Polycystic ovarian syndrome (PCOS) is the most common endocrine pathology in the reproductive age female around the world. Stein and Leventhal initially described it in 1935. The prevalence ranges around 5% to 15% depending on the diagnostic criteria applied. It is widely accepted among specialty society guidelines that the diagnosis of PCOS must be based on the presence of at least two of the following three criteria: chronic anovulation, hyperandrogenism (clinical or biological), and polycystic ovaries. It is a diagnosis of exclusion and disorders that mimic clinical features of PCOS must be excluded. These include thyroid disease, hyperprolactinemia, and non-classical congenital adrenal hyperplasia. Selected patients may need more extensive workup if clinical features suggest other causes.
Despite its high prevalence, PCOS is underdiagnosed and frequently takes more than one visit or different physicians to get identified, and these usually occur in more than a one-year timeframe. It is a very frustrating process for the patient. Delay in diagnosis can lead to progression of comorbidities making more difficult to implement lifestyle intervention, which is critical for improvement of features of PCOS and quality of life.
Multiple morbidities are associated with PCOS including infertility, metabolic syndrome, obesity, impaired glucose tolerance, type 2 diabetes mellitus (DM-2), cardiovascular risk, depression, obstructive sleep apnea (OSA), endometrial cancer, and nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis (NAFLD/NASH). There are different screening recommendations for each of these pathologies, but the clinician must have a low threshold for workup if any manifestation is shown in PCOS patients.
PCOS is a multifactorial disease. Several susceptible genes have been identified as contributors to the pathophysiology of the disease. These genes are involved in various levels of steroidogenesis and androgenic pathways. Twin studies have estimated about 70% heritability. Also, the environment is a fundamental component in the expression of these genes and development and progression of the disease.
Two popular hypotheses postulate that individuals with a genetic predisposition exposed to certain environmental factors lead to the expression of PCOS features. Most common environmental factors include obesity and insulin resistance. Some hypotheses also include fetal androgen exposure.
PCOS is the most common endocrine pathology in the reproductive-aged female around the world. The prevalence ranges around 5% to 15% depending on the diagnostic criteria. Rotterdam criteria include a broader prevalence than National Institute of Health 1990 Criteria. Based on the NIH 2012 workshop report, it is estimated that PCOS affects about 5 million reproductive-aged females in the United States, and the cost to the healthcare system for diagnosing and treating PCOS is approximate $4 billion annually not including the cost of serious comorbidities associated with PCOS.
Multiple conditions have been associated with PCOS including infertility, metabolic syndrome, obesity, impaired glucose tolerance, DM-2, cardiovascular risk, depression, OSA, endometrial cancer, NAFLD/NASH. Higher prevalence has been associated in first-degree relatives with PCOS, prepubertal obesity, congenital virilizing disorders, above average or low birth weight for gestational age, premature adrenarche, use of valproic acid as an antiepileptic drug. Studies have also suggested that there is a higher prevalence in Mexican-Americans than non-Hispanic whites and African Americans.
PCOS is a hyperandrogenic state with oligo-anovulation that cannot be explained by any other disorder. It is a diagnosis of exclusion. Nevertheless, it accounts for the majority of hyperandrogenic presentations.
Nearly all causes of PCOS are due to functional ovarian hyperandrogenism (FOH). Two-thirds of PCOS presentations have typical functional ovarian hyperandrogenism, characterized by dysregulation of androgen secretion with an over-response of 17-hydroxyprogesterone (17-OHP) to gonadotropin stimulation. The remaining PCOS with atypical FOH lack of overresponse of 17-OHP, but testosterone elevation can detect it after the suppression of adrenal androgen production. About 3% of PCOS patients have a related isolated functional adrenal hyperandrogenism. The rest of PCOS cases are mild. These lack evidence of steroid secretory abnormalities; most of these patients are obese, which practitioners postulate accounts for their atypical PCOS. Specific testing for FOH subpopulation has low clinical utility in our present day.
