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Polycystic Ovarian Syndrome (PCOS)
Polycystic ovarian syndrome (PCOS) is a common endocrinopathy typified by oligo-ovulation or anovulation, signs of androgen excess, and multiple small ovarian cysts. These signs and symptoms may vary widely between women as well as within individuals over time.
Polycystic ovarian syndrome is the most common endocrine disorder of reproductive-aged women and affects approximately 4 to 12 percent. Although symptoms of androgen excess may vary between ethnicity, PCOS appears to equally affect all races and nationalities.
In 2003 in Rotterdam, Netherlands, a consensus meeting between the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine (ESHRE/ASRM) redefined PCOS. Affected individuals must have two out of the following three criteria: (1) oligo- and/or anovulation, (2) hyperandrogenism (clinical and /or biochemical), and (3) polycystic ovaries on sonographic examination.
The underlying cause of PCOS is unknown. However, a genetic basis is suspected, as there is a well-documented aggregation of the syndrome within families. Specifically, an increased prevalence has been noted between affected individuals and their sisters and mothers.
When speaking about the pathophysiology of polycystic ovarian syndrome, hormones must be involved.
Anovulation in women with PCOS is characterized by inappropriate gonadotropin secretion. Alterations in gonadotropin-releasing hormone (GnRH) pulsatility lead to preferential production of luteinizing hormone (LH) compared with follicle-stimulating hormone (FSH). It is currently unknown whether hypothalamic dysfunction is a primary cause of PCOS or is secondary to abnormal steroid feedback. In either case, serum LH levels rise, and increased levels are observed clinically in approximately 50 percent of affected women. Similarly, luteinizing hormone:follicle-stimulating hormone (LH:FSH) ratios are elevated and rise above 2 in approximately 60 percent of patients.
- Insulin Resistance
Women with PCOS also display greater degrees of insulin resistance and compensatory hyperinsulinemia than nonaffected women. Both lean and obese women with PCOS are found to be more insulin resistant than nonaffected weight-matched controls.
Insulin resistance has been associated with an increase in several disorders including type 2 diabetes mellitus, hypertension, dyslipidemia, and cardiovascular disease
Both insulin and LH stimulate ovarian theca cell androgen production. As a result, affected ovaries secrete elevated levels of testosterone and androstenedione. Specifically, elevated free testosterone levels are noted in 70 to 80 percent of women with PCOS. In turn, elevated androstenedione levels contribute to an increase in estrone levels through peripheral conversion of androgens to estrogens by aromatase.
- Sex Hormone-Binding Globulin
Women with PCOS display decreased levels of sex hormone-binding globulin (SHBG). This glycoprotein, produced in the liver, binds most sex steroids. Only about 1 percent of these steroids are unbound and thus free and bioavailable. The synthesis of SHBG is suppressed by insulin as well as androgens. Because of suppressed SHBG production, less circulating androgen is bound and thus more remains available to bind with end-organ receptors. It is for this reason that some women with PCOS will have total testosterone levels in the normal range, but will be clinically hyperandrogenic due to elevated free testosterone levels.
The precise mechanism leading to anovulation is unclear, but hypersecretion of LH has been implicated in menstrual irregularity. In addition, anovulation may result from insulin resistance, as a substantial number of anovulatory patients with PCOS may resume ovulatory cycles when treated with metformin, an insulin sensitizer.
Signs and Symptoms
In women with PCOS, complaints stem from varied endocrine effects and may include menstrual irregularities, infertility, manifestations of androgen excess, or other endocrine dysfunction. Symptoms classically become apparent within a few years of puberty.
Menstrual dysfunction in women with PCOS may range from amenorrhea to oligomenorrhea to episodic menometrorrhagia with anemia. Chronic estrogen exposure unopposed by the effects of postovulatory progesterone produces constant mitogenic stimulation of the endometrium. The instability of the thickened endometrium results in an unpredictable bleeding pattern.
Hyperandrogenism is typically manifested clinically by hirsutism, acne, and/or androgenic alopecia. In contrast, signs of virilization such as increased muscle mass, deepening of the voice, and clitoromegaly are not typical of PCOS. Virilization reflects higher androgen levels and should prompt investigation for an androgen-producing tumor of the ovary or the adrenal gland.
In a female, hirsutism is defined as the presence of coarse, dark, terminal hairs distributed in a male pattern. Polycystic ovarian syndrome accounts for 70 to 80 percent of cases of hirsutism.
