POLYCYSTIC OVARIAN SYNDROME (PCOS)

EPIDEMIOLOGY

In the United States, polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders of reproductive-age women, with a prevalence of 4-12%.^(1,2) Up to 10% of women are diagnosed with PCOS during gynecologic visits.⁽³⁾ In some European studies, the prevalence of PCOS has been reported to be 6.5-8 %.^(4,5)

In Pakistani women of reproductive age group PCOS was found to be 20.7 %.⁽⁶⁾

PATHOPHYSIOLOGY:

HYPERANDROGENISM:

• Hyperandrogenism is the most characteristic feature of PCOS, and some argue that it is the defining feature of the disease.
• Hyperandrogenism is exacerbated by hyperinsulinemia and antral follicle arrest and may itself increase the risk of follicle arrest.
• Similar ovarian characteristics have been noted in women with other conditions of androgen excess such as congenital adrenal hyperplasia.

NEUROENDOCRINE ABNORMALITIES:

• Women with PCOS have an increase in the frequency of GnRH pulses; shorter pulses preferentially promote the production of luteinizing hormone (LH)and result in a decrease in the production of follicle stimulating hormone (FSH).
• Patients with PCOS often exhibit an increase in the LH:FSH ratio, which may contribute to the ovarian excess of androgens relative to estrogens.
• It is unclear if patients with PCOS have an intrinsically faster GnRH pulsation mechanism which initiates hyperandrogenism in the ovaries, or if oligoanovulation itself promotes more rapid pulsations in GnRH via a reduction in circulating
• Normally, progesterone is released from the corpus luteumfollowing ovulation.
• Progesterone acts to slow GnRH pulsation.
• In PCOS, a decrease in ovulatory events may cause a decrease in circulating progesterone.
• Exposure to androgens in utero or prepubertally may decrease the inhibitory effects of estrogen and progesterone on the hypothalamus and contribute to increased pulsatility.

INSULIN RESISTANCE AND TYPE 2 DM:

• 50-70% of patients with PCOS exhibit metabolic abnormalities, including poor glucose tolerance and hyperinsulinemia.
• This is not solely a consequence of increased visceral obesity; rather, obesity and hormonal abnormalities are thought to make additive contributions to insulin resistance.
• Patients with PCOS exhibit a greater degree of insulin resistance than patients with the same BMI and visceral adiposity who do not have PCOS.
• Functional insulin resistance is considered a consequence of defects in insulin-mediated glucose transport and signaling in adipocytes and myocytes; this may be the result of a dysregulation in adipokine production and signaling from adipose tissues but the mechanism is incompletely understood.
• The resulting hyperinsulinemia leads to insulin spillover into other tissues, most commonly the skin. Insulin acts via insulin-like growth factor receptors to cause excess keratinocyte growth, producing velvety skin patches known as acanthosis nigricans.

POLYCYSTIC OVARIES:

• Polycystic ovaries are present in 20-30% of women and are not essential for the diagnosis of PCOS.
• The “cysts” in polycystic ovaries are not true cysts, but rather antral follicles which have arrested in development.
• This is thought to occur because of hormonal abnormalities:
• Hyperandrogenism:arrest occurs when the granulosa cells of the ovaries normally begin to produce estrogen by aromatizing androstenedione produced by the theca cells; excess 5a-reduced androgens in the ovaries are thought to inhibit the action of aromatase and therefore reduce estradiol synthesis, which is required for further maturation.
• Hyperinsulinemia:exacerbates ovarian hyperandrogenism by:

1. increasing 17a-hydroxylase activity in theca cells and promoting androstenedione and testosterone production;
2. promoting LH- and IGF1-stimulated androgen production; and
3. elevating free testosterone by decreasing the production of sex hormone binding globulin (SHBG).

