Polycystic ovary syndrome: reviewing diagnosis and management of metabolic disturbances

Síndrome dos ovários policísticos: revisando o diagnóstico e o manejo dos distúrbios metabólicos

Abstracts

Polycystic ovary syndrome (PCOS) is a common condition in women at reproductive age associated with reproductive and metabolic dysfunction. Proposed diagnosed criteria for PCOS include two out of three features: androgen excess, menstrual irregularity, and polycystic ovary appearance on ultrasound (PCO), after other causes of hyperandrogenism and dysovulation are excluded. Based on these diagnostic criteria, the most common phenotypes are the “classic PCOS” – hyperandrogenism and oligomenorrhea, with or without PCO; the “ovulatory phenotype” – hyperandrogenism and PCO in ovulatory women; and the “non-hyperandrogenic phenotype”, in which there is oligomenorrhea and PCO, without overt hyperandrogenism. The presence of obesity may exacerbate the metabolic and reproductive disorders associated with the syndrome. In addition, PCOS women present higher risk for type 2 diabetes and higher prevalence of cardiovascular risk factors that seems to be associated with the classic phenotype. The main interventions to minimize cardiovascular and metabolic risks in PCOS are lifestyle changes, pharmacological therapy, and bariatric surgery. Treatment with metformin has been shown to improve insulin sensitivity, lowering blood glucose and androgen levels. These effects are more potent when combined with lifestyle interventions. In conclusion, besides reproductive abnormalities, PCOS has been associated to metabolic comorbidities, most of them linked to obesity. Confounders, such as the lack of standard diagnostic criteria, heterogeneity of the clinical presentation, and presence of obesity, make management of PCOS difficult. Therefore, the approach to metabolic abnormalities should be tailored to the risks and treatment goals of each individual woman.

PCOS; obesity; insulin resistance; metformin

A síndrome dos ovários policísticos (PCOS) é um distúrbio frequente em mulheres em idade reprodutiva, associado com disfunção reprodutiva e metabólica. Os critérios diagnósticos atuais para PCOS incluem pelo menos dois dos três seguintes: hiperandrogenismo, irregularidade menstrual e aparência policística dos ovários à ultrassonografia (PCO), após exclusão de outras causas de hiperandrogenismo e anovulação. Com base nesses critérios diagnósticos, os fenótipos mais comuns são “PCOS clássico”– hiperandrogenismo e oligomenorreia, com ou sem PCO; o “fenótipo ovulatório” – hiperandrogenismo e PCO em mulheres ovulatórias; e o “fenótipo não hiperandrogênico”– no qual ocorrem oligomenorreia e PCO sem hiperandrogenismo evidente. A presença de obesidade pode exacerbar os distúrbios metabólicos e reprodutivos associados com a síndrome. Além disso, mulheres com PCOS apresentam maior risco para diabetes tipo 2 e maior prevalência de fatores de risco cardiovascular, que parecem estar associados com o fenótipo clássico. As principais intervenções para minimizar riscos metabólicos e cardiovasculares em PCOS são mudanças de estilo de vida, tratamento farmacológico e cirurgia bariátrica. O tratamento com metformina melhora a sensibilidade à insulina, reduz a glicemia e os níveis de androgênios. Esses efeitos são mais evidentes quando a metformina é associada às mudanças de estilo de vida. Em conclusão, além das anormalidades reprodutivas, a PCOS tem sido associada com comorbidades metabólicas ligadas à obesidade. Fatores confundidores, como a falta de critérios diagnósticos padronizados, heterogeneidade da apresentação clínica e presença de obesidade, tornam difícil o manejo clínico de PCOS. Assim, a abordagem das anormalidades metabólicas deve ser individualizada para os riscos e objetivos terapêuticos de cada mulher.

PCOS; obesidade; resistência insulínica; metformina

INTRODUCTION

Polycystic ovary syndrome (PCOS) is the most common endocrine disease affecting women of reproductive age. The prevalence of PCOS varies according to the diagnostic criteria used, with estimates ranging from 9% in women of reproductive age, according to NIH criteria, up to 18%, with the Rotterdam criteria (¹-³).