Functional ovarian hyperandrogenism PCOS presents with the primary features: hyperandrogenism, oligo anovulation, and polycystic ovaries morphology. Functional ovarian hyperandrogenism is multifactorial, with a combination of hereditable and environmental factors. Causes for this dysregulation include insulin excess, which is known to sensitize the ovary to luteinizing hormone (LH), by interfering with the process of homologous desensitization to LH in normal ovulation cycle, as well as, intrinsic imbalance among intraovarian regulatory systems. Theca cells in PCOS have overexpression of most steroidogenic enzymes and proteins involved in androgen synthesis, which suggested a prominent abnormality at the level and activity of steroidogenic enzymes including P450c17, which has been highly identified. Granulosa cells prematurely luteinize primarily as a result of androgen and insulin excess.
Androgen excess enhances the initial recruitment of primordial follicles into the growth pool. Simultaneously, it initiates premature luteinization, which impairs the selection of the dominant follicle. This results in classical PCOS histopathologic and gross anatomic changes that constitute PCOM. PCOS is perpetuated by increased LH but it is not caused by it. LH excess is common and is necessary for the expression of gonadal steroidogenic enzymes and sex hormone secretion, but is less likely to be primary cause of ovarian androgen excess because of LH induced desensitization of theca cells.
About one-half of patients with functional ovarian hyperandrogenism have an abnormal degree of insulin-resistant hyperinsulinism, which acts on theca cell increasing steroidogenesis and prematurely luteinizes granulosa cells and stimulates fat accumulation. Hyperandrogenemia provokes LH excess, which then acts on both theca and luteinized granulosa sustaining cycle.
Ovarian hormonal dysregulation alters the pulsatile gonadotropin-releasing hormone (GnRH) release may lead to a relative increase in LH versus follicle-stimulating hormone (FSH) biosynthesis and secretion. LH stimulates ovarian androgen production, while the relative decrease of FSH prevents adequate stimulation of aromatase activity within the granulosa cells, thereby decreasing androgen conversion to the potent estrogen estradiol. This becomes a self-perpetuating noncyclic hormonal pattern.
Elevated serum androgens are converted in the periphery to estrogens, mostly estrone. As conversion occurs primarily in the stromal cells of adipose tissue, estrogen production will be augmented in obese PCOS patients. This conversion results in chronic feedback at the hypothalamus and pituitary gland, in contrast to the normal fluctuations in feedback observed in the presence of a growing follicle and rapidly changing levels of estradiol. Unopposed estrogen stimulation of the endometrium may lead to endometrial hyperplasia.
A complete history and physical exam are critical for diagnosis of PCOS. Two out of three diagnostic criteria rely on history and physical exam which includes menstrual history and features of hyperandrogenism. Additionally, PCOS represents a diagnosis of exclusion, identifying clinical presentation of other conditions should be done.
Most society guidelines have accepted that diagnosis of PCOS; most meet two out of three criteria: chronic anovulation, (clinical or biological hyperandrogenism, and polycystic ovaries morphology in the absence of any other pathology. These clinical features are part of the Rotterdam Criteria. The National Institute of Health criteria also require clinical or biochemical hyperandrogenism and oligo or anovulation. The American Excess PCOS Society requires hyperandrogenism with one of two of the remaining criteria.
Disorders that mimic the clinical features of PCOS should be excluded. These include thyroid disease, hyperprolactinemia, and non-classic congenital adrenal hyperplasia with 21-hydroxylase deficiency, for which measurement of serum 17-hydroxyprogesterone (17-OHP) should be done, which may require further testing with adrenocorticotropin stimulation test.
PCOS in Adolescents
Diagnosing PCOS in adolescents is especially challenging given the developmental issues in this group. Many features of PCOS are common in normal puberty, for example, acne, menstrual irregularities, and hyperinsulinemia. Menstrual irregularities with anovulatory cycles occur due to the immaturity of the hypothalamic-pituitary-ovarian axis during the first 2 to 3 years after menarche. Persistent oligomenorrhea beyond this period predicts ongoing menstrual irregularities and a higher chance of underlying ovarian or adrenal dysfunction. Ultrasound is also not very helpful in adolescent because they commonly have large, multicystic ovaries.