LONG TERM MORBIDITY:

• Subfertility: This is largely a consequence of oligoanovulation, but may also result from abnormalities in oocyte development due to hormonal or other abnormalities.
• Miscarriage: There is an increased risk of miscarriage in PCOS patients who do conceive; however, this risk is confounded by the high rate of obesity in this population, which is also a risk factor for miscarriage.
• Cardiovascular disease: Patients with PCOS often exhibit dyslipidemia, which is likely related both to hyperinsulinemia and hyperandrogenism.
• T2DM: Patients with PCOS are thought to have an increased risk of developing T2DM above the risk conferred by their level of insulin resistance and as many as 10% may develop T2DM by their fourth decade.
• Malignancies: A combination of hyperinsulinemia, hyperandrogenism, and oligoanovulation increases the risk of endometrial cancer and other endometrial disorders.
• Psychiatric disorders: Women with PCOS have an increased risk of anxiety, depression, binge-eating disorder, and bipolar disorder.

NATURAL HISTORY:

Ideally, PCOS should be diagnosed as early as possible to prevent worsening or the onset of metabolic conditions such as insulin resistance and dyslipidemia and infertility. Unfortunately, PCOS is widely overlooked in adolescence because many of the signs and symptoms overlap with normal puberty concerns such as acne and irregular menses. One of the earliest signs that a young girl has PCOS is early puberty.

Other signs of PCOS in young women include acne and hair growth in the central part of the body (between breasts, belly button, and inner thighs). These symptoms can indicate higher levels of testosterone. Weight gain tends to occur during puberty. Adolescence is a stage of growth with higher levels of insulin during this time. In young girls with PCOS who tend to have higher levels of insulin compared to girls without PCOS, this can contribute to excess weight gain in the abdominal area.

SIGN AND 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

RATIONALE FOR SCREENING:

The Royal College of Obstetricians and Gynaecologists (RCOG) recommends the following baseline screening tests for women with suspected polycystic ovarian syndrome (PCOS): thyroid function tests, serum prolactin levels, and a free androgen index (defined as total testosterone divided by sex hormone binding globulin [SHBG] × 100, to give a calculated free testosterone level).⁽⁷⁾

Patients who are having difficulty conceiving should receive an adequate workup, along with their partners, to rule out factors that might contribute to infertility.

Samples for laboratory studies should be drawn early in the morning, with the patient in a fasting state; in women with regular menses, samples should be taken between days 5 and 9 of the menstrual cycle.⁽⁸⁾ A serum human chorionic gonadotropin (hCG) level should be checked to rule out pregnancy in women with oligomenorrhea or amenorrhea.

SCREENING LABORATORIES STUDIES:

Late-onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency can be ruled out by measuring serum 17-hydroxyprogesterone levels after a cosyntropin stimulation test. A 17-hydroxyprogesterone level of less than 1000 ng/dL—measured 60 minutes after cosyntropin stimulation, rules out late-onset congenital adrenal hyperplasia.

Women with PCOS should be screened for Cushing syndrome or acromegaly only if there is a clinical suspicion of these conditions. Cushing syndrome can be ruled out by checking a 24-hour urine sample for free cortisol and creatinine levels of urinary free cortisol that are 4 times the upper limit of normal are diagnostic for Cushing syndrome.⁽⁹⁾ An overnight dexamethasone suppression test is also useful for screening for Cushing syndrome.

A serum insulin-like growth factor (IGF) ̶ 1 level should be checked to rule out acromegaly. Serum IGF-1 is a sensitive and specific marker of growth hormone (GH) excess. Normal levels rule out GH excess.

A small percentage of patients with PCOS have elevated prolactin levels (typically >25 mg/dL). Hyperprolactinemia can be excluded by checking a fasting serum prolactin concentration.

DIAGNOSTIC TESTS:

On examination, findings in women with PCOS may include the following:

• Virilizing signs
• Acanthosis nigricans
• Hypertension
• Enlarged ovaries: May or may not be present; evaluate for an ovarian mass.