PCOS is a multifactorial disease, and the individual susceptibility is probably determined by multiple genetic and environmental risk factors. It is primarily characterized by ovulatory dysfunction and hyperandrogenism (¹, ²), but the clinical presentation is heterogeneous and patients may present some of various signs and symptoms (Table 1). This heterogeneity seems to be modulated by multiple factors, such as prenatal androgen exposure, nutritional status in the uterus, genetic factors, as well as ethnicity, insulin resistance of puberty and/or exaggerated adrenarche and changes in body weight (⁴-⁶). Environmental factors, such as obesity, appear to exacerbate the underlying genetic predisposition. Concerning ethnicity, the presence of hirsutism is less frequent in Asian patients (around 10%), compared to Caucasian ones (70%) (¹, ⁶).

Table 1.
Clinical presentation of PCOS

Hirsutism, acne, alopecia
Irregular menstrual cycles, oligomenorrhea, amenorrhea
Ovulatory dysfunction and infertility
Increased risk for T2 diabetes, dyslipidemia, hypertension

Hirsutism is defined as a score of 8 or more on the modified Ferriman–Gallwey index (⁷). Oligo/amenorrheic cycles are defined as 8 or less cycles per year and biochemical androgen determinations should be performed in the follicular phase in patients with preserved menstrual cycles.

DIAGNOSTIC CRITERIA

Proposed diagnosed criteria for PCOS include the NIH Consensus (⁸), defined, in 1990, as the presence of clinical and/or biochemical hyperandrogenism and oligomenorrhea/anovulation (Table 2). Later, in 2003, the Rotterdam Consensus (⁹) introduced the polycystic ovary appearance (PCO) on ultrasound as a new criterion to be added to the two previous criteria of the NIH, and the diagnosis requires two out of these three criteria. In turn, the Androgen Excess and PCOS Society (¹⁰) considered that androgen excess is a central event in the pathogenesis and development of PCOS, and established that this criterion should be present and accompanied by one of the others: oligomenorrhea and/or PCO (Table 2). In all cases, exclusion of other androgen excess disorders, such as non-classical congenital adrenal hyperplasia (NC-CAH), Cushing’s syndrome, androgen-secreting tumors, hyperprolactinemia, thyroid diseases, drug-induced androgen excess should be excluded, as well as other causes of oligomenorrhea or anovulation.

Table 2.
Diagnostic criteria for PCOS

NIH Consensus 1990	Rotterdam Consensus 2003	AEPCOS definition 2006
(all required)	(two out of three required)	(androgen excess and one other criterion)
Clinical and/or biochemical hyperandrogenism	Clinical and/or biochemical hyperandrogenism	Clinical and/or biochemical hyperandrogenism
Oligo/amenorrhea, anovulation	Oligo/amenorrhea, anovulation	Oligo/amenorrhea, anovulation
	Polycystic ovaries appearance on ultrasound	Polycystic ovaries appearance on ultrasound

• Exclusion of other androgen excess disorders: NC-CAH, Cushing’s syndrome, androgen secreting tumors, hyperprolactinemia, thyroid diseases, drug-induced androgen excess. Other causes for anovulation should also been excluded.

In consequence, new phenotypes have arisen in addition to the classic phenotype, in which patients present hyperandrogenism and oligomenorrhea with or without PCO on ultrasound. These new phenotypes are the “ovulatory phenotype”, which means hyperandrogenism and PCO in an ovulatory woman, and the “non-hyperandrogenic phenotype”, in which there is oligomenorrhea and PCO, without overt hyperandrogenism.

