Sex differences in the effects of androgens acting in the central nervous system on metabolism

Dialogues Clin Neurosci. 2016;18(4):415-424.

One of the most sexually dimorphic aspects of metabolic regulation is the bidirectional modulation of glucose and energy homeostasis by testosterone in males and females. Testosterone deficiency predisposes men to metabolic dysfunction, with excess adiposity, insulin resistance, and type 2 diabetes, whereas androgen excess predisposes women to insulin resistance, adiposity, and type 2 diabetes. This review discusses how testosterone acts in the central nervous system, and especially the hypothalamus, to promote metabolic homeostasis or dysfunction in a sexually dimorphic manner. We compare the organizational actions of testosterone, which program the hypothalamic control of metabolic homeostasis during development, and the activational actions of testosterone, which affect metabolic function after puberty. We also discuss how the metabolic effect of testosterone is centrally mediated via the androgen receptor.

Author Affiliations: 
Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, Louisiana, USA (Jamie Morford, Franck Mauvais-Jarvis) 
Address for correspondence: 
Abbreviations and acronyms: 
androgen receptor
arcuate nucleus
central nervous system.
dorsomedial hypothalamus
estrogen receptor
polycystic ovarian syndrome
type 2 diabetes
ventromedial hypothalamus


The role of sex and gender in disease is a fundamental issue in medicine. Elucidating the molecular, biochemical, and physiological determinants of these biological sex differences is a necessary step toward precision, gender-specific medicine. There are fundamental aspects of the control of metabolic homeostasis that are regulated differently in males and females and that probably influence both the development of diabetes and obesity, as well as the response to pharmacological intervention.[1] Perhaps one of the most sexually dimorphic aspects of metabolic regulation is the bidirectional modulation of glucose and energy homeostasis by the male hormone testosterone in males and females.[2] Indeed, testosterone deficiency predisposes men to obesity, metabolic syndrome, and type 2 diabetes (T2D).[2]-[5] In contrast, testosterone excess predisposes women to obesity and T2D.[2],[5],[6] Considering that men with androgen deficiency and women with androgen excess represent a large segment of the population, it is vital to understand the determinants of sex differences in testosterone's effects on metabolism.[3],[4],[6] This review will discuss how androgens act in the central nervous system (CNS) to impact metabolism in a sexually dimorphic manner in males and females.

Causes of sex differences in physiology

Perinatal programming by testosterone

Extensive evidence relates sexually dimorphic aspects of physiology to brain masculinization by the testicular perinatal testosterone surges in males.[7]-[10] Hypothalamic structure and function are modified by testosterone, leading to sex differences in reproductive behavior and physiology.[10]

The organizational-activational hypothesis of hormone action in the nervous system has gathered substantial attention since the publication of the seminal paper by Phoenix et al.[11],[12] These authors demonstrated that prenatal testosterone exposure in female rodents reduced the ability of estrogen administered in adulthood to elicit female mating behavior. This paper set the framework for the organizational-activational hypothesis, which states that: (i) organizing actions of testosterone occur during a critical period of development in which testosterone acts on the brain to cause permanent changes that persist in the absence of hormone, in effect programming the brain to be masculinized (and defeminized); and (ii) activational actions of testosterone occur after puberty when the hormone acts transiently and reversibly on circuitry that has already been established.[12],[13]

The idea that there is a critical period in which testosterone exerts organizing effects is key to the organizational-activational hypothesis.[12],[13] Testosterone exposure must occur during this critical period for the brain to be masculinized. In human and nonhuman primate fetuses, the testicular testosterone surge occurs during the second trimester of pregnancy, which coincides with the development of the hypothalamus, the brain region that regulates both reproduction and metabolism.[14],[15] In rodents, the testicular testosterone surge occurs in the first week of neonatal life, which coincides with the development of the hypothalamus.[16],[17] During this critical period, testicular testosterone is capable of masculinizing the brain in males, and exogenous testosterone is capable of masculinizing the brain in females.[7],[10]

In the brain, testosterone can be converted via aromatase to estradiol, which exerts its actions via estrogen receptors (ERs), or via 5α-reductase to dihydrotestosterone (DHT), which exerts its effects via androgen receptors (ARs).[18] Theoretically, either of these hormones could be responsible for the effects of testosterone on brain masculinization because both of these enzymes are expressed in the developing brain.[18] However, neonatal estradiol exposure is sufficient to masculinize the brain and elicit male-typical behavior in rodents.[7] Moreover, male mice with CNS-specific AR deficiency retain male behavior, but the frequency is reduced.[19],[20] This suggests that the brain is organized to perform male behavior in the absence of AR but that AR is required to activate male behavior.

Although the available evidence clearly demonstrates that AR is not necessary for organizational effects on behavior in rodents, this is not the case in primates. Prenatal administration of DHT to female rhesus macaques during the critical period programs more male behavior in offspring.[21] Similarly, prenatal exposure to DHT programs less female sexual behavior in female macaques.[22] This is consistent with the observation of men with complete androgen insensitivity syndrome who have nonfunctional ARs but normal-to-high testosterone levels.[23] These individuals often identify as females and display female-typical behaviors. Also in contrast to rodents, estrogen appears not to play a role in the masculinization of behavior in humans because men with aromatase deficiency or ER mutation show normal male-typical behaviors and gender identity.[24] In females, the polycystic ovarian syndrome (PCOS) is an endocrine disorder characterized by androgen excess throughout life, including prenatally.[25],[26],[27] Lesbian women have a significantly higher prevalence of PCOS than heterosexual women, suggesting that prenatal androgen exposure programs male-typical sexual preferences.[28] Together, these results suggest that, unlike in rodents, estradiol is not necessary for the organizational effects of testosterone and that AR is responsible for brain masculinization in primates, including humans. The role of central AR in masculinizing the brain with respect to metabolism will be discussed below.

