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Management of polycystic ovary syndrome in childhood and adolescence

Clinical Practice Committee Publication
RE SE ARCH I N
Accepted: August 14, 2010 Published online: September 22, 2010 PÆDIATRIC S
Management of Polycystic Ovary
Syndrome in Childhood and Adolescence

M. Ojaniemi a P. Tapanainen a L. Morin-Papunen b   a Department of Pediatrics and Adolescence, Institute of Clinical Medicine, and b Department of Obstetrics and Gynecology, Oulu University Hospital and University of Oulu, Oulu , Finland Key Words
tervention, however, increasing evidence suggests that Adolescence ؒ Hyperandrogenism ؒ Insulin resistance ؒ met formin and estrogen-progestin combination pill may Metabolic syndrome ؒ Polycystic ovary syndrome be beneficial. Conclusions: PCOS is a lifelong condition that
carries long-term health risks. Several risk factors for PCOS
have been identified and clinicians should be alert for this
Abstract
condition already in childhood and adolescence. Early inter- Introduction: Polycystic ovary syndrome (PCOS) is a com-
vention and counseling might be the key for prevention of mon endocrinopathy in women. It may manifest as early as in the first decade of life. Most often it becomes clinically apparent during adolescence with maturation of the hypo-thalamic-pituitary-ovarian axis. Clinical Features: Typical
features in adolescence include irregular menstrual cycles, Introduction
acne, hirsutism, obesity and signs of insulin resistance such as acanthosis nigricans. Biochemical hyperandrogenism and The polycystic ovary syndrome (PCOS) is a common polycystic ovaries are often present. However, some adoles- syndrome affecting 5–10% of women [1] and is increas- cents have no evidence of clinical and biochemical hyperan- ingly identified in the adolescent population. The Rotter- drogenism despite dysfunctional polycystic ovaries. Patho-
dam 2004 Consensus Workshop (Revised 2003) pro- genesis: The pathogenesis of PCOS is uncertain, however,
posed that PCOS is a syndrome of ovarian dysfunction both genetic and environmental factors play a role, resulting and recommended that 2 of the following criteria should in key features of the syndrome; disordered gonadotropin be present to establish the diagnosis: (1) chronic oligo- or release, dysregulated steroidogenesis, ovarian and adrenal anovulation for more than 6 months; (2) clinical and/or hyperandrogenism and hyperinsulinism. PCOS is often ac- biochemical evidence of hyperandrogenism, and (3) companied by metabolic syndrome, with abnormalities in polycystic ovaries on ultrasound examination. Other dis- Treatment:
Treatment of orders that mimic PCOS phenotype should be excluded PCOS is symptomatic. Lifestyle changes are a first-line in- Department of Pediatrics and Adolescence, Institute of Clinical Medicine Oulu University Hospital and University of Oulu Tel. +358 8 315 5822, Fax +358 8 315 5559, E-Mail marja.ojaniemi   @   oulu.fi Clinical Features
adolescent PCOS patients may have normal androgen lev-els [9] with moderate hirsutism compared to adults [10] .
The classic PCOS in a teenager is characterized by ir- The syndrome is also characterized by disordered pi- regular menstrual cycles, generally less than 6 menses per tuitary function, with high LH secretion in relation to year, by clinical or biochemical features of hyperan- FSH, resulting in increased thecal production of andro- drogenism and polycystic ovaries on ultrasound exami- gens. Androgen excess interferes with the negative feed- nation. More than 50% of PCOS patients have metabolic back of progesterone and estradiol on LH secretion [11, syndrome, including obesity, insulin resistance and dys- 12] , resulting in persistent high levels of LH and increased lipidemia [3] . The incidence of obesity and dyslipidemia production of androgens from the ovary.
