and the age of onset of breast development and pubic hair as a function of body mass index, which is a good surrogate measure of body fat. These studies are nearly all cross-sectional, so many questions remain unanswered. However, at least several studies show that girls who have relatively higher body mass index are more likely to have earlier menses, as well as a relationship between body mass index and other measures of pubertal onset. The evidence published to date suggests that obesity may be causally related to earlier puberty in girls rather than that earlier puberty causes an increase in body fat. In contrast, few studies have found a link between body fat and earlier puberty in boys. A growing body of evidence from both rodent and human studies suggests that leptin may be the critical link between body fat and earlier puberty. Leptin-deficient mice and humans fail to enter puberty unless leptin is administered, and rodent studies indicate that very low levels of leptin stimulate gonadotropin secretion both at the hypothalamic and the pituitary level. Current evidence indicates that leptin appears to play a permissive role rather than act as the critical metabolic signal initiating puberty. The linkage between body fat and the reproductive axis in girls may have evolved in mammals as a mechanism for ensuring that pregnancy will not occur unless there are adequate fat stores to sustain both the mother and the growing fetus.

The growth hormone (GH) and insulin-like growth factor (IGF) system in girls and women with Turner syndrome

Growth hormone (GH), its receptor and signaling cascade and the insulin-like growth factor (IGF) system are important regulators of growth and metabolic homeostasis. The GH–IGF axis in girls and women with Turner syndrome has been studied by many groups. A variety of distinct abnormalities as to synthesis and secretion of GH and IGFs as well as perturbed signaling and impaired biologic responses to GH and/or IGFs have been reported. This chapter summarizes the literature and gives a synopsis of current knowledge as to findings related to the GH and IGF system in girls and women with Turner syndrome.

Entero-insular axis in children with anorexia nervosa

Entero-insular axis plays an important role in generating satiety signal. Thus disturbances in this axis may influence the course of anorexia nervosa. The aim of the study was analysis of the function of the hormonal part of the entero-insular axis in girls with anorexia nervosa. Thirteen girls with anorexia nervosa and in 10 healthy girls were studied. Each girl was subjected to oral glucose tolerance test and standard meal test. Blood was collected before stimulation and within 15, 30, 60, and 120 min thereafter. The concentrations of all peptides were determined by radioimmunoassay commercial kits. Fasted and postprandial levels of these peptides as well as integrated outputs were measured. Fasting insulin concentration was significantly higher in the group of girls with anorexia nervosa than in the control group (p<0.03). What more in girls with anorexia the integrated output of insulin was significantly lower in oral glucose tolerance test than after the meal (p<0.001). Also the integrated output of glucagon in both tests was higher in the group of girls with anorexia than in the control group. The mean output of pancreatic polypeptide and cholecystokinin in anorexia group was significantly higher (p<0.001 in both cases) than that in the control group but only after the test meal. The integrated outputs of gastric inhibitory peptide in both tests were significantly higher in anorectic girls than those in the control group (oral glucose tolerance test, p<0.02; meal test, p<0.001), However, mean values of the integrated output of glucagon-like peptide 1 in both tests were significantly higher in the control group than in the girls with anorexia (p<0.001 in each case). Highly significant correlation was found between glucose concentration and the concentrations of insulin, cholecystokinin, and gastric inhibitory peptide in both tests and for the both groups. In the anorectic girls, significant correlation between insulin concentration and the concentration of gastric inhibitory peptide was found after both stimulation tests and between insulin and cholecystokinin after oral glucose only. the disturbed secretion of the hormones of entero-insular axis after the meal in anorectic girls may have negative influence on the course of anorexia nervosa. This disease has no effect on the incretin function of cholecystokinin, gastric inhibitory peptide and glucagon-like peptide 1.

Serum Inhibin A and Inhibin B in Central Precocious Puberty before and during Treatment with GnRH Agonists

Serum levels of the gonadal hormones inhibin A and inhibin B are undetectable or low in prepubertal girls, and rise during puberty. In girls with central precocious puberty (CPP) the hypothalamic-pituitary-gonadal axis is prematurely activated, if the girl is thereafter treated with GnRH agonists both gonadotropins and estradiol levels become suppressed. We therefore investigated serum levels of inhibin A and inhibin B in girls with CPP at diagnosis and during treatment in order to test the hypothesis that inhibin secretion would increase and decrease in parallel with the activation and suppression of the hypothalamic-pituitary-gonadal axis. Serum levels of inhibin A and inhibin B were significantly (p < 0.0005) elevated in 42 girls at diagnosis of CPP (inhibin A: 7 pg/ml (<7–139), inhibin B: 80 pg/ml (<20–294) (median, range)) compared to levels in age-matched healthy schoolgirls (inhibin A: all values <7 pg/ml, inhibin B: 21 pg/ml (<20–122) (median, range)), but were appropriate for Tanner stage. During treatment with GnRH agonist (intranasal buserelin and oral cyproterone acetate, treatment group 1, n = 23, or triptorelin depot injections, treatment group 2, n = 19) levels of both hormones fell significantly (p = 0.002). There was a significantly (p = 0.003) greater fall in inhibin B levels during treatment in group 2 compared to group 1, with inhibin B levels now lying below (group 2: <20 pg/ml (<20–68)) rather than within (group 1: 34.5 pg/ml (<20–93)) the age-appropriate range. It is concluded that levels of inhibin A and inhibin B are elevated and suppressed in concert with activation and suppression of the hypothalamo-pituitary-gonadal axis in girls with CPP, supporting the concept that ovarian inhibin secretion is dynamically regulated by gonadotropin stimulation.