Sex hormones after puberty

Recent evidence suggests that puberty may constitute an additional critical period in which sex hormones can exert organizational effects on the brain.[29] However, discussion of such is beyond the scope of this review. After puberty, hormones exert purely activational effects. AR is clearly required for the activation of male-typical behaviors in rodents because male mice with CNS-specific AR deficiency exhibit a reduction in the frequency of these behaviors.[19],[20] In addition, testosterone can activate aggressive behavior in adult female mice, although not to the same levels as testosterone in castrated males.[30] This suggests that the AR is required for activation of male-typical behavior in both males and females. The role of central AR activation in metabolism in adults will be discussed below.

Sex chromosomes

In addition to activational and organizational effects of hormones, sex differences in physiology can result from differences in sex chromosomes. The most obvious is the sex-determining region Y (SRY) gene on the Y chromosome, which codes the testis-determining factor and is responsible for the development of the testis and the production of testosterone.[9] In addition, the gene for the AR is located on the X chromosome.[19],[20] Males with Klinefelter syndrome, who have an extra X chromosome, show excess abdominal adiposity and have an increased risk of T2D, suggesting that the additional X chromosome promotes metabolic dysfunction.[31],[32]

In rodents, the “four core genotypes” model has been developed to differentiate the impact of gonadal sex and sex chromosomes on physiology. This model consists of XX and XY males and females. To generate these mice, the SRY gene was removed from the Y chromosome to generate XY females. To generate XX males, the SRY gene was inserted onto an autosomal chromosome. This model shows that XX animals, regardless of gonadal sex, have increased fasting insulin, increased insulin resistance, increased liver triglycerides, increased levels of fatty acid oxidation enzymes, and increased fat mass when exposed to a high-fat diet.[33] These results are in agreement with observational data from patients with Klinefelter syndrome, suggesting that the X chromosome may impair metabolic function. Interestingly, the same group showed that XY animals on a chow diet show increased fat mass and impaired glucose tolerance relative to XX animals.[34] These results suggest that the X chromosome may only contribute to impaired metabolism in conditions of nutrient excess.

Androgen developmental programming of the CNS and the resulting sex differences in metabolism

Sex differences in neural circuitry

Differences in neural circuitry between males and females are mainly an issue of quantity and not connectivity.[10] Males and females display the same connections between the same regions, but it is the strength of these connections that differs. Within the hypothalamus, the anteroventral periventricular nucleus (AVPV) sends descending projections to the arcuate nucleus (ARC), and these descending projections are more pronounced in females.[35] These neurons are responsible for controlling gonadotropin-releasing hormone release and, thus, luteinizing hormone release. The fact that these connections are more robust in the female brain makes sense functionally because females have a greater luteinizing hormone response to estradiol than males.[36] Conversely, descending projections within the hypothalamus from the medial preoptic nucleus (MPN) to the ventromedial hypothalamus (VMH), are more robust in males.[10] This pathway may be involved in the initiation of male sexual behavior.[10] The anterior olfactory bulb sends projections to the medial amygdala and bed nucleus of the striata terminalis (BNST), which both project to several hypothalamic nuclei. This pathway is involved in pheromone sensing and is more robust in males.[10] Projections from the BNST to the AVPV are also much more robust in males than females.[37] Although the role of these projections is unknown, the authors hypothesize that they may be involved in olfaction.[37] Apart from reproduction and sexual behavior, the hypothalamus is also a key area for the control of energy balance and glucose homeostasis.[38] Therefore, the striking sex differences in hypothalamic neural circuitry described above suggest that similar sex differences in the hypothalamic circuitry controlling glucose and energy homeostasis exist.

Sex differences in AR expression in the brain

Many of the regions described above that show sexually dimorphic circuitry also express the AR, suggesting that AR may be involved in programming the sexual dimorphism of this circuitry. AR is expressed in the AVPV, ARC, and VMH of both males and females with similar levels of expression.[39]-[41] AR is also expressed in the MPN and BNST, with expression levels being higher in males.[19],[39]-[42] Other sites of AR expression include the lateral septum, medial amygdala, and premamillary nucleus.[39]-[42] All of these nuclei are sexually dimorphic.[10] One study reported AR expression in the suprachiasmatic nucleus, paraventricular nucleus (PVN), lateral hypothalamus, and dorsomedial hypothalamus (DMH) in males, with no expression in females.[43] This is probably due to the poor quality of the AR antibody used. In the brain stem, there is also low AR expression in the parabrachial nucleus and the nucleus of the tractus solitarius (NTS) of males, both of which are involved in metabolism.[39],[44],[45] Perinatal exposure to testosterone or estradiol masculinizes the MPN and BNST by increasing AR expression in these nuclei.[20] Therefore, AR expression appears to result from the organizational effects of estradiol. However, DHT treatment in adult gonadectomized males and females restores AR expression to intact male levels.[40] Together, these results suggest that in rodents, estrogens can program AR expression, whereas androgens can activate AR expression.

