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treatment for hirsutism may be evaluated for PCOS. Acne affects 15% to 25% of

women with PCOS, but this prevalence may not be different from the general

population. The prevalence of alopecia occurrence varies widely with reports of 5%

to 50% of women with PCOS and presents as scalp hair loss in the crown and vertex

areas.

10,13 Although hirsutism is considered a good marker of hyperandrogenism, acne

and alopecia should not be regarded as evidence of hyperandrogenism.

Ovulatory dysfunction in PCOS is typically described as oligo-ovulation or

anovulation, presenting clinically as a woman with irregular menstrual cycles.

Overall, 95% of women with PCOS and oligo-ovulation have menstrual dysfunction,

usually oligomenorrhea or amenorrhea.

4 The menstrual disturbances usually begin in

the peripubertal years; however, menstrual cycles in women with PCOS become

more regular because they approach menopause.

14 Obesity (defined as a body mass

index [BMI] ≥30 kg/m2

) occurs in approximately 61% to 76% of women with

PCOS.

4 Central or abdominal obesity is the typical pattern. Central obesity is a risk

factor for the development of diabetes and heart disease and, when present in a

woman with PCOS, worsens the clinical features (e.g., insulin resistance) of the

syndrome.

4,15 Therefore, lifestyle modification with appropriate diet and exercise is a

cornerstone of therapy for many women with PCOS.

Pathophysiology

The pathophysiology of PCOS is complex. The primary defect in PCOS is unknown,

but at least three potential mechanisms, acting alone or synergistically, appear to

create the characteristic clinical presentation. These mechanisms include

inappropriate gonadotropin secretion, excessive androgen production, and insulin

resistance with hyperinsulinemia. Figure 50-3 displays the closely integrated

relationship between these mechanisms in the development of PCOS.

A genetic basis for PCOS has been postulated, but its mode of transmission is

unclear.

7,16 Theories include an autosomal-dominant model and a polygenic model

with genetic–environmental interactions. The complex presentation and various

mechanisms make it impossible to target just one gene locus; in fact, more than 50

candidate genes have been proposed. A familial pattern to the development of PCOS

may exist, because the incidence is higher in women with relatives with the disorder.

GONADOTROPIN SECRETION

In PCOS, there is an increased frequency of GnRH stimulation, leading to an increase

in LH pulse frequency and amplitude, whereas FSH secretion remains normal. The

development of a dominant follicle does not occur because LH secretion occurs too

early in the menstrual cycle. Therefore, a woman is left with several immature

follicles and usually will not ovulate. It is not clear whether the abnormal pulse

frequency of GnRH is an intrinsic problem in the GnRH pulse generator in the

hypothalamus or a result of relatively low progesterone concentrations from

infrequent ovulation.

17 A woman with this abnormality does not enter the luteal phase

of her menstrual cycle, leaving estrogen unopposed. Unopposed estrogen leads to

endometrial hyperplasia and increases the risk for endometrial cancer. Increased LH

stimulation also leads to increased steroidogenesis in the ovary, leading to excess

androgen production. Amenorrheic women have high antimullerian hormone (AMH)

serum concentrations and higher antral follicle counts compared with both

oligomenorrheic women and regularly cycling patients with PCOS.

4 Additionally,

concentrations of AMH tend to remain persistently elevated over time in women with

PCOS.

Figure 50-3 Pathophysiology of polycystic ovary syndrome (PCOS). (Redrawn from Wong E. McMaster

pathophysiology review. http://www.pathophys.org/pcos/pcos-2/. Accessed March 24, 2016).

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EXCESS ANDROGEN PRODUCTION

Androgen production occurs in the theca cell of the ovary to facilitate follicular

growth and estradiol synthesis in the granulosa cell. In women with PCOS,

hypersecretion of LH and insulin increases the production of androgens, causing

abnormal sex steroid synthesis, hyperandrogenism, and hyperandrogenemia. The

dysregulation in steroid synthesis and metabolism is believed to result primarily from

a dysfunction of the cytochrome P-450 (CYP) C17 enzyme in the ovaries, an enzyme

with 17-hydroxylase and 17,20-lyase activities that are required to form

androstenedione.