PCO has been defined as the presence of 12 or more follicles of 2-9 mm or ovarian volume greater than 10 cm ³ (⁹). However, with the new equipment, it is possible to visualize and count small follicles of less than 2 mm nowadays (¹¹). Therefore, the consequence of the improved ovarian imaging is the revaluation of the current follicle number threshold, and the probable increase in the number of follicles to more than 19-26 follicles per ovary and per age classes to better define PCOS (¹¹, ¹²). Anti-Müllerian Hormone (AMH) levels are correlated with follicle counts and its measurement has been useful for screening and prognosis of reproductive issues. The determination of an AMH cutoff value is still lacking, but may become an additional tool to define PCO and PCOS phenotypes in the near future (¹¹-¹³).

In turn, morphological ovarian changes are not exclusive of PCOS, and the presence of PCO in non-hirsute women with normal cycles is not negligible, varying from 2.5 to 33% in different studies (¹⁰, ¹⁴). In addition, while the inclusion of a non-hyperandrogenic phenotype of the diagnosis of PCOS is still controversial, some authors consider the presence of PCO as being itself a sign of hyperandrogenism.

Recently, an Expert Panel from a NIH Evidence-Based Methodology Workshop on PCOS reinforced the use of the wider Rotterdam Criteria to diagnose the Syndrome. Therefore, the prevalence of PCOS is now greater than before when using the NIH criteria (¹⁵). Classic PCOS is the most common phenotype, with a prevalence of around 70%, with the ovulatory and the non-androgenic phenotypes sharing the other 30% of prevalence (¹, ³, ¹³).

Clinical characterization also changes throughout the lifespan, especially during the post-menarche years and in the menopause transition.

DEFINITION AND PREVALENCE OF PCOS IN ADOLESCENT GIRLS

PCOS is a persistent challenge to the clinician, as the phenotype of the syndrome can vary widely. This is still more evident during the post-pubertal period, as signs and symptoms of PCOS overlap with normal puberty. There is a relatively high rate of menstrual irregularity and anovulatory cycles in this period, as well as some difficulties in interpreting clinical and biochemical evidence of hyperandrogenism: acne is a very common complaint during adolescence, alopecia is a rare phenomenon in girls, and hirsutism is sometimes borderline and aggravates slowly.

Uncertainty also regards the significance of polycystic ovarian morphology on ultrasound: microcysts are often seen even before menarche. In a previous study with normal girls from 1 to 13 years old, we have shown the presence of paucicystic ovaries on ultrasound (up to five follicles measuring less than 10 ml) in 7% of girls before puberty and in 18% of girls with telarche. The prevalence of multicystic ovaries (more than six follicles measuring less than 10 mL) was found in 9% of girls 12 and 13 years with initial puberty (¹⁶). In contrast, ovary volume greater than 10 mL seems to be a better marker of PCOS in adolescent girls presenting hyperandrogenism and oligo/amenorrhea for at least 2 years post-menarche (¹⁷, ¹⁸).

Because of these uncertainties, and the fact that the majority of ultrasound examinations in adolescent girls is abdominal and not transvaginal, the diagnosis of PCOS in adolescents needs all three Rotterdam criteria, and not only two (¹³). Therefore, for the diagnosis of PCOS in adolescent girls, one should consider: 1) oligo/amenorrhea at least 2 years post-menarche or primary amenorrhea at age 16 years; 2) PCO morphology including increased ovarian volume (> 10 cm ³); 3) biochemical hyperandrogenemia, and not only clinical hyperandrogenism. However, even if the diagnosis cannot be confirmed and needs to be postponed, individual manifestations (hirsutism, irregular menses) should be treated.

PCOS IN MENOPAUSAL TRANSITION AND POST-MENOPAUSE: ARE THERE SPECIFIC FEATURES?

In menopausal transition, there may be an amelioration of clinical features. In fact, there is a trend towards more regular cycles and improvement on hirsutism with aging (¹⁹). This is in part due to the well-known decrease in androgen secretion from the third for the fifth decade of life that occurs in normal women (²⁰), and has been also reported in PCOS (¹³, ¹⁹, ²¹). In addition, ovarian volume decreases along with pre-menopause and menopause transition, as previously reported (²²). Thus, alterations in ovarian volume and morphology may be less evident in PCOS during menopausal transition, and PCO criteria are not useful after menopause.