In humans, there is a positive correlation between testosterone levels and gray matter volume in the parahippocampus, putamen, amygdala, and occipital and insular cortices.[46] Additionally, men tend to have larger amygdala volumes, whereas females tend to have larger hippocampal volumes.[47] Both of these regions show strong AR expression in rodents.[39]

Thus, the association between sex differences in hypothalamic neurocircuitry and sex differences in hypothalamic AR expression suggests that androgen acting on AR in these hypothalamic areas may differentially affect metabolic function in males and females. Indeed, many of these regions that show sexually dimorphic expression of the AR are also involved in metabolic homeostasis, which will later be discussed in detail.[43]

Sex differences in androgen perinatal CNS programming of metabolism

Several rodent, sheep, and primate models have been used to show that perinatal androgen exposure in females programs metabolic dysfunction with adiposity and insulin resistance in adult offspring.[48]-[53] This is consistent with the observation that women with prenatal androgen excess, because of adrenal hyperplasia or virilizing tumors, develop central obesity and insulin resistance as adults despite normalization of androgen excess with treatment.[54],[55] However, it is unclear if these effects are due to androgen acting in the CNS or elsewhere. Nevertheless, there is extensive evidence that prenatal androgen excess alters metabolism via central actions. PCOS, for example, is characterized by hyperandrogenemia and ovarian dysfunction.[25] In a rat model of PCOS in which rats are exposed to androgen excess perinatally, an enhanced sympathetic activity is observed in adulthood that precedes the development of ovarian cysts, suggesting that increased sympathetic outflow was a result of androgen programming the CNS during the perinatal period.[56] This enhanced sympathetic activity could also contribute to the development of obesity.[57] Indeed, perinatal testosterone exposure in female mice increases fat mass in adulthood.[52] This is accompanied by increased norepinephrine turnover in white adipose tissue, a marker of increased sympathetic activity.[52] These results suggest that enhanced sympathetic activity caused by central testosterone action predisposes females to the development of obesity.[58] However, it is not known whether testosterone programmed sympathetic outflow via the AR after conversion to DHT or via ERs after conversion to estradiol. Indeed, in rodents, neonatal estradiol exposure increases adiposity in adult female offspring, whereas neonatal DHT exposure does not.[53] Instead, neonatal DHT exposure increases food intake in adult female offspring, which is accompanied by a decrease in hypothalamic expression of proopiomelanocortin (POMC), an anorexigenic peptide, and a decreased intensity of neuronal projections from POMC neurons within the ARC.[53] This is essentially a masculinization of the female hypothalamic melanocortin system regarding feeding behavior, as females exposed to DHT exhibit levels of food intake, POMC expression, and POMC neuron projections similar to those of littermate control males.[53] Thus, in mice, perinatal AR activation appears to be sufficient to program the hypothalamic melanocortin system toward male-like feeding behavior. In humans, females from opposite sex twin pairs exposed to prenatal testosterone from testis of a male co-twin also develop masculinized eating behaviors as adults.[59] However, in humans, it is unknown if this is mediated via AR or ER action. Thus, testosterone seems to play a role in the programming of the brain with respect to energyintake in both rodents and humans. However, in humans, it is unknown if this is mediated via AR or ER actions. The developmental effects of testosterone in females are summarized in (Figure 1).

Interestingly, in male offspring, perinatal testosterone excess decreases food intake, the opposite of what is seen in littermate females.[60] Paradoxically, this decrease in food intake is accompanied by a compensatory, but inefficient, increase in the hypothalamic expression of the orexigenic peptides neuropeptide Y (NPY), agoutirelated peptide (AgRP), and orexin.[60] These mice also display a secondary decrease in energy expenditure that favors adiposity, which is probably the result of increased hypothalamic expression of the orexigenic peptides.[60]-[62] This sex difference in the programming effect of neonatal testosterone in littermate male and female metabolic homeostasis underscores the potential for sex differences in metabolic diseases arising from the complements of sex-linked genes outside the testis determining gene SRY[60]

Figure 1. Testosterone excess predisposes females to type 2 diabetes and obesity. During development and adulthood, excess testosterone acts in neurons of the central nervous system to increase adiposity and insulin resistance, which predisposes females to obesity and type 2 diabetes. During development, testosterone excess may predispose to obesity by increasing sympathetic output to white adipose tissue and increasing food intake. During adulthood, testosterone excess may predispose to obesity by decreasing energy expenditure and locomotor activity, as well as increasing leptin resistance.

Sex differences in metabolism due to androgen action in the CNS during adulthood

In men, testosterone deficiency is associated with increased visceral obesity, insulin resistance, and an increased risk of T2D.[1]-[5],[63] Accordingly, male mice lacking AR develop obesity, insulin resistance, and glucose intolerance with aging.[64],[65] Testosterone deficiency is probably causative in the development of T2D, as men on androgen-deprivation therapy for the treatment of prostate cancer are more likely to develop T2D.[63],[66],[67] Evidence demonstrates that in males, testosterone maintains glucose homeostasis via action on AR in muscle, liver, and pancreatic β-cells.[1],[68] The question is whether testosterone acts in the male brain to maintain energy and glucose homeostasis and whether testosterone actions that favor metabolic homeostasis in males are mediated via AR or ERs. Testosterone action is probably mediated at least in part via the AR, as men that have AR variants with low transcriptional activity exhibit hyperinsulinemia and obesity[69] However, ERs are also involved in testosterone's metabolic effect in men, as treatment with an aromatase inhibitor blocked the ability of testosterone replacement to suppress adiposity in men.[70] More direct evidence for the role of the AR in metabolic homeostasis can be gathered from androgen-receptor knockout (ARKO) mouse models. However, in many of these models, AR is deleted developmentally, making it hard to differentiate the organizational effects from the activational effects of androgen.