17,18 Androstenedione is then converted to testosterone or is

aromatized by the aromatase enzyme to form estrone. Theca cells in women with

PCOS are more efficient at the conversion to testosterone than normal theca cells.

19

Also, a similar steroid pathway occurs in the adrenal cortex and, when

hyperandrogenism or hyperinsulinemic states exist, androgen production is further

enhanced.

Elevated androgen levels are seen in approximately 60% to 80% of women with

PCOS, mostly as increased free testosterone concentrations.

10,11 Assays for

testosterone tend, however, to be highly variable and inaccurate, so measurement of

androgen concentrations should be used only as an adjuvant test and never as the sole

criterion for diagnosis. Clinical assessment is the primary tool for assessment of

excess androgen.

INSULIN

Women with PCOS generally exhibit an increased risk of insulin resistance, yet the

cellular and molecular mechanisms for insulin resistance are different from those

seen with obesity and type 2 diabetes.

4

Insulin resistance is associated with

reproductive and metabolic abnormalities in women with PCOS and can occur in

both obese and nonobese women. There are several mechanisms by which this

occurs. One proposed mechanism is a postbinding defect in insulin-receptor

signaling.

20 Specifically, abnormal receptor autophosphorylation increases serine

phosphorylation in targeted cells, which contributes to insulin resistance.

21,22 The

insulin resistance in PCOS has been shown to be a selective, tissue-specific process

where insulin sensitivity is increased in the ovarian androgenic pathway (causing

hyperandrogenism), but insulin resistance is seen in other tissues involved with

carbohydrate metabolism, specifically in the fat and muscle. Hyperinsulinemia

results because of the compensatory increase in insulin secretion secondary to insulin

resistance.

Insulin has both direct and indirect roles in PCOS. In the ovary, insulin acts alone

or synergistically with LH to increase androgen production in theca cells. In the

liver, insulin inhibits synthesis of sex hormone–binding globulin (SHBG), a key

protein that binds to testosterone, and thus increases the free fraction of androgens

available for biologic activity. Therefore, hyperinsulinemia is a major contributor to

both hyperandrogenism and hyperandrogenemia in PCOS. Treatments targeted to

improve insulin resistance in women with PCOS have shown improvements in

ovulatory function, hirsutism, androgen levels, and metabolic profiles.

23,24

Indirectly,

insulin may enhance the amplitude of LH pulses, further exacerbating the

gonadotropin secretion defect in PCOS.

25

CASE 50-1

QUESTION 1: E.F. is a 27-year-old woman with mild hair growth above her upper lip, mild acne, and a

history of irregular menstrual periods. Since age 12, she has had six to nine periods/year at intervals that vary

from 30 to 90 days. When she does have a period, she considers them to be “normal” without pain or excessive

bleeding. Her irregular periods were not bothersome until recently when she became sexually active and

worries about becoming pregnant. She uses condoms for birth control. She reports no other medical conditions.

E.F. is 5 feet 7 inches tall and weighs 180 lb (BMI 28.2 kg/m

2

). Her vital signs today are blood pressure (BP)

118/84 mm Hg, heart rate (HR) 70 beats/minute, temperature 98.6°F, and respiratory rate (RR) 18

breaths/minute. Her physical examination is normal, with the exception of noted excessive facial hair and mild

acne. She takes a multivitamin daily and acetaminophen as needed for headaches. She has no known

medication allergies. What signs and symptoms does E.F. have that are consistent with PCOS?

E.F. exhibits several signs and symptoms that would indicate the presence of

PCOS. According to the criteria of all organizations, her history of abnormal

menstrual periods (oligomenorrhea) and clinical signs of hyperandrogenism,

including hirsutism and acne, would indicate PCOS. Furthermore, her combination of

hyperandrogenemia and oligomenorrhea signifies the highest metabolic risk among

PCOS patients.

4 E.F. is overweight, which is common in women with PCOS but is

not considered a criterion for diagnosis. Before a diagnosis of PCOS is made,

laboratory testing to exclude other related causes of her symptoms would have to be

performed. Studies may include prolactin, thyroid-stimulating hormone, testosterone,

and 17-hydroxyprogester-one concentrations to rule out hyperprolactinemia,

hypothyroidism, virilizing tumor, and congenital adrenal hyperplasia, respectively.

