CLINICAL CASE DISCUSSION

General Considerations
Polycystic ovary syndrome (PCOS) is a common endocrine disorder of unknown etiology affecting 5–10% of reproductive age
women. PCOS is characterized by chronic anovulation, polycystic ovaries, and hyperandrogenism. It is associated with hirsutism
and obesity as well as an increased risk of diabetes mellitus, cardiovascular disease, and metabolic syndrome. Patients with
PCOS are also at an increased risk for endometrial hyperplasia and carcinoma. Unrecognized or untreated PCOS is a risk factor
for cardiovascular disease. The Rotterdam Criteria identify androgen production, ovulatory dysfunction, and polycystic
ovaries as the key diagnostic features of the disorder in adult women; the emerging consensus is that at least two of these features
must be present for diagnosis. The classification system has been endorsed by the National Institutes of Health.

Signs and symptoms

These typically develop soon after menarche and can vary from woman to woman. They include:
 Menstrual disturbances — oligomenorrhea (infrequent menstruation), amenorrhea (the absence of menstruation) and
prolonged erratic menstrual bleeding
 Obesity — weight gain, being overweight and difficulty losing weight
 Hirsutism — thick, excessive hair growth on the face, neck and body
 Alopecia and/or thinning of hair on the head
 Acne as a result of hyperandrogenism;
 Acanthosis nigricans — thick, pigmented skin over the nape of neck, axilla, underarms, inner thigh and groin, which
occurs as a result of insulin resistance

Risk Factors
 Genetics: PCOS is believed to be a complex disorder, with genetic as well as environmental factors contributing to
development of the disease.
 Intrauterine exposures: exposures to testosterone in utero may predispose to the later development of PCOS
 Environment/lifestyle: several lifestyle factors and environmental exposures have been associated with a more severe
PCOS phenotype.
 Obesity: although obesity is not believed to cause PCOS, it is known to exacerbate the symptoms of the disease.

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%. Up to 10% of women are diagnosed with PCOS during gynecologic visits.
In some European studies, the prevalence of PCOS has been reported to be 6.5-8%.

A great deal of ethnic variability in hirsutism is observed. For example, Asian (East and Southeast Asia) women have
less hirsutism than white women given the same serum androgen values. In a study that assessed hirsutism in southern Chinese
women, investigators found a prevalence of 10.5%. In hirsute women, there was a significant increase in the incidence of acne,
menstrual irregularities, polycystic ovaries, and acanthosis nigricans.

PCOS affects premenopausal women, and the age of onset is most often perimenarchal (before bone age reaches 16 y).
However, clinical recognition of the syndrome may be delayed by failure of the patient to become concerned by irregular menses,
hirsutism, or other symptoms or by the overlap of PCOS findings with normal physiologic maturation during the 2 years after
menarche. In lean women with a genetic predisposition to PCOS, the syndrome may be unmasked when they subsequently gain
weight.

Clinical Findings
PCOS often presents as a menstrual disorder (ranging from amenorrhea to menorrhagia) and infertility. Skin disorders due to
peripheral androgen excess, including hirsutism and acne, are common. Patients may also show signs of insulin resistance and
hyperinsulinemia, and these women are at increased risk for early-onset type 2 diabetes and metabolic syndrome. Patients who do
become pregnant are at increased risk for perinatal complications, such as gestational diabetes and preeclampsia. In addition, they
have an increased long-term risk of endometrial cancer secondary to unopposed estrogen secretion.

Pathophysiology
Despite being one of the most common endocrinopathies, a comprehensive explanation of pathophysiology is still
lacking. The heterogeneity of PCOS may well reflect multiple pathophysiological mechanisms, but the definition of each
contributing mechanism has been slow to emerge. Traditionally, it has been useful to consider the polycystic ovary syndrome as
the result of a ‘vicious cycle’, which can be initiated at any one of many entry points. Altered function at any point in the cycle
leads to the same result: ovarian androgen excess and anovulation. Several theories have been proposed to explain the
pathogenesis of PCOS:
• A unique defect in insulin action and secretion that leads to hyperinsulinaemia and insulin resistance.
• A primary neuroendocrine defect leading to an exaggerated LH pulse frequency and amplitude.
• A defect of androgen synthesis that results in enhanced ovarian androgen production.
• An alteration in cortisol metabolism resulting in enhanced adrenal androgen production.