Male mice with global AR deficiency exhibit late-onset obesity caused by decreased energy expenditure.[64] In addition, male mice with global AR deficiency exhibit resistance to centrally administered leptin, providing indirect evidence that brain AR may also be involved in ARKO-induced leptin resistance.[43] Indeed, leptin fails to activate signal transducer and activator of transcription 3 (STAT3) in ARC neurons of male ARKO mice and does not reduce food intake or body weight.[43] The authors suggest a number of hypothalamic sites that express both AR and the leptin receptor where androgen may be acting to cause leptin resistance. These sites include the ARC, VMH, DMH, PVN, lateral hypothalamus, premamillary nucleus, and suprachiasmatic nucleus.[43] Central loss of AR function is instrumental in this phenotype, as selective neuronal AR deficiency also causes late-onset obesity in male mice.[71]

Furthermore, global AR deficiency in male mice produces glucose intolerance, insulin resistance, and increased lipogenesis.[65] CNS-specific AR deficiency produces insulin resistance, glucose intolerance, and obesity on a chow diet in aging male mice.[71] These mice exhibit hypothalamic insulin resistance with enhanced nuclear factor-κB activation leading to upregulation of protein-tyrosine phosphatase 1B (PTP1B), an inhibitor of insulin signaling.[71] This hypothalamic insulin resistance results in excess expression of the orexigenic peptide AgRP, which probably mediates the effects on obesity, insulin resistance, and glucose intolerance.[71] Clearly, hypothalamic AR action confers protection against obesity and diabetes in males, at least in part by maintaining insulin action in the hypothalamus. However, it is uncertain if the effects of AR in the brain are due to organizational or activational effects, as AR deletion may lead to developmental defects that are revealed in adulthood. The central effects of testosterone deficiency in men are summarized in (Figure 2). Testosterone deficiency predisposes males to type 2 diabetes and obesity. Testosterone deficiency predisposes men to obesity via loss of testosterone action in neurons of the central nervous system, which decreases energy expenditure and increases leptin resistance. This also predisposes to type 2 diabetes by producing late-onset insulin resistance and impaired glucose tolerance.

However, excess AR activation can also impair metabolism in males. For example, testosterone administration to castrated rats at physiological doses improves insulin sensitivity; high doses of testosterone do not.[72] Perhaps the relationship between androgen levels is parabolic, with both low levels and very high levels causing metabolic dysfunction. This curve would be shifted far to the right in males compared with females.

In women, testosterone excess increases the risk of developing T2D.[2],[5],[6],[73] Testosterone levels in women are positively correlated with insulin resistance and impairment of glucose tolerance.[6],[73],[74] PCOS is an endocrine disorder affecting 7% of women and characterized by androgen excess throughout life.[75] In the United States, 80% of women with PCOS are obese.[75] Many women with PCOS, including lean individuals, are insulin resistant and glucose intolerant.[74],[76]-[78]In fact, androgen levels in women with PCOS are positively correlated with insulin resistance.[74] Moreover, female to male transsexuals (with high testosterone levels) exhibit insulin resistance, suggesting a causal relationship between androgen excess and insulin resistance in women.[79] This also suggests that androgens exert activational effects to cause metabolic dysfunction in women, as androgens are administered during adulthood.[79] In addition, insulin resistance in hyperandrogenemic women can be partially reversed by antiandrogen treatment, suggesting a causal role of hyperandrogenemia on insulin resistance.[76]

Studies in animal models suggest that androgen excess in these women impairs metabolism via both organizational and activational effects, as both perinatal and adult androgen excess induce metabolic dysfunction in animal models.[48]-[53],[80]

In female mice with chronic androgen excess during adulthood, leptin fails to reduce body weight, leading to obesity. This is paralleled by a failure of leptin to upregulate brown adipose tissue (BAT) expression of the thermogenic uncoupling protein 1 (UCP-1), which is associated with decreased energy expenditure.[80] These results suggest that there is a disruption in neural communication between the central leptin signal and BAT. In these mice, androgen excess decreased hypothalamic POMC messenger RNA expression. Interestingly, androgen excess increased POMC intensity in neuronal bodies of the ARC while simultaneously decreasing the intensity of POMC projections to the DMH, suggesting that axonal transport of POMC from the soma to the nerve terminals was impaired. As leptin action in the DMH increases sympathetic tone to BAT and increases thermogenesis, these results suggest that in mice, androgen excess decreases energy expenditure via an alteration of the melanocortin pathway to the DMH.[80],[81] In female mice, androgen excess produced no alterations in food intake or leptin's anorectic action.[80] Similar to the female mouse model of androgen excess, deletion of the leptin receptor from POMC neurons leads to decreased POMC expression and increased fat mass without altering food intake.[82] Moreover, female rats exposed to androgen excess during adulthood showed reduced locomotor activity, suggesting that decreased locomotor activity may also be contributing to the obesity seen in females exposed to chronic androgen excess.[83] The exact site of androgen action on AR that leads to this phenotype is unknown. A previous study found that only 3% of POMC neurons express AR,[84] although there is robust expression in other ARC neurons,[39]-[40] suggesting that the alteration in POMC neurons is indirect.

Androgen excess in females also alters glucose homeostasis. Administration of DHT to adult female mice leads to insulin resistance and glucose intolerance.[2] This effect is not observed in β-cell ARKO mice, suggesting that it is β-cell AR that is responsible for the metabolic dysfunction induced by androgen excess.[2],[85],[86] Our lab is currently exploring if neuronal AR also contributes to androgen excess-induced metabolic dysfunction. The central effects of testosterone excess in adult females are summarized in Figure 1.

Interestingly, androgen signaling could be important for proper metabolic function in females. Female global ARKO mice display normal metabolic phenotypes on a chow diet, yet they develop insulin resistance, glucose intolerance, and obesity when on a high-fat diet relative to normal mice on a high-fat diet.[87] However, the authors did not explore if this obesity was due to increased food intake or decreased energy expenditure. It is also unclear if the phenotype is due to AR in the CNS and if the effects of androgen are organizational or activational. Our lab is currently exploring if these effects are mediated by central AR.

Potential sites of androgen action in CNS on glucose and energy homeostasis

There are several regions of the brain that regulate glucose and energy homeostasis and also express AR.[39]-[42] Only the most likely regions for androgen action on metabolism will be discussed here.

