228

REVIEW
The effects of androgens on metabolic functions in females
Takeshi Iwasa1, Yuri Yamamoto1, Akari Shinya1, Saki Minato1, Rie Yanagihara1, Shuhei Kamada1, Junki Imaizumi1,
Tomohiro Kagawa1, Aya Shirakawa1, Hiroki Noguchi1, Tomotaka Nakagawa1, Miyu Taniguchi1, Yuri Kadota1,
Takako Kawakita1, Kanako Yoshida1, Takeshi Kato1, Toshiyuki Yasui2, and Minoru Irahara1
Department of Obstetrics and Gynecology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan,
Department of Reproductive and Menopausal Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima,
Japan
1

2

Abstract : The metabolic effects of androgens and their underlying mechanisms in females have been revealed
by recent studies. An excess of androgens can have adverse effects on feeding behavior and metabolic functions
and induce metabolic disorders / diseases, such as obesity, insulin resistance, and diabetes, in women and experimental animals of reproductive age. Interestingly, these effects of androgens are not observed in ovariectomized
animals, indicating that their effects might be dependent on the estrogen milieu. Central and peripheral mechanisms, such as alterations in the activity of hypothalamic factors, reductions in energy expenditure, skeletal
muscle insulin resistance, and β-cell dysfunction, might be related to these androgens’ effects. J. Med. Invest. 68: 228-231, August, 2021
Keywords : androgen, metabolic function, obesity

INTRODUCTION
Energy balance and reproductive function are closely linked
in most species (1, 2). Sex hormones, i.e. estrogens and androgens, are involved in the regulation of energy metabolism, foodintake, and body weight in mammals and humans (2). Generally, estrogens prevent excess body weight gain and obesity infemales of reproductive and postmenopausal ages by suppressing food intake and increasing metabolic expenditure (2-4). On
the contrary, it is assumed that androgens increase the riskof metabolic dysfunctions and excess body weight in women of
reproductive age, however, a cause-effect relationship remains tobe established. In addition, the roles of androgens on metabolic
functions in postmenopausal women are highly controversial.
Some studies have reported that high testosterone level is associated with increased risk of insulin resistance and cardiovascular disease, whereas other studies have shown that circulating
DHEA-S level dose not affect the risk of cardiovascular disease
and mortality (5). Similarly, recent study has proposed that it isunknown whether hyperandrogenic women truly have increased
risk of mortality and cardiovascular disease later in life (6). Interestingly, contrary to case in females, it has been demonstrated
that androgens have favorable effects on metabolic functions inmales ; i.e., androgens prevent some metabolic disorders, such as
insulin resistance (IR) and obesity, in males (7).
Here, we review the available literature on the roles of androgens in metabolic functions in females of reproductive age, withspecial emphasis on the mechanisms that have recently been
proposed to underlie these roles.

Received for publication June 22, 2021 ; accepted July 4, 2021.
Address correspondence and reprint requests to Takeshi Iwasa, Department of Obstetrics and Gynecology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho,
Tokushima 770-8503, Japan and Fax : +81-88-631-2630.

EFFECTS OF ANDROGENS ON METABOLIC FUNCTION IN FEMALES OF REPRODUCTIVE AGE
Effects of endogenous androgens

It has been suggested that endogenous androgens affectmetabolic functions in women of reproductive age and that an
excess of androgens might increase the risk of some metabolic
disorders / diseases, such as visceral obesity, IR, and metabolic
syndrome. Women with polycystic ovary syndrome (PCOS),
frequently accompanied by a hyperandrogenic status, exhibit
increased prevalence rates of type 2 diabetes and metabolic
syndrome compared with women without PCOS (8, 9). Similarly,
hyperandrogenic women with PCOS display higher prevalence
rates of abdominal obesity, IR, and adverse metabolic profiles
than women without PCOS and those with non-hyperandrogenic PCOS. These effects of a hyperandrogenic status on
metabolic functions are also observed in women without PCOS.
Specifically, hyperandrogenic premenopausal women with highfree androgen indices (FAI) demonstrated higher waist circumference values, fasting glucose and insulin levels, systolic anddiastolic blood pressure levels, and serum triglyceride levels andlower serum high-density lipoprotein-cholesterol levels (10). In
addition, women with idiopathic hirsutism or PCOS displayed
greater waist-hip ratios (WHR) than age- and weight-matched
non-hirsute women, and the plasma testosterone level was foundto be positively correlated with the WHR (11). Based on thefindings of these studies regarding the relationships between
hyperandrogenic status and metabolic disorders, further studies evaluated whether antiandrogenic treatment improves themetabolic status of women with PCOS. It was demonstrated thattreatment with flutamide, an antiandrogenic medicine, during
12 months caused reductions in visceral and subcutaneous fat
mass, lipid profile improvements, and increases in insulin sensitivity in overweight-obese women with PCOS (12).
Interestingly, some studies have suggested that androgens
might affect food cravings and food preferences in young women.
For example, young women with high FAI exhibited increased
craving for certain foods, such as high-fat foods and fast foods(13), and women with PCOS displayed higher prevalence rates
of abnormal eating behaviors, such as bulimic behavior (14). In

