- Email: [email protected]
Polycystic ovary syndrome in adolescents
Accepted Manuscript Polycystic Ovary Syndrome in Adolescents Stephanie S. Rothenberg, MD, Rachel Beverley, MD, Emily Barnard, DO, Massoud Baradaran-Shoraka, BS, Joseph S. Sanfilippo, MD, MBA
PII:
S1521-6934(17)30126-8
DOI:
10.1016/j.bpobgyn.2017.08.008
Reference:
YBEOG 1741
To appear in:
Best Practice & Research Clinical Obstetrics & Gynaecology
Received Date: 31 July 2017 Accepted Date: 24 August 2017
Please cite this article as: Rothenberg SS, Beverley R, Barnard E, Baradaran-Shoraka M, Sanfilippo JS, Polycystic Ovary Syndrome in Adolescents, Best Practice & Research Clinical Obstetrics & Gynaecology (2017), doi: 10.1016/j.bpobgyn.2017.08.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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TITLE: Polycystic Ovary Syndrome in Adolescents
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AUTHORS: Stephanie S. Rothenberg, MDa Rachel Beverley, MDa
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Emily Barnard, DOa Massoud Baradaran-Shoraka, BSa
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Joseph S. Sanfilippo, MD, MBAa
AUTHOR AFFILIATIONS: a
AUTHOR EMAIL ADDRESSES:
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Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital of UPMC, 300 Halket St, Pittsburgh, PA 15213, USA
Stephanie S. Rothenberg, MD – [email protected] Rachel Beverley, MD – [email protected]
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Emily Barnard, DO – [email protected]
Massoud Baradaran-Shoraka, BS – [email protected]
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Joseph S. Sanfilippo, MD, MBA – [email protected]
CORRESPONDING AUTHOR:
Name: Joseph S. Sanfilippo, MD, MBA Email: [email protected] Address: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital, University of Pittsburgh, 300 Halket St, Pittsburgh, PA 15213, USA
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ABSTRACT Polycystic ovary syndrome (PCOS) typically manifests with a combination of menstrual dysfunction and evidence of hyperandrogenism in the adolescent population. No single cause has been identified;
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however, evidence suggests a complex interplay between genetic and environmental factors. Polycystic ovary syndrome presents a particular diagnostic challenge in adolescents as normal pubertal changes can present with a similar phenotype. Management of PCOS in the adolescent population should focus
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on a multi-modal approach with lifestyle modification and pharmacologic treatment to address
bothersome symptoms. This chapter outlines the pathogenesis of PCOS, including the effects of obesity,
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insulin resistance, genetic, and environmental factors. The evolution of the diagnostic criteria of PCOS as well as specific challenges of diagnosis in the adolescent population are reviewed. Finally, evidence for
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lifestyle modification and pharmacologic treatments are discussed.
KEY WORDS
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Polycystic ovary syndrome, adolescent, insulin resistance, hyperandrogenism
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Pathogenesis Polycystic ovary syndrome (PCOS) is considered a disorder of ovarian function. Prior to
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understanding the pathogenesis of the syndrome, it is prudent to review the process of normal androgen synthesis in the ovaries and adrenal glands. In the ovaries, luteinizing hormone (LH) stimulates theca cells to initiate the conversion of cholesterol to androstenedione, the major
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precursor to testosterone and estrogen synthesis. Androstenedione is then converted to testosterone in the theca cells via 17β-hydroxysteroid dehydrogenase (17β-HSD).
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Androstenedione also diffuses from theca cells to granulosa cells and undergoes conversion to estrone via aromatase, a process catalyzed by follicle stimulating hormone (FSH). Testosterone produced by theca cells is converted to dihydrotestosterone (DHT) in the granulosa cells via 5α-
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reductase. Estrone is subsequently converted in the granulosa cells to estradiol by 17β-HSD.
Concurrently in the adrenal cortex, the steroid biosynthetic pathway is stimulated by adrenocorticotropic hormone (ACTH). Adrenal androgen production primarily occurs in the
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zona reticularis. The pathway begins with conversion of cholesterol to pregnenolone in the zona glomerulosa. Pregnenolone is converted to progesterone via 3β-hydroxysteroid
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dehydrogenase (3β-HSD). In the zona fasiculata, 17α-hydroxylase catalyzes the formation of 17hydroxypregnenolone and 17-hydroxyprogesterone (17-OHP) from pregnenolone and progesterone, respectively. These intermediates are acted on by 17,20 lyase in the zona reticularis to form dehydroepiandrosterone (DHEA) and androstenedione. DHEA is primarily converted to dehydroepiandrosterone sulfate (DHEA-S) via steroid sulfotransferase (SUL2A1). To a lesser extent, 3β-HSD acts on DHEA to form androstenedione. Androstenedione is then
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converted to testosterone and estrone via 17β-HSD and aromatase, respectively. Additionally,
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androgens are produced peripherally in the liver, adipose and skin.[1]
No single cause for PCOS has been elicited. Rather, it is felt to be a syndrome related to the interplay of genetic and environmental factors.[1] In vitro studies of theca cells from patients
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with PCOS have demonstrated overexpression of LH receptors and steroidogenic enzymes including cytochrome P450c17, 3β-HSD, and 17β-HSD. As a result, production of steroids such
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as 17-OHP and testosterone are elevated compared to controls without PCOS.[2] During puberty, there is maturation of the hypothalamic–pituitary–ovarian axis and subsequent increase in circulating levels of LH. This increase is exaggerated in girls with a predisposition to PCOS, further amplifying androgen production [3]. Specifically, adolescents with PCOS exhibit
ratio.[4]
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increased GnRH and LH pulse frequency and amplitude, as well as an increased LH to FSH
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Insulin also plays an important role in human androgen regulation. There is a physiologic increase in insulin resistance, along with an increase in serum concentrations of fasting insulin
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during normal puberty and adolescence. As insulin levels rise, there is a reciprocal fall in sex hormone binding globulin (SHBG) by suppressing production in the liver, ultimately increasing the circulating free concentration of sex steroids.[3] Multiple studies have demonstrated that insulin resistance and hyperinsulinemia are key findings in patients with PCOS, whether or not they are obese.[5–9] In vitro studies have demonstrated elevation of LH and GnRH secretion in
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response to insulin infusion.[10] Additionally, insulin amplifies steroidogenesis in both ovarian
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theca and granulosa cells in response to LH stimulation.
Interestingly, despite the systemic state of insulin resistance in PCOS, the ovary remains
sensitive to insulin.[10] As previously discussed, insulin amplifies the effect of LH on granulosa
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cell steroidogenesis. Additionally, insulin resistance and hyperinsulinemia are also implicated in
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the underlying mechanism of anovulation by leading to arrest of follicular maturation.[3]
Obesity is thought to contribute to the pathophysiology of PCOS, leading to a more severe PCOS phenotype. Increasing adiposity has been associated with menstrual dysfunction and increasing androgen concentrations.[4] Obesity promotes insulin resistance and aggravates the
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hyperandrogenism seen in PCOS.[1] Increased androgen concentration is partially related to a decrease in sex hormone binding globulin seen in obesity. Additionally, excessive adiposity may contribute to androgen excess as adipose tissue contains several steroidogenic enzymes that
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convert androstenedione into testosterone, and testosterone into dihydrotestosterone (DHT), a more potent androgen. In multiple studies of obese adolescent girls, as body mass index (BMI)
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increases, there is a proportional rise in free testosterone concentration.[4,11–13] In normal weight patients with PCOS, insulin resistance may be present, however, insulin resistance is exaggerated when obesity is present. [10] Additionally, obese adolescent girls with PCOS demonstrate more significant insulin resistance and hyperinsulinemia compared to patients who are obese but do not carry a diagnosis of PCOS.[4] Genetics
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To date, greater than 100 candidate genes have been implicated in the pathophysiology of PCOS, with particular focus on genes affecting the biosynthesis and function of reproductive
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hormones, cellular metabolism and chronic inflammation. Several key genes related to steroidogenesis are implicated, including CYP17A1, CYP19, CYP21, HSD17B5 and HSD17B6. Sex hormones and their receptors are also involved. PCOS is also a metabolic disorder, with a
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strong association with type 2 diabetes, hyperlipidemia, obesity, and the metabolic syndrome. Associated metabolic candidate genes include genes related to insulin biosynthesis and
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function (INS (insulin gene), INSR (insulin receptor), IRS1 (insulin receptor substrate 1), IRS2, IGF, PPAR-g and CAPN10) as well as obesity-related genes (FTO (fat and obesity-associated gene)).[14,15] Finally, given the relationship of PCOS with a proinflammatory state, genes related to chronic inflammation are also involved, particularly inflammatory cytokines such as
inhibitor (PAI). [14,15]
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Environmental Exposures
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tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1A, IL-1B and plasminogen activator
Adding to the complexity of the pathophysiology of PCOS is the potential contribution of
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environmental exposures and lifestyle factors. Endocrine disrupting chemicals (EDCs) are defined as “substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction”.[16] EDCs are a broad class of molecules that include plasticizers such as phthlates and bisphenol A (BPA), as well as advanced glycation end products (AGEs).[17] The majority of human exposure is through food packaging, however, these molecules are also used
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in the production of medical devices. EDCs have been implicated in many disorders involving disordered male and female reproduction, abnormal breast development and cancer, prostate
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cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology.[16]
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Timing of exposure is of utmost importance, with evidence that fetuses and young children are the most susceptible to the adverse effects of EDCs.[16,18,19] Animal studies have shown that
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prenatal exposures to high levels of androgens during key points in gestation result in fetal programming of PCOS traits.[20,21] Parallels have been drawn, therefore, that exposure to androgen-like EDCs could result in metabolic dysfunction in adulthood, such as PCOS.[16] Adult exposures to EDCs may also be contributing to endocrine disruption in women with PCOS.
