Ovarian hormones and obesity

Abstract

Background: Obesity is caused by an imbalance between energy intake, i.e. eating and energy expenditure (EE). Severe obesity is more prevalent in women than men worldwide, and obesity pathophysiology and the resultant obesity-related disease risks differ in women and men. The underlying mechanisms are largely unknown. Pre-clinical and clinical research indicate that ovarian hormones may play a major role.

Objective and rationale: We systematically reviewed the clinical and pre-clinical literature on the effects of ovarian hormones on the physiology of adipose tissue (AT) and the regulation of AT mass by energy intake and EE.

Search methods: Articles in English indexed in PubMed through January 2016 were searched using keywords related to: (i) reproductive hormones, (ii) weight regulation and (iii) central nervous system. We sought to identify emerging research foci with clinical translational potential rather than to provide a comprehensive review.

Outcomes: We find that estrogens play a leading role in the causes and consequences of female obesity. With respect to adiposity, estrogens synergize with AT genes to increase gluteofemoral subcutaneous AT mass and decrease central AT mass in reproductive-age women, which leads to protective cardiometabolic effects. Loss of estrogens after menopause, independent of aging, increases total AT mass and decreases lean body mass, so that there is little net effect on body weight. Menopause also partially reverses women's protective AT distribution. These effects can be counteracted by estrogen treatment. With respect to eating, increasing estrogen levels progressively decrease eating during the follicular and peri-ovulatory phases of the menstrual cycle. Progestin levels are associated with eating during the luteal phase, but there does not appear to be a causal relationship. Progestins may increase binge eating and eating stimulated by negative emotional states during the luteal phase. Pre-clinical research indicates that one mechanism for the pre-ovulatory decrease in eating is a central action of estrogens to increase the satiating potency of the gastrointestinal hormone cholecystokinin. Another mechanism involves a decrease in the preference for sweet foods during the follicular phase. Genetic defects in brain α-melanocycte-stimulating hormone-melanocortin receptor (melanocortin 4 receptor, MC4R) signaling lead to a syndrome of overeating and obesity that is particularly pronounced in women and in female animals. The syndrome appears around puberty in mice with genetic deletions of MC4R, suggesting a role of ovarian hormones. Emerging functional brain-imaging data indicates that fluctuations in ovarian hormones affect eating by influencing striatal dopaminergic processing of flavor hedonics and lateral prefrontal cortex processing of cognitive inhibitory controls of eating. There is a dearth of research on the neuroendocrine control of eating after menopause. There is also comparatively little research on the effects of ovarian hormones on EE, although changes in ovarian hormone levels during the menstrual cycle do affect resting EE.

Wider implications: The markedly greater obesity burden in women makes understanding the diverse effects of ovarian hormones on eating, EE and body adiposity urgent research challenges. A variety of research modalities can be used to investigate these effects in women, and most of the mechanisms reviewed are accessible in animal models. Therefore, human and translational research on the roles of ovarian hormones in women's obesity and its causes should be intensified to gain further mechanistic insights that may ultimately be translated into novel anti-obesity therapies and thereby improve women's health.

Keywords: adipose tissue; central nervous system; eating; energy expenditure; estrogens; obesity; ovarian hormones; progestins; weight regulation; women.

© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Figures

Figure 1

Sex differences in prevalences of severe obesity (BMI ≥35 kg/m2) in representative population samples of adults aged ≥18 years in 200 countries worldwide. From NCD Risk Factor Collaboration, represented by Ezzati (2016), used with permission.

Figure 2

Female-typical adiposity and associated cardiometabolic risk. Following puberty, girls and women (F) tend to deposit excess triacylglycerol as gluteofemoral SC AT, whereas males (M) tend to deposit it as abdominal SC AT; males also have more visceral AT, i.e. AT whose vasculature enters the portal vein and liver. Gluteofemoral AT is cardiometabolically benign (green) because it traps triacylglycerol, so contributes little to plasma lipid levels, and because it is resistant to inflammation. In contrast, abdominal SC AT and visceral AT are cardiometabolically toxic (red) because they have higher relative rates of lipolysis, which increases plasma lipids, and because they are prone to inflammation, which leads to increased levels of circulating proinflammatory molecules. The relative amounts of upper-body SC AT are variable, and its cardiometabolic consequences are poorly understood (blue). For further explanation, see text. SC AT, subcutaneous adipose tissue.

Figure 3

Daily food intake during the ovarian cycle in women. Note the progressive decrease in energy intake during the follicular phase, the nadir around ovulation and the high level during most of the luteal phase. Data are amounts eaten per day (kcal, means and standard errors of the mean) calculated from three studies in which food intake was measured by weighing and the cycle phase was monitored with urinary luteinizing hormone tests and reports of menses in a total of 34 women. In each study, data were averaged across the early-follicular (eF; 4 d), midfollicular (mF; ~9 d), peri-ovulatory (PO; 4 d) and luteal (L; ~11 d) phases. *Significantly different from luteal phase. Original data are from Fong and Kretsch (1993), Gong et al. (1989) and Lyons et al. (1989), and the figure is reprinted from Asarian and Geary (2013); used with permission.

Figure 4

Some brain areas where estrogens affect the control of eating, based on animal (A) and human (B) research. Shown in red are brain areas where estrogens act directly via estrogen receptor 1 (Esr1) to affect eating; in blue are areas where estrogen may affect neural processing directly or indirectly through actions in other brain areas. (A) A schematic mid-sagittal section of the human brain highlighting areas in which estrogens affect eating. In the cmNTS, estrogen actions on Esr1 reduce meal size, in part by increasing the satiating potency of CCK; in the dorsal raphe nucleus (DR), estrogens bind to Esr1 to change serotonergic (5HT) neurotransmission so as to reduce binge-like eating. In the ARC (just lateral to the third ventricle, 3V) estrogens affect the activity of neurons expressing AgRP to reduce food intake during the early phase of the ovarian cycle. In the paraventricular nucleus of the hypothalamus (just lateral to the 3V), estrogens affect the activity of neurons expressing MC4R to reduce food intake in females (♀) more than in males (♂). Numerous fMRI studies implicate the OFC and lPFC (out of sight on the lateral surface of the cerebral hemisphere) in the neural computation of the value of food stimuli, which, as explained in the text, includes reinforcement, approach generation and affect. Ovarian hormones influence these processes. For example, visual food stimuli elicited larger responses in the lPFC in sated than in hungry women when tested during the late follicular phase, but not when tested during the early-follicular phase. (B) A schematic frontal section of the ventromedial area of the frontal lobes at the level shown by the green line in A. fMRI studies implicate the dorsal striatum (which consists of the head of the caudate and the putamen), the nucleus accumbens and the globus pallidus in the neural computation of food value. Again, ovarian hormones influence these processes; for example, pictures of high energy-foods elicited larger responses in women tested during the peri-ovulatory phase than during the luteal phase. See text for details. Abbreviations: LV, lateral ventricle; CC, corpus callosum; EC, extreme capsule; IC, internal capsule; SP, septum pellucidum; ARC, arcuate nucleus of the hypothalamus; CCK, cholecystokinin; lPFC, lateral prefrontal cortex; fMRI, functional MRI. Brain schematics are from http://www.clker.com/clipart-90953.html; the frontal lobe section was originally published in Haines (2012); used with permission.

Figure 5

Summary of the principal effects of estrogens, represented by relative estradiol concentrations, on eating, EE and AT through women's life cycles. Note: Estradiol concentrations and durations of epochs are not to scale. See text for details. EE, energy expenditure; AT, adipose tissue.