Polycystic ovary syndrome Part 2

Differential Diagnosis

Idiopathic hirsutism

Idiopathic hirsutism is defined as hirsutism in a woman with regular, ovulatory menstrual cycles. Women with idio-pathic hirsutism have circulating testosterone and androstene-dione concentrations at the upper limit of the normal range, but in these patients, such levels are lower than the levels observed in women with PCOS. Women with idiopathic hir-sutism often have sisters with PCOS, and they tend to have a lower BMI than the sisters with PCOS.16,17 Many authorities believe that idiopathic hirsutism is a mild form of PCOS in which hyperandrogenism is present but the disease has not progressed to the point where ovulatory menses have become disrupted. Other authorities believe that idiopathic hirsutism is the result of overactive skin conversion of weak precursor an-drogens (e.g., as androstenedione) to potent androgens (e.g., dihydrotestosterone) directly in the pilosebaceous unit. Regardless of the etiology, idiopathic hirsutism is best treated with the same approach as that for hirsutism in women with PCOS (see below).

Virilization syndromes

Women with the rapid onset of virilization or a serum testosterone level greater than 2 ng/ml (200 ng/dl) should be evaluated for an adrenal or ovarian tumor. Use of magnetic resonance imaging to screen for an adrenal tumor and use of pelvic sonography to screen for an ovarian tumor are helpful.

Adrenal carcinoma presents with the rapid onset of viriliza-tion; it is often associated with systemic symptoms such as fatigue, weakness, and weight loss. DHEAS concentration is often greater than 8 |ig/ml, and 24-hour urinary 17-ketosteroid excretion is markedly increased, to about 30 mg/dl.


Ovarian hyperthecosis

Careful histologic examination of ovaries from women with PCOS often reveals islands of luteinized, steroid-secreting stro-mal cells (stromal hyperthecosis) in the medullary portion of the ovary that are not associated with follicular structures.18 Severely hyperthecotic ovaries may contain only a small number of follicles, each 4 to 8 mm in diameter. PCOS patients with more severe hyperinsulinemia seem to be at highest risk for hyperthecosis.

Only a small subset of women with hyperandrogenism have stromal hyperthecosis. The diagnosis should be considered in a patient who presents with virilization, a total serum testosterone concentration of greater than 2 ng/ml, a normal LH level, and marked insulin resistance and hyperinsulinemia. Pathologic confirmation of the diagnosis, which requires removal of the ovaries, is not necessary.

In response to an oral glucose challenge, nonobese women with PCOS experience an exaggerated increase in circulating insulin compared with weight-matched control subjects; the increase persists for over 3 hours.

Figure 3 In response to an oral glucose challenge, nonobese women with PCOS experience an exaggerated increase in circulating insulin compared with weight-matched control subjects; the increase persists for over 3 hours.

Differentiation of ovarian hyperthecosis from PCOS is important because women with ovarian hyperthecosis often do not have significant suppression of circulating testosterone when treated with estrogen-progestin contraceptive alone. Instead, treatment with a GnRH analogue (e.g., leuprolide acetate depot, 3.75 mg intramuscularly every 4 weeks) plus an es-trogen-progestin contraceptive often results in the normalization of circulating androgens.19 A possible interpretation of this observation is that LH must be profoundly suppressed to decrease ovarian androgen production in women with hyperthe-cotic ovaries. Low-dose estrogen-progestin contraceptives alone do not suppress pituitary LH secretion as completely as they do in combination with a GnRH agonist analogue.

Treatment

Treatment for PCOS may be general—directed at the underlying hormonal imbalance—or specific to a particular manifestation (e.g., hirsutism or infertility) [see Table 3]. PCOS should be treated, because it poses long-term risks of endometrial cancer, diabetes mellitus, and possibly cardiovascular disease.

Regardless of the patient’s presenting complaint, treatment of PCOS in a woman who smokes cigarettes includes smoking cessation. Discontinuance of smoking may result in a reduction in circulating androgens; also, smoking is a contraindication to the use of oral contraceptives, which are often prescribed for patients with PCOS.