It must be accepted, however, that each of these are artificial stating points understanding of the metabolic–ovarian–
pituitary circuitry being closely interrelated

Diagnosis
There's no test to definitively diagnose PCOS. The doctor is likely to start with a discussion of your medical history,
including the patient’s menstrual periods and weight changes. A physical exam will include checking for signs of excess hair
growth, insulin resistance and acne.

Your doctor might then recommend:

1. A pelvic exam. The doctor visually and manually inspects your reproductive organs for masses, growths or other
abnormalities.
2. Blood tests. Your blood may be analyzed to measure hormone levels. This testing can exclude possible causes of
menstrual abnormalities or androgen excess that mimics PCOS. You might have additional blood testing to measure
glucose tolerance and fasting cholesterol and triglyceride levels.
3. An ultrasound. Your doctor checks the appearance of your ovaries and the thickness of the lining of your uterus. A
wandlike device (transducer) is placed in your vagina (transvaginal ultrasound). The transducer emits sound waves that
are translated into images on a computer screen.

If there is a diagnosis of PCOS, the doctor might recommend additional tests for complications. Those tests can include:
1. Periodic checks of blood pressure, glucose tolerance, and cholesterol and triglyceride levels
2. Screening for depression and anxiety
3. Screening for obstructive sleep apnea

Differential Diagnosis
Anovulation in the reproductive years may also be due to (1) premature ovarian failure (high FSH and LH levels); (2) rapid
weight loss, extreme physical exertion (normal FSH and LH levels for age), or obesity; (3) discontinuation of hormonal
contraceptives (anovulation for 6 months or more occasionally occurs); (4) pituitary adenoma with elevated prolactin
(galactorrhea may or may not be present); and (5) hyperthyroidism or hypothyroidism. To rule out other etiologies in women
with suspected PCOS, serum FSH, LH, prolactin, and TSH should be checked. Because of the high risk of insulin resistance and
dyslipidemia, all women with suspected PCOS should have a hemoglobin A 1C and fasting glucose along with a lipid and
lipoprotein profile. Women with clinical evidence of androgen excess should have total testosterone and sex hormone–binding
globulin or free (bioavailable) testosterone, and 17-hydroxyprogesterone measured. Women with stigmata of Cushing syndrome
should have a 24-hour urinary free-cortisol or a low-dose dexamethasone suppression test. Congenital adrenal hyperplasia and
androgen-secreting adrenal tumors also tend to have high circulating androgen levels and anovulation with polycystic ovaries;
these disorders must also be ruled out in women with presumed PCOS.