The cycle length of more 35 days suggest chronic anovulation, but cycle length between 32 to 35-36 day needs to be assessed for ovulatory dysfunction. The threshold for oligomenorrhea is 35 days cycles in adults and 40 days in adolescents. Assessment in a patient with cycles shorter than 35 days can be done measuring progesterone levels in mid-luteal phase (days 20 to 21). Implications of ovulatory dysfunction include infertility, endometrial hyperplasia, and endometrial cancer.
Clinical hyperandrogenism is diagnosed in adult women with hirsutism, alopecia, and acne, and these are a good substitute of biochemical hyperandrogenism. However adolescent only hirsutism should be considered as a substitute of biochemical hyperandrogenism. Hair loss patterns are variable, typically in a vertex, crown or diffuse pattern. Women with more severe hyperandrogenemia may suffer from bitemporal hair loss and loss of the frontal hairline. Adolescents with severe or resistant acne to oral and topical antibiotics may have 40% likelihood of developing PCOS. THere is high suspicion for hyperandrogenism in females in their mid-20s to 30s with persistent or exacerbated acne.
Hirsutism is defined as coarse, dark, terminal hairs distributed in a male pattern. Signs of virilization such as increased muscle mass, decreased breast size, deepening of the voice, and clitoromegaly are not typical of PCOS. Virilization reflects higher androgen levels, and further investigation should be done, the clinician should have higher suspicion for an androgen-producing tumor of the ovary or the adrenal gland.
Free testosterone levels are more sensitive than the measurement of total testosterone for establishing the existence of androgen excess. Methodologic problems in commercial testosterone assays have emerged. The physician should be aware of the method used by the laboratory. Equilibrium dialysis technique such as mass spectrometry coupled with liquid chromography have the highest sensitivity and specificity and give accurate results. Direct analogue radioimmunoassay does not give reliable results though RIA with purification techniques has shown to be more accurate. It is preferable to rely on calculated free testosterone when equilibrium dialysis method is not available.
The value of measuring levels of androgens other than free testosterone is relatively low. Although dehydroepiandrosterone sulfate (DHEAS) levels are increased in 30% to 35% of PCOS patients, it has been estimated that 5% of patients have an exclusive increase in DHEAS.
Polycystic Ovaries Morphology
Ovarian morphology assessment is more accurate when done by transvaginal ultrasound. New ultrasound machines allow the diagnosis of PCOM (polycystic ovarian morphology) in patients having at least 25 small follicles (2 mm to 9 mm) in the whole ovary. Ovarian size at 10 ml remains the normal size cutoff. 2004 Rotterdam criteria indicate PCOM by the presence of at least 12 follicles measuring 2 mm to 9 mm in the whole ovary or by increased ovarian size more than 10 ml. Ultrasound technology has advanced and is able to improve on the diagnosis of PCOS. Androgen Excess and PCOS Society has reviewed current data and published updated guidelines for PCOM diagnosis, increasing to follicle count to 25. Ovary size has not been modified. Recent studies have been shown evidence that measuring anti-Mullerian hormone can be useful for determining the diagnosis of PCOS when no accurate ovarian ultrasound is available.
PCOS represents a higher risk for cardiovascular, metabolic and other comorbidities. Appropriate evaluation and interventions need to be done.
Endocrine Society Guidelines recommend screening for ovulatory status in all patients. Even a patient with eumenorrheic menstrual cycles may have anovulation which can be measured by mid-luteal serum progesterone. Excluding other causes of infertility is also recommended.
Multiple studies have shown an increased risk of endometrial cancer in patients with PCOS. Multiple risk factors are shared between both pathologies. Endocrine Society suggests against routine ultrasound (US) endometrial thickness screening in asymptomatic patients. But women should be counseled to report unexpected or abnormal uterine bleeding.
