Progesterone Inhibition of the Hypothalamic Gonadotropin-Releasing Hormone Pulse Generator: Evidence for Varied Effects in Hyperandrogenemic Adolescent Girls

Chhabra, Sandhya; McCartney, Christopher R.; Yoo, Richard Y.; Eagleson, Christine A.; Chang, R. Jeffrey; Marshall, John C.

doi:10.1210/jc.2004-2359

Cited by 106 publications

(54 citation statements)

References 19 publications

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“…Decreased sensitivity to P 4 feedback is seen in about one-half of PCOS patients and HA adolescents (22,68), and has also been reported in adult female sheep that were treated prenatally with T (72). Visual inspection of the current data (see Fig.…”

Section: Discussionmentioning

confidence: 61%

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Effects of hyperandrogenemia and increased adiposity on reproductive and metabolic parameters in young adult female monkeys

McGee

Bishop

Pohl

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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McGee WK, Bishop CV, Pohl CR, Chang RJ, Marshall JC, Pau FK, Stouffer RL, Cameron JL. Effects of hyperandrogenemia and increased adiposity on reproductive and metabolic parameters in young adult female monkeys. Am J Physiol Endocrinol Metab 306: E1292-E1304, 2014. First published April 15, 2014; doi:10.1152/ajpendo.00310.2013.-Many patients with hyperandrogenemia are overweight or obese, which exacerbates morbidities associated with polycystic ovary syndrome (PCOS). To examine the ability of testosterone (T) to generate PCOS-like symptoms, monkeys received T or cholesterol (control) implants (n ϭ 6/group) beginning prepubertally. As previously reported, T-treated animals had increased neuroendocrine drive to the reproductive axis [increased luteinizing hormone (LH) pulse frequency] at 5 yr, without remarkable changes in ovarian or metabolic features. To examine the combined effects of T and obesity, at 5.5 yr (human equivalent age: 17 yr), monkeys were placed on a high-calorie, high-fat diet typical of Western cultures [Western style diet (WSD)], which increased body fat from Ͻ2% (pre-WSD) to 15-19% (14 mo WSD). By 6 mo on WSD, LH pulse frequency in the controls increased to that of T-treated animals, whereas LH pulse amplitude decreased in both groups and remained low. The numbers of antral follicles present during the early follicular phase increased in both groups on the WSD, but maximal follicular size decreased by 50%. During the late follicular phase, T-treated females had greater numbers of small antral follicles than controls. T-treated monkeys also had lower progesterone during the luteal phase of the menstrual cycle. Although fasting insulin did not vary between groups, T-treated animals had decreased insulin sensitivity after 1 yr on WSD. Thus, while WSD consumption alone led to some features characteristic of PCOS, T ϩ WSD caused a more severe phenotype with regard to insulin insensitivity, increased numbers of antral follicles at midcycle, and decreased circulating luteal phase progesterone levels. testosterone; obesity; amenorrhea; insulin insensitivity; ovarian follicle POLYCYSTIC OVARY SYNDROME (PCOS) affects 4 -8% of reproductive-aged women (5, 48) and is characterized by hyperandrogenemia (HA), irregular menstrual cycles, and polycystic ovaries, in addition to rapid luteinizing hormone (LH) pulse frequency, increased LH response to gonadotropin-releasing hormone (GnRH), decreased sensitivity to progesterone (P 4 ) negative feedback, and decreased insulin sensitivity (SI) (13,20,90). Moreover, up to 90% of women with PCOS are overweight or obese, which is higher than the general population of the United States, where 65% of women over the age of 20 are overweight or obese (6, 33). Women with PCOS also tend to have a central distribution of adiposity, which is associated with increased rates of high blood pressure and cardiovascular disease (23, 51).Being overweight or obese aggravates many symptoms of PCOS. Basal production of testosterone (T) and free T are reportedly elevated in obese, compar...

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Section: Discussionmentioning

confidence: 61%

“…Like adults with PCOS, obese girls with HA have increased levels of LH and decreased sensitivity to P 4 negative feedback (22,49). In late puberty, girls with obesity reportedly have increased frequency of pulsatile LH release compared with nonobese girls (57).…”

mentioning

confidence: 99%

Effects of hyperandrogenemia and increased adiposity on reproductive and metabolic parameters in young adult female monkeys

McGee

Bishop

Pohl

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Centrally, androgen excess may reduce hypothalamic feedback inhibition, resulting in increased GnRH pulsatility, particularly during puberty [40]. GnRH stimulation results in an increase in LH/FSH ratio in women with PCOS and recent studies have revealed that women with PCOS have higher baseline and GnRH-stimulated LH concentrations [41].…”

