Alessandro D. Genazzani1 , Alessia Prati1, Giulia Despini1, Giulia Marini1 and Federica Ricchieri1
(1)
Department of Obstetrics and Gynecology, Gynecological Endocrinology Center, University of Modena and Reggio Emilia, Modena, Italy
Alessandro D. Genazzani
Email: algen@unimo.it
7.1 Introduction
Polycystic ovary syndrome occurs in as many as 8–10 % of women of reproductive age [1], with onset manifesting as early as puberty [2]. From the very beginning, diagnostic criteria proposed by the NIH for PCOS were the presence of hyperandrogenism and chronic anovulation with clear exclusion of related ovulatory or other androgen excess disorders (i.e., hyperprolactinemia, thyroid diseases, androgen-secreting tumors, and adrenal dysfunction/hyperplasia) [3]. These criteria did not include the presence of polycystic ovaries at ultrasound examination because it was observed that polycystic ovaries could also be present in healthy eumenorrheic women [4]. A few years later, during the European Society of Human reproduction and Embryology (ESHRE)/American Society for reproductive Medicine (ASRM) conference, the diagnostic criteria were expanded and PCOS was considered as present when at least two of three features were diagnosed: oligo or anovulation, clinical/biochemical hyperandrogenism, and polycystic ovaries as assessed by ultrasound examination [4]. This evolution was relevant because it permitted the inclusion of women with PCOS who were excluded by previous NIH criteria [3]: those with polycystic ovaries affected by hyperandrogenism and ovulatory cycles, or chronic anovulation and normal androgen levels.
More recently, the Androgen Excess and PCOS Society indicated that PCOS should always be considered an androgen excess disorder and concluded that PCOS was, above all, a disorder of androgen biosynthesis, utilization, and/or metabolism in women [5].
Despite the diagnostic criteria, PCOS is still an unclear disease in terms of pathogenesis, both genetic and environmental factors may contribute to the onset of PCOS features [6, 7]. On such genetic predisposition, environmental factors may play a key role, such as peculiar lifestyle, types of food, living conditions, and also the impact during the intrauterine growth [7].
7.2 Endocrine Profile of PCOS Patients
Polycystic ovary syndrome is characterized by increased ovarian and adrenal androgens, increased luteinizing hormone (LH) levels, high estrogen levels (especially estrone) due to extraglandular conversion from androgens, lower levels of sex hormone-binding globulin (SHBG), and higher levels of insulin, the latter often in presence of overweight or obesity. Hyperandrogenism is a key feature of the syndrome, although it is not constant [8]. It is mainly of ovarian origin with an adrenal contribution, since a certain percentage of PCOS patients might show a mild steroidogenetic defect in adrenal glands (such as for 21-hydroxylase) or just a higher adrenal hyperactivation due to stress [9]. Androstenedione and testosterone are the best markers of ovarian androgen secretion, whereas dehydroepiandrosterone sulfate (DHEAS) is the best marker of adrenal secretion. Great part of testosterone is derived from peripheral conversion of androstenedione and from direct ovarian production. Dysregulation of cytochrome p450c17, the androgen-forming enzyme in both the adrenal glands and the ovaries, is the central pathogenic mechanism underlying hyperandrogenism in PCOS [10]. Additionally, estrone plasma levels, a weak estrogen with biological activity 100 times less than estradiol, are increased as a result of peripheral conversion of androstenedione by aromatase activity. All this results in a chronic hyperestrogenic state with the reversal of the estrone:estradiol ratio that might predispose to endometrial proliferation and to a possible increased risk for endometrial cancer [11].
Normally, <3 % of testosterone circulates as unbound in the serum. In fact, most circulating androgens are bound to SHBG, thus being biologically inactive. The presence of hyperandrogenism reduces the hepatic synthesis of SHBG and lead to a relative excess of free circulating androgens. In PCOS, hirsutism usually occurs with decreased SHBG levels and obesity [12, 13].
A great percentage of PCOS patients show overweight up to severe obesity, and typically any excess of weight can induce a reduction of peripheral tissues sensitivity to insulin, thus inducing the compensatory hyperinsulinism. It is relevant to say that hyperinsulinemia may be central to the pathogenesis of the syndrome in many cases, because it can induce higher ovarian androgen production and anovulation [14, 15], sustained also by the abnormal LH secretion, with a higher frequency of menstrual abnormalities than in normoinsulinemic women with PCOS [16]. Insulin resistance and compensatory hyperinsulinemia are metabolic disturbances easily observable in at least 45–65 % of PCOS patients, and frequently appear to be related to excessive serine phosphorylation of the insulin receptor [10, 17].
