Androgens and polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is a mainly hyperandrogenic disorder and is possibly the most frequent endocrinopathy in premenopausal women. Androgen excess is the primary defect in PCOS, because ovarian theca cells secrete increased amounts of androgens even after several passes in primary culture. Excessive androgen amounts might favor the visceral deposition of body fat in affected women, resulting in insulin resistance, compensatory hyperinsulinism and further androgen excess. This vicious circle starts early during life in women with PCOS, even during fetal development, manifests clinically during puberty and does not end after menopause. All the steps in the vicious circle contribute to the association of PCOS with metabolic dysfunction and cardiovascular risk factors. Fortunately, most, if not all, of the therapeutic strategies currently in use for the management of PCOS, including lifestyle modification and diet, oral contraceptives, antiandrogens and insulin sensitizers, may ameliorate androgen excess and its long-term consequences.

Keywords::

• abdominal adiposity
• androgen excess
• antiandrogens
• fetal programming
• insulin resistance
• insulin sensitizers
• lifestyle modification
• oral contraceptives

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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/expertendo; (4) view/print certificate.

Release date: 6 December 2011; Expiration date: 6 December 2012

Learning objectives

Upon completion of this activity, participants will be able to:

• • Evaluate evidence for hyperandrogenism beginning early in life among women with PCOS

• • Distinguish diagnostic criteria for PCOS

• • Analyze the effects of treatment for PCOS on serum androgen levels and clinical manifestations of PCOS

• • Assess changes in serum androgen levels associated with menopause

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Editorial Director, Future Science Group, London, UK.

Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD

Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure:Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Macarena Alpañés, MD

Diabetes, Obesity and Human Reproduction Research Group, Hospital Universitario Ramón y Cajal & Universidad de Alcalá & Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS & CIBER Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM, Madrid, Spain.

Disclosure:Macarena Alpañés, MD, is supported by grants PI080944 and PI110357 from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spanish Ministry of Health and Innovation. CIBER Diabetes y Enfermedades Metabólicas Asociadas is also an inititative of Instituto de Salud Carlos III.

Elena Fernández-Durán, BS

Diabetes, Obesity and Human Reproduction Research Group, Hospital Universitario Ramón y Cajal & Universidad de Alcalá & Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS & CIBER Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM, Madrid, Spain.

Disclosure:Elena Fernández-Durán, BS, is supported by grants PI080944 and PI110357 from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spanish Ministry of Health and Innovation. CIBER Diabetes y Enfermedades Metabólicas Asociadas is also an inititative of Instituto de Salud Carlos III.

Héctor F Escobar-Morreale, MD, PhD

Diabetes, Obesity and Human Reproduction Research Group, Hospital Universitario Ramón y Cajal & Universidad de Alcalá & Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS & CIBER Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM, Madrid, Spain.

Disclosure:Héctor F Escobar-Morreale, MD, PhD, is supported by grants PI080944 and PI110357 from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spanish Ministry of Health and Innovation. CIBER Diabetes y Enfermedades Metabólicas Asociadas is also an inititative of Instituto de Salud Carlos III.

Figure 1. Unifying hypothesis explaining the interplay between the polycystic ovary syndrome and abdominal adiposity.

This interplay is the result of a vicious circle represented by the solid arrows: androgen excess favors the abdominal deposition of body fat, and visceral fat facilitates androgen excess of ovarian and/or adrenal origin by the direct effects (dashed arrow) of several autocrine, paracrine and endocrine mediators, or indirectly by the induction of insulin resistance and hyperinsulinism.

Reproduced from [6], with permission. © Elsevier (2007).

Figure 2. Polycystic ovary syndrome as the result of the interaction of a primary abnormality in androgen synthesis, manifesting as androgen excess, with environmental factors such as abdominal adiposity, obesity and insulin resistance.

In one extreme (†), in some patients, the disorder is severe enough to result in polycystic ovary syndrome even in the absence of triggering environmental factors. In the other extreme (‡), a very mild defect in androgen secretion is amplified by the coexistence of abdominal adiposity, obesity and/or insulin resistance. Between the two extremes, there is a spectrum in the severity of the primary defect in androgen secretion, explaining the heterogeneity of polycystic ovary syndrome patients with regards to the presence of obesity and metabolic comorbidities. However, patients share a primary defect in androgen secretion.