Women with PCOS exhibit increased gonadotropin-releasing hormone (GnRII) pulsatility, suggesting impairment of hypothalamic GnRH neurons.[88] It is proposed that androgen activation of AR in ARC y-aminobutyric acid (GABA)ergic neurons upstream of GnRII neurons downregulates the progesterone receptor, whose activity leads to suppression of GnRH pulsatility.[88] Perhaps AR action in these ARC neurons also contributes to metabolic dysfunction. The studies described above suggest that the ARC is a probable site at which androgen is acting to impact metabolism.[43],[53],[60],[71] Indeed, in mice, impairment of GABAergic signaling within the ARC reduces energy expenditure by reducing thermogenesis without altering food intake, a phenotype similar to that of the model of adult androgen excess in female mice.[80],[89] Additionally, androgen could target the ARC in females to induce leptin resistance and hepatic insulin resistance in female mice. Indeed, several mouse models implicate insulin or leptin receptors in POMC neurons of the ARC in hepatic glucose production and the prevention of hepatic insulin resistance.[90]-[93]

The VMH is another site of AR expression that could mediate androgen action on metabolic regulation.[39],[40] Early studies showed that lesions of the VMH, which also encompassed part of the ARC, produced hyperinsulinemia that was blocked by vagotomy, suggesting that the VMII is involved in control of glucose homeostasis via autonomic output.[94],[95] More recent studies have revealed that pharmacological and genetic manipulations of the VMH in mice alter insulin sensitivity.[96],[97] In contrast to the ARC, the VMII influences insulin sensitivity by controlling glucose uptake in skeletal muscle.[97],[98] In addition, the VMH lesions discussed above also produced obesity independent of food intake.[95] Other early studies showed that electrical stimulation of the VMH enhanced BAT thermogenesis, suggesting that the VMH regulates energy expenditure.[99] In fact, VMH-specific deletion of forkhead box O1 (FOXO1) reduced fat mass by increasing energy expenditure, supporting the conclusion that the VMH is also involved in regulating energy expenditure and fat mass.[97]

As discussed above, the DMH is a key nucleus that regulates BAT thermogenesis and energy expenditure and could be a target of androgen action.[81],[100] Indeed, in female mice exposed to chronic androgen excess, we see reduced intensity of POMC fibers in the DMII and a reduced decrease in body weight in response to the melanocortin receptor agonist, melanotan II.[80]


The studies reviewed here demonstrate that testosterone acts in the CNS to differentially impact glucose homeostasis and energy balance in males and females. In males, loss of central AR action (as can be observed during testosterone deficiency) decreases energy expenditure and predisposes to adiposity and insulin resistance. In females, androgen excess during the perinatal period or adulthood (as can be observed in PCOS) negatively impacts metabolic homeostasis. Perinatal androgen excess most likely involves central AR, as we observe alterations in the hypothalamic melanocortin system. Nevertheless, more studies are needed to determine the exact hypothalamic sites and mechanisms of androgen action that promote metabolic homeostasis or metabolic dysfunction during male androgen deficiency and female androgen excess. Additional studies are also needed to characterize the role of AR in female metabolic homeostasis.