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The Journal of Medical Investigation Vol. 68 August 2021
addition, women with bulimia nervosa tended to have higher
androgen levels than normal women (15), and antiandrogenic
oral contraceptive use reduced meal-related hunger and eating
behavior in bulimic women (16).
Thus, endogenous androgens play roles in the regulation of
metabolic functions and feeding behavior in women of reproductive age, and an excess of androgens might increase the risk ofmetabolic disorders / diseases.

Effects of exogenous androgens
The hypothesis that an excess of androgens is related tovarious metabolic disorders / diseases, has been supported bystudies that evaluated the effects of exogenous androgens on
metabolic functions. Androgen-treated female-to-male transsexual patients exhibited higher HOMA-IR (homeostatic model
assessment of insulin resistance) values than those who did
not receive hormonal treatment (17), indicating that exogenous
androgens might increase IR. In addition, the administrationof methyltestosterone reduced glucose uptake during insulin
infusions in non-obese premenopausal women, suggesting that
hyperandrogenemia induces IR (18). These phenomena can be
reproduced in experimental animals via the chronic administration of androgens. The chronic (4 weeks) administrationof dihydrotestosterone (DHT) increased visceral adiposity infemale mice of reproductive age (19), and the administration of
testosterone (around 2 weeks) increased visceral and subcutaneous fat weight and body weight in female rats of reproductiveage (20, 21) (Table 1). Interestingly, such effects of androgenon fat and body weight are observed in gonadally intact or
estradiol-supplemented ovariectomized rats, but not in non-supplemented ovariectomized rats (20, 21) (Table 1). Animals
that were subjected to longer-term (5 to 19 weeks) androgen
treatment display increased food intake and body weight gain,
IR, and hyperlipidemia, as well as irregular estrous cycles andmorphological ovarian changes (22-24). In addition, the chronic
administration of testosterone also increased the preference offemale rats of reproductive age for a high-fat diet (25), indicatingthat the effects of androgens on feeding behavior can also be
reproduced in animal models.
Table 1. Effects of androgen administration on body weight, foodintake, fat amount, and hypothalamic factors in ovariectomized with
E2 administered and ovariectomized female rats.
ovarictomy+E2

ovariectomy

Body weight↑↓

Food intake→↓

Fat amount↑↓

Adipocyte size↑↓

Hypothalamic Aromatase→↑

Hypothalamic androgen receptor↓→

Hypothalamic IL-1, TNFα↑↓

E2 ; estradiol, IL-1 ; interleukin-1, TNF-α ; tumor necrosis factor-α, ↑ ; increase, ↓ ; decrease

HYPOTHESES OF THE MECHANISMS OF ANDROGENS’ EFFECTS
Changes in hypothalamic functions

It has been shown that an excess of androgens alters theactivity and mRNA expression of some hypothalamic factors,
and these alterations might be involved in the adverse effects ofandrogens on metabolic functions. The chronic administration229