may be even higher in the adolescent than in the adult Insulin resistance and hyperinsulinism also play im- population [4] . Most often the syndrome poses little di- portant roles in PCOS pathophysiology. High insulin lev- agnostic challenge; however, there is variability in the els promote ovarian hyperandrogenemia by simulating clinical, biochemical and pathological findings, making steroidogenesis from ovaries [13] , and by increasing the the spectrum of PCOS phenotype wide, including adoles- LH secretion from the pituitary, resulting in elevated LH/ cents with no evidence of clinical and biochemical hyper- FSH ratio and anovulation. In addition, the levels of sex- androgenism despite dysfunctional polycystic ovaries.
hormone binding globulin decrease in the hyperinsulin- PCOS may have its origin in fetal life, and may mani- emic state, elevating free testosterone. Although insulin fest as soon as the first decade of life by premature adre- resistance plays the most important role in the develop- narche and pubarche. However, most often it becomes ment of metabolic disturbances, hyperandrogenemia clinically manifest during adolescence with maturation also appears to be an important risk factor for develop-of the hypothalamic-pituitary-ovarian axis [5] .
Although PCOS is a common disorder, the diagnosis may be overlooked during adolescence, as during puber-ty insulin sensitivity is decreased, irregular menses with Risk Factors for PCOS
anovulatory cycles are common following menarche, and obesity and evidence of androgen excess such as acne are Several independent prepubertal risk factors for PCOS have been identified and should alert the clinician to the possibility of PCOS. These include conditions with hy-perandrogenemia or hyperinsulinemia, such as congeni- Pathogenesis
tal virilizing disorders, above average or low birth weight for gestational age, premature or exaggerated adrenarche, Although the pathogenesis of PCOS is still uncertain, atypical sexual precocity, intractable obesity with acan- there is evidence that both genetic [6] and environmental thosis nigricans, hyperinsulinism and metabolic syn- factors may play a role, resulting in key features of the drome and pseudo-cushing syndrome or pseudo acro-syndrome: disordered gonadotropin release, dysregulat- megaly [15] . In addition, family history of PCOS, diabetes ed steroidogenesis, ovarian and adrenal hyperandrogen- mellitus or cardiovascular disease are known risk factors.
Transition from adrenarche to gonadarche and to full The main pathogenetic mechanism for development of reproductive competence is a PCOS-like state (hyperan- PCOS is hyperandrogenism, which can occur due to the drogenemia, polycystic ovaries, insulin resistance, an-dysregulation of steroidogenesis [8] . Most often the prin- ovulatory cycles). It has been suggested that PCOS may cipal source of androgens is the ovary; however, adrenal develop from abnormal pubertal development caused by hyperandrogenism may also play a role. Interestingly, dysregulated progression from the early androgen-dom-congenital adrenal hyperplasia characterized by hyperan- inated phase to the later estrogenic state of puberty [16] . drogenism also results in a PCOS-like state. Testosterone Therefore, PCOS can be seen as a persistent adrenarche-is the principal circulating androgen in women, produced like state with excess adrenal androgen production, or as from ovarian and adrenal precursors (androstendione a state of persistent hyperandrogenemia due to excessive and epiandrostendione) and metabolized in peripheral stimulation of ovaries by LH and/or insulin. Indeed, pa-tissues. Despite normal total testosterone levels, the levels tients with premature pubarche carry about 15–20% risk of bioavailable testosterone are often elevated due to the for developing PCOS, and the risk is even higher with low sex-hormone binding globulin levels. However, some those having exaggerated adrenarche with hyper-respon- siveness to ACTH stimulation consistent with functional ameliorates hyperandrogenism and irregular menses in adrenal hyperandrogenism [17] . Low birth weight is also adolescents. Metformin is also beneficial in normalizing known to pose an increased risk for premature adre- narche, insulin resistance and polycystic ovaries [18] . Metformin has been administered at doses varying However, the risk for postmenarcheal hyperandrogenism from 1.5 to 2.5 mg/day and it is generally divided into 2 in small-for-gestational-age patients seems low in most or 3 doses. Mild side-effects such as gastrointestinal populations [15] . In a large Finnish cohort, weight at symptoms (nausea, metallic taste in the mouth and birth, gestational age, being small for gestational age or changes in bowel movement frequency) occur in about growth retardation at birth were not associated with 5–10% of cases, but the drug is well tolerated if the dose PCOS symptoms in adulthood (at 31 years) [19] . Congen- is increased gradually. Its most feared complication is lac- ital androgenization such as CAH or children with PCOS tic acidosis which is fortunately very rare and almost al- mothers are also susceptible to PCOS [15] .