women.[22,23]
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Women with PCOS have been found to have higher levels of EDCs compared to ovulatory
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Diagnosis
Evolution of Diagnostic Criteria
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PCOS presents a unique diagnostic challenge in the field of gynecology, which is further complicated in the adolescent population. By its nature as a syndrome, PCOS is a collection of findings, both clinical and diagnostic, as well as a diagnosis of exclusion among other androgen excess disorders. The characterization of a patient with PCOS is made difficult by a history of variable and contradictory diagnostic criteria. Increasingly, a system of phenotypic description of the spectrum of PCOS has been proposed to standardize and aid in diagnosis.
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In 1990, the first guidelines for PCOS diagnosis were proposed at a conference sponsored by
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the National Institute of Child Health and Human Disease of the US National Institutes of Health (NIH). A panel of experts concluded that two criteria were essential for the diagnosis of PCOS: (1) hyperandrogenism and (2) oligoovulation. This remained the sole diagnostic criteria until the
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proposal of the “Rotterdam Criteria” in 2003.[24] This updated guideline concluded that for diagnosis, two of three criteria must be met: (1) signs of clinical or biochemical
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hyperandrogenism (2) oligo/anovulation and/or (3) polycystic ovaries. (Table 1) With the addition of the radiologic findings, a new cohort of patients was included in the diagnosis of PCOS: women with oligo/anovulation and polycystic ovaries, but with no evidence of hyperandrogenism. The establishment of this criteria significantly increased the prevalence of
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PCOS, as well as the variability of phenotype in the patient population.
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In 2006, the Androgen Excess Society released their own guideline proposing that hyperandrogenism is a requisite component for the diagnosis of PCOS, with the addition of
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either ovulatory dysfunction or polycystic ovaries.[25,26] They proposed that patients without hyperandrogenism who met the Rotterdam criteria did not truly represent the same pathophysiology and should therefore be excluded. The resulting discord temporarily stalled academic investigation and created clinical confusion regarding the diagnosis of PCOS.
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In an attempt to reconcile the proposed criteria, the NIH sponsored an Evidence-Based Methodology PCOS Workshop in 2012.[27] The resulting recommendations reinforced the use
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of the 2003 Rotterdam criteria, but with the addition of a phenotypic classification system to aid in clinical classification and epidemiologic research. This reinforced the core diagnostic criteria of PCOS to include (1) clinical/biochemical hyperandrogenism (HA) (2) chronic ovulatory
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dysfunction (OD) and (3) polycystic ovarian morphology (PCOM). (Table 2) The broadened term of ovulatory dysfunction contained the previously recognized oligoovulation, but also included
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polymenorrhea and abnormal uterine bleeding. As a result of the introduction and broad usage of the phenotypic system, strides in epidemiologic research have been made to further characterize the risks and long term health effects of PCOS, including reproductive abnormalities, endometrial hyperplasia and malignancy, insulin resistance and type 2 diabetes
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anxiety/depression.
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mellitus, coronary heart disease, dyslipidemia and cerebrovascular morbidity, and
In 2016, Lizneva et al further refined the phenotypic approach.[28] They proposed three PCOS
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phenotypes based on the 2012 modified Rotterdam criteria: “Classic” PCOS (phenotypes A/B), “Ovulatory PCOS” (phenotype C), and “Nonhyperandrogenic PCOS” (phenotype D). (Table 2) “Classic PCOS” accounted for more than 2/3 of women diagnosed with PCOS in their study. Compared to the other phenotypes, women with “Classic PCOS” appeared to have more severe symptoms, as well as an increased risk of significant long term health effects such as pronounced menstrual dysfunction, higher rates of insulin resistance, higher prevalence of
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obesity and more severe dyslipidemia.[28] Women with “Ovulatory PCOS” had an intermediate severity of symptoms and long term health risks, while women with “Nonhyperandrogenic
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PCOS” had the mildest symptoms and smallest long term health risks, though still present. This system more accurately represents PCOS as a true spectrum of findings with variable severity and long term health effects. As research continues, more accurate and patient-specific
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counseling regarding these factors will be possible. Diagnosis of PCOS in Adolescents
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As noted above, the diagnosis of PCOS is established by the presence of two out of three of the following criteria: (1) signs of clinical or biochemical hyperandrogenism (HA) (2) chronic ovulatory dysfunction (OD) and (3) polycystic ovarian morphology (PCOM). However, the adolescent population requires special consideration, as these criteria were developed for
Laboratory Evaluation
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diagnosis in adults; during adolescence, PCOS can present differently.
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The most prevalent characteristic seen in adolescents is hyperandrogenism.[29] Contrary to the
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adult population, the sole presence of acne and/or hirsutism should not be considered clinical evidence of hyperandrogenism in adolescent girls. However, more severe cases of such clinical findings could be an indication of hyperandrogenism. For example, comedal acne and mild hirsutism is common in all adolescent females. Moderate-severe inflammatory acne (defined as more than 11 inflammatory lesions) unresponsive to topical medications and moderate-severe hirsutism (based on Ferriman-Gallwey scoring system) would be an indication to initiate testing for hyperandrogenism.[30]
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Biochemical assessment of hyperandrogenism requires reliable assays with well-defined cut
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offs. Measurements of serum testosterone levels are recommended as the initial step in evaluating hyperandrogenism.[29] Free testosterone is the bioactive portion of serum total testosterone, making it the most sensitive indicator for elevated androgen levels. The
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circulating level of free testosterone is governed by sex hormone binding globulin (SHBG) which is affected by several physiological conditions. Other serum androgens such as
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androstenedione and DHEA-S are widely measured, but the cost effectiveness of routinely measuring an extensive array of androgens has not been well substantiated.[30] Shortly after menarche, serum testosterone reaches adult levels, making use of adult reference ranges appropriate.[30] There are several factors that make the interpretation of these lab results
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challenging, however. This includes lack of testosterone assay standardization among hospitals and laboratories as well as lack of sensitivity, specificity, and accuracy of the assays used. Clinical Symptoms
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Irregular menses and anovulatory cycles can be seen in the early stages of normal maturation of the hypothalamic-pituitary-ovarian axis. In the first year after menarche, approximately 85%
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of menstrual cycles are anovulatory, dropping to 25% six years after menarche.[29] Nevertheless, approximately two-thirds of adolescents with PCOS will present with menstrual symptoms. While difficult to differentiate oligomenorrhea due to PCOS from that of normal physiology, cycles outside 19 to 90 days, lack of menses by 16 years or 2-3 years after thelarche, and persistent oligomenorrhea 2 years beyond menarche require further evaluation.[30]
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It is critical to keep in mind that PCOS is a diagnosis of exclusion. Evaluation of women with suspected PCOS should exclude alternative disorders that can lead to androgen excess such as
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androgen-secreting tumors, either in the adnexa or adrenal glands, or congenital adrenal hyperplasia. There is agreement that screening for non-classic congenital adrenal hyperplasia (NCCAH) is prudent in women presenting with symptoms of PCOS. NCCAH accounts for 1-4% of
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patients with hyperandrogenic anovulation in reproductive age women.[30] Follicular phase 17OHP levels should be the initial screening tool in these patients. Levels higher than 200 ng/dL
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are concerning for NCCAH, with a 92-98% sensitivity.[30] Such a finding should be confirmed with an ACTH stimulation test. For patients with rapid progression of central obesity, hirsutism, or hypertension, Cushing syndrome should be considered. Late-night salivary cortisol, 24-hour urinary free cortisol excretion, or an overnight 1 mg dexamethasone suppression test are
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appropriate screening tests for Cushing syndrome. Screening for hypothyroidism and hyperprolactinemia are also recommended as they can present with menstrual irregularity.[30] The extent of evaluation and screening should be individualized based on patient presentation
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Imaging
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and associated symptomatology.
