Journal of Endocrinological Investigation

, Volume 41, Issue 4, pp 383–388 | Cite as

Androgen excess and metabolic disorders in women with PCOS: beyond the body mass index

  • R. A. Condorelli
  • A. E. Calogero
  • M. Di Mauro
  • L. M. Mongioi’
  • R. Cannarella
  • G. Rosta
  • S. La Vignera



Insulin resistance is a common feature among women with polycystic ovary syndrome (PCOS), especially in those patients with hyperandrogenism and chronic anovulation. PCOS women are at risk for developing metabolic syndrome, impaired glucose tolerance and type II diabetes mellitus (DM II).


The aim of this review is to explore the existing knowledge of the interplay between androgen excess, pancreatic β-cell function, non-alcoholic fatty liver disease (NAFLD), intra-abdominal and subcutaneous (SC) abdominal adipocytes in PCOS, providing a better comprehension of the molecular mechanisms of diabetologic interest.


A comprehensive MEDLINE® search was performed using relevant key terms for PCOS and DM II.


Insulin-induced hyperandrogenism could impair pancreatic β-cell function, the SC abdominal adipocytes’ lipid storage capacity, leading to intra-abdominal adipocyte hypertrophy and lipotoxicity, which in turn promotes insulin resistance, and could enhance NAFLD. Fetal hyperandrogenism exposure prompts to metabolic disorders. Treatment with flutamide showed to partially reverse insulin resistance.


Metabolic impairment seems not to be dependent only on the total fat mass content and body weight in women with PCOS and might be ascribed to the androgen excess.


PCOS Insulin resistance Obesity Hyperandrogenism 





American Association of Clinical Endocrinology


American College of Endocrinology


Body mass index


Dehydroepiandrosterone sulfate




Type II diabetes mellitus


De novo methyl-transferase 3


Free fatty acids


First phase insulin response


Impaired glucose tolerance


LDL receptor


Metabolic syndrome


Non-alcoholic fatty liver disease


Non-alcoholic steatoepatitis


National Institutes of Health




Oral glucose tolerance test


Polycystic ovary syndrome




Sex hormone-binding globulin


Steady-state plasma glucose




Polycystic ovary syndrome (PCOS) is the most common endocrine disorder occurring in females [1]. Currently, its diagnosis requires the exclusion of other hormones or androgen excess conditions, and is based on the presence of clinical and/or biochemical signs of hyperandrogenism, in association with markers of ovarian dysfunction, such as oligo-ovulation or anovulation, polycystic ovaries and menstrual dysfunction (Table 1) [2]. When the diagnosis is performed using the US National Institutes of Health (NIH) criteria, its prevalence ranges from the 6% to the 10%, reaching the 15% when the Rotterdam criteria are applied [1].
Table 1

Polycystic ovary syndrome diagnostic criteria according to the main Societies’ Position Statement (2)


ESHRE/ASRM (Rotterdam criteria) 2004

AES 2006

Includes all the following

Includes two of the following

Includes all the following

Clinical and/or biochemical hyperandrogenism

Clinical and/or biochemical hyperandrogenism

Clinical and/or biochemical hyperandrogenism

Menstrual dysfunction

Oligo-ovulation or anovulation polycystic ovaries

Ovarian dysfunction and/or polycystic ovaries

AES Androgen Excess Society, ESHRE/ASRM European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine, NIH/NICH National Institutes of Health/National Institute of Child Health and Human Disease

Women with PCOS may require advice for many reasons: hyperandrogenism-related symptoms (which, in turn, include acne, hirsutism and alopecia in adult women, and only hirsutism during adolescence [2]), chronic anovulation and infertility, menstrual disorders [2], oncologic prevention in case of endometrial hyperplasia [3] and for the clinical management of the main metabolic disorders related to obesity and insulin resistance.

Insulin resistance is a prominent feature of PCOS, especially among those women with hyperandrogenism and chronic anovulation [1]. Methodologically, the gold standards for the assessment of insulin resistance are the euglycemic hyperinsulinemic clamp and the steady-state plasma glucose (SSPG) tests [4].

In the clinical practice, the quantitative analysis of insulin resistance may be performed through the homeostatic model assessment of insulin resistance (HOMA-IR), which seems to weakly correlate with the insulin sensitivity measured by SSPG test [5].

