Hospital Medicine

Polycystic ovarian syndrome

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I. What every physician needs to know.

Polycystic Ovarian Syndrome used to be known as Stein-Leventhal syndrome and is a syndrome that involves androgen excess and ovulatory dysfunction. PCOS is a very common female endocrine disorder. It is the most common cause of female infertility and carries with it an increased risk of metabolic syndrome/diabetes mellitus and the downstream effects of insufficient progesterone secretion which can lead to endometrial hyperplasia and cancer. This syndrome is occasionally referred to as functional ovarian hyperandrogenism or ovarian hyperthecosis.

II. Diagnostic Confirmation: Are you sure your patient has Polycystic Ovarian Syndrome?

There are multiple groups that have clinical criteria for PCOS. The two that are most commonly used are the NIH consensus criteria (released in 1990) and the Rotterdam criteria (released in 1993). The NIH criteria requires that a woman have menstrual irregularity (oligoovulation), evidence of hyperandrogenism (clinical or on lab testing) AND no other cause of hyperandrogenism and menstrual irregularity. The Rotterdam criteria requires 2 of 3 criteria: Oligoovulation and/or anovulation, evidence of hyperandrogenism (clinical or on lab testing), polycystic ovaries by ultrasound. By not requiring evidence of hyperandrogenism, the Rotterdam encompasses far more patients than the NIH criteria.

A. History Part I: Pattern Recognition:

PCOS has various clinical presentations. The primary features are related to the high androgens and lack of ovulation. However, women with PCOS frequently have obesity and insulin resistance.

Menstrual irregularity typically begins in puberty. Women with PCOS can have fewer periods or amenorrhea. In addition, there is often heavy bleeding with the periods. Some will present with late menarche others with precocious puberty.

Unless a woman is trying to get pregnant, it is typically the hyperandrogenism that is the most disturbing to the patient. Classic symptoms are hirsutism, acne, or male pattern balding. Hirsutism does not need to be present in adolescence as the hyperandrogenism may not be evolved fully when the menstrual disturbances begin. Excess sweating and hidradenitis suppurative are also signs of hyperandrogenism, especially in adolescents.

Ovarian cysts are a key finding. The cysts are multiple and small, found in the periphery of the ovary. Rotterdam ultrasound criteria for PCOS is defined as 12 or more follicles in both ovaries (each 2-9mm) and/or increased ovarian volume (>10mL). However, this finding is common in almost all causes of anovulation and androgenopathies so it should not be used as the sole criteria.

LH/FSH ratio: This is one of the most frequently discussed findings for PCOS but is actually not part of the clinical criteria and is not a reliable indicator of this syndrome. Peripheral aromatization of androgens leads to estrogen excess which feeds back to decrease FSH decretion and increases LH secretion. The subsequent increase in LH causes ovarian stromal hyperplasia and a higher production of androgens. The best time to test for LH and FSH is on day 3 of the menstrual cycle.

Obesity is seen in more than half of patients with this syndrome.

Insulin resistence, glucose intolerance and dyslipidemia are all associated with polycystic ovarian syndrome.

The presentation of PCOS is typically an overweight or obese young woman with irregular periods and acne and/or facial hair. However, this syndrome is only recognized retrospectively when women are being evaluated for infertility.

B. History Part 2: Prevalence:

Women with a family history of type 2 diabetes or polycystic ovarian syndrome are at increased risk for this condition. Racial disparities are unclear at this point but it does seem like Mexican-American woman are at increased risk. Women with infertility, obesity and/or insulin resistance have a higher prevalence of this syndrome but it is thought that at least some part of this is an actual manifestation of the syndrome rather than causative condition. Girls with precocious puberty will have a markedly high risk of developing PCOS later in life.