Section: Discussionmentioning

confidence: 99%

Predictors of Insulin Resistance and Metabolic Complications in Polycystic Ovarian Syndrome in an Eastern Indian Population

et al. 2012

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The purpose of this study was to assess the predictive values of central obesity and hyperandrogenemia in development of insulin resistance and dyslipidemia in the polycystic ovarian syndrome (PCOS) patients in our region. Differences of fasting blood glucose level, insulin resistance index HOMA-IR, lipid parameters, waist hip ratio (WHR), body mass index, LH/FSH ratio and testosterone levels between 45 PCOS cases and 35 age matched controls were obtained. Strength of association between different parameters in the case group was assayed by Pearson's correlation analysis. Dependence of insulin resistance and WHR on different predictors was assessed by multiple linear regression assay. Total cholesterol, LDL cholesterol, LH, FSH, LH/FSH ratio, WHR and insulin resistance were significantly higher in the case group (p \ 0.05). Serum testosterone showed strong correlation with insulin resistance and LH/FSH ratio (r = 0.432 and 0.747, p = 0.01 and 0.001 respectively) in the PCOS patients while WHR and serum testosterone level stood out to be most significant predictors for the insulin resistance (b = 0.361 and 0.498; p = 0.048 and 0.049 respectively). Hyperandrogenemia and central obesity were the major factors predicting development of insulin resistance and its related metabolic and cardiovascular complications in our PCOS patients. We suggest early monitoring for androgen level and WHR in these patients for predicting an ensuing insulin resistance and modulating the treatment procedure accordingly to minimise future cardiovascular risks.

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“…This study showed that PCOS and NC CAH women had increased LH pulse amplitude compared with control women, but only PCOS women had decreased LH interpulse interval compared with controls. Data suggesting abnormalities of LH pulsatility in PCOS women are related to a relative insensitivity to progesterone-induced LH inhibition (6,7,8,9), an abnormality that can be reversed by blockade of androgen action (10). Gonadotropin abnormalities of NC CAH women therefore appear to be intermediate between those of controls and PCOS patients (5).…”

Section: Introductionmentioning

confidence: 99%

Influence of hormonal control on LH pulsatility and secretion in women with classical congenital adrenal hyperplasia

Bachelot

Chakhtoura

Plu‐Bureau

et al. 2012

European Journal of Endocrinology

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Objective: Women with classical congenital adrenal hyperplasia (CAH) exhibit reduced fertility due to several factors including anovulation. This has been attributed to a disturbed gonadotropic axis as in polycystic ovary syndrome (PCOS), but there is no precise evaluation. Our aim was to evaluate the gonadotropic axis and LH pulsatility patterns and to determine factor(s) that could account for the potential abnormality of LH pulsatility. Design: Case/control study. Methods: Sixteen CAH women (11 with the salt-wasting form and five with the simple virilizing form), aged from 18 to 40 years, and 16 age-matched women, with regular menstrual cycles (28G3 days), were included. LH pulse patterns over 6 h were determined in patients and controls. Results: No differences were observed between patients and controls in terms of mean LH levels, LH pulse amplitude, or LH frequency. In CAH patients, LH pulsatility patterns were heterogeneous, leading us to perform a clustering analysis of LH data, resulting in a two-cluster partition. Patients in cluster 1 had similar LH pulsatility patterns to the controls. Patients in cluster 2 had: lower LH pulse amplitude and frequency and presented menstrual cycle disturbances more frequently; higher 17-OH progesterone, testosterone, progesterone, and androstenedione levels; and lower FSH levels. Conclusions: LH pulsatility may be normal in CAH women well controlled by hormonal treatment. Undertreatment is responsible for hypogonadotropic hypogonadism, with low LH pulse levels and frequency, but not PCOS. Suppression of progesterone and androgen concentrations during the follicular phase of the menstrual cycle should be a major objective in these patients.

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Progesterone Inhibition of the Hypothalamic Gonadotropin-Releasing Hormone Pulse Generator: Evidence for Varied Effects in Hyperandrogenemic Adolescent Girls

Cited by 106 publications

References 19 publications

Effects of hyperandrogenemia and increased adiposity on reproductive and metabolic parameters in young adult female monkeys

Effects of hyperandrogenemia and increased adiposity on reproductive and metabolic parameters in young adult female monkeys

Predictors of Insulin Resistance and Metabolic Complications in Polycystic Ovarian Syndrome in an Eastern Indian Population

Influence of hormonal control on LH pulsatility and secretion in women with classical congenital adrenal hyperplasia

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