Polycystic Ovarian Syndrome

Introduction

Women with polycystic ovarian syndrome (PCOS) have abnormalities in the metabolism of androgens and estrogen and in the control of androgen production. PCOS can result from abnormal function of the hypothalamic-pituitary-ovarian (HPO) axis. A woman is diagnosed with polycystic ovaries (as opposed to PCOS) if she has 20 or more follicles in at least 1 ovary.

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.

Associated Anatomy

The ovary is an organ found in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary (from Latin ovarium, meaning ‘egg, nut’) found on the left and right sides of the body. The ovaries also secrete hormones that play a role in the menstrual cycle and fertility. The ovary progresses through many stages beginning in the prenatal period through menopause. It is also an endocrine gland because of the various hormones that it secretes.

Causes

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.

Differential Diagnosis

Following conditions should be considered for the differential diagnosis of PCOS:

• Use of androgenic steroids
• Hypothyroidism
• Late-onset congenital adrenal hyperplasia
• Idiopathic/familial hirsutism
• Ovarian malignancies

Drugs

Metformin (Glucophage, Glumetza, Riomet, Fortamet)

Metformin reduces insulin resistance; it is an insulin sensitizer. Hepatic glucose output is decreased and peripheral, insulin-stimulated uptake is increased. Metformin may also decrease TSH levels in hypothyroidism patients with polycystic ovarian syndrome (PCOS), regardless of whether they are treated with thyroxine or not (off-label use).

Insulin isophane human/insulin regular human (Humulin 70/30, Novolin 70/30)

Insulin is effective when metformin cannot control hyperglycemia. Several short-acting and long-acting dosage forms are available. Insulin must be initiated in conjunction with dietary assessment and nutritional management by a registered clinical dietitian as part of an overall weight-management system. Insulin is seldom indicated as a first-line agent for PCOS, unless a patient also has a diagnosis of diabetes.

Spironolactone (Aldactone)

Spironolactone is an antiandrogen agent that is a nonspecific androgen-receptor blocker. It may be used in conjunction with oral contraceptive pills to treat hirsutism by reducing hair diameter. Initiate oral contraceptive pills first to avoid worsening of menstrual irregularities and to prevent pregnancy, because spironolactone may have feminizing effects on the male fetus. Periodically assess adverse effects (eg, fluid and electrolyte abnormalities). Spironolactone is also used as a potassium-sparing diuretic.

Leuprolide (Lupron, Eligard)

Leuprolide is not a first-line agent in PCOS and therefore is not used often for this syndrome. This agent suppresses ovarian and testicular steroidogenesis by decreasing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Gonadotropin-releasing hormone (GnRH) analogs with oral contraceptive pills are an option to consider for hirsutism in women who fail to respond to combined therapy with spironolactone and oral contraceptive pills. Anatomic effects of androgens (eg, clitoromegaly and deepening of the voice) are not responsive to GnRH analogs.

Finasteride (Proscar, Propecia)

Finasteride is a 5-alpha-reductase inhibitor that is approved for use in benign prostatic hypertrophy and in male-pattern alopecia. This agent blocks conversion of testosterone to its more active metabolite, dihydrotestosterone. Finasteride tends to be a second-line agent for hirsutism in PCOS, when hirsutism persists despite the use of first-line agents (ie, oral contraceptives). This agent is more effective when used in combination with oral contraceptive pills. Due to the potential for teratogenic effects (eg, risk of genital ambiguity in male fetuses), finasteride therapy must be used in conjunction with a reliable form of contraception in sexually active women.

Eflornithine (Veniqa)

Eflornithine is indicated for the reduction of unwanted facial hair in women. It interferes with ornithine decarboxylase (needed for hair growth) in skin hair follicles. Eflornithine does not have a depilatory action; instead, it appears to retard hair growth and improve appearance where applied. Improvement may be seen in as short a period as 4-8 weeks, although 6 months of treatment may be required. Keep in mind that in clinical studies, hair returned to its previous condition 8 weeks after discontinuation of eflornithine (ie, hirsutism may return following discontinuation of eflornithine).

Ethinyl estradiol

Ethinyl estradiol reduces the secretion of LH and FSH from the pituitary by decreasing the amount of GnRH. Use ethinyl estradiol 30-35 mg combined with any form of progesterone. Restoration of the regular menstrual cycles prevents endometrial hyperplasia associated with anovulation. Improvement of hyperandrogenic effects are seen in 60-100% of women, but usually, at least 6-12 months of use are required. Perform a pregnancy test before therapy. If the patient has had no menstrual period for 3 months, induce withdrawal bleeding with medroxyprogesterone acetate (Provera) 5-10 mg/day for 10 days; then, begin therapy with oral contraceptives.