In the adult population, the role of imaging in diagnosing PCOS has been well established. Histopathologically, polycystic ovarian morphology (PCOM) is due to an excess number of small follicles that arrest before the preovulatory stage of development. PCOM is defined as an antral follicle count (follicles measuring 2-9mm) ≥12 in at least one ovary or an ovarian volume of >10.0 cm3.[24] However, ovaries with multiple follicles are normal and commonly seen around the time of menarche; approximately 50% of normal adolescents would meet the criteria of
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polycystic ovarian morphology.[31] Furthermore, anovulatory cycles due to inconsistent recruitment of a dominant follicle in the early years post menarche can contribute to the
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multifollicular appearance of the ovaries characteristically seen during puberty.[32]
In the adolescent population, the diagnosis of PCOS should not be based solely upon the
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symptoms of anovulation and polycystic-appearing ovaries on ultrasound, particularly within two years of menarche.[29] The Endocrine Society guidelines caution against the use of PCOM
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as diagnostic criteria for adolescents.[29] However, imaging can be used as a confirmatory test for adolescents in whom the diagnosis of PCOS remains uncertain after clinical and laboratory evaluation.
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Ultrasound. Transvaginal ultrasound (TVUS) is the modality of choice for evaluation of pelvic anatomy in the adult female population. (Figure 1) While optimal for evaluating pelvic anatomy, careful consideration should be taken prior to attempting a transvaginal ultrasound in an
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adolescent, particularly if she is virginal. Alternatively, performing a transabdominal ultrasound (TAUS) in an obese adolescent is technically challenging and often does not provide reliable
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imaging of the ovaries.[33] As a result, an antral follicle count it difficult to define by this modality.[32]
Magnetic Resonance Imaging (MRI). Compared to ultrasound, MRI in the adolescent population provides the most accurate view of the ovaries. (Figure 2) This modality has the advantage of being accessible for all ages given its noninvasive nature. In a study comparing
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obese adolescents with PCOS to obese adolescents without PCOS, it was demonstrated that MRI findings using Rotterdam criteria had a specificity of 77-82%.[34] In patients with uncertain
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clinical and laboratory findings, MRI can be considered as an accurate diagnostic imaging modality. However, MRI is significantly more expensive than ultrasound making routine
well established.
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MANAGEMENT
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ordering impractical. Additionally, normal values and cutoffs for its use in this instance are not
Management of PCOS in adolescents is multimodal, requiring consideration of lifestyle modification as well as pharmacotherapy.
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Lifestyle modification
Approximately 50% of patients with PCOS are overweight or obese, which is an important association as obesity itself is linked to an increased risk for type 2 diabetes, hypertension,
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cardiovascular disease, and menstrual dysfunction.[4,35,36] Lifestyle modification comprised primarily of a calorie-restricted diet and/or physical activity has proven effective in altering the
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disease course in PCOS.[29] Studies comparing exercise as an intervention to treat PCOS typically recommend 30 to 45 minutes of vigorous exercise 3 times per week.[37,38]
A meta-analysis of 583 PCOS patients demonstrated improvement in fasting glucose and insulin levels in patients undergoing lifestyle modification, which was comparable to patients who were treated with metformin.[35] Likewise, in a randomized trial comprised of 150 women with
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PCOS, improved insulin sensitivity indices were demonstrated in women who participated in a 6-month structured exercise training program. Compared to baseline, these women
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demonstrated improvement in intima media thickness (a cardiovascular marker predisposing to atherosclerosis), lipid profile, cardiopulmonary function, and frequency of menses.[37]
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In 2013, guidelines set forth by an Endocrine Society-appointed Task Force of experts
recommended lifestyle modification, with an objective of weight loss, as a first-line treatment
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for adolescent PCOS patients in the presence of overweight/obesity.[29] In normal weight women with PCOS, it is still unclear as to whether lifestyle modification will improve some aspects of the PCOS phenotype.[35] Consensus guidelines caution that for these women,
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weight loss therapy alone is likely insufficient.[29]
While there are few studies that have examined the effects of lifestyle modification in adolescents with PCOS, the results appear promising. A randomized, placebo-controlled trial
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was performed to evaluate the impact of multiple treatment modalities on PCOS in obese adolescent girls ages 12-18. One arm of this trial randomized 43 patients to a single
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intervention including metformin, placebo, a lifestyle modification program, or combined oral contraceptives (COC). With lifestyle modification alone, there was a 59% reduction in free androgen index (FAI) and 122% increase in SHBG.[38] Another prospective study sought to analyze the impact of a 1 year lifestyle intervention on menstrual irregularity, hyperandrogenism, cardiovascular risk factors and intima-media thickness in obese adolescent girls with PCOS aged 12-18 years. Of the 59 patients who completed the intervention at 1 year,
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26 patients had weight loss (reduction in BMI by mean 3.9 kg/m2), while 33 patients did not have weight loss. Researchers found that in the cohort with weight loss, the prevalence of
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amenorrhea and oligomenorrhea decreased by 42% and 19%, respectively. Additionally, this cohort also had significantly decreased testosterone concentrations and increased SHBG
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concentrations compared to patients without weight loss.[39]
It should be acknowledged that the adolescent population presents a challenge in regard to
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compliance with a diet and exercise regimen. Previous studies have utilized cohorts of adolescents and one support person, typically a parent, who attended classes instructing them in diet, exercise, and behavioral changes.[38] Greater success was seen when adolescents were encouraged to correspond outside of the instructional settings.[38] Social media can be utilized
period has ended.
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Medical Therapy
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to connect adolescents and encourage continued lifestyle changes after the intervention time
Combined hormonal contraceptives (CHCs). Combined hormonal contraceptives (CHCs), which
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contain both an estrogen (ethinyl estradiol) and a progestin, have traditionally been the firstline therapy for adolescents diagnosed with PCOS. Combined oral contraceptives (COCs) are most commonly prescribed; however, other routes of delivery are available, including the patch or vaginal ring. There is no evidence to suggest one delivery method is superior to the other, making patient preference an appropriate guide. There is also limited data to recommend the duration of CHC use in adolescents.[40] It is imperative to screen for contraindications prior to
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employing CHCs as a treatment strategy for PCOS. For example, certain comorbidities such as prior history of deep venous thromboembolism/pulmonary embolism or migraine headaches
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with aura would make estrogen-containing therapies contraindicated.[41]
In appropriately selected patients, CHCs convey multiple benefits for an adolescent with PCOS.
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CHCs have an anti-androgenic effect. The estrogen component acts to increase SHBG, which reduces the bioavailable testosterone by binding the free steroid, ultimately decreasing
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symptoms of androgen excess. The progestin suppresses LH levels, leading to a downstream decrease in ovarian androgen production. Progestins additionally inhibit 5α-reductase activity, resulting in less peripheral conversion of testosterone to dihydrotestosterone (DHT), the androgen most responsible for hirsutism.[42] In a study that compared exercise to CHCs in
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patients with PCOS, hirsutism, serum free testosterone, and FAI were significantly decreased in the CHC group (p<0.05).[37] While some progestins, such as drosperinone, have intrinsic antiandrogenic properties, the concentration of progestin in CHCs is low. In randomized
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studies, clinical benefit of anti-androgenic progestins have not been significant when compared
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to other forms of progestin.[43]
CHCs also result in menstrual regulation and endometrial protection. Adolescents with PCOS frequently have irregular and heavy menstrual cycles, which can be disruptive to their daily life. Placing them on a form of CHC can act to regulate their cycles, leading to more predictable and lighter periods. PCOS is often a cause of primary amenorrhea, and for girls with evidence of hyperandrogenism who demonstrate advanced stages of pubertal development (e.g. Tanner
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Stage IV breast development) but have not yet begun to menstruate, the recommendation is to start CHCs.[29] Adolescents who are sexually active have the secondary benefit of a
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contraceptive method. If delivered orally, however, it requires responsibility on the part of the patient to be compliant with a daily pill.