In fact, no specific clinical presentation during menopause has been established, and the diagnosis of PCOS is, in general, confirmed before this period, based on the history of oligomenorrhea and hyperandrogenism. Additionally, clinical or biochemical hyperandrogenism appearing in previously normal peri- or post-menopausal women should be carefully investigated in order to screen them for androgen-secreting tumors.

OBESITY, INSULIN RESISTANCE AND METABOLIC COMORBIDITIES

Obesity is a prevalent characteristic of PCOS (⁹, ²³), ranging from 12.5% ( ²⁴) to 100% (²⁵), with a pooled estimated prevalence of 49% (²⁶), as shown by a recent meta-analysis (²⁷). The presence of obesity may exacerbate the metabolic and reproductive disorders associated with the syndrome (²⁸), including insulin resistance, dyslipidemia, and metabolic syndrome (²³, ²⁹-³¹). A meta-analysis (³²) has shown that women with PCOS have higher levels of triglycerides (TG), LDL-cholesterol and total cholesterol (TC), and lower HDL-cholesterol levels compared with control women, regardless of body mass index (BMI). In addition, PCOS women present higher risk for type 2 diabetes (¹³, ¹⁴). PCOS is also associated with a clustering of cardiovascular risk factors (¹⁰, ¹³, ²⁹, ³³, ³⁴). However, there is no definitive evidence for increased cardiovascular events, nor data showing that PCOS alone leads to increased cardiovascular risk independent of associated risk factors. In fact, more rigorous cohort studies of long-term cardiovascular outcomes and clinical trials of risk factor modification are required for women with PCOS.

In addition, evidence suggests clinical phenotypes are related with different metabolic risks (Table 3). In this sense, insulin resistance seems to be a specific feature of the classic phenotype and, to a lesser extent, of the ovulatory phenotype (²⁹, ³⁵, ³⁶). Non-hyperandrogenic phenotype behave as a separate group that is metabolically similar to non-PCOS women (¹⁵, ³²).

Table 3.
Clinical features of different phenotypes

Classic PCOS	Ovulatory PCOS	PCOS without hyperandrogenism
Hyperandrogenism and anovulation with or without PCO	Hyperandrogenism and PCO	Anovulation and PCO
More severe menstrual disturbances and hyperandrogenism	Lesser degrees of hyperandrogenism	Minor menstrual irregularity
Higher prevalence of total and abdominal obesity and metabolic syndrome	Lower prevalence of metabolic syndrome and milder forms of dyslipidemia	Metabolic profile often similar to normal women
Higher prevalence of T2DM and cardiovascular risk factors

MANAGEMENT OF METABOLIC DISTURBANCES

Insulin resistance (and compensatory hyperinsulinemia) is an important factor in maintaining hyperandrogenemia by acting directly on theca cells inducing excess androgen production. Insulin also acts as a co-gonadotropin, increasing the effect of LH on ovarian androgen secretion. In consequence, both insulin and androgens act on the liver inhibiting SHBG secretion, leading to increased free and bioactive androgen circulating levels and making clinical hyperandrogenism worse. In addition, insulin resistance plays a central role on the pathophysiology of metabolic syndrome and on the cardiovascular risk in PCOS women.

However, insulin resistance is a common, but not universal feature of PCOS, and treatment should be directed to the consequences rather than to insulin resistance per se (³⁷). These consequences are metabolic syndrome; clinical features shown to improve with insulin-sensitizing drugs, such as acanthosis nigricans; total and abdominal adiposity, as well as impaired fasting glucose (IFG, fasting glucose equal or higher than 100 mg/dL); impaired glucose tolerance (IGT, 2 h post-glucose equal or higher than 140 mg/dL); and type 2 diabetes (T2DM) (³⁷, ³⁸).