Reproduced from [6], with permission. © Elsevier (2007).

Polycystic ovary syndrome (PCOS) is possibly the most prevalent endocrinopathy in premenopausal women [1], affecting approximately 6–8% of this population [2–4]. The complete PCOS phenotype is characterized by clinical and/or biochemical hyperandrogenism, ovulatory dysfunction and polycystic morphology of the ovaries [5], and is frequently associated with insulin resistance and obesity [6].

Current understanding of the etiology of PCOS is incomplete, yet the association of PCOS with several predisposing and protective genetic variants suggests a complex multigenic inheritance upon which several environmental factors exert a major influence [7].

Although androgen excess is the central pathophysiologic characteristic of PCOS [5,8], the frequent association of PCOS with insulin resistance, leading to compensatory hyperinsulinism, may further contribute to androgen excess because insulin facilitates androgen synthesis at the adrenals and at the ovaries [9]. In fact, reputed authors consider PCOS as another manifestation of the metabolic syndrome in women, and suggest that insulin resistance is the key mechanism leading to androgen excess in these women [10].

On the contrary, our present hypothesis [6] is that androgen excess facilitates a predominantly visceral deposition of fat in women with PCOS, and visceral fat dysfunction further facilitates androgen secretion by the adrenals and the ovaries – directly through the endocrine effects of several adipokines, and indirectly through insulin resistance and compensatory hyperinsulinism – closing a vicious circle that may start as early as fetal life in affected women (Figure 1).

In the present article, we will review the role of androgen excess throughout the life cycle of women with PCOS, highlighting the metabolic and cardiovascular consequences of hyperandrogenism and the importance of androgen excess as a target for successful long-term management of these patients.

Androgen excess & the definitions of PCOS

The original description of PCOS by Stein and Leventhal 76 years ago referred to the association of amenorrhea, hirsutism, obesity and polycystic ovaries in a group of women of childbearing age [11]. During the following years, and possibly because of its syndromic nature, the diagnosis of PCOS was quite heterogeneous and vague, severely hampering research on the issue. The first serious attempt towards a rational diagnosis of PCOS for research arose from a group of experts during a conference in 1990 sponsored by the National Institute of Child Health and Human Development (NICHD). Although a true consensus was never reached, most attendees agreed that a diagnosis of PCOS could be sustained in women presenting with clinical and/or biochemical hyperandrogenism together with menstrual dysfunction, provided that secondary etiologies such as hyperprolactinemia or congenital adrenal hyperplasia had been excluded [12].

The broad application of these criteria during the next decade resulted in huge advances in our knowledge of PCOS; however, this definition was seldom used in countries from the Commonwealth and Northern Europe, as ultrasound evaluation of polycystic ovarian morphology was possibly the most popular diagnostic tool for PCOS in these countries, and polycystic ovarian morphology was not considered in the NICHD definition.

Aiming towards a worldwide consensus on the definition of PCOS, the European Society of Human Reproduction and Embryology and the American Society of Reproductive Medicine sponsored a conference held in 2003 in Rotterdam, The Netherlands [13]. The experts invited to this conference concluded that the diagnosis of PCOS requires the presence of two out of the three following criteria: oligo-anovulation; clinical and/or biochemical signs of hyperandrogenism; and polycystic ovarian morphology, and maintained the requisite of excluding secondary etiologies [13].

Therefore, according to the Rotterdam definition, a diagnosis of PCOS can be made in the absence of any evidence of hyperandrogenism in women presenting with oligo-anovulation and polycystic ovarian morphology. This particular phenotype of the Rotterdam definition was followed by an intense debate [14,15] as many experts were unconvinced that PCOS could be diagnosed in the absence of androgen excess.

