Modulation of Gonadotropin-Releasing Hormone Pulse Generator Sensitivity to Progesterone Inhibition in Hyperandrogenic Adolescent Girls—Implications for Regulation of Pubertal Maturation

Blank, Susan K.; McCartney, Christopher R.; Chhabra, Sandhya; Helm, Kristin D.; Eagleson, Christine A.; Chang, R. Jeffrey; Marshall, John C.

doi:10.1210/jc.2008-2606

Cited by 108 publications

(52 citation statements)

References 23 publications

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“…Our sensitivity analysis, excluding girls with transient thelarche, showed similar (17). Furthermore, insulin resistance increases the levels of hyperandrogenemia (14), which in combination may facilitate the GnRH pulsatile secretion and increase pituitary secretion (37) and androgen secretion at the ovarian theca cells (16). Additionally, in adults, insulin and IGF1 stimulate breast cell division (7,8); thus, they could be involved in breast development in early puberty (9).…”

Section: Resultsmentioning

confidence: 74%

“…First, obesity may trigger central gonadotropin secretion by increasing leptin levels that play a permissive role in gonadotropin secretion (13). Another possibility is that insulin resistance increases adrenal androgen concentration in blood (14,15), which in combination with insulin and leptin may further facilitate GnRH pulsatile secretion and thus increase androgen synthesis by ovarian theca cells (16). Alternatively, circulating sex steroid hormones can be higher in obese children due to increased aromatase activity, leading to peripheral conversion of androgens to estrone and estradiol (11).…”

Section: Introductionmentioning

confidence: 99%

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Ultrasensitive estrogen levels at 7 years of age predict earlier thelarche: evidence from girls of the growth and obesity Chilean cohort

Pereira

Uauy

Klein

et al. 2015

European Journal of Endocrinology

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Objective: Prepubertal estradiol equivalents have been inconsistently linked to age at thelarche; elucidating this relationship becomes relevant given the worldwide decline in the age of puberty onset. Thus, our aim is to assess whether prepubertal girls with higher serum levels of estradiol equivalents at age 7 have a greater risk of presenting early thelarche (ET). Design: Nested case-control study within the Growth and Obesity Cohort Study of 1196 low-middle income children (w50% girls) from Santiago, Chile. Girls were defined as cases (ET; nZ61) if breast bud appeared prior to 8 years of age; controls (nZ91) had thelarche O8 years. Methods: At 6.7 years, weight, height and waist circumference were measured and a fasting blood sample was obtained for measuring estrogen equivalent (ultrasensitive recombinant cell bioassay), DHEAS, leptin, insulin and IGF1. Beginning at 7 years old, Tanner staging was assessed prospectively twice a year and the appearance of breast bud was assessed by palpation. Results: Mean serum estradiol-equivalent at 6.7 years was 3.9G3.6 pg/ml for cases and 3.6G2.3 pg/ml for controls. Girls with ET had a higher risk of presenting elevated estradiol-equivalent (R5 pg/ml) at 7 years (ORZ2.05, 95% CI: 0.96-4.36) than controls that was borderline significant. However, after adjusting by BMI, insulin and IGF1 at age 7, the association between estradiol-equivalent and ET was significant (ORZ2.29 (95% CI: 1.05-5.01)). Conclusions: Chilean girls from low to middle socioeconomic status with ET exhibited double the risk of having high levels of estradiol-equivalent at 7 years than girls with a later age of thelarche. Whole-body adiposity and increased adrenal activity did not explain the observed prepubertal estrogen increase.

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Section: Resultsmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Ultrasensitive estrogen levels at 7 years of age predict earlier thelarche: evidence from girls of the growth and obesity Chilean cohort

Pereira

Uauy

Klein

et al. 2015

European Journal of Endocrinology

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“…It has been suggested that increased androgen concentrations in prepubertal girls could facilitate a pubertal increase in GnRH secretion, possibly leading to early pubertal onset [78]. Leptin and insulin functions in various target tissues are shown in Figure 1.…”

