PCOS

Polycystic ovarian syndrome (PCOS), also known by the name Stein-Leventhal syndrome, is a hormonal problem that causes women to have a variety of symptoms. It should be noted that most women with the condition have a number of small cysts in the ovaries. However, women may have cysts in the ovaries for a number of reasons, and it is the characteristic constellation of symptoms, rather than the presence of the cysts themselves, that is important in establishing the diagnosis of PCOS. PCOS occurs in 5% to 10% of women and is the most common cause of infertility in women. The symptoms of PCOS may begin in adolescence with menstrual irregularities, or a woman may not know she has PCOS until later in life when symptoms and/or infertility occur. Women of all ethnicities may be affected.

What causes polycystic ovarian syndrome (PCOS)?

No one is quite sure what causes PCOS, and it is likely to be the result of a number of both genetic (inherited) as well as environmental factors. Women with PCOS often have a mother or sister with the condition, and researchers are examining the role that genetics or gene mutations might play in its development. The ovaries of women with PCOS frequently contain a number of small cysts, hence the name poly=many cystic ovarian syndrome. A similar number of cysts may occur in women without PCOS. Therefore, the cysts themselves do not seem to be the cause of the problem. A malfunction of the body's blood sugar control system (insulin system) is frequent in women with PCOS, who often have insulin resistance and elevated blood insulin levels, and researchers believe that these abnormalities may be related to the development of PCOS. It is also known that the ovaries of women with PCOS produce excess amounts of male hormones known as androgens. This excessive production of male hormones may be a result of or related to the abnormalities in insulin production. Another hormonal abnormality in women with PCOS is excessive production of the hormone LH, which is involved in stimulating the ovaries to produce hormones and is released from the pituitary gland in the brain. Other possible contributing factors in the development of PCOS may include a low level of chronic inflammation in the body and fetal exposure to male hormones.

Pathophysiology
Women with PCOS have abnormalities in the metabolism of androgens and estrogen and in the control of androgen production. High serum concentrations of androgenic hormones, such as testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEA-S), may be encountered in these patients. However, individual variation is considerable, and a particular patient might have normal androgen levels. PCOS is also associated with peripheral insulin resistance and hyperinsulinemia, and obesity amplifies the degree of both abnormalities. Insulin resistance in PCOS can be secondary to a postbinding defect in insulin receptor signaling pathways, and elevated insulin levels may have gonadotropin-augmenting effects on ovarian function.

In addition, insulin resistance in PCOS has been associated with adiponectina hormone secreted by adipocytes that regulates lipid metabolism and glucose levels; both lean and obese women with PCOS have lower adiponectin levels than women without PCOS. 3 A proposed mechanism for anovulation and elevated androgen levels suggests that, under the increased stimulatory effect of luteinizing hormone (LH) secreted by the anterior pituitary, stimulation of the ovarian theca cells is increased. In turn, these cells increase the production of androgens (eg, testosterone, androstenedione). Because of a decreased level of follicle-stimulating hormone (FSH) relative to LH, the ovarian granulosa cells cannot aromatize the androgens to estrogens, which leads to decreased estrogen levels and consequent anovulation. Growth hormone (GH) and insulin-like growth factor1 (IGF-1) may also augment the effect on ovarian function.4 Hyperinsulinemia is also responsible for dyslipidemia and for elevated levels of plasminogen activator inhibitor-1 (PAI-1) in patients with PCOS. Elevated PAI-1 levels are a risk factor for intravascular thrombosis. Polycystic ovaries are enlarged bilaterally and have a smooth thickened capsule that is avascular. On cut sections, subcapsular follicles in various stages of atresia are seen in the peripheral part of the ovary. The most striking ovarian feature of PCOS is hyperplasia of the theca stromal cells surrounding arrested follicles. On microscopic examination, luteinized theca cells are seen.

