Despite the popularity of ultrasound in making a diagnosis of PCOS, it is an unreliable single criterion; 36% of normally cycling women meet the strictest ultrasound criterion for PCOS, whereas 34% of PCOS patients have sonographically normal ovaries.[20]
Blood testing is an essential part of PCOS evaluation. Hyperandrogenism can be evaluated with a free testosterone level. Although this test is much more expensive than a total testosterone, it accounts for the decrease in SHBG seen in PCOS. This decrease can artifactually reduce total testosterone into the normal range in women. If the patient is hirsute or there is suspected adrenal disease, then androstenedione and dehydroepiandrosterone sulfate (DHEAS) should also be measured. Although dihydrotestosterone is the most potent androgen its effects are purely local within the ovary and the hair follicles. It circulates in negligent amounts, and is therefore not required.[21]
FSH and LH should be measured. There is no specific ratio which is perfectly diagnostic; however, there is typically FSH:LH inversion (i.e., LH is higher than FSH). These hormones should be measured on day 3–5 of the menstrual cycle. If the patient is amenorrheic, they may be measured at any time. Although the ratio is not predictive of PCOS, it is relevant in evaluation and management of infertility.[21]
TSH and prolactin should be measured to exclude thyroid disease and hyperprolactinemia, respectively. Mild elevations of prolactin are common in PCOS, and these should not be confused with significant hyperprolactinemia. Subclinical hypothyroidism is also much more common in patients with PCOS.[22] A simple and adequate screening for adult-onset congenital adrenal hyperplasia is 17-hydroxy progesterone. ACTH stimulatory testing is not indicated. The incidence of Cushing’s disease is approximately 1:1,000,000, making suppressive adrenal testing similarly unwarranted.[17]
The metabolic problems associated with PCOS have multisystem implications, as detailed in the next section. Evaluation must therefore include screening for diabetes, hypertension, and hyperlipidemia. A summary of testing recommendations is listed in Table 28-3.
| Labs fasting, day 3–5 of cycle (any day if amenorrheic) |
|---|
| Serology |
| FSH |
| LH |
| TSH |
| Prolactin |
| Testosterone (free) |
| 17-OH progesterone |
| Fasting blood sugar |
| Cholesterol/HDL/LDL/triglycerides |
| Liver function tests |
| If hirsute or suspected adrenal disease, add: |
| 0800 cortisol |
| DHEAS |
| Androstenedione |
| If suspected metabolic syndrome, add: |
| 2-hour oral glucose tolerance test |
After exclusion of other causes of amenorrhea and hirsutism, the diagnosis of PCOS is based on one of two sets of criteria: the Rotterdam criteria or the Androgen Excess Society (AES) criteria. These are listed, along with the 1990 NIH criteria, in Table 28-4.[2–4]
| Clinical finding | NIH 1990 | Rotterdam 2003 | AES 2007 |
|---|---|---|---|
| Hyperandrogenism* | Required | Any 2 of 3 criteria | Required |
| Oligomenorrhea** | Required | Any 1 of 2 criteria | |
| Polycystic ovaries*** | Not included |
Research into anti-müllerian hormone (AMH) has shown promise for diagnosis of PCOS. One paper suggests that a cut-off of 20 pgs/mL for AMH is as effective as measurement of androgens, sonography, or clinical examination.[23]
Long-term and other consequences of PCOS
PCOS is a systemic disorder and has multiple nongynecologic consequences. All women’s health practitioners must be aware of these and provide appropriate screening and follow-up for them.
Protracted exposure to a high estrogen environment increases the risk of endometrial hyperplasia and cancer. Screening by ultrasound assessment of the endometrial stripe or endometrial biopsy is appropriate in high-risk individuals.
