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VOLUME 7 2 . No. 4 . AUGUST 2 0 VOLUME 72 . No.4 . AUGUST 2020 © 2020 EDIZIONI MINERVA MEDICA Minerva Pediatrica 2020 August;72(4):288-311 Online version at http://www.minervamedica.it DOI: 10.23736/S0026-4946.20.05861-2 REVIEW MANAGEMENT OF THE MAIN ENDOCRINE AND DIABETIC DISORDERS IN CHILDREN Current treatment for polycystic ovary syndrome: focus on adolescence Maria E. STREET 1 *, Francesca CIRILLO 1, Cecilia CATELLANI 1, 2, Marco DAURIZ 3, 4, Pietro LAZZERONI 1, Chiara SARTORI 1, Paolo MOGHETTI 4 1Division of Pediatric Endocrinology and Diabetology, Department of Mother and Child, Azienda USL – IRCCS di Reggio Emilia, Reggio Emilia, Italy; 2Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy; 3Section of Endocrinology and Diabetes, Department of Internal Medicine, Bolzano General Hospital, Bolzano, Italy; 4Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy *Corresponding author: Maria E. Street, Division of Pediatric Endocrinology and Diabetology, Department of Mother and Child, Azienda USL – IRCCS di Reggio Emilia, Viale Risorgimento 80, 42123 Reggio Emilia, Italy. E-mail: [email protected] ABSTRACT Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder in women and it is associated with an in- creased rate of infertility. Its etiology remains largely unknown, although both genetic and environmental factors play a role. PCOS is characterized by insulin resistance, metabolic disorders and low-grade chronic inflammation. To date, the treatment of PCOS is mainly symptomatic and aimed at reducing clinical signs of hyperandrogenism (hirsutism and acne), at improving menstrual cyclicity and at favoring ovulation. Since PCOS pathophysiology is still largely unknown, the therapeutic interventions currently in place are rarely cause-specific. In such cases, the therapy is mainly directed at improving hormonal and metabolic dysregulations typical of this condition. Diet and exercise represent the main envi- ronmental factors influencing PCOS. Thus, therapeutic lifestyle changes represent the first line of intervention, which, in combination with oral contraceptives, represent the customary treatment. Insulin resistance is becoming an increasingly studied target for therapy, most evidence stemming from the time-honored metformin use. Relatively novel strategies also include the use of thiazolidinediones and GLP1-receptor agonists. In recent years, a nutraceutical approach has been added to the therapeutic toolkit targeting insulin resistance. Indeed, emerging data support inositol and alpha-lipoic acid as alternative compounds, alone or in combination with the aforementioned strategies, with favorable effects on ovulation, insulin resistance and inflammation. Nevertheless, additional studies are required in adolescents, in order to assess the effectiveness of diet supplements in preventing negative impacts of PCOS on fertility in adult age. This review focuses on the main therapeutic options for PCOS to date. (Cite this article as: Street ME, Cirillo F, Catellani C, Dauriz M, Lazzeroni P, Sartori C, et al. Current treatment for polycystic ovary syndrome: focus on adolescence. Minerva Pediatr 2020;72:288-311. DOI: 10.23736/S0026-4946.20.05861-2) KEY WORDS: Polycystic ovary syndrome; Oral contraceptives; Metformin; Inositol; D-chiro-inositol-galactosamine; In- sulin resistance. olycystic ovary syndrome (PCOS) is a het- tic criteria for adult women, established in a Perogeneous clinical condition, which is con- joint consensus workshop of the European Soci- sidered the most frequent endocrine disorder in ety for Human Reproduction and Embryology women of reproductive age. Its etiology remains (ESHRE) and the American Society for Repro- unknown, although there is evidence that both ductive Medicine (ASRM), held in Rotterdam in genetic and environmental factors may contrib- 2003, PCOS may be diagnosed by the presence ute to its origin.1 According to current diagnos- of at least two of the following three clinical fea- 288 MINERVA PEDIATRICA August 2020 CURRENT TREATMENT FOR PCOS STREET tures: clinical and/or biochemical hyperan- genemic versus normoandrogenemic subjects, drogenism, chronic oligo-anovulation, and the as many as 30% of women with PCOS.9 Assess- micro-polycystic morphology of the ovary ment of ovarian morphology is another prob- (PCOm).2 Nevertheless, no alterations are spe- lematic issue. In particular, it has been argued cific to PCOS, and other disorders that can po- that the cut-off value for distinguishing an ab- tentially cause these abnormalities, such as late- normal follicle count should be adapted accord- onset congenital adrenal hyperplasia, hyperpro- ing to available probes, from the traditional fig- lactinemia or androgen-secreting