Treatment

Birth control pills, or oral contraceptives, contain female hormones that help to regulate menstrual cycles. Contraceptives also help to lower levels of androgens, reducing abnormal hair growth and improving acne. Insulin-sensitizing medications used to treat adult-onset diabetes are useful for many women with PCOS. While these medications have not been approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of PCOS, they seem to improve the regularity of menstrual cycles by lowering insulin levels. Metformin is the most commonly used drug, but doctors should prescribe it with caution. There is not enough research at this time to recommend this drug for all women with PCOS. Ovulation Induction. In some women who wish to become pregnant, inducing ovulation, which is the release of an egg, is necessary. In current methods of reproductive endocrinology, the initial treatment to induce ovulation is usually an oral medication called clomiphene citrate, which is taken for five days. If clomiphene is not effective, the next order of treatment often includes an injection of gonadotropins. Gonadotropins are hormones that the body produces to stimulate ovulation. Other infertility treatments may include additional medications or laparoscopic surgery. High-tech treatments include in-vitro fertilization, in which an egg fertilized with sperm is implanted in the uterus. The insulin sensitizer metformin appears to be helpful in inducing ovulation and conception in some patients, but it is generally less effective than clomiphene or gonadotropins in inducing pregnancy. Metformin appears to work better in normal weight, rather than obese PCOS patients. At this time there is no consensus on its safety if also used during pregnancy. Androgen-blocking (anti-androgen) medications can be used to treat several PCOS symptoms, including excess or unwanted hair growth and, to a limited degree, acne and scalp hair loss. Spironolactone, flutamide, finasteride and cyproterone acetate (which is not available in the United States) can help to relieve the symptoms of excessive facial and bodily hair, as well as thinning hair on the scalp and acne. These medications can be taken along with oral contraceptives. Note that although there is extensive worldwide experience with their use in PCOS, none of these medications have been approved for use in the treatment for PCOS by the FDA. Topical anti-hair-growth medications also can help to slow the growth of facial hair in women with PCOS, specifically a lotion containing eflornithine hydrochloride. The active ingredient in this medication blocks an enzyme found in the hair follicle of the skin needed for hair growth. This results in slower hair growth within a few weeks of treatment. This medication is FDA-approved for use on the face only.

Other methods of treatment for excess hair caused by PCOS include bleaching, depilatory creams, and shaving excess hair. These treatments are safe and easy approaches, although waxing and tweezing, particularly of sensitive skin areas are discouraged, as they can damage the skin. Electrolysis and laser treatments to remove hair also can be effective. Treatments for hair loss tend not to work for everyone. Some women find improvements with the use of anti-androgen pills. Others find that minoxidil - a topical medication - can help as well. Proper nutrition, and dietary restriction if overweight, is a critical aspect of treatment for PCOS. Some women with PCOS find success by reducing their total intake of refined carbohydrates (sugars and starches) and replacing them with complex carbohydrates (fruits and vegetables). Refined carbohydrates include white flour foods such as cereals, breads, and pastas. Complex carbohydrates, in comparison, are less processed foods such as those prepared with stone ground whole-wheat flour. Replacing manufactured white-flour foods with a wide variety of whole grains, fruits, and vegetables can help to reduce your insulin response. Your diet should also include enough protein to control the amount of sugar in your blood. Exercise helps the body use insulin more effectively and is highly recommended as well. It helps with weight loss and keeping off weight. Many scientific studies have shown that exercising for at least 30 minutes a day, about five days a week, is highly beneficial to your health. Acne treatments sold over the counter also can help to control the skin blemishes related to polycystic ovary syndrome, although some patients may require additional medications, such as isotretinoin. Skin problems other than acne may be treated in different ways. You can ask your doctor or dermatologist to remove skin tags using just a simple anesthetic on your skin. The dark blemishes on your skin may fade if you can reduce your insulin level by weight loss or through the use of insulin-sensitizer medications. Other treatments include tretinoin gel, 15% urea, alpha hydroxy acid, and salicylic acid.

Metabolic derangements o Diet and exercise: In patients with PCOS who are obese, endocrine-metabolic parameters markedly improve after 4-12 weeks of dietary restriction. Their SHBG levels rise and free testosterone levels fall by 2-fold. Serum insulin and IGF-1 levels also decrease. Weight loss in patients with PCOS who are obese is associated with a reduction of hirsutism and a return of ovulatory cycles in 30% of women. A moderate amount of daily exercise increases of levels of IGF-1 binding protein and decreases IGF1 levels by 20%. Modest weight loss of 2-5% of total body weight can help restore ovulatory menstrual periods in obese patients with PCOS. A daily 500-1000 calorie deficit with 150 minutes of exercise per week can cause ovulation. The Androgen Excess and Polycystic Ovary Syndrome Society recommends lifestyle management as the primary therapy in overweight and obese women with PCOS for the treatment of metabolic complications.19 o Metformin: This antidiabetic drug improves insulin resistance and decreases hyperinsulinemia in patients with PCOS.20 Metformin also has a small but beneficial effect on metabolic syndrome. Ascertain that kidney and liver function are normal and that the patient does not have advanced congestive heart failure before starting metformin. The usual starting dose is 500 mg given orally twice a day. Common adverse effects are nausea, vomiting, and diarrhea. Patients who develop these adverse effects can be instructed to decrease the dosage to once a day for a week and then gradually increase the dosage. Also, inform patients that they have a high likelihood of having ovulatory cycles while taking metformin. The US Food and Drug Administration has not approved metformin for this indication; therefore, this use is off label.