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CHCs can also improve a patient’s lipid profile. While no data are available for long-term effects, in the short term, an increase in HDL cholesterol is a favorable aspect of the estrogen
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component of CHCs. Total cholesterol and LDL-cholesterol are decreased for users of CHCs.[37]
Metformin. Metformin is another commonly prescribed medication for adolescents with PCOS. Metformin is a biguanide commonly used to treat Type 2 Diabetes Mellitus, which acts to
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decrease glucose production in the liver and increase the sensitivity of peripheral tissue to insulin.[44,45] Studies are limited for long-term use in adolescents. Metformin’s largest impact is improvement in glucose tolerance and other components of the metabolic syndrome that
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can be seen in both obese and non-obese adolescents with PCOS. Approximately 18-24% of
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adolescents with PCOS have abnormal glucose metabolism.[46]
The role of metformin in the management of PCOS was evaluated in a small, randomized placebo-controlled trial. Seventy-nine obese adolescents were randomized to a single treatment trial of various interventions on clinical and laboratory characteristics seen in PCOS patients. Interventions included Metformin, COCs, lifestyle modification and placebo alone.
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With metformin, there was a significant difference from baseline in improving triglycerides and
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fasting blood glucose, though notably, COCs were more effective.
Menstrual regularity is also improved with metformin therapy in adolescents. In individuals who have a contraindication to CHCs, metformin is an excellent second line option for
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significantly improve hirsutism or acne.[29]
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improvement in irregular cycles, though it does not exert any anti-androgen effects and will not
Spironolactone. Spironolactone is another adjunctive medication used to treat those with PCOS and hirsutism. This drug is an aldosterone-antagonist diuretic. Its mechanism of action includes inhibiting ovarian and adrenal biosynthesis of androgens, directly competing for the androgen
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receptor in the hair follicle and inhibiting 5α-reductase activity.[47] Effects are dose-dependent and occur over about six months of treatment. Side effects are common, and low doses (25 mg/day) are recommended to minimize hypotension, tachycardia and vaginal spotting.[48] This
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medication should not be used in adolescents with hyperkalemia or with other drugs that increase the level of potassium, but monitoring is not required in those with normal renal
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function. An effective form of contraception is essential given the risk for fetal virilization with spironolactone if pregnancy were to occur. To date, no studies have evaluated this medication in the adolescent population; however, studies in adults have shown significant beneficial effects in reducing DHEAS level and hirsutism score with the addition of low-dose spironolactone to patients with PCOS already taking metformin.[48]
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The authors’ recommendation for treatment would be to take a shared decision-making approach with the adolescent and their guardian as appropriate. Discussion should focus on
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which symptoms are most bothersome to the patient in order to determine the optimal treatment approach. Clinicians must also recognize that PCOS is a metabolic process and
comprehensive treatment will target underlying glucose intolerance and weight loss. Exercise
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pharmacologic modalities as appropriate.
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and dietary modifications should always be encouraged as a primary treatment with adjunctive
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SUMMARY Polycystic ovary syndrome (PCOS) is a heterogenous condition that typically manifests with a
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combination of menstrual dysfunction and hyperandrogenism in the adolescent population. The etiology is unclear but evidence suggests a combination of genetic, metabolic and
environmental factors. Ovarian androgen production is disordered, leading to increased
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synthesis of testosterone in proportion to estrogen. Insulin resistance can affect the hormonal milieu and contribute to arrest of follicular maturation, which is accentuated in obese
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adolescents. Diagnosis of PCOS is challenging in adolescents as the immaturity of the hypothalamic-pituitary access and other normal pubertal changes present similarly to an adolescent with PCOS.
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Optimal treatment utilizes a multi-modal approach, incorporating lifestyle changes and exercise in both the obese and non-obese adolescent. Pharmacologic therapies can address bothersome symptoms associated with PCOS. CHCs are utilized for menstrual regulation and also benefit the
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adolescent by decreasing testosterone levels through a rise in sex hormone binding globulin. Metabolic dysfunction can be mitigated with metformin, which demonstrates weight loss and
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improved glucose tolerance in its users in randomized trials. Spironolactone can aid in the treatment of hirsutism and acne.
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ACKNOWLEDGEMENTS: Ultrasound images: Kathleen Gustafson, Supervisor, Imaging Services, Magee-Womens Hospital of UPMC
Stephanie Rothenberg, MD – Conflicts of interest: None Emily Barnard, DO – Conflicts of interest: None Rachel Beverley, MD – Conflicts of interest: None
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Massoud Baradaran-Shoraka, BS – Conflicts of interest: None
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CONFLICT OF INTEREST STATEMENT:
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MRI images: Christiane Hakim, MD, Department of Radiology, Magee-Womens Hospital of UPMC
Joseph Sanfilippo, MD, MBA – Conflicts of interest: None
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Anovulation and polycystic ovarian morphology can be normal in young women. Diagnosis of PCOS in adolescents should be made with persistent oligomenorrhea and evidence of hyperandrogenism Other disorders that lead to androgen excess should be considered and excluded prior to diagnosing PCOS In the adolescent population, the diagnosis of PCOS should not be based solely upon polycysticappearing ovaries on ultrasound, particularly within two years of menarche. Imaging can be used as a confirmatory test but should not be the first step of evaluation. Exercise and dietary modifications should always be encouraged as primary and adjunctive treatment to pharmacologic therapies. First line medical therapy includes combined hormonal contraceptives. In select populations, spironolactone and metformin can be considered
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RESEARCH AGENDA: -Relationship between obesity and development of PCOS -Relationship between endocrine disrupting chemicals and PCOS
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-Long term risk factors for PCOS based on phenotype -Long term cardiovascular and metabolic outcomes in women diagnosed with PCOS as adolescents -Normal values and cutoffs for MRI evaluation of the ovaries
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-The benefit of lifestyle modification in normal weight adolescents with PCOS -Effects of long term use of metformin in adolescents with PCOS
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-Efficacy and safety profile of spironolactone in adolescents with PCOS
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Diamanti-Kandarakis E, Katsikis I, Piperi C, et al. Increased serum advanced glycation endproducts is a distinct finding in lean women with polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf). 2008;69(4):634–41.
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Timothy R.B. Johnson, M.D., FACOG, Lorrie Kline Kaplan, CAE, Pamela Ouyang, M.B.B.S., Robert A. Rizza MD. National Institues of Health, Evidence-based Methodology Workshop on Polycystic Ovary Syndrome December 3-5, 2012. Executive Summary [Internet]. Centers for Medicare &. 2012. Available from: http://nefmc.org/herring/meetsum/herring_may12_ap.pdf
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randomized controlled trial. Clin Endocrinol (Oxf). 2016; Hoeger K, Davidson K, Kochman L, et al. The Impact of Metformin, Oral Contraceptives, and Lifestyle Modification on Polycystic Ovary Syndrome in Obese Adolescent Women in Two Randomized, Placebo-Controlled Clinical Trials. J Clin Endocrinol Metab. 2008;
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Lass N, Kleber M, Winkel K, et al. Effect of lifestyle intervention on features of polycystic ovarian syndrome, metabolic syndrome, and intima-media thickness in obese adolescent girls. J Clin Endocrinol Metab. 2011;96(11):3533–40.
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van Vloten WA, van Haselen CW, van Zuuren EJ, et al. The effect of 2 combined oral Contraceptives containing either drospirenone or cyproterone acetate on acne and seborrhea. Cutis. 2002;69(4 Suppl):2–15.
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Gooding HC, Milliren C, St. Paul M, et al. Diagnosing dysglycemia in adolescents with polycystic ovary syndrome. J Adolesc Heal. 2014;55(1):79–84.
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Mazza A, Fruci B, Guzzi P, et al. In PCOS patients the addition of low-dose spironolactone induces a more marked reduction of clinical and biochemical hyperandrogenism than metformin alone. Nutr Metab Cardiovasc Dis. 2014;24(2):132–9.