Section: Sex Hormones and Growth During Pubertymentioning

confidence: 99%

Putative Effects of Obesity on Linear Growth and Puberty

Shalitin

Kieß²

2017

Horm Res Paediatr

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Childhood obesity is a major public health problem that has grown to epidemic proportions throughout the world. Obesity is influenced by genetic and environmental factors. The nutritional status plays an important role in growth and body weight regulation. Excess adiposity during childhood can affect the process of growth and puberty. Obese children are frequently tall for their age, with accelerated epiphyseal growth plate maturation despite low growth hormone levels. Several regulatory hormones may affect the process of linear growth in the constellation of obesity, as high levels of insulin and leptin are observed in obese children. Leptin can act as a skeletal growth factor, with a direct effect on skeletal growth centers. The finding that overweight children, especially girls, tend to mature earlier than lean children has led to the hypothesis that the degree of body fatness may trigger the neuroendocrine events that lead to the onset of puberty. Leptin receptors have been identified in the hypothalamus, as well as in gonadotrope cells, ovarian follicular cells, and Leydig cells. The increased leptin and androgen levels seen in obese children may be implicated in their earlier onset of puberty and accelerated pubertal growth. This review is focused on the interaction between childhood obesity and growth and pubertal processes.

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“…puberty) and pathological conditions [93,94,95]. In a recent study, the expression of P 4 receptor membrane component 1 (PgRMC1) and its partner SERPINE1 mRNA-binding protein 1 (SERBP1) has been shown in GnRH neurons.…”

Section: Discussionmentioning

confidence: 99%

Differential Gene Expression in Gonadotropin-Releasing Hormone Neurons of Male and Metestrous Female Mice

et al. 2015

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Background: Gonadotropin-releasing hormone (GnRH) neurons play a pivotal role in the regulation of the hypothalamic-pituitary gonadal axis in a sex-specific manner. We hypothesized that the differences seen in reproductive functions of males and females are associated with a sexually dimorphic gene expression profile of GnRH neurons. Methods and Results: We compared the transcriptome of GnRH neurons obtained from intact metestrous female and male GnRH-green fluorescent protein transgenic mice. About 1,500 individual GnRH neurons from each sex were sampled with laser capture microdissection followed by whole-transcriptome amplification for gene expression profiling. Under stringent selection criteria (fold change >1.6, adjusted p value 0.01), Affymetrix Mouse Genome 430 PM array analysis identified 543 differentially expressed genes. Sexual dimorphism was most apparent in gene clusters associated with synaptic communication, signal transduction, cell adhesion, vesicular transport and cell metabolism. To validate microarray results, 57 genes were selected, and 91% of their differential expression was confirmed by real-time PCR. Similarly, 88% of microarray results were confirmed with PCR from independent samples obtained by patch pipette harvesting and pooling of 30 GnRH neurons from each sex. We found significant differences in the expression of genes involved in vesicle priming and docking (Syt1, Cplx1), GABAergic (Gabra3, Gabrb3, Gabrg2) and glutamatergic (Gria1, Grin1, Slc17a6) neurotransmission, peptide signaling (Sstr3, Npr2, Cxcr4) and the regulation of intracellular ion homeostasis (Cacna1, Cacnb1, Cacng5, Kcnq2, Kcnc1). Conclusion: The striking sexual dimorphism of the GnRH neuron transcriptome we report here contributes to a better understanding of the differences in cellular mechanisms of GnRH neurons in the two sexes.

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Modulation of Gonadotropin-Releasing Hormone Pulse Generator Sensitivity to Progesterone Inhibition in Hyperandrogenic Adolescent Girls—Implications for Regulation of Pubertal Maturation

Abstract: Hyperandrogenism is variably associated with reduced GnRH pulse generator sensitivity to P-mediated slowing during adolescence. In addition to androgen levels, insulin resistance may modulate P sensitivity.

Cited by 108 publications

References 23 publications

Ultrasensitive estrogen levels at 7 years of age predict earlier thelarche: evidence from girls of the growth and obesity Chilean cohort

Ultrasensitive estrogen levels at 7 years of age predict earlier thelarche: evidence from girls of the growth and obesity Chilean cohort

Putative Effects of Obesity on Linear Growth and Puberty

Differential Gene Expression in Gonadotropin-Releasing Hormone Neurons of Male and Metestrous Female Mice

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