- Pathophysiology of Hirsutism
Elevated androgen levels play a major role in determining the type and distribution of hair Within a hair follicle, testosterone is converted by the enzyme 5 a-reductase to dihydrotestosterone (DHT). Although both testosterone and DHT convert short, soft vellus hair to coarse terminal hair, DHT is markedly more effective than testosterone. Conversion is irreversible, and only hairs in androgen-sensitive areas are changed in this manner to terminal hairs. As a result the most common areas affected with excess hair growth in women with PCOS include the upper lip, chin, sideburns, chest, and linea alba of the lower abdomen.
The concentration of hair follicles per unit area does not differ between men and women, however, racial and ethnic differences do exist. Individuals of Mediterranean descent have a higher concentration of hair follicles than Northern Europeans, and a much higher concentration than Asians. For this reason, Asians with PCOS are much less likely to present with overt hirsutism than other ethnic groups. Additionally, there is also a strong familial tendency for the development of hirsutism, due to genetic differences in target tissue sensitivity to androgens and in the activity of 5a-reductase.
Acne vulgaris is a frequent clinical finding in adolescents. However, acne that is particularly persistent or of late onset should suggest PCOS , one study found that 50 percent of adolescents with PCOS have moderate acne.
In women with androgen excess, overstimulation of androgen receptors in the pilosebaceous unit results in increased sebum production that eventually leads to inflammation and comedone formation). Inflammation leads to the main long-term side effect of acne—scarring.
Female androgenic alopecia is a less common finding in women with PCOS, Its pathogenesis involves an excess of 5 a-reductase activity in the hair follicle leading to a rise in DHT levels. In addition, there is an increased expression of androgen receptors in these individuals.
Other Endocrine Dysfunctions
the association between insulin resistance, hyperandrogenism, and PCOS has long been recognized. Although obesity is known to exacerbate insulin resistance, one classic study demonstrated that both lean and obese women with PCOS have increased rates of insulin resistance and type 2 diabetes mellitus (DM) compared with weight-matched controls without PCOS.
- Acanthosis Nigricans
This skin condition is characterized by thickened, gray-brown plaques seen in areas of flexure such as the back of the neck, the axillae, the crease beneath the breast, the waist, and the groin). Thought to be a cutaneous marker of insulin resistance, acanthosis nigricans may be found in individuals with or without PCOS.
- Impaired Glucose Tolerance and Type 2 Diabetes Mellitus
Women with PCOS are at increased risk for impaired glucose tolerance (IGT) and type 2 DM. Based on oral glucose tolerance testing of obese women with PCOS, the prevalence of IGT and DM is approximately 30 percent and 7 percent, respectively.
The classic atherogenic lipoprotein profile seen in PCOS is characterized by elevated low-density lipoproteins (LDL), triglyceride levels, and total cholesterol:high-density lipoprotein (HDL) ratios, and by depressed HDL levels. These changes may increase the risk of cardiovascular disease in women with PCOS independent of total cholesterol levels.
Compared with age-matched controls, women with PCOS are more likely to be obese, as reflected by an elevated body mass index (BMI) and waist:hip ratio , This ratio reflects an android or central pattern of obesity, which itself is an independent risk factor for cardiovascular disease.
Obstructive Sleep Apnea
Obstructive sleep apnea is more common in women with PCOS and is likely related to central obesity and insulin resistance , some research has determined that the risk of sleep apnea is 30- to 40-fold higher in women with PCOS compared with weight-matched controls.
Metabolic Syndrome and Cardiovascular Disease
This syndrome is characterized by insulin resistance, obesity, atherogenic dyslipidemia, and hypertension. The metabolic syndrome is associated with an increased risk of cardiovascular disease (CVD) and type 2 DM. The prevalence of metabolic syndrome is reported to be approximately 45 percent in women with PCOS compared with 4 percent in age-adjusted controls.
In women with PCOS, a threefold increased risk of endometrial cancer has been reported. neoplastic changes in the endometrium are felt to arise from chronic unopposed estrogen.
Few women who develop endometrial cancer are younger than 40 years, and most of these premenopausal women are obese or have chronic anovulation or both. Thus, the American College of Obstetricians and Gynecologists (2000) recommends endometrial assessment in any woman older than 35 years with abnormal bleeding, and in those younger than 35 years who are suspected of having anovulatory uterine bleeding refractory to medical management.