Diabetes is significantly more common in women with PCOS with or without Metabolic Syndrome. Approximately 7% of women with PCOS have abnormal glucose tolerance tests (GTTs) at presentation; 12% more develop abnormal glucose tolerance over six years, and one-third of PCOS patients with abnormal glucose tolerance at presentation will progress to overt type 2 diabetes within six years.[24] The lifetime risk of type 2 diabetes in PCOS is seven- to tenfold higher than in controls. Regular diabetic screening is an essential part of long-term management of PCOS.[25]
Hypertension is found in 19% of PCOS patients compared to 12% of controls.[26] Long-term observation of blood pressure and medical control is indicated. The hyperlipidemia and hyperandrogenism of PCOS is reflected in a higher risk of cardiovascular events beyond age 65.[27] The relative risk of cardiovascular events in this age group was 12.9. Even for the lowest risk subgroup, the relative risk was 2.6, making PCOS an important risk factor for cardiovascular disease.[28] Such increased risk has not been demonstrated for women under age 65, although carotid plaque deposition is increased in PCOS patients in their forties.[29]
Among women with irregular menses and elevated androgens, the incidence of elevated liver function tests (LFTs) was 15%. Among those with persistently elevated liver function tests, all biopsies showed nonalcoholic steatotic hepatitis (NASH).[30] On this basis it is reasonable and desirable to check liver function tests on all women with PCOS. It is cheap – and the patients in any event must have lab work drawn – and will exclude a serious condition that can affect surgery and pregnancy. Patients with elevated LFTs require ongoing evaluation and referral as appropriate.
Psychiatric disorders are more prevalent among women with PCOS. These include social anxiety and depression. Ongoing screening for emotional symptoms is appropriate.[31] The incidence of depression and other psychiatric disorders was not increased among slender women with PCOS. It thus appears that the psychiatric associations of PCOS are not caused by an endocrine derangement but rather by the negative social and personal judgments made on obesity and hirsutism in women.[32]
Pregnancy outcomes are substantially worse in PCOS patients.[33] Miscarriage rates are increased, presumably because of luteal phase defects in oligo-ovulatory women.[34] The risk of gestational diabetes is greatly increased. Low APGAR scores and low birth weight are also more common in PCOS patients treated for infertility than in women with tubal infertility.[35]
Management and outcomes
Although management of menstrual irregularities is one important part of treatment of PCOS, it is by no means sufficient to consider only the woman’s menstrual cyclicity in treatment. The management of PCOS requires consideration of multiple medical issues and the individual’s goals. This is consistent with the multiorgan system involvement of PCOS.
PCOS management will depend on its presentation and the goals of the patient. A woman desiring childbearing who has amenorrhea must be considered differently from a woman with regular menses but hirsutism and abnormal lipids. Broadly speaking the goals of treatment are:
All aspects of management are best achieved by weight loss.[36] Modest weight loss is more effective than clomiphene for induction of ovulation, and is effective in reduction of circulating androgens and improvement of lipids and blood sugars. One study found no higher an incidence of metabolic syndrome in PCOS patients than in obese women without PCOS, suggesting that obesity itself predisposes to metabolic syndrome, rather than PCOS.[37] Weight loss is thus an integral part of all aspects of PCOS management. However, given the difficulties of long-term lifestyle modification and weight loss, other medical modalities are typically required.
Menstrual regulation
It is necessary for patients to have a withdrawal bleed at least once every three months to prevent risk of endometrial hyperplasia. Thus, women who have regular or semi-regular withdrawal bleeds that are of normal intensity do not require medical regulation of their menses. Medical control is needed for prevention of endometrial hyperplasia in women who have irregular, prolonged and/or heavy bleeding. For management purposes this bleeding is defined as lasting more than seven days at a time or in one month; bleeding less than every three months or at least four times yearly; passage of clots; need for combined pads and tampons; or soiling of bedding or clothes.
