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Genetic, Hormonal and Metabolic Aspects of PCOS: an Update V

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Genetic, Hormonal and Metabolic Aspects of PCOS: an Update V De Leo et al. Reproductive Biology and Endocrinology (2016) 14:38 DOI 10.1186/s12958-016-0173-x REVIEW Open Access Genetic, hormonal and metabolic aspects of PCOS: an update V. De Leo*, M. C. Musacchio, V. Cappelli, M. G. Massaro, G. Morgante and F. Petraglia Abstract Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting 5–10 % of women of reproductive age. It generally manifests with oligo/anovulatory cycles, hirsutism and polycystic ovaries, together with a considerable prevalence of insulin resistance. Although the aetiology of the syndrome is not completely understood yet, PCOS is considered a multifactorial disorder with various genetic, endocrine and environmental abnormalities. Moreover, PCOS patients have a higher risk of metabolic and cardiovascular diseases and their related morbidity, if compared to the general population. Keywords: PCOS, Genetic, Insulin-resistance, Hyperandrogenism, Infertility, Metformin, Oral contraceptives, Myo-inositol Background genetically predisposed subjects, it manifests clinically at Definition and diagnostic criteria puberty, continues during the reproductive years. It can Polycystic ovary syndrome (PCOS) is the most common also expose patients to increased risk of cardiovascular endocrine disorder in women and major cause of an- disease, hypertension, diabetes and other metabolic com- ovulatory infertility. PCOS patients can present a wide plications, especially after menopause [4]. During the range of signs and symptoms, which make difficult the fertile period it may cause anovulatory infertility and precise grading of the condition. Diagnosis of PCOS is could be associated with increased prevalence of gesta- currently based on the criteria of the ESRHE/ASRM tional complications, such as miscarriage, gestational Rotterdam consensus meeting in 2003 [1], which broad- diabetes and preeclampsia [5]. Early diagnosis is there- ened the previous NIH classification of 1990 [2]. It based fore crucial by enabling close follow-up and in an at- on at least two of the following features: oligo- tempt to reduce the risk of such complications. anovulation, hyperandrogenism and polycystic ovaries by It is now widely recognised that insulin resistance, ultrasound [1]. In 2006, the Androgen Excess Society manifesting above all in obese or overweight women, (AES) set up a committee of experts to review all the but often also in lean PCOS women, is one of the key to data published on PCOS for the purpose of simplifying this complex disorder. It determines hyperandrogenism diagnosis [3]. The AES criteria require clinical and/ by acting synergically with luteinising hormone (LH) on or biochemical hyperandrogenism simultaneously ovarian steroidogenic enzymes and on sex hormone- with oligo/anovulation and ultrasonographic evidence binding globulin (SHBG) production by the liver [5]. of polycystic ovaries. Diagnostic workup includes hormonal evaluation of Although the aetiology of PCOS is not completely androgen levels, clinical evaluation of hirsutism trough understood yet, PCOS is considered a multifactorial Ferriman-Gallwey score and ultrasonographic examin- disorder with various genetic, metabolic, endocrine and ation of the number of antral follicles and ovarian vol- environmental abnormalities [4] ume. Insuline resistance should be evaluated by HOMA There is increasing evidence suggesting that PCOS INDEX (product of fasting plasma insulin [mU/L] and affects the whole life of a woman, can begin in utero in glucose [mmol/L] concentrations divided by 22.5). Fu- ture diagnostic approaches could be ultrasonographic * Correspondence: [email protected] 3D evaluation of follicles and is under discussion the Department Molecular Medicine and Development, University of Siena, role of anti-mullerian hormone (AMH) [6, 7]. Policlinico Le Scotte, Viale Bracci, 53100 Siena, Italy © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. De Leo et al. Reproductive Biology and Endocrinology (2016) 14:38 Page 2 of 17 Etio-pathogenesis and pathophysiology: role of genetic, critical mid-gestational age for target organ differenti- environmental and endocrine factors ation [9], studies at the time of birth, are likely to be too Genetic and endocrine factors, together with environ- late to detect any remaining hormonal differences [18, mental influences. In the research of etiopathogenesis of 19]. The mid-gestational T excess in human female