Screening for obesity must be done for PCOS women and adolescents by body mass index (BMI) calculation and waist circumference. Obesity increases the risk of hyperandrogenemia and metabolic disorders, which has a negative impact on PCOS. Blood pressure measurement and lipid screening should be done.
Insulin resistance has been associated highly with PCOS. Around one to two-thirds of PCOS have an abnormal degree of insulin resistance. Obesity prevalence is similar, with considerable variability among populations. Obesity increases insulin resistance, and the result is increased hyperinsulinism further aggravates hyperandrogenism. Some obese women with PCOS, metabolic abnormalities related to insulin resistance and obesity are in many instances more important in the mechanism of anovulation in PCOS than androgen excess.
Endocrine society guidelines recommend the use of oral glucose tolerance test, with fasting and 2-hour glucose after a 75 g oral glucose load to screen for IGT and type-2 diabetes mellitus. OGTT is preferred over HbA1c due to decrease sensitivity with PCOS patients. Rescreening should be done every 3 to 4 years due to more frequent risk factors than the general population.
Additionally, the obese and overweight patients should be screened for symptoms of OSA and referred for sleep studies when this test is positive.
Evidence for the increased rate of depression symptoms was found for PCOS women compared to non-BMI-matched controls. Major depression, recurrent depression, and suicide attempts were also higher in PCOS women. Screening and identifying depression and anxiety disorder should be done. Appropriate treatment should be given.
In overweight and obese PCOS women and adolescents, exercise and calorie-restrictive diets are best first-line interventions for weight loss and IGT. Different studies have shown that hirsutism can improve as well as regulation of menstrual cycle and ovulation. Low-carbohydrate diets have been used hoping that these will have a better effect on hyperinsulinism, but studies have shown no difference outcomes with low-carbohydrate diets.
First-line treatment for menstrual abnormalities and hirsutism and acne is hormonal contraceptive, either oral contraceptive, patch or vaginal rings. The Endocrine Society does not favor any presentation over another. Progestin component decreases LH levels indirectly decreasing ovarian androgen production and by increasing sex hormone–binding globulin. Additionally, some progestins have been shown to have direct antiandrogenic properties as a direct inhibitor 5 alpha-reductase activity to prevent the conversion of free testosterone to its more potent form, 5 alpha-dihydrotestosterone, for this they are highly effective for symptoms of hyperandrogenism as well as controlling the menstrual cycle.
Screening for contraindication for hormonal contraceptive should be done in all patients. Women 35 or older who smoke more than 15 cigarettes daily, uncontrolled hypertension greater than 160/100, uncontrolled diabetes with severe peripheral vascular disease are an absolute contraindication. The United States medical eligibility criteria for the use of contraceptives is a valuable tool when multiple comorbidities are present. Patients with diabetes and without vascular complications do not have any contraindications to use hormonal contraceptives.
Regarding the metabolic effect of hormonal contraceptives, higher estrogen activity increases HDL-cholesterol and decreases LDL-cholesterol. No impact on body weight and fat distribution between PCOS and healthy women.
Oral contraceptive initial dosing of 20 mcg of ethinyl estradiol combined with a progestin antiandrogenic properties such as desogestrel and drospirenone or neutral effect like or norethindrone acetate. Progestin with antiandrogenic properties has been shown to have a higher risk of venous thromboembolism (VTE). If hyperandrogenic symptoms are not controlled completely with this initial dose, ethinyl estradiol can be increased to 30 mcg to -35 mcg.
Endocrine Society recommends starting metformin in PCOS patients with DM2 or IGT who fail lifestyle modifications. It decreases progression from IGT to DM2.
Metformin is also second-line therapy for menstrual irregularities in patients with a contraindication for hormonal contraceptives. It is commonly used in the adolescent as monotherapy, and it helps restore normal menses, weight loss, and insulin resistance, and even though it should not use primarily to treat clinical hyperandrogenism, it can improve androgen excess symptoms.