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ESRE/ASRM 2003 Diagnostic Criteria for PCOS [24] “Rotterdam Criteria” Patient must meet 2 out of 3 criteria
Oligo- or anovulation
(2)
Clinical and/or biochemical signs of hyperandrogenismi
(3)
Polycystic ovariesii and exclusion of other etiologiesiii
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(1)
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i- Hirsutism, severe acne and/or elevation of total/free testosterone or DHEA-S ii- Presence of 12 or more follicles in each ovary measuring 2-9 mm in diameter and/or increased ovarian volume (>10cm3) iii- Including congenital adrenal hyperplasia, androgen-secreting tumors, Cushing’s syndrome
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Phenotype A: HA + OD + PCOM Phenotype B: HA + OD
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Phenotype C: HA + PCOM Phenotype D: OD +PCOM
Lizneva 2016 [28]
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NIH 2012 extension of ESHRE/ASRM 2003 [27]
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The Phenotypic System of PCOS Diagnosis
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HA: clinical and/or biochemical hyperandrogenism OD: ovulatory dysfunction PCOM: polycystic ovarian morphology
“Classic” PCOS
“Ovulatory” PCOS
“Nonhyperandrogenic” PCOS
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Ultrasound appearance of polycystic ovaries
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MRI appearance of polycystic ovaries
Images courtesy of
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PCOS is a metabolic disorder The pathophysiology of PCOS is multifactorial Diagnosis in adolescents requires persistent oligomenorrhea and hyperandrogenism Exercise and dietary modifications are considered first line therapy in obese PCOS patients Medical therapy includes combined hormonal contraceptives, spironolactone and metformin
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• • • • •
PII:
S1521-6934(17)30126-8
DOI:
10.1016/j.bpobgyn.2017.08.008
Reference:
YBEOG 1741
To appear in:
Best Practice & Research Clinical Obstetrics & Gynaecology
Received Date: 31 July 2017 Accepted Date: 24 August 2017
Please cite this article as: Rothenberg SS, Beverley R, Barnard E, Baradaran-Shoraka M, Sanfilippo JS, Polycystic Ovary Syndrome in Adolescents, Best Practice & Research Clinical Obstetrics & Gynaecology (2017), doi: 10.1016/j.bpobgyn.2017.08.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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TITLE: Polycystic Ovary Syndrome in Adolescents
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AUTHORS: Stephanie S. Rothenberg, MDa Rachel Beverley, MDa
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Emily Barnard, DOa Massoud Baradaran-Shoraka, BSa
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Joseph S. Sanfilippo, MD, MBAa
AUTHOR AFFILIATIONS: a
AUTHOR EMAIL ADDRESSES:
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Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital of UPMC, 300 Halket St, Pittsburgh, PA 15213, USA
Stephanie S. Rothenberg, MD – [email protected] Rachel Beverley, MD – [email protected]
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Emily Barnard, DO – [email protected]
Massoud Baradaran-Shoraka, BS – [email protected]
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Joseph S. Sanfilippo, MD, MBA – [email protected]
CORRESPONDING AUTHOR:
Name: Joseph S. Sanfilippo, MD, MBA Email: [email protected] Address: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital, University of Pittsburgh, 300 Halket St, Pittsburgh, PA 15213, USA
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ABSTRACT Polycystic ovary syndrome (PCOS) typically manifests with a combination of menstrual dysfunction and evidence of hyperandrogenism in the adolescent population. No single cause has been identified;
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however, evidence suggests a complex interplay between genetic and environmental factors. Polycystic ovary syndrome presents a particular diagnostic challenge in adolescents as normal pubertal changes can present with a similar phenotype. Management of PCOS in the adolescent population should focus
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on a multi-modal approach with lifestyle modification and pharmacologic treatment to address
bothersome symptoms. This chapter outlines the pathogenesis of PCOS, including the effects of obesity,
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insulin resistance, genetic, and environmental factors. The evolution of the diagnostic criteria of PCOS as well as specific challenges of diagnosis in the adolescent population are reviewed. Finally, evidence for
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lifestyle modification and pharmacologic treatments are discussed.
KEY WORDS
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Polycystic ovary syndrome, adolescent, insulin resistance, hyperandrogenism
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Pathogenesis Polycystic ovary syndrome (PCOS) is considered a disorder of ovarian function. Prior to
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understanding the pathogenesis of the syndrome, it is prudent to review the process of normal androgen synthesis in the ovaries and adrenal glands. In the ovaries, luteinizing hormone (LH) stimulates theca cells to initiate the conversion of cholesterol to androstenedione, the major
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precursor to testosterone and estrogen synthesis. Androstenedione is then converted to testosterone in the theca cells via 17β-hydroxysteroid dehydrogenase (17β-HSD).
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Androstenedione also diffuses from theca cells to granulosa cells and undergoes conversion to estrone via aromatase, a process catalyzed by follicle stimulating hormone (FSH). Testosterone produced by theca cells is converted to dihydrotestosterone (DHT) in the granulosa cells via 5α-
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reductase. Estrone is subsequently converted in the granulosa cells to estradiol by 17β-HSD.
Concurrently in the adrenal cortex, the steroid biosynthetic pathway is stimulated by adrenocorticotropic hormone (ACTH). Adrenal androgen production primarily occurs in the
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zona reticularis. The pathway begins with conversion of cholesterol to pregnenolone in the zona glomerulosa. Pregnenolone is converted to progesterone via 3β-hydroxysteroid
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dehydrogenase (3β-HSD). In the zona fasiculata, 17α-hydroxylase catalyzes the formation of 17hydroxypregnenolone and 17-hydroxyprogesterone (17-OHP) from pregnenolone and progesterone, respectively. These intermediates are acted on by 17,20 lyase in the zona reticularis to form dehydroepiandrosterone (DHEA) and androstenedione. DHEA is primarily converted to dehydroepiandrosterone sulfate (DHEA-S) via steroid sulfotransferase (SUL2A1). To a lesser extent, 3β-HSD acts on DHEA to form androstenedione. Androstenedione is then
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converted to testosterone and estrone via 17β-HSD and aromatase, respectively. Additionally,
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androgens are produced peripherally in the liver, adipose and skin.[1]
No single cause for PCOS has been elicited. Rather, it is felt to be a syndrome related to the interplay of genetic and environmental factors.[1] In vitro studies of theca cells from patients
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with PCOS have demonstrated overexpression of LH receptors and steroidogenic enzymes including cytochrome P450c17, 3β-HSD, and 17β-HSD. As a result, production of steroids such
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as 17-OHP and testosterone are elevated compared to controls without PCOS.[2] During puberty, there is maturation of the hypothalamic–pituitary–ovarian axis and subsequent increase in circulating levels of LH. This increase is exaggerated in girls with a predisposition to PCOS, further amplifying androgen production [3]. Specifically, adolescents with PCOS exhibit
ratio.[4]
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increased GnRH and LH pulse frequency and amplitude, as well as an increased LH to FSH
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Insulin also plays an important role in human androgen regulation. There is a physiologic increase in insulin resistance, along with an increase in serum concentrations of fasting insulin
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during normal puberty and adolescence. As insulin levels rise, there is a reciprocal fall in sex hormone binding globulin (SHBG) by suppressing production in the liver, ultimately increasing the circulating free concentration of sex steroids.[3] Multiple studies have demonstrated that insulin resistance and hyperinsulinemia are key findings in patients with PCOS, whether or not they are obese.[5–9] In vitro studies have demonstrated elevation of LH and GnRH secretion in
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response to insulin infusion.[10] Additionally, insulin amplifies steroidogenesis in both ovarian
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theca and granulosa cells in response to LH stimulation.