7.3 Metabolism and PCOS
In PCOS patients, there is an increased risk of developing type 2 diabetes and coronary heart disease (CHD) [18, 19]. Such risk has also been demonstrated to be higher in postmenopausal women, previously demonstrated to be PCOS during fertile life [20]. PCOS has been reported to have an increased risk of metabolic syndrome (MS), which refers to a clustering within the same individual of hyperinsulinemia, mild-to-severe glucose intolerance, dislipidemia, and hypertension, and an increased risk for cardiovascular disease (CVD) and diabetes [21, 22].
In 2006, the International Diabetes Federation defined the features of the MS, and defined central obesity as present when the waist circumference is above 80 cm; in European women, this was considered as a necessary prerequisite risk factor for the diagnosis of MS [23]. However, it is of great relevance to point out that although the MS has been identified for more than 80 years, only in these last years has controversy about its definition emerged [21].
The risk factors for MS are: waist circumference is over 80 cm, elevated triglycerides (≥1.7 mmol/l), reduced HDL (<1.29 mmol/l in women), specific treatment for lipid abnormalities, elevated blood pressure (systolic ≥130 mmHb or diastolic ≥85 mmHg), specific treatment or precedent diagnosis of hypertension, fasting plasma glucose at least 5.6 mmol/l, and previous diagnosis of type 2 diabetes mellitus.
The prevalence of MS in polycystic women is approximately 40–45 % [24], and the main predictor factors are the elevated free serum testosterone and reduced serum SHBG level [25]. The association of MS with PCOS appears to be particularly strong in those PCOS women who are young (<30 years) and overweight or obese (BMI >27 kg/m2) [26].
Women with PCOS have lower HDL levels, higher LDL:HDL ratios, and higher triglyceride levels than healthy eumenorrheic women [27]. All these are inductors of subclinical atherosclerosis as demonstrated by the increased thickness of the carotid intima media and by the higher endothelial dysfunction observed in PCOS patients [28], probably related to the insulin resistance and/or to the higher free testosterone plasma level [29, 30].
Indeed, several studies reported an increased risk factor profile for CVD in women with PCOS [31]. It is of great relevance the fact that women with PCOS have an increased risk for impaired glucose tolerance and type 2 diabetes mellitus [32, 33], with a tendency to an early development of glucose intolerance state [34]. In fact, the decrease of insulin sensitivity in PCOS women appears to be quite similar to that observed in patients with type 2 diabetes mellitus and to be relatively independent from obesity, fat distribution, and lean body mass [35]. On the other hand, there is strong evidence that obesity, particularly the abdominal phenotype, represents an important independent risk factor for glucose intolerance in PCOS women [31].
7.4 Lifestyle in PCOS Patients
Lifestyle modification is very important in the treatment for PCOS, as weight loss and exercise have been shown to lead to improved fertility and lowering of androgen levels. It also reduces the long-term risk of diabetes, heart disease, and possibly endometrial cancer.
Useful changes include the following: dietary modification (reduction in calories by limiting daily intake to 1,400 kcal, avoid sugary drinks, avoid snacking between meals, and have more low glycaemic index fruits and vegetables), regular moderate exercise (at least 30 min a day at the very least), stopping smoking, and moderate alcohol/caffeine intake.
Some studies [36, 37] have shown that lifestyle changes (in this case, intensive exercise with a goal of ≥150 min/week of activity) resulting in weight loss reduced the risk of type 2 diabetes [38]. The same studies found lifestyle changes to be superior to metformin administration. Thus, all women with PCOS should be encouraged to follow a healthy diet and to engage in regular exercise. Their chance to achieve a pregnancy will improve and the risks during pregnancy will be reduced. A healthier lifestyle will also reduce their long-term risks for diabetes, hypertension, dyslipidemia, and CVD. It is important for all primary care providers to identify patients who may have PCOS. These patients need to undergo the appropriate screening tests and should be counseled about diet and exercise. Pharmacologic intervention could be combined with this approach as appropriate, but the above-mentioned studies suggest that lifestyle modification is the first-line treatment.
7.5 Rationale of Metformin Use in PCOS Women
As additional therapeutical factor to counteract insulin resistance is the insulin sensitizers administration. The logic for the use of insulin sensitizer drugs, such as metformin, to treat patients with PCOS is the fact that 45–65 % of PCOS patients have been demonstrated to have insulin resistance and a compensatory hyperinsulinemia that negatively affect ovarian function in terms of steroid biosynthesis and follicular recruitment and maturation [6, 39]. Obviously, when insulin resistance is present independently from obesity, whatever the weight gain that might occur, it certainly exaggerates insulin resistance and more severely alters the glucose metabolism and, later on, the hormonal profile.
Excess insulin increases androgen concentrations blocking follicular maturation and increasing cytochrome P450c17a activity, a key enzyme in the synthesis of both ovarian and adrenal androgens [6, 34]. This situation typically increases 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone plasma levels. The excess of intraovarian androgens negatively modulates follicular function and ovarian activity, thus inducing the typical stromal hypertrophy and maintaining ovarian atresia and anovulation [6, 40].