First-line therapy for infertility in PCOS patients is clomiphene citrate. This is a selective estrogen receptor modulator (SERM), competitive inhibitors of estrogen receptors (ERs) and has mixed agonist and antagonist activity.
Clomiphene enhances fertility and ovulation especially by its effect on hypothalamus where it binds for a prolonged period to estrogen receptors and depletes them, blocking negative feedback inhibition effect of circulating endogenous estrogen.This results in the pulsatile release of a hypothalamic gonadotropin-releasing hormone (GnRH) which promotes secretion of FSH and LH and indirectly stimulating ovulation.
New evidence for estrogen modulators such as letrozole shown that it can be used in ovulatory infertility. This is an aromatase inhibitor which blocks estrogen synthesis, reducing negative estrogenic feedback at the pituitary. A National Institute of Health founded double-blind, multicenter trial reported that letrozole, compared to clomiphene, was associated with higher live-birth and ovulation rates among infertile women with polycystic ovary syndrome. Additional studies regarding relative teratogenicity need to be done, but future guideline can change after this new evidence.
Metformin is suggested as an adjuvant treatment for infertility helping prevent ovarian hyperstimulation syndrome in a patient undergoing in vitro fertilization. It has shown higher benefits in obese patients. After pregnancy is confirmed, it is recommended discontinuation due to lack of evidence for benefits during pregnancy, and it can exacerbate maternal gastrointestinal disturbances.
Treatment for Hyperandrogenism
Clinical hyperandrogenism requires long-term treatment and takes several months before effects are evident.
Cosmetic interventions should be initiated while medications start working. These can be bleaching and temporary methods of hair removal; using galvanic or blended electrolysis for localized areas with the experienced operator; using laser photo-epilation for generalized hirsutism.
Pharmacological interventions include topical eflornithine for face hirsutism which can be an expensive treatment with potentially serious side effects if the body absorbs it.
First-line treatment of hirsutism is low-dose neutral or antiandrogenic oral contraceptives which effectively lowers androgens level and effect. Additionally, contraceptive properties are beneficial when combined with antiandrogenic drugs, because the later requires reliable contraception as they are highly teratogenic. Mild hirsutism can be treated OCP alone.
Adjuvant antiandrogen administration can be done for moderate, severe hirsutism and mild hirsutism without adequate hair growth control after 6 months to 1 year of OCP. As this drugs have similar efficacy, Androgen Excess and the PCOS Society suggest prescribing finasteride, cyproterone acetate which is not available in the United States, or spironolactone, instead of flutamide when an antiandrogen is needed, due to potential side effects like hepatotoxicity. They act by blocking androgens effects over the hair follicle; finasteride also has inhibition of 5 alpha-reductase.
PCOS affects many organ systems and is best managed by a multidisciplinary team of healthcare professionals. There is no cure for the disorder, and hence the aim of treatment is to reduce the risk of complications and improve lifestyle. A dietary and physical therapy consult are highly recommended as these are considered first-line treatment. The women often require a number of medications to manage the hirsutism, anovulation and menstrual irregularities; hence the pharmacist should ensure that the patient is not developing any adverse reactions to these drugs. All women with PCOS should be encouraged to exercise as this can reduce insulin resistance, body weight, blood lipids, and glucose; more importantly, exercise also enhances self-esteem. Because these women can develop a wide range of complications, close follow up is highly recommended. Women with POS are at a high risk for developing gestational diabetes, preeclampsia, and preterm deliveries. Finally, all women with PCOS should be encouraged to join a support group to help reduce the stress and boost their confidence. (Level V)
More evidence is accumulating that women with PCOS may be at a high risk for CNS and cardiovascular disease. Many of these women have extremely high levels of serum lipoprotein, blood glucose, and cholesterol- which also increase the risk of insulin resistance. Women with PCOS may also be at a high risk for endometrial cancer. (Level V)
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