Treatment of hirsutism

The mainstay of the treatment of hirsutism resulting from androgen excess is the combination of an estrogen-progestin oral contraceptive (used in regular or long cycles) and an antiandrogen. Patients should be advised that response to therapy tends to be slow; for more immediate results, patients may prefer the use of techniques that directly destroy the hair follicle.

Oral Contraceptives

Cyclic estrogen-progestin oral contraceptives produce multiple beneficial effects in patients with PCOS. These effects include the following: (1) decreased LH secretion, which suppresses ovarian androgen production; (2) increased liver production of sex hormone-binding globulin, which decreases free testosterone concentration; (3) decreased adrenal androgen production, through an unidentified pathway; (4) prevention of en-dometrial hyperplasia; and (5) regular uterine withdrawal bleeding. Of course, oral contraceptives also prevent pregnancy. The choice of agent does not seem important; it appears that any oral contraceptive, regardless of the estrogen dose or the pro-gestin employed, can be effective in the treatment of hirsutism.

By suppressing both ovarian and adrenal androgen production, oral contraceptives decrease the stimulus to terminal hair growth. In patients with hirsutism, therapy with an oral contraceptive first brings a decrease in the diameter of the hair shaft and in the intensity of pigment in the hair—the unwanted hair becomes thinner and lighter in color. With prolonged treatment, the linear rate of hair growth diminishes. Ultimately, the hair follicle becomes senescent. If no new hair follicle starts to grow, the hirsutism then diminishes.

Long-cycle oral contraceptives When oral contraceptives are used in a standard cyclic manner (21 days of active pills followed by 7 days of inactive pills), LH secretion tends to increase during the 7 days in which inactive pills are taken. This stimulates a small rise in ovarian testosterone secretion, which, in turn, can stimulate hair growth. As an alternative, oral contraceptives can be taken in a continuous manner. In the initial treatment of hirsutism caused by PCOS, use of continuous oral contraceptives may be more effective than use of cyclic oral contraceptives for the suppression of LH and androgen production.

Table 3 Treatment of Hirsutism, Anovulatory Infertility, and Endometrial Hyperplasia in Women with PCOS

Presenting Problem

Standard Treatment

Alternative Treatment

Hirsutism

Oral contraceptive used in a long-cycle regimen, plus spironolactone

Oral contraceptive plus spironolactone

Oral contraceptive plus GnRH analogue

Weight loss

Insulin sensitizer, preferably metformin

Finasteride

Acne

Oral contraceptive

Topical agents, oral antibiotics

Infertility

Weight loss

Clomiphene

Metformin plus clomiphene

Ovarian surgery

Clomiphene plus glucocorticoids

IVF-ET

Low-dose FSH injections

Low-dose FSH injections plus metformin

Endometrial hyperplasia

Oral contraceptives

Weight loss

High-dose progestins

FSH—follicle-stimulating hormone

GnRH—gonadotropin-releasing hormone

IVF-ET—in vitro fertilization with embryo transfer

Most women with PCOS would like to restore a regular pattern of menses. To accommodate this desire while maximally suppressing LH levels, the clinician can employ the following regimen: the patient takes an active pill daily for 63 days (using the active pills from three packs), then takes inactive pills for 7 days. This long-cycle oral contraceptive regimen may induce regular withdrawal bleeding every other month and produce better suppression of LH and testosterone than oral contraceptives used in monthly cycles.

Antiandrogens

Antiandrogens are a cornerstone of therapy for hirsutism. In a 1-year trial, antiandrogen therapy using cyproterone acetate, 50 mg daily, plus ethinyl estradiol on cycle days 16 through 25, was compared with glucocorticoid suppression with hydrocortisone, 20 mg daily. Although hydrocortisone was more effective at normalizing plasma androgen levels, cyproterone provided superior treatment of hirsutism.21 This study demonstrated that in established hirsutism, suppressing circulating androgens to normal levels is less important than blocking peripheral androgen action in the piloseba-ceous unit.