In order to shed some light on this issue, the Androgen Excess and PCOS Society charged a task force to review all available data and recommend an evidence-based definition for PCOS, whether already in use or not, to guide clinical diagnosis and future research. The task force concluded that PCOS was mainly a hyperandrogenic disorder and that the diagnosis of PCOS required clinical and/or biochemical hyperandrogenism to be present, together with oligo-ovulation and/or polycystic ovarian morphology [5,8], and always excluding secondary etiologies. The association of oligo-anovulation with polycystic ovarian morphology was no longer diagnostic of PCOS. Of note, recent data indicating that this phenotype lacks the metabolic associations of PCOS [16] and the fact that with newer equipment polycystic ovarian morphology may be present in as many as 60% of normal young women [17] further support this exclusion.

Androgen excess in PCOS throughout the life cycle

Nowadays, androgen excess is considered to be the cornerstone to the pathogenesis of PCOS. Ovarian theca cells synthesize C19 androgens under the stimulus of luteinizing hormone, and androgens are then converted to estradiol by aromatase in granulosa cells [18]. Increased androgen biosynthesis is a stable phenotype of PCOS theca cells in long-term culture, indicating that increased androgen secretion is a primary characteristic of these women [19]. Considering that expression of p450c17α – the essential enzyme for the synthesis of dehydroepiandrosterone and androstendione – in primary and theca interstitial cells of the fetal primordial follicle is present at 3 months of fetal life in humans and increases through pregnancy [20], it is quite possible that androgen excess may be present during fetal life in affected women.

Adrenal hyperandrogenism is also frequent in patients with PCOS. However, the mechanisms leading to excessive androgen secretion by the adrenals remain elusive, possibly because ethical constraints preclude obtaining adrenal samples from patients with PCOS, as the adrenals are essential for life.

Molecular genetic studies targeting adrenal steroidogenesis failed to reveal mutations and polymorphisms in the genes encoding for the enzymes responsible for androgen synthesis [21–25]. However, abnormalities in peripheral cortisol metabolism may stimulate adrenal androgen secretion secondarily to mild reduction in cortisol levels. In cortisone-reductase deficiency, impaired regeneration of active cortisol from inert cortisone by 11β-hydroxysteroid dehydrogenase (11β-HSD1; HSD11B1 gene) may result in increased cortisol clearance, compensatory activation of the hypothalamic–pituitary–adrenal axis and adrenocorticotropin-mediated adrenal hyperandrogenism [26]. To act as an oxoreductase catalyzing the activation of glucocorticoids, 11β-HSD1 requires a high NADPH/NADP+ ratio in the endoplasmic reticulum, and this is provided by hexose-6-phosphate dehydrogenase (H6PDH; H6PD gene) [27]. Cortisone reductase deficiency is caused by mutations in either HSD11B1[28] or H6PD[29]. Prelimiary data suggest that polymorphisms in HSD11B1[30] and H6PD[31] influence adrenal hyperandrogenism and metabolic function in patients with PCOS.

Evidence supporting prenatal androgen excess in PCOS

The hypothesis of developmental programming in PCOS proposes that prenatal testosterone excess could program reproductive and metabolic dysfunctions during adulthood, as suggested by animal models in which prenatal exposure to androgen excess leads to biochemical and clinical features of PCOS after birth [32].

In a remarkable series of experiments in rhesus monkeys, Abbot and colleagues showed how prenatal administration of testosterone propionate recreates the PCOS phenotype in adulthood including hyperandrogenemia, increased secretion of androgens in response to recombinant human chorionic gonadotropin, oligo-ovulation and polyfollicular ovaries, and these abnormalities are accompanied by accumulation of visceral fat, insulin resistance and impaired insulin secretion, especially in animals exposed to androgens early during gestation [33].

Similar results were found in sheep and rodents, indicating that testosterone administration during pregnancy may program PCOS-like phenotypes in other species [34,35].

Familial clustering suggests an inherited basis for PCOS [7], and therefore affected female fetuses may inherit the genes related to PCOS from their parents and start producing an excessive amount of androgens in utero, programming their reproductive and metabolic function, as occurs in animal models of androgenization.

Obviously, experimental exposure to high levels of androgens during pregnancy has not been studied in humans because of ethical concerns. However, there are clinical disorders in which female fetuses develop in an androgenic environment including hyperandrogenic congenital adrenal hyperplasia and congenital adrenal virilizing tumors [36–38].

