Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hyperandrogenism and chronic anovulation. Depending on diagnostic criteria, 6% to 20% of reproductive aged women are affected. Symptoms of PCOS arise during the early pubertal years. Both normal female pubertal development and PCOS are characterized by irregular menstrual cycles, anovulation, and acne. Owing to the complicated interwoven pathophysiology, discerning the inciting causes is challenging. Most available clinical data communicate findings and outcomes in adult women. Whereas the Rotterdam criteria are accepted for adult women, different diagnostic criteria for PCOS in adolescent girls have been delineated. Diagnostic features for adolescent girls are menstrual irregularity, clinical hyper- androgenism, and/or hyperandrogenemia.
The female hypothalamic-pituitary–ovarian (HPO)axis is a meticulously synchronized and tightly regulated network ultimately responsible for reproductive competence and survival of the species. The HPO axis responds to internal signals (i.e., hormonal and neuronal) and external factors (i.e., environment influences). Beginning during gestation, these factors impact future generations through epigenetic factors affecting the brain and the developing germ cells
Polycystic ovary syndrome (PCOS), a disorder primarily characterized by signs and symptoms of androgen excess and ovulatory dysfunction, disrupts HPO axis function.Typical clinical features include hirsutism, irregular mens chronic anovulation, and infertility. The persistent hyperandrogenism is associatedwith impaired hypothalamic–pituitary feedback, LH hypersecretion, premature granulosa cell luteinization, aberrant oocytematuration,and premature arrest of activated primary follicle.
By the time the diagnosis is established, PCOS presents as a phenotype reflecting a self- perpetuating vicious cycle involving neuroendocrine, metabolic, and ovarian dysfunction. Over the years, numerous hypotheses have been proposed regarding the proximate physiologic origins for PCOS. PCOS reflects the interactions among multiple proteins and genes influenced by epigenetic and environmental factors. PCOS develops during the early pubertal years.
Fig :1 Factors potentially Impacting pathophysiology of PCOS are shown in the circle
PCOS is characterized by excessive ovarian and/or adrenal androgen secretion. Intrinsic ovarian factors such as altered steroidogenesis and factors external to the ovary such as hyperinsulinemia contribute to the excessive ovarian androgen production. Characteristic features include more growing follicles in women with PCOS compared with normal controls with premature growth arrest of antral follicles at 5 to 8 mm. The stages of follicular maturation are briefly reviewed (Fig. 2). Developing during gestation, primordial follicles are comprised of meiotically arrested oocytes surrounded by pregranulosa cells. Hence, a woman’s ovaries have been exposed to the ambient maternal environment during gestation. Ovaries are relatively quiescent until the onset of puberty.
Presumably a balance of factors influences the options—continuation in a resting state or activation. One such factor appears to be follicle density. Following activation from the resting pool, initial follicular growth is gonadotropin-independent until the antral stage.
Anti-Mu¨ llerian hormone (AMH), a glycoprotein secreted by granulosa cells, inhibits initial follicular recruitment and indicates follicular reserve. Once FSH-stimulated granulosa cell estradiol concentrations achieve the necessary threshold, estradiol suppresses AMH expression.
Figure 2. Ovarian follicle development. This illustration shows ovarian follicular development during developmental periods.
Increased LH pulse frequency, LH pulse amplitude, and increased LH/FSH ratios are de- scribed in women with PCOS. The initial features of PCOS emerge during the early pubertal years, concomitant with reactivation of the hypothalamic GnRH pulse generator, increased gonadotropin secretion, and subsequent increased ovarian estrogen production.Rather than initiating puberty, the GnRH pulse generator and GnRH neurons represent downstream nodes modulated by other hormones and neurosecretory factors. In other words, activation of excitatory inputs and in- activation of inhibitory inputs moderated by multiple influences regulate the output of the GnRH pulse generator to govern the timing of puberty. This process culminates in increased GnRH and gonadotropin secretion.
Valproic acid (VPA), a branched short-chain fatty acid derived from valeric acid, is used to treat epilepsy,bipolar disorders, and prevent migraine headaches.VPAincreases GABA levels by interfering with GABA degradation pathways.GABA signaling could influence the neuroendocrine changes associated with PCOS such as LH pulse frequency.
Insulin is the hormone primarily responsible for glucose homeostasis and lipogenesis.In addition to its effects on carbohydrate, fat, and protein metabolism, insulin functions as a mitogenic hormone. Insulin actions are mediated by insulin receptors, which are found in numerous tissues of the HPO axis. In steroidogenic tissues such as the ovary and the adrenal cortex, insulin potentiates the cognate trophic hormones to promote steroidogenesis. This leads to the paradox of insulin signaling in PCOS; liver, skeletal muscle, and adipose tissue exhibit IR, whereas steroid-producing tissues and the pituitary retain insulin sensitivity.The prevalence of the metabolic syndrome defined as obesity, hypertension, dyslipidemia, and hyperglycemia is approximately threefold higher in women with PCOS. Although a consensus definition of metabolic syndrome in adolescents include a combination of elevated triglyceride concentration, elevated low high-density lipoprotein cholesterol concentration, fasting blood glucose 110 mg/dL, increased waist circumference.