Cyproterone acetate is not available in the United States. However, spironolactone has proved to be an effective antian-drogen, and its effects on hirsutism are similar to those of cyproterone acetate.22 Because spironolactone has been used for many decades in the treatment of hirsutism and has an excellent safety profile, it should be considered the first-line agent for this indication in the United States. The usual dosage of spironolactone as an antiandrogen is 100 mg once daily.

The 5a-reductase inhibitor finasteride, which the Food and Drug Administration has approved only for treatment of men with benign prostatic hyperplasia, also reduces hirsutism in women.23 The dosage of finasteride is 5 mg daily.

The androgen receptor antagonist flutamide (Eulexin) is as effective as spironolactone and finasteride in the treatment of hirsutism, but flutamide has liver toxicity and may cause fulminant liver failure.24 Although the risk of liver failure with flu-tamide is small, hirsutism is a benign condition, so treatment regimens must have a high degree of safety.

Spironolactone, finasteride, and flutamide are believed to be human teratogens and may induce abnormal genital tract development in male fetuses. Women taking these agents need to use effective birth control. In addition, spironolactone, finas-teride, and flutamide do not protect against endometrial hy-perplasia and are not likely to induce regular menstrual cycles. These considerations support the use of an oral contraceptive in combination with an antiandrogen in the treatment of hir-sutism in women of reproductive age.

Weight Loss

Numerous studies have demonstrated the benefits of weight loss in hyperandrogenic, insulin-resistant women.25-27 In these studies, mean weight loss ranging from about 10 to 20 kg has been associated with a decrease in insulin levels and testosterone concentration and with ovulation and subsequent pregnancy in many women.28-30

Weight loss is difficult to achieve. A structured program that includes consultation with a nutritionist, encouragement by the physician, a low-calorie diet, and initiation of an exercise program may be the most effective nonsurgical approach in these patients. Surgical methods of weight reduction can be very effective, especially in women whose BMI is greater than 40.

Gonadotropin-Releasing Hormone Agonists

Women with hirsutism who do not respond to treatment with an oral contraceptive plus an antiandrogen can often be successfully treated with a combination of a GnRH agonist (e.g., leuprolide acetate) and an oral contraceptive,31 with or without an antiandrogen. It is likely that the combination of leuprolide and an oral contraceptive produces greater suppression of LH and androgens than the oral contraceptive alone. Leuprolide is not ordinarily recommended as a first-line therapy for hirsutism because it is expensive (costing approximately $400 a month). Also, when used as a single agent, a GnRH agonist produces profound hypoestrogenism and accelerated bone loss. The addition of an oral contraceptive prevents GnRH agonist-induced hypoestrogenism and vasomotor symptoms and preserves bone density.

Glucocorticoids

Treatment with glucocorticoids may be appropriate in women with ACTH-dependent adrenal androgen overproduction, such as those with nonclassic adrenal hyperplasia resulting from 21-hydroxylase deficiency,32,33 but it is not appropriate for the treatment of hirsutism in PCOS. A major problem with glu-cocorticoid therapy is that the complete suppression of ACTH production often requires giving more glucocorticoid than would normally be produced by the adrenal glands. As a result, patients receiving long-term glucocorticoid treatment are at increased risk for iatrogenic Cushing syndrome, osteoporosis, and diabetes mellitus. In addition, the corticotropin-releasing hormone-ACTH-cortisol axis may become so suppressed that the adrenal response to stress is blunted. For those reasons, I avoid using glucocorticoids to treat hirsutism. If the clinician does decide to use glucocorticoid therapy, use of low-dose glu-cocorticoids (5 or 7.5 mg of prednisone daily) or an alternate-day regimen of glucocorticoids may minimize those risks. Also, because almost all women treated with glucocorticoids gain weight and many develop osteoporosis, the clinician should carefully monitor weight and bone density in these patients.