TESTING:

Exclude all other disorders that can result in menstrual irregularity and hyperandrogenism, including adrenal or ovarian tumors, thyroid dysfunction, congenital adrenal hyperplasia, and hyperprolactinemia, acromegaly, and Cushing syndrome.^(10,11,12)

Baseline screening laboratory studies for women suspected of having PCOS include the following:

• Thyroid function tests⁽¹²⁾ (e.g. TSH, free thyroxine)
• Serum prolactin level⁽¹²⁾
• Total and free testosterone levels
• Free androgen index⁽¹²⁾
• Serum hCG level
• Cosyntropin stimulation test
• Serum 17-hydroxyprogesterone (17-OHPG) level
• Urinary free cortisol (UFC) and creatinine levels
• Low-dose dexamethasone suppression test
• Serum insulinlike growth factor (IGF)–1 level

Other tests used in the evaluation of PCOS include the following:

• Androstenedione level
• FSH and LH levels
• GnRH stimulation testing
• Glucose level
• Insulin level
• Lipid panel

IMAGING TESTS:

The following imaging studies may be used in the evaluation of PCOS:

• Ovarian ultrasonography, preferably using transvaginal approach
• Pelvic CT scan or MRI to visualize the adrenals and ovaries.

PROCEDURES:

An ovarian biopsy may be performed for histologic confirmation of PCOS; however, ultrasonographic diagnosis of PCOS has generally superseded histopathologic diagnosis. An endometrial biopsy may be obtained to evaluate for endometrial disease, such as malignancy.

PATIENT SELECTION FOR TREATMENT:

Treatment for PCOS in adolescents is primarily directed at the major clinical manifestations, which are:

• Abnormal uterine bleeding – menstrual irregularity or excessive bleeding
• Cutaneous hyperandrogenism – primarily hirsutism and persistent acne
• Obesity and insulin resistance

THERAPY CONSIDERATIONS:

Pharmacologic treatments are reserved for so-called metabolic derangements, such as anovulation, hirsutism, and menstrual irregularities. Medications for such conditions include oral contraceptives, metformin, prednisone, leuprolide, clomiphene, and spironolactone.

Mean platelet volume (MPV) is a marker associated with adverse cardiovascular events, and women with newly diagnosed PCOS appear to have significantly elevated MPV levels.⁽¹³⁾ Kabil Kucur et al reported that use of ethinyl estradiol / cyproterone acetate or metformin for the treatment of women with PCOS seemed to have similar beneficial effects in reducing MPV.⁽¹³⁾ 

Consultation with an endocrinologist is necessary for performing an adrenocorticotropic hormone (ACTH) stimulation test or for other causes of menstrual irregularity such as thyroid disease or pituitary adenoma. A reproductive endocrinologist should be consulted if the patient is infertile and desires pregnancy.⁽¹⁴⁾

In October 2013, the Endocrine Society released practice guidelines for the diagnosis and treatment of PCOS. The following were among their conclusions:⁽¹⁵⁾

• Use the Rotterdam criteria for diagnosing PCOS (presence of 2 of the following: androgen excess, ovulatory dysfunction or polycystic ovaries).
• In adolescents with PCOS, hyperandrogenism is central to the presentation; hormonal contraceptives and metformin are treatment options in this population.
• Postmenopausal women do not have a consistent PCOS phenotype.
• Exclude alternate androgen-excess disorders and risk factors for cardiovascular disease, diabetes, endometrial cancer, mood disorders, and obstructive sleep apnea.
• For menstrual abnormalities and hirsutism / acne, hormonal contraceptives are first-line treatment.
• For infertility, clomiphene is first-line treatment.
• For metabolic / glycemic abnormalities and for improving menstrual irregularities, metformin is beneficial.
• Metformin is of limited or no benefit for managing hirsutism, acne, or infertility.
• Overall, thiazolidinediones have an unfavorable risk-benefit ratio.
• More investigation is needed to determine the roles of weight loss and statins in PCOS.