Pelvic ultrasound is an essential part of management of menstrual bleeding in PCOS. The thickness and character of the endometrial stripe must be documented. Recommendations for management based on endometrial stripe thickness vary. Hyperplasia can occur in women less than 35 years old with an endometrial stripe less than 15 mm. A stripe thickness less than 5 mm assures absence of endometrial cancer or hyperplasia. If the stripe is greater than 12 mm, or bleeding has been heavy and prolonged, then endometrial biopsy is the best way to exclude endometrial pathology before beginning treatment.[10, 13]
The optimum medication for bleeding control in women not desiring pregnancy is unclear. Despite the frequency of bleeding as a symptom there is very little data on the superiority of one management over another. Oral contraceptive pills reduce endometrial cancer rates, but this is true of all women, not merely women with PCOS.[38] Oral contraceptives offer many benefits. They not only regulate menses but they provide for contraception. Oral contraceptive pills also decrease LH stimulation of the ovarian stroma, thereby reducing androgen production. They additionally reduce 5aR in the hair follicles, further reducing androgen activity in the skin. Additional noncontraceptive benefits include a reduction in risk of ovarian cancer and endometrial hyperplasia.
Oral contraceptives may be started at any time in a woman with amenorrhea, provided a urine pregnancy test is negative. If the endometrial stripe is thin (less than 5 mm) then priming with estrogens for 5–10 days will reduce the incidence of breakthrough bleeding in the first few cycles of use. Conjugated equine estrogens 1.25 mgs twice daily or micronized estradiol 2 mgs daily is adequate. Alternatively the same management may be used only if breakthrough bleeding occurs.
Progestational agents are an alternative for induction of regular menses and prophylaxis against endometrial hyperplasia. Medroxyprogesterone acetate 10 mgs daily for 10–14 days every three months is sufficient protection against endometrial hyperplasia. The same medication may also be used monthly for those desiring monthly bleeding as a reassurance. Depot preparations provide very effective contraception and also will suppress LH and ovarian androgen production, at the expense of a higher incidence of breakthrough bleeding.
The lifetime risk of endometrial hyperplasia and cancer in these women make regular vaginal sonography an important tool. Periodic biopsy is invasive and painful and not warranted as a routine screening measure, although it is indicated in selected, symptomatic patients.
Induction of ovulation
PCOS patients vary markedly in the ease of ovulation induction. Successful management requires more than clomiphene citrate. The success of ovulation induction is strongly associated with metabolic syndrome. Fertile PCOS patients had an 11.5% incidence of metabolic syndrome, as opposed to 23.1% in clomiphene-responding PCOS patients, and 41.4% in clomiphene-resistant patients.[39] Higher day 3 baseline FSH values are associated with lower rates of clomiphene success, and PCOS is associated with higher rates of multifetal pregnancy on clomiphene.
Metformin has been used for ovulation induction. It is not more successful than clomiphene used as a single agent. Metformin and clomiphene used together have mixed results, but the preponderance of trials does not show added benefit for two drug management. There does appear to be benefit to adding metformin to clomiphene for patients who have failed clomiphene alone.[40–43] Two large reviews comprehensively address the use of metformin in PCOS-associated infertility as well as its use in other PCOS settings.[44, 45]
Given the potential for multifetal pregnancy and the high rate of failure, ovulation induction in PCOS patients may be best done by physicians with significant specialized endocrine training.
Hirsutism
Manifestations of hyperandrogenism are some of the most troubling symptoms for PCOS patients.[14] Hirsutism and obesity both are more strongly associated with emotional and psychiatric sequelae of PCOS than is PCOS itself.[31, 32] Managing hyperandrogenic symptoms is thus of great personal meaning to the patient. The mainstays of hirsutism management are oral contraceptives and spironolactone. These medications have three synergistic effects that ultimately reduce the amount of dihydrotestosterone.
Spironolactone acts in the skin to reduce the activity of 5aR. Oral contraceptives reduce ovarian androgen production, thus reducing available testosterone as substrate for 5aR. The progestational component of oral contraceptives also serves as a competitive substrate for 5aR. These effects are summarized in Table 28-5.