Ovarian Surgery

Ovarian surgery can be used to decrease the mass of andro-gen-secreting thecal and stromal tissue. No randomized, controlled trials have been published concerning the benefits and risks of ovarian surgery for hyperandrogenism. In my opinion, the risks of ovarian surgery are greater than the potential benefits for women with hirsutism. I recommend ovarian surgery only for women with PCOS and infertility in whom conservative therapy has failed (see below).

Laser, Electrolysis, and Depilatory Treatment

Techniques that directly destroy the hair follicle are helpful in the treatment of hirsutism. Mechanical techniques include plucking, waxing, and shaving. These methods do not lead to a worsening of hirsutism, as some people believe, but may cause skin irritation. Electrolysis can destroy both the hair and the cells responsible for the growth of the hair, thereby producing a more prolonged beneficial effect than mechanical techniques.

Laser therapy is an evolving technique that is highly effective in the treatment of hirsutism. Multiple case series have been reported using the ruby laser to treat hirsutism. The melanin in the hair is used as a natural chromophore. The energy delivered by the ruby laser causes photothermal damage to the hair and key cells surrounding the hair, which may prevent hair regrowth. In one study, two treatments with the ruby laser resulted in a 50% reduction in hair follicle density.34 Unwanted side effects of laser treatment of hirsutism include skin hyper-pigmentation and hypopigmentation and pitting of the skin surface. Most of these changes resolve spontaneously over 6 months.35

A new chemical inhibitor of hair growth is eflornithine 13.9% cream (Vaniqa). Eflornithine irreversibly inhibits the activity of skin ornithine decarboxylase, an enzyme that is necessary for the synthesis of polyamines and hence for hair growth. In clinical studies, which excluded pregnant and nursing women, eflornithine reduced facial hirsutism.36

Treatment of acne

As with treatment of hirsutism, treatment of acne in PCOS patients begins with an oral contraceptive. Randomized, placebo-controlled clinical trials have demonstrated the benefits of combination estrogen-progestin oral contraceptives for acne after 6 months of treatment.37, 38 Because norgestrel is more andro-genic than gestodene and desogestrel, some authorities recommend, on theoretical grounds, that oral contraceptives containing one of the latter progestins be used to treat acne.

Topical agents and oral antibiotics may also be indicated for acne in women with PCOS [see 2:X1I Acne Vulgaris and Related Disorders].

Treatment of anovulation

Ovulation induction in PCOS follows a stepwise approach [see Table 4]. If the BMI is greater than 27, weight loss is an important goal. If normalization of the BMI cannot be achieved, clomiphene citrate is often prescribed because it is relatively inexpensive and has an excellent safety profile. Hyperandro-genic, insulin-resistant women are more likely to fail to ovulate and become pregnant with clomiphene than are women who are not insulin resistant. If both weight loss and clomiphene do not induce ovulation and result in pregnancy, the currently available choices for ovulation induction include insulin-sensitizing agents (for patients with insulin resistance), FSH injec-tions, ovarian surgery, and in vitro fertilization with embryo transfer (IVF-ET).

Table 4 A Stepwise Approach to the Induction of Ovulation in Infertile Women with PCOS*

Step 1: if BMI is > 27, weight loss of at least 10%

Step 2: clomiphene

Step 3: if DHEAS > 2 |g/ml (200 |g/dl), clomiphene plus gluco-corticoid therapy

Step 4: metformin for 8 to 12 wk

Step 5: metformin plus clomiphene

Step 6: low-dose FSH therapy

Step 7: metformin plus low-dose FSH therapy

Step 8: in vitro fertilization

Step 9: laparoscopic ovarian surgery to reduce ovarian androgen production

*Steps proceed in order of increasing resource intensity.

Weight Loss

Many women with PCOS are overweight or obese. In such women, weight loss (see above) is associated with a decrease in insulin secretion, a decrease in LH secretion, and a decrease in androgen production. The result is often a resumption of regular ovulation and, in some women, pregnancy.