Interestingly, despite the systemic state of insulin resistance in PCOS, the ovary remains
sensitive to insulin.[10] As previously discussed, insulin amplifies the effect of LH on granulosa
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cell steroidogenesis. Additionally, insulin resistance and hyperinsulinemia are also implicated in
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the underlying mechanism of anovulation by leading to arrest of follicular maturation.[3]
Obesity is thought to contribute to the pathophysiology of PCOS, leading to a more severe PCOS phenotype. Increasing adiposity has been associated with menstrual dysfunction and increasing androgen concentrations.[4] Obesity promotes insulin resistance and aggravates the
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hyperandrogenism seen in PCOS.[1] Increased androgen concentration is partially related to a decrease in sex hormone binding globulin seen in obesity. Additionally, excessive adiposity may contribute to androgen excess as adipose tissue contains several steroidogenic enzymes that
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convert androstenedione into testosterone, and testosterone into dihydrotestosterone (DHT), a more potent androgen. In multiple studies of obese adolescent girls, as body mass index (BMI)
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increases, there is a proportional rise in free testosterone concentration.[4,11–13] In normal weight patients with PCOS, insulin resistance may be present, however, insulin resistance is exaggerated when obesity is present. [10] Additionally, obese adolescent girls with PCOS demonstrate more significant insulin resistance and hyperinsulinemia compared to patients who are obese but do not carry a diagnosis of PCOS.[4] Genetics
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To date, greater than 100 candidate genes have been implicated in the pathophysiology of PCOS, with particular focus on genes affecting the biosynthesis and function of reproductive
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hormones, cellular metabolism and chronic inflammation. Several key genes related to steroidogenesis are implicated, including CYP17A1, CYP19, CYP21, HSD17B5 and HSD17B6. Sex hormones and their receptors are also involved. PCOS is also a metabolic disorder, with a
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strong association with type 2 diabetes, hyperlipidemia, obesity, and the metabolic syndrome. Associated metabolic candidate genes include genes related to insulin biosynthesis and
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function (INS (insulin gene), INSR (insulin receptor), IRS1 (insulin receptor substrate 1), IRS2, IGF, PPAR-g and CAPN10) as well as obesity-related genes (FTO (fat and obesity-associated gene)).[14,15] Finally, given the relationship of PCOS with a proinflammatory state, genes related to chronic inflammation are also involved, particularly inflammatory cytokines such as
inhibitor (PAI). [14,15]
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Environmental Exposures
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tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1A, IL-1B and plasminogen activator
Adding to the complexity of the pathophysiology of PCOS is the potential contribution of
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environmental exposures and lifestyle factors. Endocrine disrupting chemicals (EDCs) are defined as “substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction”.[16] EDCs are a broad class of molecules that include plasticizers such as phthlates and bisphenol A (BPA), as well as advanced glycation end products (AGEs).[17] The majority of human exposure is through food packaging, however, these molecules are also used
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in the production of medical devices. EDCs have been implicated in many disorders involving disordered male and female reproduction, abnormal breast development and cancer, prostate
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cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology.[16]
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Timing of exposure is of utmost importance, with evidence that fetuses and young children are the most susceptible to the adverse effects of EDCs.[16,18,19] Animal studies have shown that
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prenatal exposures to high levels of androgens during key points in gestation result in fetal programming of PCOS traits.[20,21] Parallels have been drawn, therefore, that exposure to androgen-like EDCs could result in metabolic dysfunction in adulthood, such as PCOS.[16] Adult exposures to EDCs may also be contributing to endocrine disruption in women with PCOS.
women.[22,23]
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Women with PCOS have been found to have higher levels of EDCs compared to ovulatory
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Diagnosis
Evolution of Diagnostic Criteria
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PCOS presents a unique diagnostic challenge in the field of gynecology, which is further complicated in the adolescent population. By its nature as a syndrome, PCOS is a collection of findings, both clinical and diagnostic, as well as a diagnosis of exclusion among other androgen excess disorders. The characterization of a patient with PCOS is made difficult by a history of variable and contradictory diagnostic criteria. Increasingly, a system of phenotypic description of the spectrum of PCOS has been proposed to standardize and aid in diagnosis.
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In 1990, the first guidelines for PCOS diagnosis were proposed at a conference sponsored by
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the National Institute of Child Health and Human Disease of the US National Institutes of Health (NIH). A panel of experts concluded that two criteria were essential for the diagnosis of PCOS: (1) hyperandrogenism and (2) oligoovulation. This remained the sole diagnostic criteria until the
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proposal of the “Rotterdam Criteria” in 2003.[24] This updated guideline concluded that for diagnosis, two of three criteria must be met: (1) signs of clinical or biochemical
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hyperandrogenism (2) oligo/anovulation and/or (3) polycystic ovaries. (Table 1) With the addition of the radiologic findings, a new cohort of patients was included in the diagnosis of PCOS: women with oligo/anovulation and polycystic ovaries, but with no evidence of hyperandrogenism. The establishment of this criteria significantly increased the prevalence of
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PCOS, as well as the variability of phenotype in the patient population.
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In 2006, the Androgen Excess Society released their own guideline proposing that hyperandrogenism is a requisite component for the diagnosis of PCOS, with the addition of
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either ovulatory dysfunction or polycystic ovaries.[25,26] They proposed that patients without hyperandrogenism who met the Rotterdam criteria did not truly represent the same pathophysiology and should therefore be excluded. The resulting discord temporarily stalled academic investigation and created clinical confusion regarding the diagnosis of PCOS.
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In an attempt to reconcile the proposed criteria, the NIH sponsored an Evidence-Based Methodology PCOS Workshop in 2012.[27] The resulting recommendations reinforced the use
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of the 2003 Rotterdam criteria, but with the addition of a phenotypic classification system to aid in clinical classification and epidemiologic research. This reinforced the core diagnostic criteria of PCOS to include (1) clinical/biochemical hyperandrogenism (HA) (2) chronic ovulatory
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dysfunction (OD) and (3) polycystic ovarian morphology (PCOM). (Table 2) The broadened term of ovulatory dysfunction contained the previously recognized oligoovulation, but also included
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polymenorrhea and abnormal uterine bleeding. As a result of the introduction and broad usage of the phenotypic system, strides in epidemiologic research have been made to further characterize the risks and long term health effects of PCOS, including reproductive abnormalities, endometrial hyperplasia and malignancy, insulin resistance and type 2 diabetes
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anxiety/depression.
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mellitus, coronary heart disease, dyslipidemia and cerebrovascular morbidity, and
In 2016, Lizneva et al further refined the phenotypic approach.[28] They proposed three PCOS
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phenotypes based on the 2012 modified Rotterdam criteria: “Classic” PCOS (phenotypes A/B), “Ovulatory PCOS” (phenotype C), and “Nonhyperandrogenic PCOS” (phenotype D). (Table 2) “Classic PCOS” accounted for more than 2/3 of women diagnosed with PCOS in their study. Compared to the other phenotypes, women with “Classic PCOS” appeared to have more severe symptoms, as well as an increased risk of significant long term health effects such as pronounced menstrual dysfunction, higher rates of insulin resistance, higher prevalence of
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obesity and more severe dyslipidemia.[28] Women with “Ovulatory PCOS” had an intermediate severity of symptoms and long term health risks, while women with “Nonhyperandrogenic
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PCOS” had the mildest symptoms and smallest long term health risks, though still present. This system more accurately represents PCOS as a true spectrum of findings with variable severity and long term health effects. As research continues, more accurate and patient-specific
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counseling regarding these factors will be possible. Diagnosis of PCOS in Adolescents
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As noted above, the diagnosis of PCOS is established by the presence of two out of three of the following criteria: (1) signs of clinical or biochemical hyperandrogenism (HA) (2) chronic ovulatory dysfunction (OD) and (3) polycystic ovarian morphology (PCOM). However, the adolescent population requires special consideration, as these criteria were developed for
Laboratory Evaluation
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diagnosis in adults; during adolescence, PCOS can present differently.
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The most prevalent characteristic seen in adolescents is hyperandrogenism.[29] Contrary to the
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adult population, the sole presence of acne and/or hirsutism should not be considered clinical evidence of hyperandrogenism in adolescent girls. However, more severe cases of such clinical findings could be an indication of hyperandrogenism. For example, comedal acne and mild hirsutism is common in all adolescent females. Moderate-severe inflammatory acne (defined as more than 11 inflammatory lesions) unresponsive to topical medications and moderate-severe hirsutism (based on Ferriman-Gallwey scoring system) would be an indication to initiate testing for hyperandrogenism.[30]
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Biochemical assessment of hyperandrogenism requires reliable assays with well-defined cut
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offs. Measurements of serum testosterone levels are recommended as the initial step in evaluating hyperandrogenism.[29] Free testosterone is the bioactive portion of serum total testosterone, making it the most sensitive indicator for elevated androgen levels. The
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circulating level of free testosterone is governed by sex hormone binding globulin (SHBG) which is affected by several physiological conditions. Other serum androgens such as
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androstenedione and DHEA-S are widely measured, but the cost effectiveness of routinely measuring an extensive array of androgens has not been well substantiated.[30] Shortly after menarche, serum testosterone reaches adult levels, making use of adult reference ranges appropriate.[30] There are several factors that make the interpretation of these lab results
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challenging, however. This includes lack of testosterone assay standardization among hospitals and laboratories as well as lack of sensitivity, specificity, and accuracy of the assays used. Clinical Symptoms
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Irregular menses and anovulatory cycles can be seen in the early stages of normal maturation of the hypothalamic-pituitary-ovarian axis. In the first year after menarche, approximately 85%
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of menstrual cycles are anovulatory, dropping to 25% six years after menarche.[29] Nevertheless, approximately two-thirds of adolescents with PCOS will present with menstrual symptoms. While difficult to differentiate oligomenorrhea due to PCOS from that of normal physiology, cycles outside 19 to 90 days, lack of menses by 16 years or 2-3 years after thelarche, and persistent oligomenorrhea 2 years beyond menarche require further evaluation.[30]
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It is critical to keep in mind that PCOS is a diagnosis of exclusion. Evaluation of women with suspected PCOS should exclude alternative disorders that can lead to androgen excess such as
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androgen-secreting tumors, either in the adnexa or adrenal glands, or congenital adrenal hyperplasia. There is agreement that screening for non-classic congenital adrenal hyperplasia (NCCAH) is prudent in women presenting with symptoms of PCOS. NCCAH accounts for 1-4% of
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patients with hyperandrogenic anovulation in reproductive age women.[30] Follicular phase 17OHP levels should be the initial screening tool in these patients. Levels higher than 200 ng/dL
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are concerning for NCCAH, with a 92-98% sensitivity.[30] Such a finding should be confirmed with an ACTH stimulation test. For patients with rapid progression of central obesity, hirsutism, or hypertension, Cushing syndrome should be considered. Late-night salivary cortisol, 24-hour urinary free cortisol excretion, or an overnight 1 mg dexamethasone suppression test are
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appropriate screening tests for Cushing syndrome. Screening for hypothyroidism and hyperprolactinemia are also recommended as they can present with menstrual irregularity.[30] The extent of evaluation and screening should be individualized based on patient presentation
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Imaging
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and associated symptomatology.