Medroxyprogesterone (Depo-Provera, Provera)

Medroxyprogesterone has no effect on androgen production. Progestins stop the proliferation of endometrial cells, allowing organized sloughing of cells after withdrawal.

Clomiphene citrate (Clomid, Serophene)

Clomiphene acts directly by producing a surge of luteinizing hormone and could cause ovulation within days.

Tretinoin topical cream 0.02–0.1%; topical gel 0.01–0.1%; topical solution 0.05% (Retin A, Renova, Atralin, Avita, Refissa, Retin-A Micro, Tretin-X)

The exact mechanism of tretinoin is unknown. It appears to decrease cohesiveness of follicular epithelial cells with a decrease microcomedo formation. This agent also increases turnover of follicular cells to cause extrusion of comedones.

Adapalene topical cream 0.1%; gel 0.1 and 0.3%; lotion 0.1% (Differin)

Adapalene binds to specific retinoic acid nuclear receptors and modulates cellular differentiation, keratinization, and inflammatory processes. Its exact mechanism of action for treatment of acne is unknown.

Erythromycin topical 2% (AkneMycin, Ery)

Although its exact mechanism of action is unknown, erythromycin inhibits protein synthesis in susceptible organisms by reversibly binding to 50S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis.

Clindamycin topical 1% (Cleocin T, ClindaReach, ClindaDerm, Clindagel, ClindaMax, Clindets, Evoclin)

Clindamycin is an antibacterial agent that binds to the 50S ribosomal subunits of susceptible bacteria and prevents elongation of peptide chains by interfering with peptidyl transfer, thereby suppressing protein synthesis. This agent reduces surface fatty acids on the skin; however, its exact mechanism of action in treating acne is unknown.

Sodium Sulfacetamide topical 10% (Klaron)

Sodium sulfacetamide is a para-aminobenzoic acid (PABA) inhibitor. This agent restricts folic acid synthesis that is required for bacterial growth.

Epidemiology

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. Based on the NIH 2012 workshop report, it is estimated that PCOS affects about 5 million reproductive-aged females in the United States.

A great deal of ethnic variability in hirsutism is observed. For example, Asian (East and Southeast Asia) women have less hirsutism than white women given the same serum androgen values. In a study that assessed hirsutism in southern Chinese women, investigators found a prevalence of 10.5%. In hirsute women, there was a significant increase in the incidence of acne, menstrual irregularities, polycystic ovaries, and acanthosis nigricans.

PCOS affects premenopausal women, and the age of onset is most often perimenarchal (before bone age reaches 16 y). However, clinical recognition of the syndrome may be delayed by failure of the patient to become concerned by irregular menses, hirsutism, or other symptoms or by the overlap of PCOS findings with normal physiologic maturation during the 2 years after menarche. In lean women with a genetic predisposition to PCOS, the syndrome may be unmasked when they subsequently gain weight.

Natural Progression

If left untreated patients with PCOS may progress to cardiovascular diseases due to elevated cholesterol and increased levels of androgens. Increased lengths of time without a menstrual period leads to unopposed exposure of endometrium to estrogen which may result in uterine cancer.

Pathophysiology

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.

Possible Complications

Complications that can develop as a result of polycystic ovary syndrome are:

• Endometrial hyperplasia and endometrial cancer
• Insulin resistance/Type II diabetes
• High blood pressure
• Dyslipidemia
• Cardiovascular disease
• Strokes
• Miscarriage
• Infertility

Possible Treatment

Lifestyle Modification

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.

Hormonal Contraceptive

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.

Metformin

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.

Infertility Treatment

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.

Metformin or other insulin sensitizers are not considered target treatment for hirsutism due to no consistent evidence showing superior effect than placebo.

Prognosis

Evidence suggest that women with polycystic ovarian syndrome (PCOS) may be at increased risk for cardiovascular and cerebrovascular disease. Women with hyperandrogenism have elevated serum lipoprotein levels similar to those of men. 

Approximately 40% of patients with PCOS have insulin resistance that is independent of body weight. These women are at increased risk for type 2 diabetes mellitus and consequent cardiovascular complications.

The American Association of Clinical Endocrinologists and the American College of Endocrinology recommend screening for diabetes by age 30 years in all patients with PCOS, including obese and nonobese women. In patients at particularly elevated risk, testing before 30 years of age may be indicated. Patients who initially test negative for diabetes should be periodically reassessed throughout their lifetime.

Patients with PCOS are also at an increased risk for endometrial hyperplasia and carcinoma. The chronic anovulation in PCOS leads to constant endometrial stimulation with estrogen without progesterone, and this increases the risk of endometrial hyperplasia and carcinoma. The Royal College of Obstetricians and Gynaecologists (RCOG) recommends induction of withdrawal bleeding with progestogens a minimum of every 3-4 months. 