Anovulation o Evidence suggests that metformin frequentlybut not universallyimproves ovulation rates in women with PCOS.21 In addition, pretreatment with metformin has been shown to enhance the efficacy of clomiphene for inducing ovulation. 22 Whether short-course metformin pretreatment (less than 4 weeks) is as effective as conventional long-course metformin remains uncertain.23 N-acetylcysteine may also enhance the effect of clomiphene.24 Management of infertility: Patients with PCOS who are infertile but desire pregnancy should be referred to a reproductive endocrinologist for further evaluation and management of infertility.

Hirsutism o Hair removal: Short-term nonpharmacologic treatments of hirsutism include shaving and use of chemical depilatories and/or bleaching cream. 25 Plucking or waxing unwanted hair can result in folliculitis and ingrown hairs. Long-term measures include techniques such as electrolysis and laser treatment of unwanted hairs. Weight reduction: Weight reduction decreases androgen production in women who are obese; therefore, losing weight can slow hair growth. Oral contraception: Women who do not wish to become pregnant can be effectively treated for hirsutism with oral contraceptives.26 Oral contraceptives slow hair growth in 60100% of women with hyperandrogenemia. Therapy can be started with a preparation that has a low dose of estrogen and a nonandrogenic progestin. Preparations that have norgestrel and levonorgestrel should be avoided because of their androgenic activity. Spironolactone: Antiandrogens, such as spironolactone, are effective for hirsutism.27 Spironolactone 50-100 mg twice daily is an effective primary therapy for hirsutism. Because of the potential teratogenic effects of spironolactone, patients require an effective form of contraception (eg, an oral contraceptive). Adverse effects of spironolactone include GI discomfort, and irregular menstrual bleeding (which can be managed by adding an oral contraceptive). Eflornithine: Eflornithine (Vaniqa) is a topical cream that can be used to slow hair growth. Eflornithine works by inhibiting ornithine decarboxylase, which is essential for the rapidly dividing cells of hair follicles.

Menstrual irregularity o This is treated with an oral contraceptive, which not only inhibits ovarian androgen production but also increases SHBG production. Pregnancy should be excluded before therapy with oral contraceptives is started.

Surgical Care
Surgical management is aimed mainly at restoring ovulation.

Ovarian wedge resection: This procedure has fallen out of favor because of postoperative adhesion formation and the introduction of ovulation-inducing medications. Laparoscopic surgery: Various laparoscopic methods, including electrocautery, laser drilling, and multiple biopsy, have been used with the goal of creating focal areas of damage in the ovarian cortex and stroma. Potential complications include formation of adhesions (although this is less common than with traditional surgical approaches) and ovarian atrophy. Multiple pregnancy rates are lower with ovarian drilling than with gonadotrophin treatment (1% versus 16%), but there are ongoing concerns about the long-term effects on ovarian function. 28

What conditions or complications can be associated with PCOS?

Women with PCOS are at a higher risk for a number of illnesses, including high blood pressure, diabetes, heart disease, andcancer of the uterus (endometrial cancer). Because of the menstrual and hormonal irregularities, infertility is common in women with PCOS. Because of the lack of ovulation, progesterone secretion in women with PCOS is diminished, leading to long-term unopposed estrogen stimulation of the uterine lining. This situation can lead to abnormal periods, breakthrough bleeding, or prolonged uterine bleeding in some women. Unopposed estrogen stimulation of the uterus is also a risk factor for the development of endometrial hyperplasia and cancer of the endometrium (uterine lining). However, medications can be given to induce regular periods and reduce the estrogenic stimulation of the endometrium

Pathophysiology of the Chronic Anovulation

A growing body of evidence indicates that disordered insulin action precedes the increase in androgens in PCOS. The administration of insulin to women with PCOS increases circulating androgen levels. The administration of glucose to hyperandrogenic women increases circulating levels of insulin and androgen. Weight loss decreases levels of insulin and androgens.The suppression of circulating insulin levels experimentally by diazoxide reduces androgen levels. The suppression of androgen secretion to normal levels with GnRH agonists does not lead to normal insulin responses to glucose tolerance testing in obese women with PCOS.160, 171, 172 The hyperinsulinemia may cause hyperandrogenemia by binding to IGF-I receptors in the ovary. Activation of ovarian IGF-I receptors by insulin can lead to increased androgen production by thecal cells. Moreover, independent of any effect on ovarian steroid production, increased insulin inhibits the hepatic synthesis of SHBG. Insulin directly inhibits insulin-like growth factor binding protein-1 in the liver, permitting greater local activity of IGF-I in the ovary. Regardless of the cause of PCOS, it is possible to construct a rational pathophysiologic mechanism to explain the disorder. (Fig.7)