Neuroendocrine mechanisms mediating awakening of the human gonadotropic axis in puberty.

The hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator presides over the pulsatile and feedback-regulated activities of the pituitary-gonadal axis. Awakening of synchronous activity of the GnRH neuronal ensemble in the earliest stages of puberty heralds the onset of full activation of the reproductive axis in girls and boys. Progression from prepuberty to adulthood in boys is directed by marked (30-fold) amplitude enhancement of pulsatile luteinizing hormone (LH) secretion, as assessed by an ultrasensitive immunofluorometric assay and deconvolution analysis. There is a much less apparent rise in LH secretory burst frequency (approximately 1.3-fold increase). Consequently, human puberty is an amplitude-driven neuroendocrine maturational process. However, less is known about pulsatile follicle-stimulating hormone (FSH) release in puberty. Multiple pathophysiologies that result in hypogonadotropic hypogonadism can converge on a final common mechanism of attenuated hypothalamic GnRH pulse generator output and hence reduced LH (and FSH) secretion. Disturbances may take the form of reduced GnRH pulse frequency and/or attenuated GnRH secretory burst mass. When the pathophysiology of hypogonadism originates exclusively in a failed GnRH pulse generator, then either treatment of the primary disease process where possible (e.g., by refeeding in starvation, improved metabolic control in diabetes mellitus, dopamine agonist treatment in hyperprolactinemia, etc) and/or treatment with pulsatile GnRH (e.g., in Kallmann's syndrome, isolated hypothalamic lesions, etc.) can provide relevant therapeutic options in children and adults.

Dynamics of basal pituitary gonadotropin secretion and responsiveness to LRH following estradiol benzoate in normal girls.

The influence of a single intramuscular injection of estradiol benzoate (E2B), 2.5-15 micrograms/kg, on the basal plasma estradiol, LH and FSH and their response to LRH stimulation (50 micrograms/m2, i.v.) performed 20 h after E2B injection, was studied in 50 normal girls aged 6-17 years. It was found that the minimal dose of E2B which caused a significant change in the basal and/or LRH stimulated LH and FSH levels was 10 micrograms/kg. This dose increased plasma estradiol level by 10-35 pg/ml, i.e. still within the normal range for the appropriate pubertal stage of the subjects. The same dose of E2B significantly suppressed the basal FSH level in most of the prepubertal (n = 8), early-pubertal (n = 9) and late-pubertal (n = 14) girls and the FSH response to LRH in most prepubertal girls. The basal LH was suppressed in most pre- and early-pubertal girls, but increased significantly in 50% of the late-pubertal girls. The LH response to LRH was significantly increased in most of the girls at all pubertal stages. It is suggested that endogenous estradiol is an important mediator in the maturation of the hypothalamo-pituitary axis in girls from mid-puberty onwards, and that the low physiological level of estradiol present in adolescence is sufficient to induce a gradual increase in pituitary sensitivity to LRH and a positive hypothalamo-pituitary feedback.

Dynamics of basal pituitary gonadotropin secretion and responsiveness to LRH following estradiol benzoate in normal boys.

The influence of a single intramuscular injection of estradiol benzoate (E2B), 2.5-15 micrograms/kg, on the basal estradiol, LH and FSH and their response to LRH stimulation (50 micrograms/m2, i.v.) performed 20 h after E2B injection, was studied in 52 normal boys aged 6-16 9/12 years. The minimal effective dose of E2B was found to be 10 micrograms/kg. This same dose of E2B which increased plasma estradiol level from 15 +/- 8 to 22 +/- 15 pg/ml (mean +/- SD) at 20 h after the intramuscular injection, suppressed basal plasma LH and FSH and their response to LRH in the prepubertal (n = 12), early-pubertal (n = 12) and late-pubertal (n = 8) boys. It is suggested that the maturation of the hypothalamo-pituitary axis in boys during puberty is under the influence of endogenous estradiol.