of DHT reduced the hypothalamic mRNA expression of proopiomelanocortin (POMC), which is an anorectic factor, and POMC
neuronal innervation into other hypothalamic regions in female
mice of reproductive age (19). In addition, we observed thatchronic testosterone administration reduced the hypothalamicmRNA expression of estrogen receptor-α (ER-α) and / or increased the mRNA expression of pro-inflammatory cytokines(20, 21). It has been established that the favorable effects of estrogens on metabolic functions are partly mediated by hypothalamic ER-α (2-4) and that low-grade hypothalamic inflammation
undermines homeostatic responses that protect against obesity(26). Therefore, the downregulation of ER-α expression and theupregulation of pro-inflammatory cytokine expression in the
hypothalamus, which were observed in our studies, might underlie androgen-induced metabolic disorders. We also found thatsuch alterations in hypothalamic ER-α and pro-inflammatory
cytokine expression, as well as increases in fat mass, occurred ingonadally intact or estradiol-supplemented ovariectomized rats,
but not in ovariectomized rats (20, 21). This indicates that theeffects of androgens on metabolic functions might depend on the
estrogen milieu ; i.e., androgens have adverse effects on femalesof reproductive age, whereas their effects might be decreased orreversed in post-menopausal females and males.

Reductions in energy expenditure
It has been reported that an excess of androgens reduces
energy expenditure, which is associated with visceral obesity.
In female mice of reproductive age, chronic DHT administration prevented the leptin-induced activation of brown adipose
tissue (BAT) thermogenesis, resulting in a reduction in energy
expenditure and an increase in visceral fat mass (19). Similarly,
chronic dehydroepiandrostenedione (DHEA) administration
reduced BAT activity, body temperature, and O2 consumption infemale rats of reproductive age, whereas the transplantation of
BAT from rats that had not been administered DHEA negatedthese DHEA-induced changes and normalized systemic insulin
sensitivity (27). These results indicate that reductions in endogenous BAT activity are closely related to the adverse effects ofandrogens on metabolic functions.

Skeletal muscle insulin resistance
It has been shown that an excess of androgens can induce IRin women and female experimental animals. High testosterone
levels produced IR, which was detected using the hyperglycemicand euglycemic hyperinsulinemic clamp tests, in pre-menopausal women (18, 28), and such testosterone-induced IR mightmainly occur in skeletal muscle (18). The administration of testosterone also induced IR in muscles, together with reductions
and increases in the relative numbers of type 1 and type 2 muscle fibers, respectively, in female rodents (29, 30). Although thedetailed mechanisms by which androgens promote muscular IR
remain unclear, it has been suggested that androgens might act
as aggravating factors rather than as initiators of IR.

β-cell dysfunction
It has been suggested that an excess of androgens causes a
predisposition towards pancreatic β-cell dysfunction by activating some β-cell stressors. Hyperandrogenic women exhibit β-cell
hyperfunction, which might induce secondary β-cell dysfunction(31). In addition, excess testosterone induced β-cell dysfunction
via an androgen receptor-dependent mechanism (32) in female
mice, and direct androgen exposure to isolated pancreatic islets
induced an impaired response to glucose stimulation (32, 33).
These effects of androgens on β-cells might be caused by systemicoxidative stress, low-grade inflammation, and / or IR (32, 34).

T. Iwasa, et al. Androgen’s effects in female

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EFFECTS OF ANDROGENS ON METABOLIC FUNCTIONS IN POSTMENOPAUSAL WOMEN
As noted above, the effects of androgens on metabolic functionsin postmenopausal women are disputed. It has been reported
that androgen activity is higher in postmenopausal women with
impaired glucose tolerance than in normal women (35) and thathigh testosterone levels in postmenopausal women predict insulin resistance and the future incidence of type 2 diabetes (36).
On the other hand, higher serum estradiol levels are strongly
related to the pathogenesis of type 2 diabetes in postmenopausal
women (37). These findings indicate that excesses of estrogenand androgens might act as risk factors for metabolic disorders
in postmenopausal women. Interestingly, some data have shownthat testosterone therapy has favorable effects on body composition and cardiovascular function, as well as on libido, bone,
and cognitive performance (38). Thus, contrary to endogenous
androgens, exogenous androgens might help to protect against
metabolic disorders.

CONCLUSION
Androgens affect metabolic functions and feeding behaviors
in females of reproductive age, and an excess of androgens might
increase the risk of metabolic-related disorders / diseases. It canbe assumed that increased consumption of high-fat diet mightenhance the adverse effects of androgens on metabolic functions.
Central and peripheral mechanisms are considered to contributeto these effects of androgens (Figure 1).

CONFLICT OF INTEREST
The author declares no conflicts of interest.

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