1. Mauvais-Jarvis F. Sex differences in metabolic homeostasis, diabetes, and obesity. Biol Sex Differ. 2015;6:14 [ Pub Med ]
2. Navarro G, Allard C, Xu W, Mauvais-Jarvis F. The role of androgens in metabolism, obesity, and diabetes in males and females. Obesity. 2015;23(4):713-719 [ Pub Med ]
3. Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab. 2006;91(11):4335-4343 [ Pub Med ]
4. Zitzmann M. Testosterone deficiency, insulin resistance and the metabolic syndrome. Nat Rev Endocrinol. 2009;5(12):673-681 [ Pub Med ]
5. Ding EL, Song Y, Makik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systemic review and meta-analysis. JAMA. 2006;295(11):1288-1299 [ Pub Med ]
6. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84(1):165-169 [ Pub Med ]
7. Arnold AP, Gorski RA. Gonadal steroid induction of structural sex differences in the central nervous system. Annu Rev Neurosci. 1984;7:413-442 [ Pub Med ]
8. MacLusky NJ, Naftolin F. Sexual differentiation of the central nervous system. Science. 1981;211(4488):1294-1302 [ Pub Med ]
9. Morris JA, Jordan CL, Breedlove SM. Sexual differentiation of the vertebrate nervous system. Nat Neurosci. 2004;7(10):1034-1039 [ Pub Med ]
10. Simerly RB. Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain. Annu Rev Neurosci. 2002;25(1):507-536 [ Pub Med ]
11. Phoenix CH, Goy RW, Gerall AA, Young WC. Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology. 1959;65(3):369-382 [ Pub Med ]
12. Wallen K. The organizational hypothesis: reflections on the 50th anniversary of the publication of Phoenix, Goy, Gerall, and Young (1959). Horm Behav. 2009;55(5):561-565 [ Pub Med ]
13. Arnold AP. The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. Horm Behav. 2009;55(5):570-578 [ Pub Med ]
14. Abramovich DR. Human sexual differentiation-in utero influences. J Obstet Gynaecol Br Commonw. 1974;81(6):448-453 [ Pub Med ]
15. Koutcherov Y, Mai JK, Ashwell KW, Paxinos G. Organization of human hypothalamus in fetal development. J Comp Neurol. 2002;446(4):301-324 [ Pub Med ]
16. Corbier P, Edwards DA, Roffi J. The neonatal testosterone surge: a comparative study. Arch Int Physiol Biochim Biophys. 1992;100(2):127-131 [ Pub Med ]
17. Bouret SG, Draper SJ, Simerly RB. Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci. 2004;24(11):2797-2805 [ Pub Med ]
18. Celotti F, Melcangi RC, Martini L. The 5 alpha-reductase in the brain: molecular aspects and relation to brain function. Front Neuroendocrinol. 1992;13(2):163-215 [ Pub Med ]
19. Raskin K, de Gendt K, Duittoz A, et al . Conditional inactivation of androgen receptor gene in the nervous system: effects on male behavioral and neuroendocrine responses. J Neurosci. 2009;29(14):4461-4470 [ Pub Med ]
20. Juntti SA, Tollkuhn J, Wu MV, et al . The androgen receptor governs the execution, but not programming, of male sexual and territorial behaviors. Neuron. 2010;66(2):260-272 [ Pub Med ]
21. Thornton J, Zehr JL, Loose MD. Effects of prenatal androgens on rhesus monkeys: a model system to explore the organizational hypothesis in primates. Horm Behav. 2009;55(5):633-645 [ Pub Med ]
22. Thornton J, Goy RW. Female-typical sexual behavior of rhesus and defeminization by androgens given prenatally. Horm Behav. 1986;20(2):129-147 [ Pub Med ]
23. Imperato-McGinley J, Peterson RE, Gautier T, et al . Hormonal evaluation of a large kindred with complete androgen insensitivity: evidence for secondary 5a-reductase deficiency. J Clin Endocrinol Metab. 1982;54(5):931-941 [ Pub Med ]
24. Grumbach MM, Auchus RJ. Estrogen: consequences and implications of human mutations in synthesis and action. J Clin Endocrinol Metab. 1999;84(12):4677-4694 [ Pub Med ]
25. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352(12):1223-1236 [ Pub Med ]
26. Abbott DH, Barnett DK, Bruns CM, Dumesic DA. Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? Hum Reprod Update. 2005;11(4):357-374 [ Pub Med ]
27. Xita N, Tsatsoulis A. Review: fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical, and genetic association studies. J Clin Endocrinol Metab. 2006;91(5):1660-1666 [ Pub Med ]
28. Agrawal R, Sharma S, Bekir J, et al . Prevalence of polycystic ovaries and polycystic ovary syndrome in lesbian women compared with heterosexual women. Fertil Steril. 2004;82(5):1352-1357 [ Pub Med ]
29. Romeo RD. Puberty: a period of both organizational and activational effects of steroid hormones on neurobehavioural development. J Neuroendocrinol. 2003;15(12):1185-1192 [ Pub Med ]
30. Barkley MS, Goldman BD. Testosterone-induced aggression in adult female mice. Horm Behav. 1977;9(1):76-84 [ Pub Med ]
31. Bojesen A, Kristensen K, Birkebaek NH, et al . The metabolic syndrome is frequent in Klinefelter's syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care. 2006;29(7):1591-1598 [ Pub Med ]
32. Bojesen A, Host C, Gravholt CH. Klinefelter's syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition. Mol Hum Reprod. 2010;16(6):396-401 [ Pub Med ]
33. Chen X, McClusky R, Chen J, et al . The number of X chromosomes causes sex differences in adiposity in mice. PLoS Genet. 2012;8(5):e1 002709 [ Pub Med ]
34. Chen X, McClusky R, Itoh Y, Reue K, Arnold AP. X and Y chromosome complement influence adiposity and metabolism in mice. Endocrinology. 2013;154(3):1092-1104 [ Pub Med ]
35. Gu GB, Simerly RB. Projections of thesexuallydimorphicanteroventral periventricular nucleus in the female rat. J Comp Neurol. 1997;384(1):142-164 [ Pub Med ]
36. Yamaji T, Dierschke DJ, Hotchkiss J, Bhattacharya AN, Surve AH, Knobil E. Estrogen induction of LH release in the rhesus monkey. Endocrinology. 1971;89(4):1034-1041 [ Pub Med ]