The main interventions to minimize cardiovascular and metabolic risks in PCOS are lifestyle changes, pharmacological therapy, and bariatric surgery (Table 4). Lifestyle modification is the first form of therapy combining behavioral (reduction of psychosocial stressors), dietary, and exercise management. Frequently, however, it will be necessary to add an insulin-sensitizing drug (ISD) to the treatment. Metformin and thiazolidinediones (pioglitazone) are the main available ISD. However, due to the eventual weight gain and cancer risks of thiazolidinediones, the prescription of these drugs has been limited to diabetic patients and will not be discussed here.

Table 4.
Treatment of metabolic comorbidities in PCOS

Non pharmacological interventions
Physical activity
Diet and lifestyle changes
Insulin sensitizing drugs
Metformin
Specific treatment for diabetes, hypertension, dyslipidemia and obesity
Bariatric surgery

Metformin, a biguanide, has been widely used for PCOS patients, and evidence indicates it is beneficial for women with PCOS with metabolic syndrome and/or obesity, as well as for affected women who have impaired glucose tolerance, since the efficacy of metformin for diabetes prevention has been demonstrated in individuals with pre-diabetes (³⁸). Its main action is in the liver, with suppression of gluconeogenesis and hepatic glucose output, but it also enhances peripheral insulin action, and reduces glucose absorption from the digestive tract, with no significant direct effect on pancreatic insulin production (³⁹). Metformin also directly inhibits thecal androgen production (⁴⁰).

In women with PCOS, treatment with metformin has been shown to ameliorate the cardiometabolic profile by improving insulin sensitivity, lowering blood glucose and androgen levels and possibly by its effects on body weight (⁴¹-⁴⁴). These effects of metformin are more potent when it is combined with lifestyle intervention (⁴¹). Diets with low caloric intake are part of the treatment and those with low glycemic index appear to be better adjusted for PCOS patients (²⁶, ⁴³).

It is important to underscore, however, that the first-line treatment for hirsutism, menstrual irregularities and infertility are anti-androgens, contraceptive steroids, and clomiphene citrate, respectively. While metformin is more effective than oral contraceptives in reducing fasting insulin and not increasing triglycerides, it is less effective in improving menstrual pattern, hirsutism or decreasing testosterone (⁴⁵). Importantly, there is no evidence of benefits in the absence of insulin resistance.

Metformin is also a reasonable treatment option for those women to whom oral contraceptives may not be recommended, such as PCOS patients presenting moderate to severe high blood pressure, high triglycerides levels, class II or III obesity and/or metabolic syndrome. In this case, and especially if antiandrogen drugs are added to the treatment, other options for contraception should be recommended, including progestogen-only pills (mini-pill) or IUDs.

The usual dose of metformin for PCOS is 1,500 to 2,500 mg per day. A main limitation can be side effects, which are predominantly gastroenterological, consisting of abdominal discomfort, nausea, and diarrhea. These symptoms are usually dose-dependent and can be minimized by gradually increasing the dose of metformin over a period of 1-2 months. Initial doses should be 250-500 mg/day, taken just before the main meal. In the case gastrointestinal side effects recidivate, the current dose may be reduced for a period of 7-10 days, followed by a resumption of the dosage increase. Hepatic and renal function should be monitored before and during treatment.

Specific additional treatment for high blood pressure, dyslipidemia or obesity may be needed for individual PCOS women. Additionally, bariatric surgery may be another option for severe obesity or obesity with metabolic comorbidities (¹³, ⁴⁶).

In conclusion, besides reproductive abnormalities, PCOS has been associated to metabolic comorbidities, most of them, but not all, linked to obesity. Confounders, such as the lack of standard diagnostic criteria, the heterogeneity of the clinical presentation, and the presence of obesity, make the management of PCOS difficult. Therefore, the approach to metabolic abnormalities should be tailored to the risks and treatment goals of each individual woman.

Acknowledgements:

This work was supported, in part, by a grant from Brazilian National Institute of Hormones and Women’s Health/Conselho Nacional de Desenvolvimento Científico e Tecnológico [CNPq INCT 573747/2008-3], Brazil.

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Publication Dates

• Publication in this collection
  Mar 2014

History

• Received
  9 Oct 2013
• Accepted
  26 Nov 2013