Girls with classic 21-hydroxylase deficiency are exposed to excessive androgen levels of adrenal origin during pregnancy and may present with a variable degree of virilization at birth, whereas girls with the less severe phenotype, nonclassic 21-hydroxylase deficiency, do not show any clinical signs of virilization at birth but present with a PCOS-like phenotype later in life [39]. Prenatal programming by androgen excess may contribute to insulin resistance [40] and a predominantly abdominal distribution of fat [41] in these women. The fact that masculine-type behavior, including preference for masculine toys [42] and homosexual/bisexual orientation [43], are relatively common in girls and women with 21-hydroxylase deficiency further supports exposure to excessive prenatal androgens at critical stages of brain development during pregnancy.

The possibility of a maternal contribution to fetal androgen excess is unlikely because the physiological increase in sex hormone-binding globulin and especially placental aromatization typically protects the fetus from the potential virilizing effects of maternal androgens in cases where the mother is also affected by PCOS. Hence, androgen excess in the mother does not cause virilization of the fetus unless the levels of androgens are as high as levels observed after administration of exogenous virilizing drugs, Krukemberg tumors or placental aromatase deficiency [44].

For this hypothesis to be plausible, female fetuses from women with PCOS should inherit the defects leading to androgen excess more frequently than fetuses from women without hyperandrogenism and, as a group, female newborns from women with PCOS should have increased serum levels of androgens because the fetal ovary continues secreting steroid hormones a few weeks after birth.

Instead of obtaining blood samples directly from the newborns, in most, if not all, of the studies conducted to date addressing this question, blood was sampled from the umbilical cord, possibly explaining the controversial results observed. Fetal blood reaches the placenta via the two umbilical arteries in the villi whereas placental blood reaches the fetus through a single umbilical vein. Therefore, when aiming to study androgen concentrations in newborns by cordocentesis, blood should ideally be obtained from the umbilical artery as blood of the umbilical vein actually represents blood coming from the mother, although serum androgens appear to correlate between the umbilical arteries and veins [45,46].

However, studies aiming to measure androgen excess during pregnancy have not obtained blood samples from the umbilical artery. Barry et al. compared the levels of total testosterone in the umbilical vein of babies born to mothers with PCOS with those of babies born to mothers without androgen excess, and found that serum testosterone concentrations were higher in the former, and comparable to those of male newborns [47]. On the contrary, no differences in serum androgen levels among newborns from women with and without PCOS have been found when using mixed umbilical cord blood, so there is no definite answer at present to the question of whether or not androgen excess is present during pregnancy in girls with PCOS.

Androgen excess during childhood, adolescence & adulthood

Although in most girls PCOS presents clinically after adolescence, premature pubarche (isolated growth of pubic hair in girls before 8 years of age) and premature adrenarche (premature pubarche with mildly increased adrenal androgen levels) are possibly the earliest clinical manifestations of PCOS in affected women. Almost half of the girls with premature pubarche/adrenarche develop PCOS after puberty [48]. This association is especially important in girls born small for gestational age [49,50], suggesting that intrauterine growth restriction might program the metabolic function of these girls towards a thrifty phenotype characterized by early catch-up growth and development of visceral adiposity and insulin resistance [51].

Furthermore, these girls are prone to develop obesity and metabolic derangements in association with insulin resistance and hyperinsulinemia, increased IGF-1 levels and lower IGF-binding protein 1 concentrations, all of which may be present even before puberty [52–56].

Although these early findings may be considered as evidence supporting insulin resistance as the cause of androgen excess in women with PCOS, as stated previously, these girls may have been programmed towards abdominal adiposity and insulin resistance by androgen excess during fetal life [6,33].

The fact that PCOS and related disorders usually become apparent peripubertally may be related to the fact that the growth hormone/IGF-1 axis is especially active during this period. As occurs with insulin, IGF-1 stimulates the synthesis of androgens at the ovary and the adrenals [57,58] and reduces sex hormone-binding globulin synthesis and secretion in human hepatoma cell lines [59], resulting in increased free testosterone levels. Of note, overtreatment with IGF-1 in women with insensitivity to growth hormone leads to androgen excess [60], further demonstrating the potent effects of this growth factor on androgen synthesis in vivo. Furthermore, the decline in the activity of the growth hormone/IGF-1 axis with age may be related to the well-known amelioration in androgen levels and hyperandrogenic symptoms found in certain patients with PCOS as they grow older [61].