C. History Part 3: Competing diagnoses that can mimic Polycystic Ovarian Syndrome.

Congenital Adrenal Hyperplasia (CAH): Late onset CAH (called "nonclassic") is the one that is usually confused with PCOS since the "classic" CAH is typically diagnosed in infancy. Ovaries will appear cystic on ultrasound. This is distinguished from PCOS with a morning 17 hydroxyprogesterone. Testing for this condition is generally reserved for patients in high risk ethnic groups (Ashkenazi Jewish, Hispanic, Slavic, or Italian women).

Thyroid disease: This is distinguished on blood testing.

Cushing syndrome: Women with features of Cushing's syndrome should have a cortisol evaluation but this is not typically screened for in women who lack a dorsal fat pat, hypertension, striae, or muscle weakness.

Hyperprolactinemia: This is distinguished on blood testing.

Virilizing tumor: Women who present with symptoms of severe virilization or those who have a rapid onset of symptoms should have a thorough evaluation for a virilizing tumor. Worrisome symptoms are cliteromegaly, an increase in muscle mass (typically in the shoulder girdle area), deepening of the voice, progression over one year, frontal balding, severe pustular acne, loss of breast tissue, sudden onset more than 10 years from the onset of puberty). Any evidence of virilization should prompt testing for DHEAS, testosterone (free and total) and a 17-hydroxyprogesterone. Imaging of the ovaries and adrenal glands should also be considered and can be chosen based on results of other hormone testing.

Idiopathic hirsutism: The decision to attribute symptoms to idiopathic hirsutism is always difficult. Certainly women with a family history of hirsutism are at increased risk. If there is no evidence of virilization and the patient is not in an at risk ethnic group (see above), prolactin levels and thyroid testing in addition to the routine work up for PCOS should be sufficient. However, if the patient has severe hirsutism, an endocrine evaluation similar to that done for patients with virilization is warranted.

Insulin resistance syndromes: Patients with severe insulin resistance can have PCOS or PCOS like features.

Drugs (valproic acid, steroids, danazol for example).

Obesity.

Other causes of anovulation: Women with chronic anovulation from any cause will have ovarian cysts similar to those seen in PCOS. Each month, the follicles are recruited and if there is no released egg with its subsequent production of progesterone to suppress the growing follicles, these follicles will persist. Lack of other clinical criteria for PCOS is important in this situation.

D. Physical Examination Findings.

The physical exam findings are variable.

Hirsutism is often seen with excessive sexual and facial hair. Hair is thick and in a male distribution.

Patients can have acne, alopecia and hyperhidrosis.

Obesity is commonly seen - typically similar to the metabolic syndrome with abdominal obesity.

Insulin resistance is seen with increased frequency and the associated acanthosis nigricans can be a presenting sign of PCOS.

E. What diagnostic tests should be performed?

Patients should have a skin exam that includes a genital exam and evaluation for acne, excess hair, and other skin disorders like acanthosis nigricans and hidradinitis suppurativa.

BMI should be calculated and the patient should be evaluated for the metabolic syndrome (blood pressure, waist circumference measurement).

Increased ovarian mass is typically not appreciated on physical exam.

Instruction

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Laboratory testing is largely dependent on the patient presentation.

LH/FSH testing is frequently sent but is not part of the diagnostic criteria for PCOS. FSH testing can be helpful in ruling out premature ovarian failure and for evaluation of women with infertility but although the LH concentration will be elevated in women with polycystic ovarian syndrome, it is neither necessary or particularly useful. In the event that the provider decides to send these tests looking for the classic elevation in LH/FSH, it is best measured on day 3 of the menstrual cycle.

Testosterone levels should be measured. Women with polycystic ovarian syndrome will quite frequently have a mild elevation in the total and free testosterone levels. The free testosterone is actually the most sensitive of the assays but can be unreliable from many laboratories.

HCG, TSH, and prolactin levels should be sent for all patients with menstrual disturbances.

DHEA-S testing should be reserved for patients with more severe hirsutism or signs of virilization.

