Polycystic Ovarian Syndrome

INTRODUCTION

Background: Stein and Leventhal were first to recognize an association between the presence of polycystic ovaries and signs of hirsutism amenorrhea (eg, oligomenorrhea, obesity). Subsequently, it was reported that after successful wedge resection of the ovaries in women diagnosed with Stein-Leventhal syndrome, menstrual cycles became regular and these patients were able to conceive. Consequently, it was thought that a primary ovarian defect was the main culprit, and the disorder came to be known as polycystic ovarian disease. Further biochemical, clinical, and endocrinologic studies have shown an array of underlying abnormalities; hence, the condition is now referred to as polycystic ovary syndrome, though it may occur in women without ovarian cysts.

Pathophysiology: Women with polycystic ovary syndrome (PCOS) have abnormalities in the metabolism of androgens and estrogen and in the control of androgen production. High serum concentrations of androgenic hormones, such as testosterone, androstenedione, and dehydroepiandrosterone sulfate, may be encountered in these patients. However, significant individual variation exists, and a particular patient might have normal androgen levels. PCOS also is associated with peripheral insulin resistance and hyperinsulinemia, and the degree of both abnormalities is amplified by the presence of obesity. The insulin resistance is not due to defects in insulin binding to the insulin receptors; rather, it involves postbinding signaling pathways. The elevated insulin levels may have gonadotropin-augmenting effects on ovarian function.

A proposed mechanism for anovulation and elevated androgen levels suggests that under the increased stimulatory effect of luteinizing hormone (LH) secreted by the anterior pituitary, there is increased stimulation of the ovarian theca cells. In turn, these cells increase the production of androgens (eg, testosterone, androstenedione). Because of a decreased level of follicle stimulating hormone (FSH), the ovarian granulosa cells are not able to aromatize the androgens to estrogens, leading to decreased estrogen levels and consequent anovulation. It is believed that growth hormone (GH) and insulinlike growth factor 1 (IGF-1) also may have an augmenting effect on the ovarian function. Hyperinsulinemia also is responsible for dyslipidemia and elevated levels of plasminogen activator inhibitor (PAI-1) in patients with PCOS. Elevated PAI-1 levels constitute a risk factor for intravascular thrombosis. Polycystic ovaries are enlarged bilaterally and have a smooth-thickened capsule that is avascular. On cutsection, subcapsular follicles in various stages of atresia are seen in the peripheral part of the ovary. The most striking feature of the PCOS ovary is the hyperplasia of the theca stromal cells surrounding arrested follicles. On microscopic examination, luteinized theca cells are seen.

Frequency:
　

• In the US: Approximately 6-10% of women in the US are believed to have PCOS.

Sex: PCOS is present in women.

CLINICAL

History: Patients with PCOS may complain of the following:

• Menstrual dysfunction: Most common presentation is erratic menstruation due to anovulation. Some women have oligomenorrhea (fewer than 9 menstrual periods in a year) or amenorrhea (no menstrual periods for 3 or more months). The onset of menstrual irregularities usually is peripubertal.

• Hyperandrogenism: This is manifested clinically by excess terminal body hair in a male distribution pattern. These are commonly seen on the upper lip, chin, around the breast nipples, and along the linea alba of the lower abdomen. These patients may also have acne, male pattern balding or alopecia, increased muscle mass, deepening voice, or clitoromegaly.

• Infertility: A subset of women with PCOS is infertile. Most women with PCOS ovulate intermittently and may take longer to conceive or have fewer children than planned.

• Obesity: Obesity may be present in one half of women with PCOS.

• Diabetes mellitus: About 10% of obese women with PCOS have type 2 diabetes mellitus by age 40 years. About 35% of obese women with PCOS have impaired glucose tolerance by age 40 years.

Physical: Physical examination is significant for the following:

• Hirsutism: Excess body hair in a male distribution pattern and acne may be seen. In some patients with PCOS virilizing signs, such as male pattern balding or alopecia, increased muscle mass, deepening voice, or clitoromegaly, may be encountered and should prompt the search for other causes of hyperandrogenism.

• Obesity: About 50% of patients with PCOS are obese.