TREATMENT OPTIONS:

LIFE STYLE MODIFICATIONS:

Lifestyle modifications are considered first-line treatment for women with PCOS. Such changes include the following:^(16,17)

• Diet
• Exercise
• Weight loss

PHARMACOLOGICAL:

Pharmacologic treatments are reserved for so-called metabolic derangements, such as anovulation, hirsutism, and menstrual irregularities. First-line medical therapy usually consists of an oral contraceptive to induce regular menses.

Medications used in the management of PCOS include the following:

ORAL CONTRACEPTIVE AGENTS: Oral contraceptive agents reduce the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland by decreasing the amount of gonadotropin-releasing hormone (GnRH). All oral contraceptives decrease ovarian androgen production. By inhibiting gonadotropin secretion and, therefore, tertiary follicle development, ovarian secretion of testosterone and androstenedione is decreased. All oral contraceptives increase sex hormone-binding globulin (SHBG) and, therefore, reduce free testosterone. Evidence indicates that high doses of contraceptive progestins may inhibit 5-alpha reductase. Oral contraceptives also decrease the production of adrenal androgens, particularly dehydroepiandrosterone sulfate (DHEA-S).

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. Improvements 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 5-10 mg / day for 10 days; then, begin therapy with oral contraceptives.

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

SPIRONOLACTONE: 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 (e.g. fluid and electrolyte abnormalities). Spironolactone is also used as a potassium-sparing diuretic.

LEUPROLIDE: 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 (e.g. clitoromegaly and deepening of the voice) are not responsive to GnRH analogs.

FINASTERIDE: 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 (i.e. oral contraceptives). This agent is more effective when used in combination with oral contraceptive pills. Due to the potential for teratogenic effects (e.g. risk of genital ambiguity in male fetuses), finasteride therapy must be used in conjunction with a reliable form of contraception in sexually active women.

METFORMIN: 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: 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.

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

EFLORNITHINE: 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 (i.e. hirsutism may return following discontinuation of eflornithine).

BENZOYL PEROXIDE: Benzoyl peroxide elicits action by releasing active oxygen; this agent is effective in vitro against Propionibacterium acnes, an anaerobe found in sebaceous follicles and comedones. Benzoyl peroxide also elicits a keratolytic and desquamative effect, which may also contribute to its efficacy.

TRETINOIN TOPICAL CREAM (0.02–0.1%) / GEL (0.01–0.1%) / SOLUTION (0.05%): 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%, 0.3%) / SOLUTION (0.1%): 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%: 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%: 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%: Sodium sulfacetamide is a para-aminobenzoic acid (PABA) inhibitor. This agent restricts folic acid synthesis that is required for bacterial growth.

SURGICAL:

Surgical management of PCOS is aimed mainly at restoring ovulation. Various laparoscopic methods include the following:

• Electrocautery
• Laser drilling
• Multiple biopsy

GOALS OF THERAPY:

The overall goals of therapy of women with PCOS include:

• Amelioration of hyperandrogenic symptoms (hirsutism, acne, scalp hair loss).
• Management of underlying metabolic abnormalities and reduction of risk factors for type 2 diabetes and cardiovascular disease.
• Prevention of endometrial hyperplasia and carcinoma, which may occur as a result of chronic anovulation.
• Contraception for those not pursuing pregnancy, as women with oligomenorrhea ovulate intermittently and unwanted pregnancy may occur.
• Ovulation induction for those pursuing pregnancy.

GUIDELINES:

Treatment for PCOs is based on guidelines from prestigious societies such as endocrine society.

To review the endocrine guidelines, click on the link below

https://www.guideline.gov/content.aspx?id=47899

LONG TERM MONITORING:

Polycystic ovarian syndrome (PCOS) is a disease with many long-term complications. Patients need regular follow-up with their physicians for early detection and management of any untoward sequelae associated with the syndrome.