Overweight and obesity are common among adolescent girls and adult women with PCOS. In response to nutrient excess, adipocytes can enlarge (hypertrophy) or form new adipocytes(hyperplasia). Early b-cell dysfunction in first-degree female relatives with overweight/obesity of women with PCOS compared with control girls with overweight/obesity
The developmental theory of PCOS proposes that exposure of the female fetus to elevated androgen concentrations contributes to the development of PCOS. Potential mechanisms include effects on steroidogenesis, insulin signaling, pancreatic b-cell function, hypothalamic– pituitary organization, neuroendocrine secretory patterns, and epigenetic modifications Fetal, neonatal, prepubertal, and/or pubertal ovaries may be genetically predisposed to increased androgen secretion.
The classic features of PCOS include clinical or biochemical hyperandrogenism, oligome- norrhea or amenorrhea associated with chronic anovulation, and polycystic ovary syndrome morphology [122]. However, delineating appropriate diagnostic criteria for PCOS among adolescent girls has been problematic because irregular menses, cystic acne, mild hyperandrogenis.
Multifollicular ovarian morphology occur during normal pubertal maturation.
With reactivation of the GnRH pulse generator, increased gonadotropin secretion stimulates ovarian estrogen secretion and follicular development. Estrogen promotes uterine growth and endometrial proliferation; endometrial estrogen exposure eventually culminates in vaginal withdrawal bleeding and menarche.
Hirsutism, defined as excessive terminal hair growth in male pattern distribution in women, is the primary clinical sign of hyperandrogenism. The extent of the clinical features of hyperandrogenism represents the interactions between circulating androgen. concentrations, local androgen concentrations, and sensitivity of the pilosebaceous unit/hair follicle to androgens. The severity of hirsutism does not correlate with circulating androgen concentrations.
Polycystic ovary morphology (PCOM) is defined as enlarged ovaries with increased stroma and more small peripheral cysts. assessment of ovarian morphology is difficult in the adolescent girl because the increased gonadotropin stimulation leads to increased ovarian volume and follicular growth, giving rise to the appearance of multifollicular ovaries in adolescent girls.
The approach to the evaluation of a girl with signs and symptoms suggestive of PCOS begins with a thorough history, including detailed family history and complete physical exami- nation. The individualized laboratory evaluation typically includes thyroid function studies as well as the determination of prolactin, total testosterone, androstenedione, SHBG, DHEAS, and 17-hydroxyprogesterone concentrations. Direct free testosterone assays should be avoided due to inadequate sensitivity, accuracy, and reproducibility of available assays. Fasting glucose, HbA1c, and lipid concentrations should be determined.
Adolescents presenting with PCOS features, before the diagnosis is confirmed, often require management of their symptoms [125–127]. The management of adolescents with a clear diagnosis of PCOS should include education about the condition and lifestyle interventions. The interventions can be individualized to target the foremost complaints and symptoms.Interventions include metformin, combined oral contraceptive pills (COCPs), spironolactone, and local treatments for hirsutism and acne. Management should also include management of comorbidities, regular follow-up, and a plan for transition.
With reactivation of the GnRH pulse generator, increased gonadotropin secretion stimulates ovarian estrogen secretion and follicular development. Estrogen promotes uterine growth and endometrial proliferation; endometrial estrogen exposure eventually culminates in vaginal withdrawal bleeding and menarche.
Hirsutism, defined as excessive terminal hair growth in male pattern distribution in women, is the primary clinical sign of hyperandrogenism. The extent of the clinical features of hyperandrogenism represents the interactions between circulating androgen. concentrations, local androgen concentrations, and sensitivity of the pilosebaceous unit/hair follicle to androgens. The severity of hirsutism does not correlate with circulating androgen concentrations.
Polycystic ovary morphology (PCOM) is defined as enlarged ovaries with increased stroma and more small peripheral cysts. assessment of ovarian morphology is difficult in the adolescent girl because the increased gonadotropin stimulation leads to increased ovarian volume and follicular growth, giving rise to the appearance of multifollicular ovaries in adolescent girls.
The approach to the evaluation of a girl with signs and symptoms suggestive of PCOS begins with a thorough history, including detailed family history and complete physical exami- nation. The individualized laboratory evaluation typically includes thyroid function studies as well as the determination of prolactin, total testosterone, androstenedione, SHBG, DHEAS, and 17-hydroxyprogesterone concentrations. Direct free testosterone assays should be avoided due to inadequate sensitivity, accuracy, and reproducibility of available assays. Fasting glucose, HbA1c, and lipid concentrations should be determined.
Adolescents presenting with PCOS features, before the diagnosis is confirmed, often require management of their symptoms . The management of adolescents with a clear diagnosis of PCOS should include education about the condition and lifestyle interventions. The interventions can be individualized to target the foremost complaints and symptoms.Interventions include metformin, combined oral contraceptive pills (COCPs), spironolactone, and local treatments for hirsutism and acne. Management should also include management of comorbidities, regular follow-up, and a plan for transition to adult care providers.