PCOS is primarily diagnosed by clinical assessment; therefore, these tests assist only

in confirming or excluding a diagnosis. To determine the presence of polycystic

ovaries, defined as more than eight follicles per ovary that are less than 10 mm

(usually 2–8 mm) in diameter, a transvaginal ultrasound should be performed.

Long-Term Complications

CASE 50-1, QUESTION 2: E.F has a mother with diabetes and hypertension and a father with diabetes,

hypertension, and dyslipidemia. Her significant laboratory values include the following:

Fasting glucose, 102 mg/dL

Low-density lipoprotein (LDL), 150 mg/dL

High-density lipoprotein (HDL), 52 mg/dL

Triglycerides, 130 mg/dL

Total cholesterol, 228 mg/dL

What risk does E.F. have for experiencing long-term complications from PCOS?

E.F. has an increased risk for experiencing impaired glucose tolerance, diabetes,

and metabolic syndrome, especially considering her family history. Furthermore, the

diagnosis of PCOS places her at possible increased risk for sleep apnea and

endometrial cancer.

IMPAIRED GLUCOSE TOLERANCE AND DIABETES

Studies have shown that women with PCOS have a higher prevalence of impaired

glucose tolerance, gestational diabetes,

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diabetes, and insulin resistance compared with women without the syndrome.

4,26,27 A

family history increases the risk of these conditions further. In a study of 254 women

with PCOS, 38.6% were found to have either impaired glucose tolerance (IGT) or

undiagnosed diabetes.

28 Compared with those without PCOS, the prevalence of IGT

and diabetes was significantly higher in both obese and nonobese (BMI <27 kg/m2

)

women. Waist–hip ratio and BMI appeared to be the most clinically important

predictors of glucose intolerance. Women with PCOS who have IGT appear to

exhibit type 2 diabetes at higher rates than the general population.

26,27 Therefore,

screening and diagnosis of these conditions is important for women with PCOS. E.F.

is overweight, and her mildly elevated fasting glucose and overweight suggest that

she may be at increased risk for impaired glucose tolerance.

Glucose tolerance should be assessed in all women with PCOS using a fasting and

2-hour oral (75 g) glucose tolerance test.

4,26,29 Routine screening for diabetes with an

oral glucose tolerance test should be performed for all women with PCOS by the age

of 30 years.

30 The American Diabetes Association or World Health Organization

criteria should be used for the appropriate diagnosis of IGT or diabetes. Insulin

concentrations are typically not obtained in clinical settings because they are

inaccurate.

METABOLIC SYNDROME AND CARDIOVASCULAR RISK

Approximately one-third to one-half of women with PCOS have metabolic syndrome.

Using the National Cholesterol Education Panel-Adult Treatment Panel III

criteria,

31–34 metabolic syndrome is present when the patient exhibits any three of

these symptoms: abdominal obesity (>40 inches in men and >35 inches in women),

triglycerides greater than or equal to 150 mg/dL, low HDLcholesterol (<40 mg/dLin

men and <50 mg/dL in women), blood pressure greater than or equal to 130/85 mm

Hg, and fasting glucose greater than or equal to 110 mg/dL. The incidence of a

metabolic syndrome in women with PCOS is significantly higher than the rate for the

general US population (45% vs. 6%, ages 20–29 years; 53% vs. 14%, ages 30–39

years) and independent of body weight.

34

It is believed that insulin resistance and

hyperandrogenism are contributing factors to metabolic syndrome in women with

PCOS.

35

Insulin resistance in the metabolic syndrome has been associated with a

twofold increased risk of cardiovascular disease and a fivefold increased risk of

type 2 diabetes.

36 Low HDL cholesterol (HDL-C) is seen most frequently in women

with PCOS (68%), followed by increased BMI and waist circumference (67%), high

blood pressure (45%), hypertriglyceridemia (35%), and elevated fasting glucose

(4%).

32 Another group found that elevated fasting insulin concentrations, obesity, and

a family history of diabetes conferred higher risk of having the metabolic syndrome

in women with PCOS.