Of note, several characteristics of normal adolescence in women, such as mild acne or menstrual irregularity soon after menarche, may resemble hyperandrogenic symptoms and might lead to an incorrect PCOS diagnosis. Therefore, the diagnosis of PCOS during adolescence should be especially strict to the extent that some authors recently proposed that a firm diagnosis of PCOS in this age range requires the presence of hyperandrogenemia, and not only hirsutism, in addition to chronic oligo-anovulation and polycystic ovarian morphology [62]. In girls presenting with some but not all of these characteristics, a definite diagnosis of PCOS should be delayed to be sure that these features persist for a few years after puberty [62]. It must be highlighted that the measurement of serum androgen levels during adolescence requires the use of appropriately accurate assays and that the normal ranges for such assays must be established from a carefully defined population of normal girls of the same age range.

The role of androgens in the pathophysiology of PCOS in adults has been described in detail elsewhere [6,8]. In addition to causing the cutaneous manifestations of the syndrome, including hirsutism, acne and alopecia, intra-ovarian androgen excess leads to anovulation and polycystic ovarian morphology and possibly contributes to abdominal adiposity and insulin resistance [6], metabolic disturbances, increased cardiovascular risk markers [63] and subclinical cardiovascular disease such as increased carotid intima-media thickness [64].

As a syndrome, PCOS is quite heterogeneous, and there may be a continuous spectrum with regards to the relative contribution of androgen excess and contributing factors such as abdominal adiposity and insulin resistance [6]. In one extreme of the spectrum, some women have severe enough androgen excess to result in the PCOS phenotype without the need of any other triggering factor (Figure 2). In the other extreme of the spectrum, a very mild androgen excess in some women results in the PCOS phenotype only when a triggering factor, such as severe abdominal adiposity, is present (Figure 2). However, it must be highlighted that all women with PCOS share a primary defect in androgen secretion, because even massive obesity may not lead to PCOS if such a defect is not present [65]. Therefore, targeting androgen excess for the long-term management of PCOS may prove useful not only for hyperandrogenic symptoms [66,67], but also for the amelioration of reproductive, metabolic and cardiovascular disturbances [67–72] associated with the disorder.

Androgen excess after menopause in PCOS

Menopause involves major hormonal changes including stable or slightly raised androgen levels and a fall in circulating E2 accompanied by an increase in gonadotropin levels [73]. Both the ovaries and the adrenals contribute to the androgen milieu in healthy women after menopause. The postmenopausal ovary is hormonally active and is responsible for almost half of circulating testosterone and approximately 30% of androstendione, with the remaining steroids originating from the adrenals and from peripheral conversion of androgen precursors in adipose tissue [74,75]. The major adrenal androgen, dehydroepiandrosterone sulfate, declines with age with no obvious relationship to menopause.

In healthy women, serum total testosterone concentrations remain unchanged [73,76] or show a small decline after menopause [77], but while sex hormone-binding globulin concentrations decrease, free testosterone levels increase after menopause [73].

As stated above, PCOS features may ameliorate with age, with some patients presenting with regular cycles and spontaneous amelioration of hirsutism as they grow older. Furthermore, free and total testosterone levels in 42–47-year-old patients with PCOS are reduced by half compared with 20–42-year-old women with PCOS [61], further supporting the concept that an amelioration of hyperandrogenism may occur before menopause in PCOS.

However, postmenopausal women with PCOS still have increased serum total and free testosterone, androstendione, dehydroepiandrosterone sulfate, progesterone and 17-hydroxyprogesterone concentrations, compared with postmenopausal control women [78], suggesting that the negative consequences of androgen excess on metabolic and cardiovascular comorbidities may persist after menopause.

Androgens, metabolic dysfunction & cardiovascular risk

We hypothesize that androgen excess in women with PCOS is a major cause of the metabolic dysfunction and increased cardiovascular risk present in these women, and that these associations are mediated by androgens facilitating a predominantly visceral distribution of body fat in affected women [6].

