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Follicle–stimulating hormone (FSH) is a pituitary-derived gonadotropin that plays key roles in male and female reproduction. The physiology and biochemistry of FSH have been extensively studied for many years. Beginning in the early 1990s, coincident with advances in the then emerging transgenic animal technology, and continuing till today, several gain-of-function (GOF) models have been developed to understand FSH homeostasis in a physiological context. Our group and others have generated a number of FSH ligand and receptor GOF mouse models. An FSH GOF model when combined with Fshb null mice provides a powerful genetic rescue platform. In this chapter, we discuss different GOF models for FSH synthesis, secretion and action and describe additional novel genetic models that could be developed in the future to further refine the existing models.

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Introduction Obesity is characterized by elevated lipids, insulin resistance and relative hypogonadotropic hypogonadism, reducing fertility and increasing risk of pregnancy complications and birth defects. We termed this phenotype ‘Reprometabolic Syndrome’ and showed that it can be recapitulated by acute infusions of lipid/insulin into healthy, normal weight, eumenorrheic women. Herein, we examined the broader impact of hyperlipidemia and euglycemic hyperinsulinemia on anterior pituitary trophic hormones and their targets. Methods Serum FSH, LH, TSH, growth hormone (GH), prolactin (PRL), thyroid hormones (free T4, total T3), cortisol, IGF-1, adiponectin, leptin and creatinine were measured in a secondary analysis of an interventional crossover study of 12 normal weight cycling women who underwent saline and heparin (control) infusion, or a euglycemic insulin infusion with heparin and Intralipid® (lipid/insulin), between days 2–5 in sequential menstrual cycles. Results In contrast to the decrease in gonadotropins, FSH and LH, infusion of lipid/insulin had no significant effects on other trophic hormones; TSH, PRL or GH. Thyroid hormones (fT4 and total T3), cortisol, IGF-1, adiponectin and creatinine also did not differ between saline or lipid/insulin infusion conditions. Leptin increased in response to lipid/insulin (p<0.02). Conclusion Acute hyperlipidemia and hyperinsulinemia exerted differential, cell type specific effects on the hypothalamic-pituitary-gonadal, adrenal and thyroid axes. Elucidation of mechanisms underlying the selective modulation of pituitary trophic hormones, in response to changes in diet and metabolism, may facilitate therapeutic intervention in obesity-related neuroendocrine and reproductive dysfunction.

OBJECTIVE: Obesity has a profound impact on reproductive function, reducing fertility and increasing the risk of pregnancy complications and birth defects. Obesity in women is associated with hyperlipidemia, hyperinsulinemia, and decreased basal and GnRH-stimulated FSH and LH secretion from gonadotrope cells in the pituitary.We have termed this phenotype 'Reprometabolic Syndrome'. We have previously shown that acute infusions of lipid/insulin into healthy, normal weight, cycling women recapitulates this reprometabolic phenotype of obesity. However, the underlying mechanisms are not understood. We sought to confirm that the decreased FSH and LH were not attributable to differential hemodilution, and investigated if the effects of lipid/insulin infusions were confined to gonadotropes or impacted other anterior pituitary cell types.DESIGN: 8 normal weight, regularly cycling women underwent 6-hour visits with either a saline and heparin (control) infusion, or a hyperinsulinemic-euglycemic clamp with heparin and Liposyn (Abbott laboratories). GnRH stimulation was applied at 240 minutes.MATERIALS AND METHODS: Frequent blood sampling (q10 min) was conducted at each visit, which occurred in random order, between days 2-5 in sequential menstrual cycles. Anterior pituitary hormones TSH and prolactin (PRL), thyroid hormones (free T4, total T3) and cortisol were measured in serum samples. TSH was measured in pooled samples q30 min. PRL, fT4, total T3, and cortisol samples were pooled to measure approximately 0, 30, 160, and 360 min time points. Lastly, creatinine was measured hourly in pooled samples.RESULTS: In contrast to the decrease in gonadotropins, TSH increased in the lipid/insulin-treated samples, with the most dramatic percent change after 160 minutes (28.2% increase), significantly different from TSH levels in the saline infusions (p<0.0005), which slightly decreased (-11.4%). Thyroid hormones (fT4 and total T3), PRL, cortisol, and serum creatinine did not differ between saline or lipid/insulin infusion conditions.CONCLUSIONS: Lack of change in serum creatinine showed there was no hemodilution due to variable infusion volumes. FT4 and total T3 were unchanged, suggesting that the increase in TSH was a thyrotrope cell response to lipid/insulin and not a result of altered thyroid function. Cortisol, an inhibitor of TSH production, was unaffected by infusion condition. Levels of the lactotroph hormone PRL were not impacted by lipid/insulin, confirming that effects on the pituitary are both complex and cell type specific. Our results imply that the impact of obesity on the hypothalamic-pituitary-gonadal axis is not simply suppression, and extends beyond reproductive functions. Further research is needed to elucidate mechanisms underlying the selective modulation of pituitary trophic hormones in response to changes in diet and metabolism.