Clomiphene Citrate

Clomiphene citrate is the most widely used agent for ovula-tion induction in women with PCOS. The FDA-approved doses for clomiphene are 50 or 100 mg daily for a maximum of 5 days per cycle. After a spontaneous menses or the induction of menses with a progestin withdrawal maneuver (medroxypro-gesterone acetate, 10 mg p.o. daily for 5 days), clomiphene (50 mg daily for 5 days) is started on cycle day 3, 4, or 5. In properly selected women, 50% will ovulate through the use of this clomiphene regimen. Another 25% will ovulate if the dose of clomiphene is increased to 100 mg daily. During each cycle, determination of ovulation should be attempted by use of basal body temperature charts, ultrasound monitoring of follicle growth and rupture, or luteal-phase progesterone measurements. Some clinicians use endometrial biopsies to document ovulation in cycles where conception is not attempted. In most women, ovulation occurs approximately 5 to 12 days after the last dose of clomiphene. Measurement of the urinary LH surge is recommended to assist the patient in prospectively determining the periovulatory interval.

Although the FDA has approved maximal clomiphene doses of 100 mg daily, many clinicians have used clomiphene at doses of up to 250 mg daily. Women who fail to ovulate after taking clomiphene in doses of 100 mg daily for 5 days may ovulate if they are treated with clomiphene at doses of 150 mg daily for 5 days. Some authorities advocate use of clomiphene at doses up to 250 mg daily for up to 14 days. As many as 70% of the women who fail to ovulate with doses of 100 mg daily will ovulate with higher doses, but fewer than 30% of those become pregnant. In my opinion, there are few data to support the use of clomiphene at doses greater than 150 mg daily. Women who do not become pregnant at that dose should consider other approaches to ovulation induction (see below).

Clomiphene treatment can be associated with adverse changes in the reproductive tract, including induction of a luteal-phase defect (delay of endometrial maturation) and the creation of a hostile cervical environment from low quantity and quality of cervical mucus. Some clinicians recommend en-dometrial biopsy in a test cycle of clomiphene treatment to assess whether clomiphene induces luteal-phase deficiency. Many clinicians recommend that a postcoital test be performed during the first clomiphene cycle of treatment to screen for poor cervical mucus properties.

Multiple pregnancy is a well known outcome of clomiphene use. The absolute risk of high-order multiple gestation with clomiphene treatment is low: in a manufacturer’s study of 2,369 clomiphene-induced pregnancies, 7% resulted in twins, 0.5% triplets, 0.3% quadruplets, and 0.13% quintuplets. However, because clomiphene is a heavily prescribed medication, the number of triplets resulting from clomiphene is substantial. The rate of spontaneous abortion after clomiphene-induced ovulation and pregnancy is approximately 15%. The most common side effects of clomiphene include vasomotor symptoms (20%), ad-nexal tenderness (5%), nausea (3%), headache (1%), and, rarely, blurring of vision or scotomata. Most clinicians permanently discontinue clomiphene in women who experience visual changes from the drug.

Clomiphene plus Glucocorticoid

Anovulatory women with PCOS whose serum DHEAS concentration is above the midnormal range (2 |ig/ml) appear to have reduced ovulation and pregnancy rates when they are treated with clomiphene. Some studies suggest that adding a glucocorticoid (e.g., dexamethasone) to clomiphene improves pregnancy rates in these women.39

Insulin Sensitizers

A major advance in reproductive endocrinology is the discovery that insulin sensitizers can induce ovulation in infertile women with oligo-ovulation, hyperandrogenism, and insulin resistance. Insulin sensitizers that have been approved for the treatment of diabetes include metformin, rosiglitazone, and pi-oglitazone. The insulin sensitizer D-chiro-inositol has been demonstrated to induce ovulation in hyperandrogenic insulin-resistant women, but it is currently available for use in research trials only.

Metformin An oral biguanide antihyperglycemic agent approved for the treatment of type 2 diabetes mellitus, met-formin has been evaluated in multiple studies for its ability to induce ovulation in women with hyperandrogenism and insulin resistance.

Metformin decreases blood glucose by inhibiting hepatic glucose production and enhancing peripheral glucose uptake. It increases insulin sensitivity at the postreceptor level and stimulates insulin-mediated glucose disposal. Unlike the sul-fonylureas, metformin’s mechanism of action does not involve increased insulin secretion.