• Acanthosis nigricans: Acanthosis nigricans (AN) is a diffuse velvety-thickening 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 and knuckles. Acanthosis nigricans is thought to be the result of insulin resistance in these patients.

WORKUP

Lab Studies:
　

• The minimal criteria proposed for the diagnosis of PCOS includes the following:

• Presence of menstrual irregularity

• Evidence of hyperandrogenism, whether clinical (eg, hirsutism, acne, male pattern balding) or biochemical (elevated androgen level)

• Exclusion of other causes of hyperandrogenism

• A large number of patients with PCOS have various biochemical abnormalities. Because of the heterogeneity of this syndrome, there is no clear consensus on hormonal tests that can be expected to fully diagnose this condition. The following abnormalities may be encountered:

• Elevated androgen levels can be of ovarian (eg, testosterone, androstenedione) or adrenal (dehydroepiandrosterone sulfate) origin.

• Hyperprolactinemia can be ruled out by checking a serum prolactin concentration.

• Androgen secreting ovarian or adrenal tumors also present with progressive hirsutism, signs of virilization, and amenorrhea. The serum testosterone concentration usually is higher than 150 ng/dL in cases of ovarian tumors, and adrenal tumors have serum dehydroepiandrosterone sulfate higher than 800 mg/dL. The serum LH concentration usually is low in these patients.

• Late-onset congenital adrenal hyperplasia is rare and can be ruled out by measurement of serum 17-hydroxyprogesterone levels. Basal serum 17- hydroxyprogesterone levels are greater than 200 ng/dL. The response to adrenocorticotropic hormone (ACTH) stimulation is exaggerated in these patients; most patients have values exceeding 1500 ng/dL after ACTH stimulation.

• Normal serum estradiol and increased serum estrone concentrations are abnormalities.

• Serum LH concentrations may be high, but serum FSH concentrations are normal.

• Of obese women with PCOS, 35% have impaired glucose tolerance and 10% have diabetes mellitus. Impaired glucose tolerance is defined as a plasma glucose value of 140-200 mg/dL after 2 hours of an oral glucose tolerance test with 75-gram glucose load. Diabetes mellitus is defined as a fasting plasma glucose level of greater than 126 mg/dL.

• A fasting glucose (mg/dL)-to-insulin (mU/mL) ratio of less than 4.5 is believed to have a positive predictive value of 87% and a negative predictive value of 94% as a screening test in determining insulin resistance.

• An abnormal fasting lipid profile showing elevated triglycerides, low density lipoprotein (LDL) cholesterol, and decreased high density lipoprotein (HDL) cholesterol often is encountered.

• The diagnosis of PCOS does not require the presence of polycystic ovaries. However, it is believed that 80-100% of women with PCOS have polycystic ovaries, which are defined as the presence of 8 or more small (2-8 mm) follicles in each ovary. Polycystic ovaries also can be present in other causes of androgen excess and in approximately 20% of normal women.

TREATMENT

Medical Care: Medical management is aimed at treatment of metabolic derangements, anovulation, hirsutism, and menstrual irregularity.

• Metabolic derangements

• Diet and exercise: Obese PCOS patients have a marked improvement in their endocrine-metabolic parameters after 4-12 weeks of dietary restriction. They have a twofold rise in their sex hormone-binding globulin (SHBG) levels with a fall in the free testosterone level. Serum insulin and IGF-1 levels also fall. Weight loss in obese patients with PCOS is associated with a reduction of hirsutism and return of ovulatory cycles in 30% of women. A moderate amount of daily exercise has been shown to result in an increase of insulinlike growth factor binding protein 1 (IGFBP-1) with a 20% decrease in IGF-1.

• Metformin: This is an antidiabetic medication that has been shown to improve the insulin resistance and to decrease hyperinsulinemia in these patients. It is important to ascertain that kidney and liver functions are normal and that the patient does not have advanced congestive heart failure before starting metformin. The usual starting dose is 500 mg PO bid. Commonly encountered side effects are nausea, vomiting, and diarrhea. Patients who develop these side effects can be told to decrease the dosage to once a day for a week and then gradually increase the dosage. It is important to tell these patients that there will be a high likelihood of having ovulatory cycles while on metformin.