37. Hutton LA, Gu G, Simerly RB. Development of a sexually dimorphic projection from the bed nuclei of the stria terminalistotheanteroventral periventricular nucleus in the rat. J Neurosci. 1998;18(8):3003-3013 [ Pub Med ]
38. Gao Q, Horvath TL. Neurobiology of feeding and energy expenditure. Annu Rev Neurosci. 2007;30:367-398 [ Pub Med ]
39. Simerly RB, Chang C, Muramatsu M, Swanson LW. Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study. J Comp Neurol. 1990;294(1):76-95 [ Pub Med ]
40. Brock O, De Mees C, Bakker J. Hypothalamic expression of oestrogen receptor a and androgen receptor is sex-, age-and region-dependent in mice. J Neuroendocrinol. 2015;27(4):264-276 [ Pub Med ]
41. Lu SF, McKenna SE, Cologer-Clifford A, Nau EA, Simon NG. Androgen receptor in mouse brain: sex differences and similarities in autoregulation. Endocrinology. 1998;139(4):1594-1601 [ Pub Med ]
42. Shah NM, Pisapia DJ, Maniatis S, Mendelsohn MM, Nemes A, Axel R. Visualizing sexual dimorphism in the brain. Neuron. 2004;43(3):313-319 [ Pub Med ]
43. Fan W, Yanase T, Nishi Y, et al . Functional potentiation of leptin-signal transducer and activator of transcription 3 signaling by the androgen receptor. Endocrinology. 2008;149(12):6028-6036 [ Pub Med ]
44. Campos CA, Bowen AJ, Schwartz MW, Palmiter RD. Parabrachial CGRP neurons control meal termination. Cell Metab. 2016;23(5):811-820 [ Pub Med ]
45. Dallaporta M, Himtni T, Perrin J, Orsini JC. Solitary tract nucleus sensitivityto moderate changes in glucose level. Neuroreport. 1999;10(12):2657-2660 [ Pub Med ]
46. Lentini E, Kasahara M, Arver S, Savic I. Sex differences in the human brain and the impact of sex chromosomes and sex hormones. Cereb Cortex. 2013;23(10):2322-2336 [ Pub Med ]
47. Neufang S, Specht K, Hausmann M, et al . Sex differences and the impact of steroid hormones on the developing human brain. Cereb Cortex. 2009;19(2):464-473 [ Pub Med ]
48. Eisner JR, Dumesic DA, Kemnitz JW, Colman RJ, Abbott DH. Increased adiposity in female rhesus monkeys exposed to androgen excess during early gestation. Obes Res. 2003;11(2):279-286 [ Pub Med ]
49. Nilsson C, Niklasson M, Eriksson E, Bjorntorp P, Holmang A. Imprinting of female offspring with testosterone results in insulin resistance and changes in body fat distribution at adult age in rats. J Clin Invest. 1998;101(1):74-78 [ Pub Med ]
50. Alexanderson C, Eriksson E, Stener-Victorin E, et al . Postnatal testosterone exposure results in insulin resistance, enlarged mesenteric adipocytes, and an atherogenic lipid profile in adult female rats: comparisons with estradiol and dihydrotestosterone. Endocrinology. 2007;148(11):5369-5376 [ Pub Med ]
51. Abbott DH, Tarantal AF, Dumesic DA. Fetal, infant, adolescent and adult phenotypes of polycystic ovary syndrome in prenatally androgenized female rhesus monkeys. Am J Primatol. 2009;71(9):776-784 [ Pub Med ]
52. Nohara K, Waraich RS, Liu S, et al . Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice. Am J Physiol Endocrinol Metab. 2013;304(12):E1321-E1330 [ Pub Med ]
53. Nohara K, Zhang Y, Waraich RS, et al . Early-life exposure to testosterone programs the hypothalamic melanocortin system. Endocrinology. 2011;152(4):1661-1669 [ Pub Med ]
54. Hague WM, Adams J, Rodda C, et al . The prevalence of polycystic ovaries in patients with congenital adrenal hyperplasia and their close relatives. Clin Endocrinol (Oxf). 1990;33(4):501-510 [ Pub Med ]
55. Barnes RB, Rosenfield RL, Ehrmann DA, et al . Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women. J Clin Endocrinol Metab. 1994;79(5):1328-1333 [ Pub Med ]
56. Lara HE, Ferruz JL, LuzaS. , Bustamante DA, Borges Y, Ojeda SR. Activation of ovarian sympathetic nerves in polycystic ovary syndrome. Endocrinology. 1993;133(6):2690-2695 [ Pub Med ]
57. Lansdown A, Rees DA. The sympathetic nervous system in polycystic ovary syndrome: a novel therapeutic target? Clin Endocrinol (Oxf). 2012;77(6):791-801 [ Pub Med ]
58. Mauvais-Jarvis F. Developmental androgenization programs metabolic dysfunction in adult mice: clinical implications. Adipocyte. 2014;3(2):151-154 [ Pub Med ]
59. Culbert KM, Breedlove SM, Burt SA, Klump KL. Prenatal hormone exposure and risk for eating disorders: a comparison of opposite-sex and same-sex twins. Arch Gen Psychiatry. 2008;65(3):329-336 [ Pub Med ]
60. Nohara K, Liu S, Meyers MS, et al . Developmental androgen excess disrupts reproduction and energy homeostasis in adult male mice. J Endocrinol. 2013;219(3):259-268 [ Pub Med ]
61. Cowley MA, Pronchuk N, Fan W, Dinulescu DM, Colmers WF, Cone RD. Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron. 1999;24(1):155-163 [ Pub Med ]
62. Wang J, Osaka T, Inoue S. Orexin-A-sensitive site for energy expenditure localized in the arcuate nucleus of the hypothalamus. Brain Res. 2003;971(1):128-134 [ Pub Med ]
63. Oh JY, Barrett-Connor E, Wedick NM, Wingard DL. Rancho Bernardo Study: endogenous sex hormones and the development of type 2 diabetes in older men and women. Diabetes Care. 2002;25(1):55-60 [ Pub Med ]
64. Fan WQ, Yanase T, Nomura M, et al . Androgen receptor null male mice develop late-onset obesity caused by decreased energy expenditure and lipolytic activity but show normal insulin sensitivity with high adiponectin secretion. Diabetes. 2005;54(4):1000-1008 [ Pub Med ]
65. Lin H, Xu Q, Yeh S, Wang R, Sparks JD. Insulin and leptin resistance with hyperleptinemia in mice lacking androgen receptor. Diabetes. 2005;54(6):1717-1725 [ Pub Med ]
66. Keating NL, O'Malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst. 2010;102(1):39-46 [ Pub Med ]