33

Compared with women without PCOS, women with PCOS are reported to have a

higher prevalence of cardiovascular risk factors, including hypertension,

dyslipidemia, and surrogate markers for early atherosclerosis (e.g., increased Creactive protein concentrations).

35 With increasing age, and especially as women

with PCOS become postmenopausal, the risk of hypertension increases twofold.

37

Dyslipidemia in women with PCOS typically presents as decreased HDL-C (which

is a strong predictor of cardiovascular disease in women), elevated triglycerides,

elevated LDL cholesterol (LDL-C), and higher LDL–HDL ratios.

38 Women with

PCOS are noted to have more atherogenic, small, dense LDL-C compared with

controls, and this substantially increases cardiovascular risk.

39 Altered cholesterol

levels are more severe in women with hyperandrogenism.

4 Women with PCOS may

have other surrogate markers for early atherosclerosis and cardiovascular disease,

impaired endothelial dysfunction, and other markers of cardiovascular risk such as

coronary artery calcifications and increased carotid intima-media thickness.

35

Women with PCOS are considered to be at risk when any of these risk factors are

present: obesity, cigarette smoking, hypertension, dyslipidemia, subclinical vascular

disease, IGT, or family history of premature cardiovascular disease.

40 Non-HDL and

waist measurement are the best predictors of CVD risk.

4 They are considered to be

high risk when they have metabolic syndrome, type 2 diabetes mellitus, or overt

vascular or renal disease. Although cardiovascular risk exists, data are inconclusive

about whether women with PCOS have increased rates of morbidity and mortality

from cardiovascular disease.

OBSTRUCTIVE SLEEP APNEA

Obstructive sleep apnea is cessation of breathing that occurs during sleep. It can

disrupt sleep and cause daytime fatigue. Patients may not be aware that they are

having the symptoms of sleep apnea, which include snoring and a gasping or snorting

when breathing resumes. Studies indicate that the prevalence of obstructive sleep

apnea in the PCOS is higher than expected and cannot be explained by obesity

alone.

41–43

Insulin resistance appears to be a strong predictor of sleep apnea—more

so than age, BMI, or the circulating testosterone concentration.

43 This can be treated

with continuous positive airway pressure (CPAP) and may help metabolic

dysfunction.

7

ENDOMETRIAL HYPERPLASIA AND CANCER

Chronic anovulation in women with PCOS results in an endometrium that is exposed

to the prolonged effects of estrogen unopposed by progesterone. Therefore, PCOS is

a risk factor for endometrial hyperplasia. Women with PCOS have a 2.7-fold (95%

CI 1.0–7.3) increased risk for endometrial cancer.

4

It is considered prudent

management to induce artificial withdrawal bleeding by administering a course of

progestin at least every 3 months to prevent endometrial hyperplasia in women with

PCOS who experience either amenorrhea or oligomenorrhea. Alternatively,

ultrasound scans can also be used to measure endometrial thickness and morphology

every 6 to 12 months.

Treatment Goals

CASE 50-1, QUESTION 3: E.F. worries about becoming pregnant when she does not have regular periods.

She also has mild hair growth above her upper lip which is somewhat bothersome. Given these concerns, what

are the treatment goals for E.F.?

The primary goals for E.F. are to prevent pregnancy and address her hirsutism.

Additionally, treatment goals for E.F. would include maintaining a normal

endometrium, blocking the actions of androgens at target tissues, reducing insulin

resistance and hyperinsulinemia, reducing weight, and preventing long-term

complications. Other goals of treatment in patients with PCOS may include

correcting anovulation or oligo-ovulation and improve fertility.

Therapy goals should encompass both long-term and short-term objectives because

response to nonpharmacologic and pharmacologic therapy is slow, often requiring 3

to 9 months. Addressing long-term goals can minimize the risk for future

complications, and specifying short-term goals can improve motivation and

adherence to therapy.

NONPHARMACOLOGIC TREATMENT

CASE 50-1, QUESTION 4: E.F. has indicated that she would like to lose weight. E.F. does not smoke, drinks

one to two beers on weekends, and exercises by walking 20 minutes twice weekly. What nonpharmacologic

method(s) would be most effective?

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