Visceral (omental) adipose tissue samples from obese women with PCOS show markedly different gene expression and proteomic profiles compared with similarly obese women without any evidence of androgen excess [79–81]. These differences involve biological pathways related to insulin and Wnt signaling, oxidative stress, inflammation, immune function and lipid metabolism, as well as other genes previously related to PCOS or to the metabolic syndrome. Furthermore, many of the genes showing dysregulated expression in the visceral fat of patients with PCOS showed putative androgen response elements in their promoter regions, supporting the theory that the androgen excess of these women could have played a role in their dysregulation.

The metabolic dysfunction and cardiovascular risk of PCOS is, without any doubt, amplified by obesity [82]. However, PCOS is also associated with abdominal adiposity and with several markers of metabolic dysfunction and cardiovascular risk even in the absence of obesity. In our experience, the decrease in the serum levels of the insulin-sensitizing adipokine adiponectin is characteristic of lean, overweight and obese women with PCOS [83], and an increase in carotid intima-media thickness, an early marker of subclinical atherosclerotic disease, is present in PCOS patients irrespective of their weight [64,84]. Some of these undesirable findings, such as increased circulating inflammatory markers [85,86], a non-dipper pattern in the physiological nocturnal decrease in blood pressure [87] or increased body iron stores [88], are associated with PCOS, but the association is especially strong when obesity is also present.

Mounting evidence suggests that androgen excess may be causally involved in abdominal fat accumulation and dysfunction in women. Administration of testosterone to female-to-male transsexuals increases their visceral fat and decreases their subcutaneous fat, with corresponding worsening in their lipid profiles [89,90]. Among patients with PCOS, metabolic dysfunction and cardiovascular risk markers are more prevalent in hyperandrogenic-oligo-ovulatory phenotypes compared with less severe phenotypes [16]. Amelioration of hyperandrogenism might improve the abdominal adiposity characteristic of PCOS and associated metabolic disorders: when administered in conjunction with a low-calorie diet to overweight and obese PCOS adults, the pure antiandrogen flutamide decreased visceral fat and reduced total and low-density lipoprotein cholesterol concentrations, in addition to improving hirsutism and hyperandrogenemia [91,92]; furthermore, administration of an antiandrogenic oral contraceptive pill to patients with PCOS improves the decrease in circulating adiponectin mentioned above [70] and; finally, amelioration of androgen excess by laparoscopic ovarian electrocautery improves insulin resistance in patients with PCOS [93,94].

Therapeutic implications of androgen excess in PCOS

All the steps in the vicious circle consisting of androgen excess, abdominal adiposity, insulin resistance with compensatory hyperinsulinism and further androgen secretion, increase the risk for metabolic and cardiovascular complications in PCOS women. However, interventions targeting any of these individual steps also ameliorate the other components of the pathophysiological vicious circle underlying PCOS, finally leading to a reduction of these risks.

As we have described earlier in this article, amelioration of hyperandrogenism, – that is, using an antiandrogen or an oral contraceptive pill – improves abdominal adiposity and insulin resistance in patients with PCOS [67,70,91,92,95]. Of note, the metabolic and cardiovascular risk profile of women with PCOS is not worsened with the use of modern oral contraceptive pills [67–72].

Conversely, amelioration of abdominal adiposity and/or insulin resistance also improves androgen excess. A recent Cochrane systematic review concluded that lifestyle modification in patients with PCOS improves body composition, hyperandrogenism and insulin resistance in women with PCOS [96]. The importance of weight loss for obese patients with PCOS is exemplified by the fact that the PCOS associated with morbid obesity may resolve after the marked and sustained weight loss usually attained after bariatric surgery [65]. Moreover, insulin sensitizers such as metformin not only ameliorate insulin resistance and its metabolic comorbidities in patients with PCOS, but also reduce serum androgen levels [66].

In summary, androgen excess is associated with several classic and nonclassic cardiovascular risk factors, and therapeutic interventions targeting androgen excess are effective not only for improving clinical hyperandrogenism, but also for ameliorating the undesirable cardiovascular risk profile of women with PCOS.