67. Mauvais-Jarvis F. Androgen-deprivation therapy and pancreatic -cell dysfunction in men. Diabetes Complications. 2016;30(3):389-390 [ Pub Med ]
68. Navarro G, Xu W, Jacobson DA, et al . Extranuclear actions of the androgen receptor enhance glucose-stimulated insulin secretion in the male. Cell Metab. 2016;23(5):837-851 [ Pub Med ]
69. Zitzmann M, Gromoll J, von Eckardstein A, Nieschlag E. The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men. Diabetologia. 2003;46(1):31-39 [ Pub Med ]
70. Finkelstein JS, Lee H, Burnett-Bowie SA, et al . Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369(11):1011-1022 [ Pub Med ]
71. Yu IC, Lin HY, Liu NC, et al . Neuronal androgen receptor regulates insulin sensitivity via suppression of hypothalamic NF-B-mediated PTP1B expression. Diabetes. 2013;62(2):411-423 [ Pub Med ]
72. Holmang A, Bjorntorp P. The effects of testosterone on insulin sensitivity in male rats. Acta Physiol Scand. 1992;146(4):505-510 [ Pub Med ]
73. Page-Wilson G, Goulart AC, Rexrode KM. Interrelation between sex hormones and plasma sex hormone-binding globulin and hemoglobin A1c in healthy postmenopausal women. Metab Syndr Relat Disord. 2009;7(3):249-254 [ Pub Med ]
74. Sahin S, Eroglu M, Selcuk S, et al . Intrinsic factors rather than vitamin D deficiency are related to insulin resistance in lean women with polycystic ovary syndrome. Eur Rev Med Pharmacol Sci. 2014;18:2851-2856 [ Pub Med ]
75. Sam S. Obesity and polycystic ovarian syndrome. Obes Manag. 2007;3(2):69-73 [ Pub Med ]
76. Moghetti P, Tosi F, Castello R, et al . The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J Clin Endocrinol Metab. 1996;81(3):952-960 [ Pub Med ]
77. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38(9):1165-1174 [ Pub Med ]
78. Ehrmann D, Barnes R, Rosenfield R, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22(1):141-146 [ Pub Med ]
79. Polderman KH, Gooren LJ, Asscheman H, Bakker A, Heine RJ. Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab. 1994;79(1):265-271 [ Pub Med ]
80. Nohara K, Laque A, Allard C, Munzberg H, Mauvais-Jarvis F. Central mechanisms of adiposity in adult female mice with androgen excess. Obesity. 2014;22(6):1477-1484 [ Pub Med ]
81. Enriori PJ, Sinnayah P, Simonds SE, Rudaz CG, Cowley MA. Leptin action in the dorsomedial hypothalamus increases sympathetic tone to brown adipose tissue in spite of systemic leptin resistance. J Neurosci. 2011;31(34):12189-12197 [ Pub Med ]
82. Balthasar N, Coppari R, McMinn J, et al . Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron. 2004;42(6):983-991 [ Pub Med ]
83. Feng Y, Shao R, Weijdegard B, et al . Effects of androgen and leptin on behavioral and cellular responses in female rats. Horm Behav. 2011;60(4):427-438 [ Pub Med ]
84. Fodor M, Delemarre-van de Waal HA. Are POMC neurons targets for sex steroids in the arcuate nucleus of the rat? Neuroreport. 2001;12(18):3989-3991 [ Pub Med ]
85. Navarro G, Suhuan Liu P, De Gendt K, Verhoeven G, Mauvais-Jarvis F. Importance of the beta-cell androgen receptor in type 2 diabetes. Endocr Rev. 2011;32:OR23-OR22 [ Pub Med ]
86. Morford J, Navarro G, Allard C, Mauvais-Jarvis F. Excess androgen receptor activation in beta-cells produces hyperinsulinemia, insulin resistance, and secondary beta-cell failure in female mice. Diabetes. 2016;65(suppl 1):A482 [ Pub Med ]
87. Fagman JB, Wilhelmson AS, Motta BM, et al . The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice. FASEB J. 2015;29(4):1540-1550 [ Pub Med ]
88. Moore AM, Campbell RE. The neuroendocrine genesis of polycystic ovary syndrome: a role for arcuate nucleus GABA neurons. J Steroid Biochem Mol Biol. 2015;160:106-117 [ Pub Med ]
89. Kong D, Tong Q, Ye C, et al . GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure. Cell. 2012;151(3):645-657 [ Pub Med ]
90. Huo L, Gamber K, Greeley S, et al . Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab. 2009;9(6):537-547 [ Pub Med ]
91. Berglund ED, Vianna CR, Donato J, et al . Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J Clin Invest. 2012;122(3):1000-1009 [ Pub Med ]
92. Hill JW, Elias CF, Fukuda M, et al . Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab. 2010;11(4):286-297 [ Pub Med ]
93. Hill JW, Xu Y, Preitner F, et al . Phosphatidyl inositol 3-kinase signaling in hypothalamic proopiomelanocortin neurons contributes to the regulation of glucose homeostasis. Endocrinology. 2009;150(11):4874-4882 [ Pub Med ]
94. Berthoud HR, Jeanrenaud B. Acute hyperinsulinemia and its reversal by vagotomy after lesions of the ventromedial hypothalamus in anesthetized rats. Endocrinology. 1979;105(1):146-151 [ Pub Med ]
95. Cox JE, Powley TL. Intragastric pair feeding fails to prevent VMH obesity or hyperinsulinemia. Am J Physiol. 1981;240(5):E566-E572 [ Pub Med ]
96. Luo S, Luo J, Cincotta a H. Chronic ventromedial hypothalamic infusion of norepinephrine and serotonin promotes insulin resistance and glucose intolerance. Neuroendocrinology. 1999;70(6):460-465 [ Pub Med ]
97. Kim KW, Donato J, Berglund ED, et al . FOXO1 in the ventromedial hypothalamus regulates energy balance. J Clin invest. 2012;122(7):2578-2589 [ Pub Med ]
98. Ramadori G, Fujikawa T, Anderson J, et al . SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance. Cell Metab. 2011;14(3):301-312 [ Pub Med ]
99. Perkins MN, Rothwell NJ, Stock MJ, Stone TW. Activation of brown adipose tissue thermogenesis by the ventromedial hypothalamus. Nature. 1981;289(5796):401-402 [ Pub Med ]
100. aretskaia MV, Zaretsky DV, Shekhar A, DiMicco JA. Chemical stimulation of the dorsomedial hypothalamus evokes non-shivering thermogenesis in anesthetized rats. Brain Res. 2002;928(1-2):113-125 [ Pub Med ]