Patients with known polycystic ovarian syndrome should have testing for glucose intolerance or type 2 diabetes. This can be done with a serum hemoglobin A1c or 2 hour glucose tolerance test. This should be done at least every 2 years and more frequently if there are other risk factors for diabetes or if impaired glucose tolerance is identified.

Patients with polycystic ovarian syndrome are also at risk for dyslipidemia and should have a fasting lipid evaluation which includes total cholesterol, HDL, LDL and measurement of triglyceride levels.

Cortisol should be sent in women with clinical features of cushing's syndrome.

Women who are presenting with infertility and are looking for confirmation of ovulation can have a day 20 progesterone sent. Absolute criteria are conflicting but progesterone levels greater than 10 are typically thought to be consistent with ovulation. Women with irregular menses can be easily mislead by this test.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The only imaging study used in the diagnosis of polycystic ovarian syndrome is a pelvic sonogram. Despite inclusion in the Rotterdam criteria, there is really not firm consensus in the utility of this study. The ultrasound is generally looking for multiple follicles, peripheral location of those follicles, ovarian enlargement and stromal brightness. Generally the findings of more than 10 follicles in each ovary and a peripheral distribution of those follicles is felt to be consistent with a diagnosis of PCOS. However, multiple follicles are seen on pelvic sonogram in some women that do not have polycystic ovarian syndrome and even in women who have no other clinical manifestations of endocrinopathy or menstrual irregularity.

Ovarian irregularities like those seen in PCOS are seen in many conditions and can not be used alone to make the diagnosis. Ultrasound is, however, useful in following women being evaluated and treated for infertility. Women with idiopathic hirsutism, CAH, androgenic alopecia, oligomenorrhea can all have an ultrasound that is consistent with "PCOS".

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Most women who present with symptoms of the polycystic ovarian syndrome will get an entire battery of blood tests. LH levels are very frequently sent but are not necessary and are not part of the diagnostic criteria for this syndrome. Estradiol levels and estrone levels are also not necessary to make the diagnosis. DHEA-S testing should be reserved for women with severe symptoms of hyperandrogenism or a history that is concerning for virilizing tumor. 17-hydroxyprogesterone testing should be tailored to ethnic groups that have a prevalence that justifies this test.

Some people would argue that ultrasound testing is overused for patients with polycystic ovarian syndrome. Any chronic anovulatory state can give the ultrasound appearance of multiple cysts on the ovaries and hyperandrogenism itself causes an increase in ovarian stromal area/total area. If the patient meets clinical criteria without the ultrasound, it is not necessary but can be useful in confirming the diagnosis.

III. Default Management.

Treatment of the polycystic ovarian syndrome largely depends on the patient and what she presents with and is disturbed by.

All women with PCOS and obesity should be counselled about weight loss. Weight loss alone can restore normal ovulation and decrease testosterone levels. Weight loss counseling is the same as given to all patients with obesity but there are some studies that suggest a diet lower in glycemic index can even more beneficial in this population.

For women who are not desiring pregnancy and have signs or symptoms of hyperandrogenism, the first line treatment is typically a combination oral contraceptive. This will provide endometrial protection as well as improve the symptoms of hyperandrogenism.

Women with hirsutism should initially be tried on oral contraceptives. Patients should be advised that the treatments for hirsutism will not reverse the hair that has accumulated but should slow the new hair growth and thin the hair. If oral contraceptives are not sufficient, spironolactone can be added. In addition, eflornithine hydrochloride cream can be used topically. Most women will use electrolysis, depilatories, waxing, or laser treatment for cosmetic results as well.

Acne is also improved by oral contraceptives. If the acne persists, women can be tried on other typical anti-acne regimens.

Women who present with infertility and any excess body weight should be counseled regarding weight loss. If weight loss alone does not restore ovulation, clomiphene citrate is typically used. Many doctors use metformin in this situation but the studies and clinical experience has not been as promising as the results seen with clomiphene citrate. Thiazolidinediones have also been used for ovulation induction in polycystic ovarian syndrome. Other treatments for anovulation are available (like ovarian laser electrocautery or ovarian drilling) but they are extremely rare at this point due to the efficacy of medications like clomiphene citrate.