Regardless of the source or cause of androgen excess, a vicious cycle of events causing persistent anovulation commences. The androgen is converted to estrogen, primarily estrone, in the periphery. The estrogen feeds back on the central nervous system-hypothalamic-pituitary unit to induce inappropriate gonadotropin secretion with an increased LH to FSH ratio. The estrogen stimulates GnRH synthesis and secretion in the hypothalamus, causing preferential LH release by the pituitary gland. The estrogen may also increase GnRH by decreasing hypothalamic dopamine. Selective inhibition of FSH secretion by increased ovarian inhibin may also occur in PCOS. Possible inhibition of FSH secretion by increased androgen secretion has not been considered. The increased LH secretion stimulates thecal cells in the ovary to produce excess androgen. The androgen also inhibits production of SHBG, resulting in increased free androgen and predisposing affected women to hirsutism. The morphologic ovarian changes undoubtedly are secondary to hormonal changes. The absence of follicular maturation and the reduced estradiol production by the ovaries apparently result from a combination of inadequate FSH stimulation and inhibition by the increased concentrations of intraovarian androgen. The low levels of SHBG probably facilitate tissue uptake of free androgen, leading to increased peripheral formation of estrogen and perpetuating the acyclic chronic anovulation. The androgenic basis for the inappropriate estrogen feedback is partly shifted from the site of origin to the ovaries. The increased estrogens (and perhaps androgens) may also stimulate fat cell proliferation, leading to obesity. The current data suggest that there is no defect in the hypothalamic-pituitary axis in PCOS but rather that peripheral alterations result in abnormal gonadotropin secretion.

Pathogenesis Polycystic ovaries develop when the ovaries are stimulated to produce excessive amounts of male hormones (androgens), particularly testosterone, either through the release of excessive luteinizing hormone (LH) by the anterior pituitary gland or through high levels of insulin in the blood (hyperinsulinaemia) in women whose ovaries are sensitive to this stimulus. The syndrome acquired its most widely used name due to the common sign on ultrasound examination of multiple (poly) ovarian cysts. These "cysts" are actually immature follicles, not cysts ("polyfollicular ovary syndrome" would have been a more accurate name). The follicles have developed from primordial follicles, but the development has stopped ("arrested") at an early antral stage due to the disturbed ovarian function. The follicles may be oriented along the ovarian periphery, appearing as a 'string of pearls' on ultrasound examination. The condition was first described in 1935 by Dr. Stein and Dr. Leventhal, hence its original name of SteinLeventhal syndrome. PCOS is characterized by a complex set of symptoms, and the cause cannot be determined for all patients. However, research to date suggests that insulin resistance could be a leading cause. PCOS may also have a genetic predisposition, and further research into this possibility is taking place. No specific gene has been identified, and it is thought that many genes could contribute to the development of PCOS. A majority of patients with PCOS have insulin resistance and/or are obese. Their elevated insulin levels contribute to or cause the abnormalities seen in the hypothalamic-pituitary-ovarian axis that lead to PCOS. Adipose tissue possesses aromatase, an enzyme that converts androstenedione to estrone and testosterone to estradiol. The excess of adipose tissue in obese patients creates the paradox of having both excess androgens (which are responsible for hirsutism and virilization) and estrogens (which inhibits FSH via negative feedback). Also, hyperinsulinemia increases GnRH pulse frequency, LH over FSH dominance, increased ovarian androgen production, decreased follicular maturation, and decreased SHBG binding; all these steps lead to the development of PCOS. Insulin resistance is a common finding among patients of normal weight as well as those overweight patients. PCOS may be associated with chronic inflammation, with several investigators correlating inflammatory mediators with anovulation and other PCOS symptoms. One study in the United Kingdom concluded that the risk of PCOS development was shown to be higher in lesbian women than in heterosexuals. It should be noted however that all the participants in this study were referred after infertility was discovered or highly suspected and conclusion made is purely conjecture. Until further studies have been conducted and the research collaborated there is no assumption that female homosexuality will increase the occurrence of PCOS.

Women with PCOS are at risk for the following: *Endometrial hyperplasia and endometrial cancer (cancer of the uterine lining) are possible, due to overaccumulation of uterine lining, and also lack of progesterone resulting in prolonged stimulation of uterine cells by estrogen. It is however unclear if this risk is directly due to the syndrome or from the associated obesity, hyperinsulinemia, and hyperandrogenism *Insulin resistance/Type II diabetes. A review published in 2010 concluded that women with PCOS had an elevated prevalence of insulin resistance and type II diabetes, also when controlling for body mass index (BMI). *High blood pressure *Depression/Depression with Anxiety *Dyslipidemia - disorders of lipid metabolism cholesterol and triglycerides. PCOS patients show decreased removal of atherosclerosis-inducing remnants, seemingly independent on insulin resistance/Type II diabetes.[43] *Cardiovascular disease *Strokes