ways related to coexistent hypoxic conditions, which are Peripubertal obesity may predispose to PCOS. Adipose contraindications for metformin therapy. However, tissue is the major site for conversion of circulation precur- questions about how long the treatment should be contin- sors to testosterone [20] . The hyperandrogenemia of peri- ued and long-term safety remain to be answered. Ibanez pubertal obesity may lead to increased LH secretion and et al. [25] have reported that the beneficial effects may last enhanced ovarian production of androgens. In addition, up to 1 year after treatment is discontinued. It is impor-hyperinsulinemia associated with simple obesity may re- tant to take care of contraception in metformin users be- sult in progression to PCOS in susceptible girls [20] .
cause of improvement of ovulatory function [26] . The use of insulin-sensitizing drugs improves ovulation and pregnancy rates in PCOS women, but according to a re- Long-Term Health Risks
cent Cochrane review, their effect on pregnancy out-comes and reducing the rate of metabolic syndrome in Identifying and treating adolescents with PCOS is im- portant, as the syndrome is associated with a 10-fold risk Other treatment options used in PCOS are spirono- for developing type 2 diabetes in adulthood [21, 22] and lactone and estrogen-progestin combination pills. Spi- a 2-fold increased rate of metabolic syndrome [23] . Ac- ronolactone is very rarely used in adolescents. PCOS cording to a recent study, more than half of adolescent patients with acne and hirsutism may benefit from es-PCOS patients had high-density lipoprotein levels below trogen-progestin combination pills, especially thosethe normal reference range for their sex [4] , which is a containing antiandrogenic progestins, such as cyproter-strong predictor of future cardiac risk. Infertility and in- one acetate or drosperinone [28, 29] . The metabolic risks creased endometrial cancer risks are also of importance. of long-lasting treatment with the combined estrogen-Early intervention and counseling might be the key for progestin combination pills, however, have been scarcely prevention of comorbidities of PCOS.
studied and should be kept in mind. Some studies have shown that the worsening of glucose tolerance observed during treatment with estrogen-progestin combination Treatment
pills could be reversed by the addition of metformin [30] , but further studies are needed to show the utility of this There are several aspects that need to be considered association. Insulin sensitizers, such as glitazones, im- when evaluating and treating an adolescent with PCOS. prove insulin resistance, but their use and safety in ado-Treatment aims are: (1) to regulate the menses and restore lescents is not known. Some studies have shown that the fertility; (2) to improve the metabolic disturbances of glu- association of low-dose anti-androgen flutamide with cose and lipid metabolism; (3) to normalize weight to pre- metformin plus an oral estrogen-progestin combination vent associated morbidities, and (4) to address psycho- pill could prevent progression from precocious pubarche logical aspects of the condition, e.g. poor self image, de- to polycystic ovary syndrome. Moreover, the switch to pression. Treatment of PCOS is symptomatic. Lifestyle drospirenone OC from gestodene OC was accompanied changes are a first-line intervention in adolescents with by a reduction of total and abdominal fat [31] . However, PCOS [24] . Glucose intolerance can be managed by diet the use of this polypharmacy in these young women is and exercise, and appropriate weight control. Metformin still controversial and should not be used as a routine improves insulin sensitivity and glucose metabolism, and Conclusions
style changes are the first-line intervention in young overweight women with PCOS. Management of the PCOS is common in adolescents and should be con- PCOS adolescent with metformin is beneficial and well sidered in an adolescent with irregular menses and excess tolerated, but the longer-term effects are not yet estab- weight. The metabolic syndrome is a common feature of lished. It appears that PCOS is a lifelong condition. Con-PCOS. Testing for glucose intolerance and dyslipidemia sequently, patients should be carefully monitored during is required, particularly in the presence of obesity. Life- adolescence and thereafter in adulthood.
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