foe- the syndrome and in the subsequent pathophysiological tuses can be accompanied by gestational hyperglycaemia expression play a role genetic and endocrine as well as and foetal hyperinsulinemia. Interestingly, elevated mid- environmental factors. The most interesting hypothesis gestation maternal T levels predict high AMH levels in was proposed by Franks et al. [4], who defined PCOS as adolescent daughters [20]. Since elevated AMH repre- a genetically determined ovarian pathology characterised sents a characteristic of adolescents and women with by over-production of androgens and manifesting het- PCOS [21] and daughters of PCOS women [22, 23], such erogeneously according to the interaction of this genetic associations might suggest a cross-generational relation- “predisposition” with other genetic and environmental ship between the degree of maternal hyperandrogenism factors. This hypothesis is persistent by the finding of and the development of PCOS in their daughters. polycystic ovaries in pre-pubertal girls [4, 8]. Studies in Complete manifestation of the syndrome occurs at rhesus monkeys have demonstrated that exposure of foe- adolescence, when the hypothalamus-pituitary-ovarian tuses to high levels of androgens during intrauterine life access is activated. At this time, metabolic changes lead- determines the onset of clinical manifestations of PCOS ing to modifications in the distribution of body fat also during adolescence. Studies in sheep have shown that an occur. In particular, at puberty there is a physiological excessive androgen exposure during foetal life influences increase in insulin levels, determining on one hand a re- early ovarian follicular activity and it may explain the duction in SHBG levels with amplification of the effects typical altered folliculogenesis shown in PCOS [4, 8]. of circulating androgens, and on the other hand, direct The aforementioned observations may suggest that ex- stimulation of ovarian steroidogenesis [24]. In women posure of the foetal hypothalamus-pituitary-ovarian axis with PCOS, the physiologic hyperinsulinemia of adoles- to androgen excess may trigger a series of events that cence may be a triggering factor for the development of could determine PCOS onset of at puberty. hyperandrogenism and anovulation. Girls predisposed to The source of intra-uterine androgens excess is un- insulin-resistance and overweight are even more at risk likely to be maternal, since the foetus is protected by of developing early adrenarche and subsequent PCOS at placental aromatase activity and by high maternal SHBG adolescence [24] (Fig. 1). concentrations. Daughters of women with PCOS evaluated during The expression of aromatase in the placenta of PCOS early childhood (age 4–8 years) and early puberty (age women may be diminished [9] and this could potentially 9–13 years) have exaggerated adrenarche compared with be unable to prevent foetal testosterone (T) excess in daughters of non-PCOS women of similar pubertal stage PCOS pregnancies [10]. It has been seen that the preva- and body mass index (BMI) [25]. This is consistent with lence of decreased aromatase required to carry out T a role of obesity-related insulin- resistance in causing excess in female fetuses was reported to be extremely hyperandrogenemia in these girls through an effect of rare [11]. On the other hand, recent studies on hyper- insulin on adrenal and ovarian steroidogenesis [26], tensive preeclamptic pregnancies have demonstrated a manifesting as early adrenarche [27] and subsequent significant reduction in placental ability to synthesize PCOS [28]. Such hyperandrogenemia appears to modu- oestrogens, indicating a gestational impairment of T late gonadotropin levels, as has been demonstrated in aromatization that is more common than was previously obese peri-pubertal girls who were found to have in- considered [12, 13]. creased LH frequency but low LH amplitude, and dimin- Thesourceofandrogensexcessismorelikelyto ished overnight LH pulse amplitude compared with be the foetal ovary, which is normally quiescent, but normal-weight girls [29]. These changes may reflect ini- it could produce an excess of androgens in response tial effect of obesity on LH pulses [30]. Subsequently, to maternal hCG in subjects genetically predisposed hyperandrogenemia reduces the inhibition of GnRH to PCOS. pulse frequency by progesterone, causing rapid LH pulse In newborn daughters of PCOS women, elevated T secretion and further increase in ovarian androgen pro- levels have been observed in the umbilical venous blood duction [30–32].
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