No known association with breast or ovarian cancer has been found; thus, no additional surveillance is needed

Primary Prevention

The National Institute of Child Health and Human Development’s Division of Epidemiology, Statistics, and Prevention Research (DESPR) is exploring early signs of PCOS in teenage girls by examining the relationships among ovarian shape and size, abdominal obesity, and biomarkers of insulin resistance in early PCOS.

Risk factors

Common risk factors in the development of PCOS are:

• Hyperinsulinemia secondary to insulin resistance; associated with type 2 diabetes mellitus
• Obesity
• Family history of PCOS among first-degree relatives
• Premature adrenarche
• Fetal androgen exposure
• Low birth weight

Secondary Prevention

Secondary preventive measures for PCOS include:

• Weight loss and metformin may prevent diabetes and atherosclerosis.
• Lifestyle modification, including increased physical activity and healthy diet resulting in weight loss, is also likely to prevent diabetes in PCOS.

Signs or Symptoms

The major features of PCOS include menstrual dysfunction, anovulation, and signs of hyperandrogenism. Other signs and symptoms of PCOS may include the following:

• Hirsutism
• Infertility
• Obesity and metabolic syndrome
• Diabetes
• Obstructive sleep apnea

Studies

Active Not Recruiting

Number of studies: 26

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Completed

Number of studies: 282

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Enrolling by Invitation

Number of studies: 1

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Not Yet Recruiting

Number of studies: 28

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Recruiting

Number of studies: 99

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Results Available

Number of studies: 48

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Results Not available

Number of studies: 535

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Suspended

Number of studies: 4

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Terminated

Number of studies: 26

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Withdrawn

Number of studies: 15

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Types

PCOS may be classified into 4 subtypes based upon severity of symptoms into:

• Asymptomatic form: Women with only polycystic ovarian morphology
• Mild form: Polycystic ovarian morphology along with anovulation
• Classical form: Hyperandrogenism along with ovarian dysfunction (anovulation and/or poly cystic ovarian )
• Metabolic form: Combination of mild and classical forms with presence of obesity and/or insulin resistance (abdominal obesity, insulin resistance, increased waist-hip ratio)

Typical Test

Physical examination:

Hirsutism and virilizing signs

Patients may have excessive body hair in a male distribution pattern, as well as acne. Some patients have virilizing signs, such as male-pattern balding or alopecia, increased muscle mass, deepening voice, or clitoromegaly; these findings should prompt a search for other causes of hyperandrogenism.

The modified Ferriman-Gallwey (mFG) score grades 9 body areas from 0 (no hair) to 4 (frankly virile), including the upper lip, chin, chest, upper abdomen, lower abdomen, thighs, back, arm, and buttocks. A total score of 8 or more is considered abnormal for an adult white woman; a score of 36 is the most severe.

Obesity

Approximately 50% of women with polycystic ovarian syndrome (PCOS) have abdominal obesity, characterized by a waist circumference greater than 35 inches (>88 cm).

Acanthosis nigricans

Acanthosis nigricans is a diffuse, velvety thickening and hyperpigmentation of the skin. It may be present at the nape of the neck, axillae, area beneath the breasts, intertriginous areas, and exposed areas (eg, elbows, knuckles). In patients with PCOS, acanthosis nigricans is thought to be the result of insulin resistance, although syndromic and familial variants are described. Acanthosis nigricans can also be a cutaneous marker of malignancy.

Acanthosis nigricans is staged according to the scoring system below:

• Absent (0): Not detectable on close inspection
• Present (1): Clearly present on close visual inspection, not visible to the casual observer, extent not measurable
• Mild (2): Limited to the base of the skull, usually does not extend to the lateral margins of the neck
• Moderate (3): Extends to the lateral margins of the neck but not visible anteriorly
• Severe (4): Visible anteriorly
• Severe (5): Circumferential

Blood pressure

Patients with signs and symptoms of metabolic syndrome may have elevated blood pressure, with a systolic blood pressure of 130 mm Hg or higher and a diastolic blood pressure of 85 mm Hg or higher.

Enlarged ovaries

Enlarged ovaries may not always be present. Evaluate for an ovarian mass.

Laboratory Workup

Androgens. Androgen excess can be tested by measuring total and free testosterone levels or a free androgen index. An elevated free testosterone level is a sensitive indicator of androgen excess. Other androgens, such as dehydroepiandrosterone sulfate (DHEA-S), may be normal or slightly above the normal range in patients with polycystic ovarian syndrome (PCOS). levels of sex hormone–binding globulin (SHBG) are usually low in patients with PCOS.

Androstenedione levels are also elevated in women with PCOS. This androgen precursor is 60% ovarian and 40% adrenal in derivation.