When abnormal insulin sensitivity is diagnosed, the use of metformin might be suggested [6, 41]. Metformin reduces hepatic glucose production from 9 to 30 % and on peripheral tissues, such as muscle cells and adipocytes, and acts by increasing glucose uptake through the glucose transport system.
Metformin positively acts on hormonal PCOS abnormalities through a direct and/or indirect action on steroidogenesis [6]. In fact, the recovery of normal ovulatory function is probably due to the direct modulation of metformin on the ovarian tissues and to the metformin-induced normalization of the ovarian steroidogenesis (lowering androgen production), thus determining the normal feedback on pituitary, lowering LH secretion, and LH pulse characteristics [42, 43]. Metformin improves steroidogenesis not only at the ovarian but also at the adrenal level, since insulin plays specific modulatory roles on these two distinct endocrine glands that have the same enzymatic pathways [44]. In fact, it has been demonstrated that metformin administration ameliorates adrenal enzyme activities in PCOS patients [45].
A recent meta-analysis of the published studies demonstrated that the use of insulin sensitizers do not reduce hyperandrogenism better than oral contraceptives [46], but as recently reported, the typology of PCOS to be treated is of great relevance, since only when insulin sensitivity is abnormal metformin shows a greater efficacy on all the PCOS features including hyperandrogenism [43]. Obviously, it cannot be excluded that other metabolically active hormones (e.g., leptin, resistin, adiponectin, and ghrelin) are positively activated by metformin administration and thus participate in the improvement of the reproductive function at the hypothalamus–pituitary–ovarian level [47]. However, we have to remember that metformin effectiveness on reproductive and on metabolic parameters is mainly exerted in association with a reduction of circulating insulin levels, thus supporting the hypothesis that a high insulin level is one of the main effectors/modulators of the clinical and endocrine dysfunctions of PCOS [6, 12].
7.6 Inositol Integrative Administration
In the last decade, a higher attention has been given to the role of inositolphosphoglycan (IPG) mediators of insulin action [48–50] and growing evidences suggest that a deficiency of D-chiro-inositol (DCI) containing IPG might be at the basis of insulin resistance, frequent in PCOS patients. Recent papers reported that PCOS patients have abnormally high urinary clearance of DCI [51] and that metformin administration in obese PCOS patients improves the release of DCI–IPG mediator [52].
Recently, more clinical emphasis has been given to the use of inositol, both as Myo-inositol (MYO) [50, 53] or DCI [54], keeping in mind that a precise relationship exists between MYO and DCI. In fact, DCI is synthesized by an epimerase that converts MYO into DCI and, depending on the specific needs of the two molecules, each tissue has a typical conversion rate [55]. Considering that ovaries never become insulin resistant [56] and being MYO administration able to induce regular menses in both lean and obese hyperinsulinemic PCOS patients [50], a possible modulatory role of MYO on the insulin-mediated endocrine effects has been hypothesized [50]. In fact, recent studies suggest that some abnormal action of insulin might be dependent from IPG mediators of insulin action and suggest that a deficiency in a specific DCI-containing IPG may underlie insulin resistance, similarly to type 2 diabetes. DCI administration has been demonstrated to reduce insulin resistance both in lean and obese PCOS patients improving ovarian function and decreasing hyperandrogenism [49, 57]. Such studies have suggested the putative presence of a defect in the insulin-signaling pathway in which DCI-PG is the mediator of insulin action, thus contributing to the pathophysiology of the insulin resistance of PCOS [51]. Besides DCI, MYO has been reported to be greatly correlated to ovarian function [58] and oocyte quality in patients undergoing IVF procedures, independently from circulating plasma levels [59]. Such data support a specific role also for MYO on gonadotropin-induced ovarian function [53] though not confirmed by others [51].
Indeed, MYO administration has been demonstrated to modulate insulin sensitivity in overweight PCOS patients improving all hormonal parameters and improving insulin sensitivity [50, 53]. The daily dosage was 2 g, taken during the morning. Such treatment has been reported to be effective in hyperinsulinemic obese PCOS with fasting insulin levels above 12 mU/ml [53]. Such insulin level seemed to be a putative cut off that suggests when MYO administration might give higher chances of success not only on hormonal parameters but also on hyperinsulinemia and insulin sensitivity [53].
In conclusion, PCOS is a quite complex syndrome and it cannot be considered as “an easy to treat” disease. PCOS needs a precise clinical screening that might give suggestions on what hormonal and metabolic parameters need to be treated. Recent data clearly indicate that hormonal and metabolic aspects are tightly related and the therapeutical approach for PCOS patients need to consider these two aspects together. Metformin as well as inositol integrative administration might be easily used to solve the metabolic aspects of PCOS impairments. Lifestyle as well as hormonal treatments has to be considered relevant therapeutic tools to be used together with insulin sensitizer drugs.
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