Treatment

A. Medications
1. Estrogen and progestin oral contraceptive (OCP) therapy
This is the first-line treatment of acne, hirsutism and irregular menstrual cycle. It can also be used to normalize
androgen levels and attenuate the signs of hyperandrogenism as well as to regulate menstrual cycles. This also helps to
reduce the risk of heavy and irregular menstrual bleeding associated with the loss of normal estrogen and progestrone
levels. If the patient does not desire pregnancy and does not want or is not a candidate for contraception, then medroxy-
progesterone acetate, 10 mg/day orally for the first 10 days of every 1–3 months, should be given to ensure regular
shedding of the endometrium and thus avoid endometrial hyperplasia. If contraception is desired, combination con-
traceptives (pill, ring, or patch) can be used; this is also useful in controlling hirsutism, for which treatment must be
continued for 6–12 months before results are seen.
2. Anti-androgens (e.g. spironolactone, finasteride, flutamide)
Anti-androgens are used in the treatment of acne and hirsutism. Spironolactone is useful for hirsutism in doses of 25
mg three or four times daily. Flutamide, 125–250 mg orally daily, and finasteride, 5 mg orally daily, are also effective
for treating hirsutism. Because these three agents are poten¬tially teratogenic, they should be used only in conjunction
with secure contraception. Topical eflornithine cream applied to affected facial areas twice daily for 6 months may be
helpful in the majority of women. Hirsutism may also be managed with depilatory creams, electrolysis, and laser
therapy. The combination of laser therapy and topical eflo¬rnithine may be particularly effective.
3. Metformin
Metformin is a treatment of metabolic or glucose abnormalities such as glucose intolerance, hyperinsulinemia, and
anovulation. Reducing circulating insulin levels may secondarily reduce ovarian androgen synthesis. For those women
who do not respond to weight loss and exercise, metformin therapy may be helpful, and it can improve menstrual func-
tion. Metformin has little or no benefit in the treatment of hirsutism, acne, or infertility.
4. Clomiphene citrate: for inducing ovulation for women who are seeking pregnancy and remain anovulatory.
Clomiphene is the first-line therapy for infertility.
5. Gonadotropin therapy: recombinant FSH and hCG can be used to induce ovulation in cases where treatment with
clomiphene citrate and metformin has been unsuccessful.
6. Topical hair-removal agents (eg, eflornithine)
7. Topical acne agents (eg, benzoyl peroxide, tretinoin topical cream (0.02–0.1%)/gel (0.01–0.1%)/solution (0.05%),
adapalene topical cream (0.1%)/gel (0.1%, 0.3%)/solution (0.1%), erythromycin topical 2%, clindamycin topical 1%,
sodium sulfacetamide topical 10%)

B. Surgical Intervention
Surgical management of polycystic ovarian syndrome (PCOS) is aimed mainly at restoring ovulation. Ovarian wedge
resection has fallen out of favor because of postoperative adhesion formation and the successful introduction of ovulation-
inducing medications.
1. Ovarian drilling: a laparoscopic surgical procedure that may be used to treat clomiphene citrate-resistant anovulation.
2. IVF: used for the treatment of infertility in women who have not responded to other therapies to induce ovulation.

Management
Women with PCOS should be managed aggressively and should have regular monitoring of lipid profiles and glucose. In
adolescent patients with PCOS, hormonal contraceptives and metformin are treatment options.

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.

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

A. Lifestyle modification
Lifestyle modification may help attenuate all symptoms of PCOS and reduce the long-term risk of infertility, CVD and
T2DM. This is the first line of PCOS management. Increased exercise, improved diet, and weight loss can help to reduce the
metabolic abnormalities associated with PCOS. Weight loss of as little as 5-10% has been demonstrated to correct
oligoanovulation and improve the ability of women with PCOS to conceive. This approach has been found to be comparable
to or better than treatment with medication and should therefore be considered first-line treatment in managing women with
polycystic ovarian syndrome (PCOS).

B. Diet and Activity

Patients with polycystic ovarian syndrome (PCOS) who have impaired glucose tolerance should start a comprehensive
program of diet and exercise to reduce their risk of developing diabetes mellitus. Encourage moderate physical activity,
provided the patient has no contraindications. Discourage smoking because of the increased risk of cardiovascular disease.
In addition, obese women with PCOS can benefit from a low-calorie diet for weight reduction.

A diet patterned after the type 2 diabetes diet has been recommended for PCOS patients. A diet patterned after the type 2
diabetes diet has been recommended for PCOS patients. This diet emphasizes increased fiber; decreased refined
carbohydrates, trans fats, and saturated fats; and increased omega-3 and omega-9 fatty acids. However, in some obese
patients with PCOS, weight loss has improved menstrual regularity. A study by Jamilian et al found that soy isoflavone
administration for 12 weeks in women with PCOS significantly improved markers of insulin resistance, hormonal status,
triglycerides, and biomarkers of oxidative stress.

Women with an abnormal lipid profile should be counseled on ways to manage the dyslipidemia. Such measures include
eating a diet low in cholesterol and saturated fats and increasing physical activity.

Accumulating evidence suggests an association of vitamin D deficiency with metabolic syndrome. One study found
insufficient levels of 25-hydroxyvitamin D (< 30 ng/mL) in almost 75% of PCOS patients, with lower levels in those with
metabolic syndrome (17.3 ng/mL) than in those without metabolic syndrome (25.8 ng/mL).