Recently, a meta-analyses of euglycemic hyperinsulinemic clamp studies found that women with PCOS have a 27% mean reduction in peripheral sensitivity independent of body mass index (BMI) [6]. The increase in BMI was associated with a further reduction of about 8% in insulin sensitivity [6]. Obese women with PCOS are at higher risk for metabolic syndrome (MetS) and impaired glucose tolerance (IGT) and type II diabetes mellitus (DM II). The progression rates from normal glucose tolerance to IGT and DM II may be of 5–15% within 3 years [4]. A prospective study published in Diabetes in 2012 analyzed 255 women suffering from PCOS for about 10 years (mean follow-up 17 years). Age-standardized DM2 prevalence resulted 39.3% at the end of the follow-up, significantly higher than the prevalence found in the same-age female population [7].

These observations brought the American Association of Clinical Endocrinology (AACE) and the American College of Endocrinology (ACE) to suggest the assessment of oral glucose tolerance test (OGTT) and BMI every 1–2 years in women with PCOS and a familiar history positive for DM II, and every year in those with IGT [4].

The etiopathogenesis of PCOS is still unclear. Below are reviewed physiopathological features involving women having PCOS, with specific focus on diabetological issues.

Pancreatic β-cell function and hyperandrogenism in PCOS women

There is an ever increasing number of studies focused on the progressive loss of the secretory-cell activity in women suffering from PCOS. After the administration of endovenous glucose load, insulin is released in a biphasic way. The first acute response is called first phase insulin response (FPIR) and begins within 1 min after the administration of glucose reaches its peak in 3–5 min and lasts about 10 min. In vivo, this phase is independent of pre-stimulus glycemia. Technically, FPIR is correspondent to the sum of all blood insulin levels up to 10 min. The loss of FPIR is an early marker of defective insulin secretion, which is seen in prediabetic people (both type 1 and type 2 diabetes). Changes in insulin secretion occurring after endovenous glucose load tend to happen earlier than the changes seen after oral glucose load. Disposition Index values (an indicator expressing the ratio between the increase of insulin secretion of β-cells and peripheral insulin sensitivity) prove that obese PCOS women show a significantly decreased FPIR compared to obese non-PCOS women [8]. Recent experimental surveys demonstrated an inverse relationship between the progressive FPIR loss and the activation of nuclear factor kappa light chain enhancer of B cell (NF-KB)-mediated pre-oxidation [9].

The molecular mechanisms responsible for the pancreatic β-cell impaired function need to be clarified. Insulin could impact the gonadal and adrenal steroidogenesis. The activity of P450c17α-hydroxylase enzyme is enhanced by its insulin-induced phosphorylation [10]. Therefore, hyperinsulism may result in an increased 17α-hydroxy-progesterone (17αOH-P), androstenedione (A) and testosterone (T) synthesis in ovaries, where the Δ5-steroidogenetic via occurs, and in an increased dehydroepiandrosterone sulphate (DHEAS) synthesis in the adrenal gland, though the Δ4-steroidogenetic via. Accordingly, data from several clinical trials reveal that the treatment with insulin sensitizers (metformin, myo-inositol, d-chiro-inositol) improves the hyperandrogenic state in women with PCOS [2, 11].

On the contrary, di-hydro-testosterone (DHT), which derives from peripheral T conversion, might impact on the pancreatic β-cell function. In vitro studies on human β-cell islets deriving from male subjects have shown that DHT is able to stimulate insulin production through the androgen receptor (AR) [12]. We are not aware of similar studies on the β-cell islets from females. Such studies would provide a better comprehension of whether and how androgens impact on the pancreatic insulin secretion in females. Interestingly, the literature survey shows a higher prevalence of metabolic disorders in the offspring of hyperandrogenic mothers. A study on 1216 cases found a fourfold higher risk of pre-diabetes (higher serum fasting glucose and insulin levels) in children born to women with hyperandrogenism compared to those born to normal women. The oocytes from such hyperandrogenic women showed higher insulin-like growth factor 2 (IGF2) expression rates. In addition, the in vitro DHT treatment of human oocytes from heathy women upregulated the IGF2 expression and decreased the de novo methyl-transferase 3 (DNMT3) levels. In rats, such findings have been observed also in the offspring pancreatic cells [13]. On this basis, DHT might impair the pancreatic β-cell insulin secretion, leading to metabolic disorders, interfering with their epigenetic regulation. However, also other molecular mechanisms could be hypothesized and other studies are needed to explore in depth this field.

Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) represents an isolated hepatic non-alcoholic steatoepatitis (NASH), this latter additionally characterized by focal areas of inflammation and fibrosis. Obesity and insulin resistance, which are associated with PCOS, might lead to NAFLD. In fact, insulin inhibits the glycogenolysis in the liver. When glycogen reaches its saturation point (5–6%), fatty acid synthesis increases, leading the fatty acids to move to adipose tissue, thus prompting to NAFLD. NAFLD has a higher prevalence among women with PCOS. Its prevalence may vary from 24 to 69% [14]. NASH reaches the 100% of occurrence in those studies which use both ultrasound screening and laboratory exams as well [15]. Several molecular mechanisms bring to NAFLD in PCOS women. These comprehend insulin resistance, hyperandrogenism and visceral adiposity (Fig. 1).
Fig. 1

Possible pathways underling PCOS pathogenesis. Hyperinsulinemia, occurring in patients with polycystic ovary syndrome (PCOS), could enhance P450c17α-hydroxylase activity in ovaries and adrenals, leading to increased 17α-hydroxy-progesterone (17 αOH-P), androstenedione (A), testosterone (T) and dehydroepiandrosterone sulfate (DHEAS) levels. Hyperinsulinemia also lowers sex hormone-binding globulin (SHBG) serum values, thus increasing circulating free T levels. The di-hydro-testosterone (DHT), which derives from the peripheral conversion of T, may impact the pancreatic β-cell function. Total and free T and A could impair the lipid storage capacity of SC abdominal adipocytes, which became smaller. This results in a hypertrophy of intra-abdominal adipocytes and in lipotoxicity promotion, leading to insulin resistance. The intra-abdominal adipocyte hypertrophy reflects to decreased adiponectin levels, which in turn promotes the development of non-alcoholic fatty liver disease (NAFLD). This latter is also enhanced by hyperinsulinemia and free fatty acids (FFA), and T which downregulate the LDL-receptor gene expression in the liver and induce hepatocellular apoptosis. Red lines mean increased levels when referred to hormones, enhanced activity when referred to enzymes, stimulatory effect when referred to a feature (e.g., NAFLD, intra-abdominal adipocytes hypertrophy, etc.). The blue lines have the opposite meanings. P450ssc P450 side cleavage chain (desmolase), 3β-HSD 3β-hydroxy-δ5-steroid dehydrogenase, 17-HSD 17β-hydroxy steroid dehydrogenase, P450 arom P450 aromatase

The insulin resistance has not been necessarily associated with obesity. In fact, in lean women it enhances a de novo hepatic lipogenesis, leading to free fat production in the liver and hepatic steatosis [16, 17].

Androgens may downregulate the LDL-receptor (LDL-R) gene transcription, inducing hepatic steatosis [18]. They can also enhance hepatocellular apoptosis, leading to NAFLD progression [18]. Hyperandrogenemia is associated with increased ALT levels in women with PCOS, independent of obesity and insulin resistance [19, 20, 21]. In line with these results, hyperandrogenic women with PCOS display a more severe steatosis after adjusting for BMI, insulin resistance and visceral adiposity [22]. Interestingly, studies on rats observed that the prenatal exposure to hyperandrogenism was associated with an impaired lipogenesis and fatty oxidation pathway, especially in the anovulatory phenotype, thus leading to the development of steatosis susceptibility [23]. This may provide evidence to hypothesize that the male offspring of hyperandrogenic women with PCOS might be at risk for NAFLD. As far as we know, the literature is lacking such studies.

Also visceral adiposity (abdominal circumference > 80 cm in women) plays a role in the development of NAFLD in women with PCOS. In particular, since adiponectin appears to protect against NAFLD, its reduced levels found in women with PCOS might contribute to NAFLD development [14].