• Anovulation: Metformin has been shown to cause an 8-fold increase in ovulation. When combined with clomiphene citrate, a tenfold increase in ovulation has been observed. Infertile patients with PCOS who desire to achieve pregnancy should be referred to a reproductive endocrinologist for further workup and treatment of infertility.

• Hirsutism
  • Nonpharmacologic measures
    • Hirsutism can be treated through nonpharmacologic measures including shaving, use of chemical depilatories, bleaching creams, wax depilatories, and electrolysis.
    • Weight reduction in obese women has been shown to decrease androgen production and, therefore, can slow hair growth.
    • 　
  • Pharmacologic measures include the following:
    • Oral contraceptive pills: Women who do not wish to become pregnant can be effectively treated with oral contraceptives for hirsutism. Oral contraceptives slow hair growth in 60-100% of women with hyperandrogenemia. Therapy can be started with a preparation that has a low dose of estrogen and a nonandrogenic progestin. Preparations that have norgestrel and levonorgestrel should be avoided because of their androgenic activity.

      　

    • Antiandrogens, such as spironolactone, are effective for hirsutism. Spironolactone in a dose of 50-100 mg twice daily is an effective primary therapy for hirsutism. Because of the potential teratogenic effects of spironolactone, it should be prescribed with an oral contraceptive. The side effects of spironolactone include hyperkalemia, gastrointestinal discomfort, and irregular menstrual bleeding, which can be managed by adding an oral contraceptive.

• Menstrual irregularity: It is treated with an oral contraceptive. The oral contraceptives not only inhibit ovarian androgen production but also raise sex hormone-binding globulin production. Rule out pregnancy before initiating treatment with an oral contraceptive.

Surgical Care: Surgical management mainly is aimed at restoring ovulation.

• Ovarian wedge resection: It has fallen out of favor because of postoperative adhesion formation and the introduction of ovulation-inducing medications.

• Laparoscopic surgery: Various laparoscopic methods, including electrocautery, laser drilling, and multiple biopsy have been employed with the goal to create focal areas of damage in the ovarian cortex and stroma. Potential complications include formation of adhesions and ovarian atrophy.

Consultations:

• Endocrinology - For the follow-up of biochemical and metabolic derangements

• Reproductive endocrinology - If the patient is infertile and desirous of achieving pregnancy

Diet:

• Initiate diabetic diet in consultation with a nutritionist for women with PCOS who have impaired glucose tolerance.

• Obese PCOS patients benefit from a low-calorie diet for weight reduction.

• Start patients who have derangements in lipid profile on appropriate lipid-lowering dietary regimen.

MEDICATION

The drugs used in the treatment of PCOS include metformin, spironolactone, and oral contraceptives.
　

Drug Category: Hypoglycemic agents -- Reduce blood glucose levels.

Drug Category: Antihypertensive agents -- Spironolactone has been used to treat hirsutism.

FOLLOW-UP

Further Outpatient Care:

• These patients need regular follow-up to avoid complications that may result from an untreated PCOS.

Complications:

• Women with PCOS are at risk for development of diabetes mellitus type 2, hypertension, intravascular thrombosis, coronary artery disease, and endometrial cancer.

Patient Education:
　

• Advise patients that PCOS is a disease with many long-term complications and they need to have a regular follow-up with their physicians for early detection and management of any untoward sequelae associated with PCOS.

MISCELLANEOUS

Medical/Legal Pitfalls:
　

• Failure to diagnose the PCOS in a timely fashion can jeopardize the health of these patients and expose them to complications in terms of increased morbidity and mortality from diabetes mellitus and cardiovascular disease.

Special Concerns:
　

• It is important to rule out other conditions that may mimic PCOS in their presentation before a diagnosis of PCOS is made.

• Rule out pregnancy before initiating oral contraceptive therapy.

• Inform patients who are beginning to take metformin that their menstrual cycles might become ovulatory and they may have an increased chance of becoming pregnant while on metformin.

• Patients who are infertile should have proper workup to rule out both male and female factors that might be contributing to infertility before drawing the conclusion that PCOS is the sole cause of infertility.