Metformin increases the number of ovulatory cycles in infertile women with hyperandrogenism and insulin resistance. When used together with clomiphene, metformin significantly increases the rate of ovulation and of pregnancy resulting in live-born singleton births.41-44 Metformin has also been shown to enhance response to the induction of ovulation with FSH injections in oligo-ovulatory, hyperandrogenic, insulin-resistant women.45

Metformin is commonly used at a dosage of 500 mg three times daily. To minimize gastrointestinal side effects, such as nausea, many clinicians start metformin at 500 mg daily for the first week, then increase the dosage to 500 mg twice daily for the second week, and then increase the dosage again to 500 mg three times daily. After the full dosage is reached, some clinicians switch to a regimen of 850 mg twice daily to enhance compliance. Although metformin is not approved for ovula-tion induction by the FDA, it may be significantly less expensive than FSH injections, ovarian surgery, or IVF-ET and may have fewer serious side effects than these treatments.

The most common side effects associated with metformin are GI disturbances, including diarrhea, nausea, vomiting, and abdominal bloating. In rare cases, metformin treatment has caused fatal lactic acidosis, but most of these patients had some degree of renal insufficiency or were severely hypoxic. Before starting treatment with metformin, it is advisable to confirm that the patient’s serum creatinine level is less than 1.4 mg/dl.

If a patient has not ovulated after 5 to 10 weeks of metformin treatment, clomiphene can be added (see above). If the patient becomes pregnant, metformin can be discontinued, although it is a category B drug for pregnant women and has been used by some clinicians to treat diabetes in pregnant women.46

Thiazolidinediones The thiazolidinediones increase cellular sensitivity to the effects of insulin. Agents in this category include pioglitazone, rosiglitazone, and troglitazone. Several studies of troglitazone reported a decrease not only in fasting insulin but also in LH and testosterone levels, along with an increase in ovulatory cycles.47-49 Troglitazone was reported to induce ovulation in obese, infertile women with hyperandro-genism and severe insulin resistance who had previously failed to ovulate when treated with clomiphene.50 In this study, some women ovulated and became pregnant with troglitazone alone, whereas others responded to troglitazone plus clomiphene.

Troglitazone was removed from the market because of its association with the risk of death from liver failure.51 The risk was extremely small but measurable, affecting approximately 1 in 50,000 patients treated with the drug. Pioglitazone and rosiglitazone, although now widely used in the treatment of diabetes mellitus, have not been extensively studied for their impact on ovulation. One might reasonably assume that they would offer benefits similar to troglitazone. However, until their efficacy and safety in PCOS is well established, it is probably best to use metformin as the main insulin sensitizer in women with PCOS.

Clomiphene plus Gonadotropin Induction

In women who fail to ovulate after therapy with clomiphene alone, gonadotropin injections can be added to clomiphene treatment to induce ovulation.52 Typically, the injections are started after clomiphene, 100 to 200 mg daily, has been given for 5 days. The main benefit of this combination is that it tends to reduce the quantity of gonadotropins (an expensive medication) needed to induce ovulation during each cycle, because the rise in endogenous LH and FSH levels induced by clomiphene increases the sensitivity of the follicles to the injected gonadotropins. This regimen has been associated with a 50% decrease in the dosage of gonadotropin required to induce ovulation.53

Gonadotropins

The gonadotropins currently available for ovulation induction include (1) FSH produced by recombinant DNA technology and immunopurification and (2) LH plus FSH derived from menopausal urine. The recombinant FSH preparations can be given as subcutaneous injections and are available in ampules of 37.5 or 75 IU. FSH is the primary hormone responsible for follicular recruitment and growth in humans; it can be used as a single agent to induce ovulation in most anovulatory women. Women with PCOS generally do not require exogenous LH to induce follicular development, because their levels of LH secretion are already increased.