Effects of the androgen excess on the adipose tissue

The insulin resistance in PCOS women depends on several factors and cannot be explained only with the body weight [6] since also lean PCOS women are insulin resistant. However, not all lean PCOS women display this feature and the molecular mechanisms causing insulin resistance in women with PCOS need to be further elucidated. As previously stated, among women with PCOS, insulin resistance occurs especially in those with hyperandrogenism and chronic anovulation [1, 24, 25]. Therefore, hyperandrogenism might enhance metabolic impairment in these women. Recent and increasing evidence addressed to hyperandrogenism a driving role for adipocyte hypertrophy in women with PCOS [26]. In humans, subcutaneous (SC) abdominal adiposity stores lipids, protecting against insulin resistance. The intra-abdominal tissue has the opposite effect. The impaired lipid storage by the SC abdominal tissue could enhance the free fatty acids’ (FFA) uptake in non-adipose cells and in intra-abdominal adipocytes, promoting lipotoxicity [27, 28]. This latter, rather than the excess of total body fat per se, could explain why insulin resistance occurs in some but not all lean PCOS women [29]. Recently, Dumesic and coworkers carried out a study on young, normal-weight PCOS women and age- and BMI-matched healthy women with similar body fat content. PCOS patients had higher levels of LH, T and A compared to controls. Interestingly, PCOS patients had an increased total abdominal fat mass due to preferential deposition of intra-abdominal fat distribution and an increased population of small SC abdominal adipocytes, which were positively correlated with free and total T and A levels [29]. These findings suggest that androgens may play a role in lipotoxicity promotion (thus leading to insulin resistance) impacting on the SC abdominal adipocytes’ lipid storage capacity, in normal-weight women with PCOS. Moreover, the androgen excess seems to drive adipocyte hypertrophy, thus impairing the adipokine secretion in PCOS women [26]. In agreement, free-androgen index is positively associated with BMI and HOMA index in PCOS women [30] and the treatment with flutamide administered for 3–4 months showed to partially reverse insulin resistance [31]. Interestingly, habitual physical activity is associated with improved free-androgen index in PCOS women [32].

These studies suggest new possible interplay between hyperandrogenism and the incoming metabolic disorders in women with PCOS.

Role of SHBG

Hyperinsulinism is characteristically associated with reduced sexual hormone-binding protein (SHBG) production in liver, as a consequence of the inhibitory action of insulin. In women with PCOS, reduced SHBG blood concentrations are associated with a 10% reduction in insulin sensitivity and an increase of BMI [6]. Several researches have proved a negative correlation between SHBG levels and insulin resistance [33]. In addition, most prospective studies support the role of reduced SHBG levels as a possible predictive factor of DM2 development [34]. How SHBG reduction may influence insulin sensitivity is still unknown. It is possible to assume that insulin resistance is a consequence of abnormal sexual hormone transport and thus, this causes a reduced glucose uptake in muscular tissue [34].


Androgen excess seems to play a relevant role in the development of metabolic disorders in women with PCOS, impairing the pancreatic β-cell function, the lipid storage capacity of SC abdominal adipocytes and enhancing intra-abdominal adipocytes hypertrophy. This predisposes to lipotoxicity, which, in turn, is involved in the development of insulin resistance. Furthermore, hyperandrogenism prompts to NAFLD, probably through the LDL-R gene downregulation and hepatocellular apoptosis. The evidence suggests that PCOS women have a predisposition to insulin resistance and its consequences, independent of the total fat mass and the body weight per se [4, 29]. Treatment with flutamide seems to partially reverse insulin resistance in women with PCOS, but the evidence is limited to only one study [30, 31]. Further research should be carried out to explore this issue in depth.


Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Ethical approval

This article does not contain studies with human participants or animals performed by any of the authors.

Informed consent

No informed consent.


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Copyright information

© Italian Society of Endocrinology (SIE) 2017

Authors and Affiliations

  • R. A. Condorelli
    • 1
  • A. E. Calogero
    • 1
  • M. Di Mauro
    • 1
  • L. M. Mongioi’
    • 1
  • R. Cannarella
    • 1
  • G. Rosta
    • 1
  • S. La Vignera
    • 1
  1. 1.Department of Clinical and Experimental MedicineUniversity of Catania, Policlinico “G. Rodolico”CataniaItaly

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