Education and counseling about the condition is very important. The explanation and dis- cussion of PCOS should be culturally sensitive as well as appropriate, comprehensive, and tailored to the individual.It should include an empathetic approach, promote self-care, and highlight peer support groups. Counseling about fertility concerns is important, as adolescents with PCOS are more con- cerned than theirs peers about future fertility after diagnosis.
Healthy lifestyle interventions must be incorporated in the management plan of all ado- lescents with PCOS because a large proportion of these adolescents are overweight/ obese or are at risk for gaining excessive weight.Lifestyle interventions comprise multiple components, including healthy diets, physical activity, decreased sedentary behaviors, and behavioral strategies.The interventions should also include the family, as parents’ involvement and their readiness to change affect adolescent outcomes. Engagement and adherence to lifestyle interventions can be improved by management of psychological factors such as anxiety, body image concerns, and disordered eating, which are common in adolescents.
Metformin is the single most studied insulin sensitizer in PCOS. It is commonly used in adolescents 15 to 19 years of age despite being “off label” for this indication. Metformin at a dose of 1700 to 2000 mg/d is associated with greater improvement of BMI, and COCPs are associated with improvement in menstrual irregularity and acne. Both metformin and oral contraceptives had similar beneficial effects on hirsutism, triglycerides, and high-density lipoprotein cholesterol.
Acknowledgment of the significance of the hirsutism, irrespective of the severity, for a particular adolescent is important when offering treatment options as well as understanding expectations of the treatment.Physical hair removal methods include waxing, shaving, chemical epilation, plucking, bleaching, and electrolysis. All but electrolysis are temporary hair removal methods, easily available and commonly used by adolescents even before they are evaluated for PCOS. Electrolysis is a permanent hair removal method, as it causes destruction of hair bulb, but it requires an experienced technician and can cause scaring and pigmentation changes. Topical medications such as 13.9% eflornithine cream, an irreversible inhibitor of ornithine decarboxylase, affects hair follicle growth and differentiation and can improve mild facial hirsutism in women with mild skin irritation.Professional light-based therapies include lasers (alexandrite, diode, and neodymium- doped yttrium aluminum) and intense pulsed light. These light therapies provide wave- lengths of 600 to 1100 nm that are absorbed by the melanin in the hair and destroy the hair. This approach provides a prolonged solution for hirsutism after multiple treatments. The light can also be absorbed by epidermal melanin, which is greater in darker skinned individuals, increasing the risk of blisters, dyspigmentation.
Treatment will be guided by severity of acne with the following goals of treatment: reduction of sebum production, prevention of formation of microcomedones, suppression of Propioni- bacterium acnes, and reduction of inflammation to prevent scaring . Mild acne can be managed initially with over-the-counter topical treatments such as benzoyl peroxide 0.1%/ 2.5% (Epiduo gel) or topical retinoids or the combination of the two agents as well as ap- propriate skin care. Moderate and severe forms of acne require the addition of systemic antibiotics (macrolides) for 3 or 4 months but discontinuation after new inflammatory lesions have stopped appearing.
Additional comorbidities can occur in adolescents with PCOS that might be independent of overweight status.These comorbidities include impaired glucose tolerance and type2diabetes.Additional comorbidities include decreased quality of life, depression, anxiety, eating disorders and disordered eating, and altered body image. Identification of IR, hyperinsulinemia, and obesity galvanizes efforts to investigate and initiate treatment of associated comorbidities such as impaired glucose tolerance, type 2 diabetes mellitus, dyslipidemia, and sleep apnea. Adequate screening for comorbidities should be guided by symptoms, clinical examination, and specific personal and family risks factors.
Preparation for transition to adult care will require reinforcement of education about PCOS, its comorbidities, lifestyle interventions, medical treatment, and the need of long-term follow-up.Women with PCOS are best managed by multidisciplinary health care teams comprised of endocrinologists, general physicians, gynecologists, family doctors, or general practitioners. Therapeutic options should be discussed with the adolescent or emerging adult. The selection of an appropriate specialist for adult care should be based on adolescent preferences and major complaints, local availability of health care professionals or specialized clinics, health care insurance, and the possible need of fertility management in the near future.
PCOS is a complex disorder involving multiple organ systems with onset during the early pubertal years.The list of factors involved in the pathophysiology continues to ex- pand, with accruing evidence indicating that hyperandrogenism is a pivotal factor affecting multiple tissues.At this time, an individualized treatment plan can be developed for the adolescent girl with features of PCOS. Attention to the history, physical examination, and laboratory data is important to identify adolescent girls at risk to develop PCOS. Whereas deferring diagnostic labeling may be appropriate, treatment of clinical features and comorbidities is vital to the health and self-esteem of these patients. One future goal includes prevention through timely identification of at-risk prepubertal and early pubertal girls through lifestyle interventions.
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