In the adult population, the role of imaging in diagnosing PCOS has been well established. Histopathologically, polycystic ovarian morphology (PCOM) is due to an excess number of small follicles that arrest before the preovulatory stage of development. PCOM is defined as an antral follicle count (follicles measuring 2-9mm) ≥12 in at least one ovary or an ovarian volume of >10.0 cm3.[24] However, ovaries with multiple follicles are normal and commonly seen around the time of menarche; approximately 50% of normal adolescents would meet the criteria of
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polycystic ovarian morphology.[31] Furthermore, anovulatory cycles due to inconsistent recruitment of a dominant follicle in the early years post menarche can contribute to the
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multifollicular appearance of the ovaries characteristically seen during puberty.[32]
In the adolescent population, the diagnosis of PCOS should not be based solely upon the
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symptoms of anovulation and polycystic-appearing ovaries on ultrasound, particularly within two years of menarche.[29] The Endocrine Society guidelines caution against the use of PCOM
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as diagnostic criteria for adolescents.[29] However, imaging can be used as a confirmatory test for adolescents in whom the diagnosis of PCOS remains uncertain after clinical and laboratory evaluation.
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Ultrasound. Transvaginal ultrasound (TVUS) is the modality of choice for evaluation of pelvic anatomy in the adult female population. (Figure 1) While optimal for evaluating pelvic anatomy, careful consideration should be taken prior to attempting a transvaginal ultrasound in an
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adolescent, particularly if she is virginal. Alternatively, performing a transabdominal ultrasound (TAUS) in an obese adolescent is technically challenging and often does not provide reliable
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imaging of the ovaries.[33] As a result, an antral follicle count it difficult to define by this modality.[32]
Magnetic Resonance Imaging (MRI). Compared to ultrasound, MRI in the adolescent population provides the most accurate view of the ovaries. (Figure 2) This modality has the advantage of being accessible for all ages given its noninvasive nature. In a study comparing
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obese adolescents with PCOS to obese adolescents without PCOS, it was demonstrated that MRI findings using Rotterdam criteria had a specificity of 77-82%.[34] In patients with uncertain
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clinical and laboratory findings, MRI can be considered as an accurate diagnostic imaging modality. However, MRI is significantly more expensive than ultrasound making routine
well established.
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MANAGEMENT
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ordering impractical. Additionally, normal values and cutoffs for its use in this instance are not
Management of PCOS in adolescents is multimodal, requiring consideration of lifestyle modification as well as pharmacotherapy.
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Lifestyle modification
Approximately 50% of patients with PCOS are overweight or obese, which is an important association as obesity itself is linked to an increased risk for type 2 diabetes, hypertension,
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cardiovascular disease, and menstrual dysfunction.[4,35,36] Lifestyle modification comprised primarily of a calorie-restricted diet and/or physical activity has proven effective in altering the
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disease course in PCOS.[29] Studies comparing exercise as an intervention to treat PCOS typically recommend 30 to 45 minutes of vigorous exercise 3 times per week.[37,38]
A meta-analysis of 583 PCOS patients demonstrated improvement in fasting glucose and insulin levels in patients undergoing lifestyle modification, which was comparable to patients who were treated with metformin.[35] Likewise, in a randomized trial comprised of 150 women with
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PCOS, improved insulin sensitivity indices were demonstrated in women who participated in a 6-month structured exercise training program. Compared to baseline, these women
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demonstrated improvement in intima media thickness (a cardiovascular marker predisposing to atherosclerosis), lipid profile, cardiopulmonary function, and frequency of menses.[37]
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In 2013, guidelines set forth by an Endocrine Society-appointed Task Force of experts
recommended lifestyle modification, with an objective of weight loss, as a first-line treatment
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for adolescent PCOS patients in the presence of overweight/obesity.[29] In normal weight women with PCOS, it is still unclear as to whether lifestyle modification will improve some aspects of the PCOS phenotype.[35] Consensus guidelines caution that for these women,
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weight loss therapy alone is likely insufficient.[29]
While there are few studies that have examined the effects of lifestyle modification in adolescents with PCOS, the results appear promising. A randomized, placebo-controlled trial
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was performed to evaluate the impact of multiple treatment modalities on PCOS in obese adolescent girls ages 12-18. One arm of this trial randomized 43 patients to a single
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intervention including metformin, placebo, a lifestyle modification program, or combined oral contraceptives (COC). With lifestyle modification alone, there was a 59% reduction in free androgen index (FAI) and 122% increase in SHBG.[38] Another prospective study sought to analyze the impact of a 1 year lifestyle intervention on menstrual irregularity, hyperandrogenism, cardiovascular risk factors and intima-media thickness in obese adolescent girls with PCOS aged 12-18 years. Of the 59 patients who completed the intervention at 1 year,
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26 patients had weight loss (reduction in BMI by mean 3.9 kg/m2), while 33 patients did not have weight loss. Researchers found that in the cohort with weight loss, the prevalence of
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amenorrhea and oligomenorrhea decreased by 42% and 19%, respectively. Additionally, this cohort also had significantly decreased testosterone concentrations and increased SHBG
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concentrations compared to patients without weight loss.[39]
It should be acknowledged that the adolescent population presents a challenge in regard to
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compliance with a diet and exercise regimen. Previous studies have utilized cohorts of adolescents and one support person, typically a parent, who attended classes instructing them in diet, exercise, and behavioral changes.[38] Greater success was seen when adolescents were encouraged to correspond outside of the instructional settings.[38] Social media can be utilized
period has ended.
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Medical Therapy
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to connect adolescents and encourage continued lifestyle changes after the intervention time
Combined hormonal contraceptives (CHCs). Combined hormonal contraceptives (CHCs), which
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contain both an estrogen (ethinyl estradiol) and a progestin, have traditionally been the firstline therapy for adolescents diagnosed with PCOS. Combined oral contraceptives (COCs) are most commonly prescribed; however, other routes of delivery are available, including the patch or vaginal ring. There is no evidence to suggest one delivery method is superior to the other, making patient preference an appropriate guide. There is also limited data to recommend the duration of CHC use in adolescents.[40] It is imperative to screen for contraindications prior to
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employing CHCs as a treatment strategy for PCOS. For example, certain comorbidities such as prior history of deep venous thromboembolism/pulmonary embolism or migraine headaches
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with aura would make estrogen-containing therapies contraindicated.[41]
In appropriately selected patients, CHCs convey multiple benefits for an adolescent with PCOS.
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CHCs have an anti-androgenic effect. The estrogen component acts to increase SHBG, which reduces the bioavailable testosterone by binding the free steroid, ultimately decreasing
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symptoms of androgen excess. The progestin suppresses LH levels, leading to a downstream decrease in ovarian androgen production. Progestins additionally inhibit 5α-reductase activity, resulting in less peripheral conversion of testosterone to dihydrotestosterone (DHT), the androgen most responsible for hirsutism.[42] In a study that compared exercise to CHCs in
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patients with PCOS, hirsutism, serum free testosterone, and FAI were significantly decreased in the CHC group (p<0.05).[37] While some progestins, such as drosperinone, have intrinsic antiandrogenic properties, the concentration of progestin in CHCs is low. In randomized
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studies, clinical benefit of anti-androgenic progestins have not been significant when compared
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to other forms of progestin.[43]
CHCs also result in menstrual regulation and endometrial protection. Adolescents with PCOS frequently have irregular and heavy menstrual cycles, which can be disruptive to their daily life. Placing them on a form of CHC can act to regulate their cycles, leading to more predictable and lighter periods. PCOS is often a cause of primary amenorrhea, and for girls with evidence of hyperandrogenism who demonstrate advanced stages of pubertal development (e.g. Tanner
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Stage IV breast development) but have not yet begun to menstruate, the recommendation is to start CHCs.[29] Adolescents who are sexually active have the secondary benefit of a
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contraceptive method. If delivered orally, however, it requires responsibility on the part of the patient to be compliant with a daily pill.