Infertility or subfertility is a frequent complaint in women with PCOS and results from anovulatory cycles. Moreover, in women with infertility secondary to anovulation, PCOS is the most common cause and accounts for 80 to 90 percent of cases.
Women with PCOS who become pregnant are known to experience an increased rate (30 to 50 percent) of early miscarriage compared with a baseline rate of approximately 15 percent in the general population. The etiology of early miscarriage in women with PCOS is unclear. Initially, retrospective and observational studies showed an association between LH hypersecretion and miscarria. However, one prospective study showed that lowering LH levels with GnRH agonists failed to show a benefit to this.
Others have suggested that insulin resistance is related to miscarriage in these women. To lower loss rates, an insulin level lowering drug, metformin, has been investigated. Metformin, a biguanide, lowers serum insulin levels by reducing hepatic glucose production and increasing the sensitivity of liver, muscle, fat, and other tissues to the uptake and effects of insulin.
Several retrospective studies have indicated that women with PCOS taking metformin during pregnancy have a lower incidence of miscarriage.
- Complications in Pregnancy
Several pregnancy and neonatal complications have been associated with PCOS. One large meta-analysis found women with PCOS to have a two- to threefold higher risk of gestational diabetes, pregnancy-induced hypertension, preterm birth, and perinatal mortality.
The diagnosis of PCOS is determined by exclusion of other medical conditions and the presence of two of the following conditions:
- Oligo ovulation or anovulation (manifested as oligomenorrhea or amenorrhea).
- Hyperandrogenemia (elevated levels of circulating androgens).
- Hyperandrogenism (clinical manifestations of androgen excess).
- Polycystic ovaries detected by ultrasonography.
Differential Diagnoses of Ovulatory Dysfunction and Hyperandrogenism
Causes of oligo- or anovulation: PCOS, Hyperthyroidism , Hypothirodim, Hyperprolactinemia, Hypogonadotropic hypogonadism.
Causes of hyperandrogenism: PCOS, Late-onset CAH, Androgen-secreting ovarian tumor, Androgen-secreting adrenal tumor, Cushing syndrome, Exogenous androgen use.
Sonographic criteria for polycystic ovaries from the 2003 Rotterdam conference include: >12 small cysts (2 to 9 mm in diameter) or an increased ovarian volume (>10 mL) or both. Often there is an increased amount of stroma relative to the number of follicles. Only one ovary with these findings is sufficient to define PCOS. However, criteria do not apply to women taking combination oral contraceptive pills.
In contrast, other findings are not valuable diagnostically. For example, the typical "black pearl necklace" appearance in which follicles are distributed just underneath the capsule in a row, and the perceived increase in stromal echogenicity have been eliminated as diagnostic criteria. Moreover, a polycystic ovary should not be confused with a multicystic ovary, which is normal size, contains six or more follicles without peripheral displacement, and lacks an increase in central stromal volume.
Remarkably, studies using sonography have shown that at least 23 percent of young women have ovaries that exhibit PCO morphology, yet many of these women have no other symptoms of PCOS. In addition, a polycystic appearance of the ovaries can often be found in other conditions of androgen excess, such as congenital adrenal hyperplasia, Cushing syndrome, and exogenous use of androgenic medications. For this reason, PCO morphology found during sonographic examination is not used solely to make the diagnosis of PCOS.
The choice of treatment for each symptom of PCOS depends on a woman's goals and the severity of endocrine dysfunction. Thus, anovulatory women desi ring pregnancy will undergo a significantly different treatment than adolescents with menstrual irregularity and acne.
Women with PCOS who have fairly regular cycle intervals (8 to 12 menses per year) and mild hyperandrogenism may choose not to be treated. In these women, however, periodic screening for dyslipidemia and diabetes mellitus is warranted.
For obese women with PCOS, lifestyle changes focused on diet and exercise are paramount to treatment at each stage of life. Even a modest amount of weight loss (5 percent of body weight) can result in restoration of normal ovulatory cycles in some women. This improvement results from reductions in insulin and androgen levels.