All of these treatments are given by a gynecologist or fertility expert who is familiar with their use. However, patients given metformin or thiazolidinediones for the insulin resistance or glucose intolerance associated with polycystic ovarian syndrome should be counseled about the potential for resumption of ovulation and pregnancy. At this point, most people are not using metformin over clomiphene citrate for ovulation induction but there have been studies that women who got pregnant on metformin and continued this medication through the first trimester had decreased spontaneous abortion rates than women not on metformin. Women with PCOS and infertility have a higher rate of spontaneous pregnancy loss in the first trimester and metformin may mitigate that to some extent.

All women with polycystic ovarian syndrome who have menstrual dysfunction should be considered for endometrial protection. This can be accomplished by the administration of oral contraceptives or intermittent progestin therapy.

Women found with associated glucose intolerance or diabetes are managed no differently than those without polycystic ovarian syndrome.

A. Immediate management.

NA

B. Physical Examination Tips to Guide Management.

Management changes occur mainly when the needs of the patient change or if the initial management fails to improve the symptoms of hyperandrogenism.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Repeat laboratory testing is not typically done unless the patient is being managed for fertility issues.

D. Long-term management.

Patients with polycystic ovarian syndrome should be monitored for obesity, the development of the metabolic syndrome and any evidence of glucose intolerance or type 2 diabetes.

E. Common Pitfalls and Side-Effects of Management.

Oral contraceptives carry with them mutliple side effects and an increased risk of DVT/thromboembolic disease. The risk increases in patients who are older and those who smoke. Pills with progesterones that carry the lower androgen effects are typically used (desogestrel, norgestimate, norethindrone).

Spironolactone should not be used without a form of contraception due to hormonal effects on the fetus. Most prescription acne medications are also not advised in pregnancy, so care should be used in prescribing these medications without oral contraception especially in women undergoing other therapies that can induce ovulation (weight loss, metformin, TZDs).

Women who do not desire pregnancy and not prescribed an oral contraceptive should be counseled about the chance of ovulation with therapies for polycystic ovarian syndrome (including weight loss alone).

Clomiphene citrate should not be prescribed by someone who is not an expert in fertility issues.

IV. Management with Co-Morbidities.

N/A

A. Renal Insufficiency.

Metformin is not used in patients with renal insufficiency.

B. Liver Insufficiency.

Fatty liver is associated with the metabolic syndrome and PCOS. No change in standard management but fatty liver should be considered as part of the diagnosis.

C. Systolic and Diastolic Heart Failure.

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management. May be seen more frequently in patients with PCOS.

E. Diabetes or other Endocrine issues.

Patients with PCOS have an increased incidence of insulin resistance and diabetes. No change in standard management.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

NA

B. Anticipated Length of Stay.

NA

C. When is the Patient Ready for Discharge.

Patients with PCOS become inpatients for reasons unrelated to this syndrome. It should not influence discharge.

D. Arranging for Clinic Follow-up.

Patients should have a health care provider familiar with PCOS.

1. When should clinic follow up be arranged and with whom.

Patients should be followed by someone familiar with the complications and associated disease states seen with PCOS. Typically, these patients will follow with an internist and a gynecologist. Evaluations with these doctors should be yearly or more frequently if symptoms dictate.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

None

E. Placement Considerations.

None

F. Prognosis and Patient Counseling.

Patients with polycystic ovarian syndrome are at increased risk for the metabolic syndrome and type 2 diabetes. Patients should be counseled about the importance of diet and exercise and maintaining a healthy body weight.

Patients with this syndrome should be monitored by their outpatient physicians and have interval screening for type 2 diabetes and other complications of the polycystic ovarian syndrome. Women with chronic anovulation should be monitored and treated for endometrial protection.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Polycystic ovarian syndrome is not a syndrome that requires admission other than for rarely performed ovarian surgeries.

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