tumors, must ure of 12, indicated by the Rotterdam workshop, be preliminary excluded. Therefore, PCOS is an up to 25 when using modern technology provid- exclusion diagnosis. It has been estimated that ing greater resolution, with a transducer fre- PCOS, as diagnosed by the Rotterdam criteria, quency ≥8 MHz.10 To overcome these difficul- may occur in about 10% of women of reproduc- ties, measurement of serum Anti-Müllerian hor- tive age,3 but this figure could be even higher.4, 5 mone (AMH), which is directly associated with Indeed, available epidemiologic data are limited follicle count and is increased in many women and prevalence estimates may be influenced not with PCOS, has been proposed as a potential al- only by the diagnostic criteria but also by the ternative to assess ovarian morphology on ultra- methods used for assessing these aspects as well sound.11 However, this assay still needs adequate as by the ethnic characteristics of the population standardization. Diagnostic difficulties are even investigated. In particular, hirsutism, which is more relevant in adolescents, due to the physio- the more frequent and specific clinical feature of logical presence in these subjects of features that hyperandrogenism, is strongly affected by con- mirror some clinical aspects of PCOS. In par- stitutional and ethnic factors. In this regard, the ticular, many girls exhibit a condition of tran- cut-off value for diagnosing excessive body hair sient anovulation. It has been reported that more growth when using the usually adopted method, than 80% of cycles are anovulatory during the i.e. the modified Ferriman-Gallwey score, is first year after menarche, and 25% remain dys- generally 8 for Caucasian, Middle-Eastern or functional in the sixth year.12 PCOm as well may Afro-American women, but it may be just 3 for be physiological in adolescents. This morpholo- Far-East Asian women.6 Other clinical features, gy was reported in one third of healthy girls 4 such as acne and scalp hair loss, are less specific years after menarche, without any relationship and cannot be considered signs of hyperan- to the metabolic and endocrine features of drogenism, when androgen levels are normal PCOS.13 Nevertheless, while it was hypothe- and there is no hirsutism. However, acne can be sized that isolated PCOm may anticipate ovarian found in 15-25% and scalp hair loss in 20-30% dysfunction in some girls, anovulatory adoles- of adult women with PCOS. Acne is a common, cents can show subtle endocrine alterations,14 complex, multifactorial process in which andro- suggesting a potential propensity to develop- gens play a central role, but other factors are re- ment of overt PCOS later in life. It has been sug- quired.7 Conversely, there is not an obligate link gested that age-specific cut-off values for ovari- between androgen action and female pattern hair an follicle number should be defined in adoles- loss, which may be present even in women lack- cents.15 However, transvaginal imaging cannot ing an androgen receptor. Nevertheless, in many be performed in many girls, with limitations in women with hair loss androgen action in the ovarian morphology assessment, especially in scalp may be enhanced, and assessment of a obese individuals. In this regard, when using possible androgen excess is required.8 Unfortu- transabdominal ultrasound, reporting may be nately, assessment of biochemical hyperan- best centered on ovarian volume, maintaining a drogenism can also be challenging, being ham- threshold of ≥10 mL, given the difficulty of con- pered by significant limitations of methods for sistently measuring follicle number. Finally, hir- assaying serum androgens generally used in sutism may require time to develop, whereas clinical labs. Indeed, ordinary methods may acne is a very common feature in young ages, misclassify, when distinguishing hyperandro- making it often difficult to diagnose clinical hy- Vol. 72 - No. 4 MINERVA PEDIATRICA 289 STREET CURRENT TREATMENT FOR PCOS perandrogenism. Therefore, while the definition arche, girls can be considered at risk for PCOS, of PCOS in adolescents should follow the gen- suggesting a clinical and possibly ultrasono- eral laws established for adult women, diagnos- graphic and/or AMH follow up. In these cases, ing the presence of ovarian dysfunction and risk of overdiagnosis and unnecessary interven- clinical hyperandrogenism may be a problemat- tions should be balanced against the individual ic issue in young girls, and no unanimously ac- need of a diagnosis and early therapy.20 Notably, cepted criteria for diagnosing PCOS in adoles- no current definitions of PCOS include obesity cence exist. ESHRE and ASRM, in a consensus or insulin resistance
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