Combination Oral Contraceptive Pills
A first-line treatment for menstrual irregularities is combination oral contraceptive pills (COCs), which will induce regular menstrual cycles. In addition, COCs reduce androgen levels. Specifically, COCs suppress gonadotropin release, which results in decreased ovarian androgen production. Moreover, the estrogen component increases SHBG levels. The progestin component antagonizes the endometrial proliferative effect of estrogen, thus reducing risks of endometrial hyperplasia due to unopposed estrogen.
Theoretically, progestin-containing pills that contain norethindrone, such as norgestimate or desogestrel; or the newer progestin, drospirenone, are preferred to COCs containing progestins with more androgenic properties. However, no pill has shown superiority compared with another in reducing hirsutism.
In patients who are not candidates for combination hormonal contraception, progesterone withdrawal is recommended every 1 to 3 months. Examples of regimens used include: MPA, 5 to 10 mg orally daily day for 12 days. Patients should be counseled that intermittent progestins will not reduce symptoms of acne or hirsutism nor provide contraception.
Although the use of insulin sensitizers in PCOS has not been approved by the Food and Drug Administration (FDA), they have been found to be increasingly beneficial for both metabolic and gynecologic issues. For example, metformin may be used to treat women with infertility and PCOS. This drug improves peripheral insulin sensitivity by reducing hepatic glucose production and increasing target tissue sensitivity to insulin. Metformin decreases androgens in both lean and obese women, leading to increased rates of spontaneous ovulation.
A number of studies have demonstrated that up to 40 percent of anovulatory women with PCOS will ovulate, and many will achieve pregnancy with metformin alone. Metformin is a category B drug and is safe to use as an ovulatory induction agent. As such, it may be used alone or in concert with other medications such as clomiphene. Specifically, metformin has been shown to increase the ovulatory response to clomiphene citrate in patients who were previously clomiphene-resistant.
The most common side effects are gastrointestinal, and these can be minimized by starting at a low dose and gradually increasing the dose over several weeks to an optimal level. In clinical studies , 1500 to 2000 mg in divided doses daily with meals are typically used.
In the treatment of hirsutism, a primary goal is lowering androgen levels to halt further conversion of vellus hairs to terminal ones. However, medical therapies will not eliminate abnormal hair growth already present. Moreover, treatments may require 6 to 12 months before clinical improvement is apparent. For this reason, clinicians should be familiar with temporary hair removal methods that may be used in the interim. Permanent cosmetic therapies may then be implemented once medications have reached maximal therapeutic effect.
Combination Oral Contraceptives
As described earlier, COCs are effective in establishing regular menses and lowering ovarian androgen production. As an additional effect, the estrogen component of these pills leads to increased SHBG levels. With higher SHBG levels, a greater amount of free testosterone is bound and thus becomes biologically unavailable at the hair follicle.
This antimetabolite topical cream is applied twice daily to areas of facial hirsutism and is an irreversible inhibitor of ornithine decarboxylase. This enzyme is necessary for hair follicle cell division and function, and its inhibition results in slower hair growth. It does not permanently remove hair, and thus women are required to continue routine methods of hair removal while using this medicine, Clinical results from eflornithine hydrochloride may require 4 to 8 weeks of use.
Antiandrogens are competitive inhibitors of androgen binding to the androgen receptor. Although these agents are effective in the treatment of hirsutism, they carry a risk for several side effects. Metrorrhagia may frequently develop. In addition, as antiandrogens, these drugs bear a theoretical risk of pseudohermaphroditism in male fetuses of women using such medications in early pregnancy. Accordingly, these drugs are commonly used in conjunction with oral contraceptive pills.
None of the antiandrogen agents are approved by the FDA for treatment of hyperandrogenism. Spironolactone (Aldactone), in a dosage of 50 to 100 mg orally twice daily is the primary antiandrogen used currently in the United States. In addition to its antiandrogen effects, this drug also affects hair conversion through its direct inhibition of 5a-reductase. Spironolactone is also a potassium-sparing diuretic. As such, it should not be prescribed for chronic use in combination with agents that can also raise blood potassium levels, such as angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs such as indomethacin, or other potassium-sparing diuretics.
In Europe and Canada, the preferred antiandrogen is cyproterone acetate, usually marketed in an oral contraceptive pill.
Flutamide is another nonsteroidal antiandrogen marketed for the treatment of prostate cancer, but is rarely used for hirsutism due its potential hepatotoxicity.
Conversion of testosterone to DHT may be effectively decreased by the 5a-reductase inhibitor finasteride. Most studies have used 5-mg daily doses and have found finasteride to be modestly effective in the treatment of hirsutism).