Women with PCOS who conceive are at increased risk for gestational diabetes, preeclampsia, cesarean delivery, and preterm and postterm delivery. In addition, their newborns are at increased risk of being large for gestational age, but they are not at increased risk of stillbirth or neonatal death.⁽¹⁸⁾

Participation in a peer support group may alleviate distress and improve self-management.⁽¹⁹⁾

CONSULTATION AND COUNSELING:

Discuss with patients the symptoms of polycystic ovarian syndrome (PCOS) as well as their increased risk for cardiovascular and cerebrovascular disease. Educate women with this condition regarding lifestyle modifications such as weight reduction, increased exercise, and dietary modifications.

PRECAUTIONS:

Following instructions should be given to patient:

• Maintain ideal body weight
• Exercise regularly
• Eat healthy - avoid intake of fat, starch, oily, greasy food, very sweet and salty foods.
• Take thorough gynae checkup (internal exam) and pelvic ultrasound scan, Pap smear every year.
• Thyroid levels and blood sugar levels should be checked every 6 months.
• Maintain a menstrual chart (menstrual diary)
• Do not stress out or worry.

REFERENCES:

1. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population.J Clin Endocrinol Metab. 2004 Jun. 89(6):2745-9.
2. Knochenhauer ES, Key TJ, Kahsar-Miller M, et al. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study.J Clin Endocrinol Metab. 1998 Sep. 83(9):3078-82.
3. Cahill D. PCOS.BMJ Clin Evid. 2009 Jan 15. 2009
4. Asuncion M, Calvo RM, San Millan JL, et al. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain.J Clin Endocrinol Metab. 2000 Jul. 85(7):2434-8.
5. Diamanti-Kandarakis E, Kouli CR, Bergiele AT, et al. A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile.J Clin Endocrinol Metab. 1999 Nov. 84(11):4006-11.
6. Nazir F , Saeed S , Malik M ,Aziz H , Aliya S and Rana S .Polycystic ovary Syndrome diagnosis and management in fertility deprivation .Pak J Obstet Gynecol1999 ; 12 : 59-70
7. Royal College of Obstetricians and Gynaecologists. Long-term consequences of polycystic ovary syndrome. London, UK: Royal College of Obstetricians and Gynaecologists; 2007. Green-top guideline; no. 33.
8. American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. National Guideline Clearinghouse. Available athttp://guideline.gov/summary/summary.aspx?doc_id=7108. Accessed: August 28, 2009.
9. Nieman LK. Diagnostic tests for Cushing's syndrome.Ann N Y Acad Sci. 2002 Sep. 970:112-8.
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11. American College of Obstetricians and Gynecologists. Polycystic ovary syndrome. Washington, DC: American College of Obstetricians and Gynecologists; 2009. ACOG practice bulletin; no. 108.
12. Royal College of Obstetricians and Gynaecologists. Long-term consequences of polycystic ovary syndrome. London, UK: Royal College of Obstetricians and Gynaecologists; 2007. Green-top guideline; no. 33.
13. Kabil Kucur S, Gozukara I, Aksoy A, et al. How medical treatment affects mean platelet volume as a cardiovascular risk marker in polycystic ovary syndrome?Blood Coagul Fibrinolysis. 2015 Dec. 26 (8):862-5.
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15. [Guideline] Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2013 Oct 22.
16. Vause TD, Cheung AP, Sierra S, et al. Ovulation induction in polycystic ovary syndrome.J Obstet Gynaecol Can. 2010 May. 32(5):495-502.
17. American College of Obstetricians and Gynecologists. Polycystic ovary syndrome. Washington, DC: American College of Obstetricians and Gynecologists; 2009. ACOG practice bulletin; no. 108.
18. Roos N, Kieler H, Sahlin L, et al. Risk of adverse pregnancy outcomes in women with polycystic ovary syndrome: population based cohort study.BMJ. 2011 Oct 13. 343:d6309.
19. Percy CA, Gibbs T, Potter L, Boardman S. Nurse-led peer support group: experiences of women with polycystic ovary syndrome.J Adv Nurs. 2009 Oct. 65(10):2046-55.