In women with PCOS, induction of ovulation with long-term, low-dose FSH treatment appears to result in a high pregnancy rate with a low rate of complications such as high-order multiple gestation and ovarian hyperstimulation.54 In this approach, 75 units of FSH are given daily for the first 14 days; the dose is then raised by 37.5 units every 7 days until follicular ripening is complete. If FSH treatment fails to result in pregnancy, consideration should be given to the combination of metformin and FSH, ovarian surgery, or IVF-ET.

During gonadotropin induction of ovulation, as many as 20% of patients experience mild to moderate enlargement of the ovaries. Some women treated with gonadotropins develop increased vascular permeability and accumulation of fluid in the peritoneal cavity and pleural space, a condition termed the ovarian hyperstimulation syndrome (OHSS). Clinical manifestations of OHSS include abdominal pain, abdominal disten-tion, nausea, vomiting, diarrhea, and dyspnea. Other physical and laboratory findings of OHSS include weight gain, ovarian enlargement, ascites, pleural effusion, hemoconcentration, electrolyte imbalances, renal dysfunction, and thrombosis.55 Treatment includes bed rest, maintenance of intravascular volume, prophylaxis against thrombosis, and surgical correction of ovarian torsion.

Before the utilization of repetitive estradiol measurements and sonographic evaluation of the follicular development, OHSS occurred in as many as 5% of women receiving go-nadotropin treatment. In recent series that employed intense monitoring with those techniques, the rate of OHSS was approximately 0.5%. OHSS may be more severe and have a longer course if a successful pregnancy occurs. Multiple births occur in approximately 15% of pregnancies that take place after ovulation induction with gonadotropins.

Ovarian Surgery

Many gynecologists recommend that in infertile women with PCOS, ovarian surgery be attempted before FSH injections or IVF-ET. Laparoscopic drilling of the ovary is the most widely studied surgical treatment for ovulation in PCOS; approximately 1,000 cases have been reported, although no controlled studies have been undertaken.56 These reports demonstrate that surgery to induce ovulation causes a decrease in circulating LH (50% decline) and testosterone (30% decline) and an increase in FSH (30% increase). The pregnancy rate is in the range of 50% at 12 months and 70% at 24 months.

The surgical techniques used for ovarian drilling vary between centers. However, all use a laser or electrosurgery to make multiple millimeter-size punctures in each ovary.57-59

In Vitro Fertilization with Embryo Transfer

IVF-ET has recently been demonstrated to be effective in the treatment of infertile women with PCOS who fail to become pregnant with gonadotropin injections.60 In preliminary reports, IVF-ET treatment of infertile women with PCOS has been associated with a per-cycle pregnancy rate of 0.24 to 0.27.61,62

Metabolic Abnormalities Associated with PCOS

Diabetes mellitus

Obese women with PCOS may be at high risk for diabetes. In one study, testing in 254 PCOS patients found new-onset diabetes in 7%, most of whom had a BMI greater than 30.63 Another study showed that by 40 years of age, 10% of women with PCOS will have been diagnosed with diabetes.64

It is important to assess for diabetes in an obese infertile woman with PCOS before using an ovulation-inducing agent.

Poorly controlled diabetes is associated with a significantly increased risk of fetal malformations. Sacral agenesis and caudal dysplasia are 400 times more common in the offspring of women with diabetes than in those of women with normal glucose metabolism. Other anomalies associated with diabetes include anencephaly, open spina bifida, renal agenesis, ventricular septal defects, and transposition of the great vessels. Control of diabetes before conception decreases the risk of fetal malformations.

Hyperlipidemia

Women with PCOS have hyperandrogenism, and obesity and insulin resistance are common. These conditions are often associated with hyperlipidemia. In one study, levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were higher in obese women with PCOS than in weight-matched control subjects. Elevated LDL levels were the predominant lipid abnormality observed in women with PCOS, independent of obesity.65 High-density lipoprotein (HDL) cholesterol levels were also higher, however, which could provide some degree of protection against cardiovascular disease. One epidemiologic study that included a 30-year follow-up of women with PCOS found no increase in mortality from cardiovascular disease.66

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