Side effects are low with finasteride, although decreased libido has been noted. However, as with other antiandrogens, the risk of male fetal teratogenicity is present, and effective contraception must be used concurrently.
Hirsutism is often treated by mechanical means, and these include both depilation and epilation techniques. In addition to hair removal, lightening hair color with bleach is an additional cosmetic option.
Depilation describes hair removal above the skin surface. Shaving is the most common form and does not exacerbate hirsutism, contrary to the myth that it will increase hair follicle density. Alternatively, topical chemical depilatories are also effective. Available in gel, cream, lotion, aerosol forms, these agents contain calcium thioglycolate, which breaks disulfide bonds between hair protein chains causing hair to breakdown and separate easily from the skin surface.
In contrast to depilation, epilation removes the entire hair shaft and root, and includes techniques such as plucking, waxing, threading, electrolysis, and laser treatment.
One part of acne treatment is similar to that for hirsutism and involves lowering of androgen levels. Therapy may include: (1) combination oral contraceptive pills; (2) antiandrogens such as spironolactone or flutamide, which inhibit binding of androgen to its receptor; or (3) 5a-reductase inhibitors such as finasteride.
- Topical and Systemic Antibiotics
Topical antibiotics typically include erythromycin and clindamycin, whereas oral antibiotics most often used for acne include doxycycline, minocycline, and erythromycin. Oral antibiotics are more effective than topical therapies, but can have a variety of side effects such as sun sensitivity and gastrointestinal upset.
- Topical Benzoyl Peroxide
Benzoyl peroxide is an excellent antimicrobial and anti-inflammatory agent. It is the active ingredient in many over-the-counter products used for acne. In addition to lowering androgen levels, other therapies may be added. For this reason, women with moderate to severe acne may benefit from consultation with a dermatologist.
- Topical Retinoids
Derived from vitamin A, topical retinoids regulate the follicular keratinocyte and normalize its desquamation. In addition, this group of agents also has direct anti-inflammatory properties, and thereby targets two factors linked to acne vulgaris. The most commonly used agent with retinoid activity is tretinoin. Tretinoin may cause a transient worsening of acne during the first weeks of treatment, tretinoin are category C drugs and thus are not recommended for use during pregnancy or breast feeding.
Oral isotretinoin (Accutane) is an analog of vitamin A that is highly effective for the treatment of severe recalcitrant acne. Despite its efficacy, oral isotretinoin is teratogenic if taken during the first trimester of pregnancy.
The Treatment of Hyperandrogenic Oligo-Ovulatory Infertility
In women with PCOS, there are a variety of methods available to improve ovulatory function. Weight loss is often recommended as a preconception intervention. Ovulation induction for the treatment of infertility related to androgen excess typically first includes the use of clomiphene citrate and then human gonadotropins. The introduction of insulin-sensitizing agents and preliminary data supported a beneficial role of these agents as both first-line and adjuvant therapy. However, two recent large randomized blinded trials have shown no benefit on pregnancy rates when using the combination of clomiphene and metformin compared with clomiphene alone.
Some clinicians advocate the use of metformin during early pregnancy to reduce the miscarriage rate, but the documentation for this claim is poor, based mainly on case series. Metformin is pregnancy category B, with no known human teratogenic risk. There have been no reported abnormalities associated with its use during pregnancy in women with diabetes, to women with marked hyperandrogenism during pregnancy, or to the small number of PCOS women who have conceived during treatment.
The surgical destruction of the ovarian stroma, by either wedge resection or ovarian drilling, has been reported to result in improved ovulatory and pregnancy rates in PCOS patients. In PCOS patients, ovarian drilling may have a place in the therapy of those women who are clomiphene resistant. A number of recent randomized trials have shown that ovarian ablative procedures appear to be just as successful and with a lower multiple pregnancy rate.
None of the various drilling techniques appear to offer obvious advantages, although excessive exposure to thermal energy can cause ovarian failure.
Publication Date: April 26, 2011
Prepared by: Basel Jallad
WILLIAMS GYNECOLOGY 2008, Berek & Novak's Gynecology 14th Edition Copyright 2007
Danforth's Obstetrics and Gynecology, 10th Edition Copyright 2008
Johns Hopkins Manual of Gynecology and Obstetrics The 3rd Edition Copyright 2007
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