Expert commentary

PCOS is a predominantly hyperandrogenic syndrome and the presence of androgen excess, clinical and/or biochemical, is a requisite for its diagnosis according to the latest criteria [5,8]. Ovarian hyperandrogenism, the primary feature of PCOS that has been demonstrated at the molecular level [19], might start even during fetal life in affected women, programming their reproductive and metabolic function towards PCOS, abdominal adiposity and its consequences [33]. Manifestations of androgen excess affect women with PCOS from puberty to menopause, their consequences extending after their reproductive life [78]. Therefore, diagnostic and therapeutic strategies for PCOS must always consider the central role that androgens play in the pathophysiology of the disorder, with the aim of ameliorating androgen excess and its long-term consequences.

Five-year view

Measurement of serum androgens in clinical practice may not correspond to the role that androgen plays in the pathogenesis of PCOS because of the relative insensitivity and poor performance at low concentrations of many of the immunometric assays currently in use for the determination of testosterone and other androgens. The ongoing efforts towards the development of more sensitive and accurate assays for serum androgens [97] will facilitate the understanding of PCOS as a mainly hyperandrogenic syndrome and will boost research on the epidemiology, pathogenesis, diagnosis and management of this prevalent disorder.

Key issues

• • Increased androgen secretion by ovarian theca cells is a primary defect in polycystic ovary syndrome (PCOS).

• • Androgen excess favors the development of abdominal adiposity, insulin resistance, compensatory hyperinsulinism and further androgen excess in women with PCOS, in a vicious circle that predisposes these women to metabolic dysfunction and cardiovascular risk.

• • Androgen excess might start during fetal life in affected women, becomes clinically apparent at puberty and does not end with menopause.

• • Increased androgens are responsible for the cutaneous manifestations of PCOS, and intraovarian androgen excess leads to ovulatory dysfunction and polycystic ovarian morphology.

• • In some PCOS cases, a mild excess in androgen secretion only becomes clinically apparent when associated with a triggering factor such as severe abdominal adiposity or insulin resistance.

• • At present, the diagnosis of PCOS requires the presence of clinical and/or biochemical hyperandrogenism, which should be accompanied by ovulatory dysfunction and/or polycystic ovarian morphology and exclusion of secondary etiologies.

• • Because of the vicious circle described above, all therapeutic strategies currently in use for PCOS, including lifestyle modification, oral contraceptives, antiandrogens and insulin sensitizers, may ameliorate androgen excess and their consequences.

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Androgens and polycystic ovary syndrome

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. Your patient is a 27-year-old woman who complains of the development of coarse hairs on her chin and oligomenorrhea for the last several years. Her body mass index is 33 kg/m².

You are concerned that this patient may have polycystic ovary syndrome (PCOS). What should you consider regarding this patient’s history, which would support a diagnosis of PCOS?

• □ A Almost half of girls with premature pubarche/adrenarche develop PCOS after puberty

• □ B Maternal androgen excess promotes most cases of PCOS in their offspring

• □ C There is no apparent familial clustering of cases of PCOS

• □ D A history of being small for gestational age as an infant is protective against PCOS

2. All of the following variables should be used to make the diagnosis of PCOS in this patient EXCEPT:

• □ A Obesity

• □ B Hirsutism

• □ C Oligomenorrhea

• □ D The presence of polycystic ovaries on ultrasound

3. The patient is diagnosed with PCOS. What should you consider regarding treatment options for her now?

• □ A Oral contraceptive pills can worsen insulin resistance

• □ B Antiandrogen treatment can reduce abdominal adiposity

• □ C Lifestyle modification will have no effect on hyperandrogenism

• □ D Metformin can improve insulin resistance but has no effect on serum androgen levels

4. The patient is treated successfully and continues to follow up with you over the years. As she approaches menopause, she has questions about what will happen to her PCOS and hyperandrogenism. What can you tell her?

• □ A Her serum total testosterone levels will decline significantly after menopause

• □ B Her serum free testosterone levels will increase after menopause

• □ C Serum androgen levels remain elevated to similar levels regardless of age among women with PCOS

• □ D After menopause, her serum androgen levels should fall below those of a woman of the same age without PCOS