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CHCs can also improve a patient’s lipid profile. While no data are available for long-term effects, in the short term, an increase in HDL cholesterol is a favorable aspect of the estrogen
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component of CHCs. Total cholesterol and LDL-cholesterol are decreased for users of CHCs.[37]
Metformin. Metformin is another commonly prescribed medication for adolescents with PCOS. Metformin is a biguanide commonly used to treat Type 2 Diabetes Mellitus, which acts to
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decrease glucose production in the liver and increase the sensitivity of peripheral tissue to insulin.[44,45] Studies are limited for long-term use in adolescents. Metformin’s largest impact is improvement in glucose tolerance and other components of the metabolic syndrome that
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can be seen in both obese and non-obese adolescents with PCOS. Approximately 18-24% of
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adolescents with PCOS have abnormal glucose metabolism.[46]
The role of metformin in the management of PCOS was evaluated in a small, randomized placebo-controlled trial. Seventy-nine obese adolescents were randomized to a single treatment trial of various interventions on clinical and laboratory characteristics seen in PCOS patients. Interventions included Metformin, COCs, lifestyle modification and placebo alone.
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With metformin, there was a significant difference from baseline in improving triglycerides and
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fasting blood glucose, though notably, COCs were more effective.
Menstrual regularity is also improved with metformin therapy in adolescents. In individuals who have a contraindication to CHCs, metformin is an excellent second line option for
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significantly improve hirsutism or acne.[29]
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improvement in irregular cycles, though it does not exert any anti-androgen effects and will not
Spironolactone. Spironolactone is another adjunctive medication used to treat those with PCOS and hirsutism. This drug is an aldosterone-antagonist diuretic. Its mechanism of action includes inhibiting ovarian and adrenal biosynthesis of androgens, directly competing for the androgen
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receptor in the hair follicle and inhibiting 5α-reductase activity.[47] Effects are dose-dependent and occur over about six months of treatment. Side effects are common, and low doses (25 mg/day) are recommended to minimize hypotension, tachycardia and vaginal spotting.[48] This
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medication should not be used in adolescents with hyperkalemia or with other drugs that increase the level of potassium, but monitoring is not required in those with normal renal
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function. An effective form of contraception is essential given the risk for fetal virilization with spironolactone if pregnancy were to occur. To date, no studies have evaluated this medication in the adolescent population; however, studies in adults have shown significant beneficial effects in reducing DHEAS level and hirsutism score with the addition of low-dose spironolactone to patients with PCOS already taking metformin.[48]
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The authors’ recommendation for treatment would be to take a shared decision-making approach with the adolescent and their guardian as appropriate. Discussion should focus on
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which symptoms are most bothersome to the patient in order to determine the optimal treatment approach. Clinicians must also recognize that PCOS is a metabolic process and
comprehensive treatment will target underlying glucose intolerance and weight loss. Exercise
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pharmacologic modalities as appropriate.
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and dietary modifications should always be encouraged as a primary treatment with adjunctive
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SUMMARY Polycystic ovary syndrome (PCOS) is a heterogenous condition that typically manifests with a
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combination of menstrual dysfunction and hyperandrogenism in the adolescent population. The etiology is unclear but evidence suggests a combination of genetic, metabolic and
environmental factors. Ovarian androgen production is disordered, leading to increased
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synthesis of testosterone in proportion to estrogen. Insulin resistance can affect the hormonal milieu and contribute to arrest of follicular maturation, which is accentuated in obese
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adolescents. Diagnosis of PCOS is challenging in adolescents as the immaturity of the hypothalamic-pituitary access and other normal pubertal changes present similarly to an adolescent with PCOS.
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Optimal treatment utilizes a multi-modal approach, incorporating lifestyle changes and exercise in both the obese and non-obese adolescent. Pharmacologic therapies can address bothersome symptoms associated with PCOS. CHCs are utilized for menstrual regulation and also benefit the
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adolescent by decreasing testosterone levels through a rise in sex hormone binding globulin. Metabolic dysfunction can be mitigated with metformin, which demonstrates weight loss and
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improved glucose tolerance in its users in randomized trials. Spironolactone can aid in the treatment of hirsutism and acne.
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ACKNOWLEDGEMENTS: Ultrasound images: Kathleen Gustafson, Supervisor, Imaging Services, Magee-Womens Hospital of UPMC
Stephanie Rothenberg, MD – Conflicts of interest: None Emily Barnard, DO – Conflicts of interest: None Rachel Beverley, MD – Conflicts of interest: None
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Massoud Baradaran-Shoraka, BS – Conflicts of interest: None
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CONFLICT OF INTEREST STATEMENT:
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MRI images: Christiane Hakim, MD, Department of Radiology, Magee-Womens Hospital of UPMC
Joseph Sanfilippo, MD, MBA – Conflicts of interest: None
PRACTICE POINTS:
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Anovulation and polycystic ovarian morphology can be normal in young women. Diagnosis of PCOS in adolescents should be made with persistent oligomenorrhea and evidence of hyperandrogenism Other disorders that lead to androgen excess should be considered and excluded prior to diagnosing PCOS In the adolescent population, the diagnosis of PCOS should not be based solely upon polycysticappearing ovaries on ultrasound, particularly within two years of menarche. Imaging can be used as a confirmatory test but should not be the first step of evaluation. Exercise and dietary modifications should always be encouraged as primary and adjunctive treatment to pharmacologic therapies. First line medical therapy includes combined hormonal contraceptives. In select populations, spironolactone and metformin can be considered
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• •
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RESEARCH AGENDA: -Relationship between obesity and development of PCOS -Relationship between endocrine disrupting chemicals and PCOS
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-Long term risk factors for PCOS based on phenotype -Long term cardiovascular and metabolic outcomes in women diagnosed with PCOS as adolescents -Normal values and cutoffs for MRI evaluation of the ovaries
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-The benefit of lifestyle modification in normal weight adolescents with PCOS -Effects of long term use of metformin in adolescents with PCOS
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-Efficacy and safety profile of spironolactone in adolescents with PCOS
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randomized controlled trial. Clin Endocrinol (Oxf). 2016; Hoeger K, Davidson K, Kochman L, et al. The Impact of Metformin, Oral Contraceptives, and Lifestyle Modification on Polycystic Ovary Syndrome in Obese Adolescent Women in Two Randomized, Placebo-Controlled Clinical Trials. J Clin Endocrinol Metab. 2008;
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ESRE/ASRM 2003 Diagnostic Criteria for PCOS [24] “Rotterdam Criteria” Patient must meet 2 out of 3 criteria
Oligo- or anovulation
(2)
Clinical and/or biochemical signs of hyperandrogenismi
(3)
Polycystic ovariesii and exclusion of other etiologiesiii
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i- Hirsutism, severe acne and/or elevation of total/free testosterone or DHEA-S ii- Presence of 12 or more follicles in each ovary measuring 2-9 mm in diameter and/or increased ovarian volume (>10cm3) iii- Including congenital adrenal hyperplasia, androgen-secreting tumors, Cushing’s syndrome
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Phenotype A: HA + OD + PCOM Phenotype B: HA + OD
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Phenotype C: HA + PCOM Phenotype D: OD +PCOM
Lizneva 2016 [28]
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NIH 2012 extension of ESHRE/ASRM 2003 [27]
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The Phenotypic System of PCOS Diagnosis
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HA: clinical and/or biochemical hyperandrogenism OD: ovulatory dysfunction PCOM: polycystic ovarian morphology
“Classic” PCOS
“Ovulatory” PCOS
“Nonhyperandrogenic” PCOS
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Ultrasound appearance of polycystic ovaries
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MRI appearance of polycystic ovaries
Images courtesy of
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PCOS is a metabolic disorder The pathophysiology of PCOS is multifactorial Diagnosis in adolescents requires persistent oligomenorrhea and hyperandrogenism Exercise and dietary modifications are considered first line therapy in obese PCOS patients Medical therapy includes combined hormonal contraceptives, spironolactone and metformin
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• • • • •