Ovarian hormones and obesity.
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.



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.



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.



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.



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.
Division of Reproductive Endocrinology, University Hospital Zurich, Frauenklinikstr. 10, CH 8091 Zurich, Switzerland.|Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland.
Brigitte
B
Leeners
Department of Psychiatry, Weill Medical College of Cornell University, New York, NY 10065, USA.
Nori
N
Geary
Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland.|Laboratory for Social and Neural Systems Research, Department of Economics, University of Zurich, 8006 Zurich, Switzerland.
Philippe N
PN
Tobler
Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland.|Institute of Veterinary Physiology, University of Zurich, 8057 Zurich, Switzerland.
Lori
L
Asarian
D000273:Adipose Tissue / Q000502:physiology*; D000367:Age Factors; D000818:Animals; D004435:Eating / Q000523:psychology*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D008593:Menopause / Q000502:physiology; D008597:Menstrual Cycle / Q000502:physiology; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism*; D012741:Sexual Maturation; D016387:Women's Health
D004967:Estrogens; D011374:Progesterone
adipose tissue; central nervous system; eating; energy expenditure; estrogens; obesity; ovarian hormones; progestins; weight regulation; women