Patients with androgen-secreting ovarian or adrenal tumors can present with hirsutism, amenorrhea, and signs of virilization. Although the clinical picture of symptom onset and progression is more predictive than androgen levels, their testosterone level may be greater than 150 ng/dL and their DHEA-S level may be above 800 mcg/dL. DHEA-S is derived from the adrenal gland, and therefore, elevation of DHEA-S would be suggestive of an adrenal origin.

Follicle-stimulating hormone and luteinizing hormone levels. The follicle-stimulating hormone (FSH) level should be checked to rule out primary ovarian failure. In patients with PCOS, FSH levels are within the reference range or low. Luteinizing hormone (LH) levels are elevated for Tanner stage, sex, and age. The LH-to-FSH ratio is usually greater than 3.

Stimulation testing with a long-acting gonadotropin-releasing hormone (GnRH) agonist induces a characteristic rise in ovarian-derived 17-hydroxyprogesterone after 24 hours. This is thought to be a result of excessive 17-hydroxylase activity.

Thyroid-stimulating hormone and free thyroxine levels. Thyroid dysfunction, rather than PCOS, may be the source of amenorrhea and hirsutism. (In patients with PCOS, thyroid function tests are within the reference range.)

Long-standing primary hypothyroidism can be associated with a markedly elevated circulating thyroid-stimulating hormone (TSH) level. Elevated alpha subunit delivery (from one half of the dimeric TSH molecule) can then cross-react with FSH and LH receptors on breast tissue, leading to premature thelarche and, on ovarian tissue, resulting in a PCOS–like picture. These physical findings of the van Wyk-Grumbach syndrome (ie, juvenile hypothyroidism, precocious puberty, and ovarian enlargement) resolve upon thyroxine replacement therapy.

Glucose, Insulin, and Lipids. Because the prevalence of impaired glucose tolerance and type 2 diabetes mellitus is high in women with polycystic ovarian syndrome (PCOS)—particularly those who have a body mass index (BMI) greater than 30 kg/m², have a strong family history of type 2 diabetes, or are older than 40 years—a 75-g oral glucose-tolerance test (OGTT) should be performed. A 2-hour postload glucose value of less than 140 mg/dL indicates normal glucose tolerance; a value of 140-199 mg/dL indicates impaired glucose tolerance; and a value of 200 mg/dL or higher indicates diabetes mellitus. 

Women diagnosed with prepregnancy PCOS should be screened for gestational diabetes before 20 weeks’ gestation. These women have a higher rate of gestational diabetes than women in the general population; therefore, refer them for expert obstetric diabetic consultation if abnormal results are found.

Some women with PCOS have insulin resistance and an abnormal lipid profile (cholesterol >200 mg/dL; LDL >160 mg/dL). Approximately one third of women with PCOS who are overweight have impaired glucose tolerance or type 2 diabetes mellitus by 30 years of age. 

A study concluded that insulin resistance and inflammatory markers may help identify adolescent girls with PCOS who are at the highest risk of developing the metabolic syndrome.  Metabolic heterogeneity also exists in women with PCOS according to phenotypic subgroup, with metabolic dysfunction confined to the subgroup with both oligomenorrhea and hyperandrogenic features.

Imaging tests:

Ultrasonography. Ovarian ultrasonography, preferably accomplished by using a transvaginal approach, can be performed to assess ovarian morphology. Perform ultrasonography if the pelvic examination is inadequate, the patient has abdominal pain, testosterone levels are unusually high (eg, >200 ng/dL), it is needed to support the diagnostic criteria, or the patient is amenorrheic (to assess the endometrial thickness and exclude anatomic causes of amenorrhea).

CT scan and MRI. If a tumor is suspected, obtain a computed tomography (CT) scan or magnetic resonance image (MRI) to visualize the adrenals and ovaries. MRI is an excellent method for imaging the ovaries and is a useful alternative in very obese women in whom the ovaries might not be visualized with transvaginal ultrasonography (TVUS) and in those patients in whom TVUS is inappropriate, such as adolescent girls.

Histologic Findings:

In polycystic ovarian syndrome (PCOS), histologic changes of the ovary include enlarged, sclerotic, multiple cystic follicles. As previously stated, a woman is diagnosed with polycystic ovaries (as opposed to PCOS) if she has 20 or more follicles in at least 1 ovary, measuring 2-9 mm in diameter, or a total ovarian volume greater than 10 cm3.

 

References:

https://emedicine.medscape.com/article/256806-overview
https://www.ncbi.nlm.nih.gov/books/NBK459251/
https://www.wikidoc.org/index.php/Polycystic_ovary_syndrome
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737989/
https://www.mayoclinic.org/diseases-conditions/pcos/symptoms-causes/syc-20353439