Pathogenesis

Polycystic ovaries develop when the ovaries are stimulated to produce excessive amounts of

male hormones (androgens), particularly testosterone, by either one or a combination of the

following (almost certainly combined with genetic susceptibility[28]):

the release of excessive luteinizing hormone (LH) by the anterior pituitary gland[citation

needed]

through high levels of insulin in the blood (hyperinsulinaemia) in women whose ovaries

are sensitive to this stimulus[9]

Alternatively or as well, reduced levels of sex-hormone binding globulin can result in

increased free androgens.[citation needed]

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.[citation needed]

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. Hyperinsulinemia increases GnRH pulse frequency, LH over

FSH dominance, increased ovarian androgen production,[9] decreased follicular maturation,

and decreased SHBG binding; all these steps contribute to the development of PCOS.[citation

needed] Insulin resistance is a common finding among patients of normal weight as well as

overweight patients.[7][18]

In many cases PCOS is characterised by a complex positive feedback loop of insulin

resistance and hyperandrogenism. In most cases it can not be determined which (if any) of

those two should be regarded causative. Experimental treatment with either antiandrogens

or insulin sensitizing agents improves both hyperandrogenism and insulin resistance.[citation

needed]

\

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).[31]

PCOS may be associated with chronic inflammation,[9][32] with several investigators

correlating inflammatory mediators with anovulation and other PCOS symptoms.[33][34]

It has previously been suggested that the excessive androgen production in PCOS could be

caused by a decreased serum level of IGFBP-1, in turn increasing the level of free IGF-

I which stimulates ovarian androgen production, but recent data concludes this mechanism

to be unlikely.[35]

PCOS has also been associated with a specific FMR1 sub-genotype. The research suggests

that women who have heterozygous-normal/low FMR1 have polycystic-like symptoms of

excessive follicle-activity and hyperactive ovarian function.[36][37]

Getting Pregnant When Syndrome O Is Getting In Your WayBy Ronald F. Feinberg M.D., Ph.D., OBGYN.net Editorial Advisor and Lesa Childers, OBGYN.net Editorial

Advisor | November 10, 2011

Much has changed in the fertility world since 1935, when two Chicago gynecologists — Dr. Irving Stein and Dr. Michael Leventhal — first described an unusual cluster of symptoms in seven of their patients1,2.  To the doctors, it seemed more than coincidental that these womenmanifested absent menstrual periods, hirsutism (excess hair growth on the face, chest, abdomen, and thighs), and enlarged ovaries.  As astute surgeons of that era, Drs. Stein and Leventhal performed abdominal surgery on these women.   Fortunately, no cancer cells were found but under the microscope, portions of the enlarged ovaries contained multiple simple cysts.  One unexpected benefit of surgery was the resumption of menstrual cycles, and even some pregnancies!Gynecology textbooks have classically viewed Stein-Leventhal syndrome, (also called polycystic ovary syndrome, or PCOS), as a curiosity, with no apparent cause or cure.  What is most interesting,  however,   is  how  common  this problem has become, and how

dramatic an impact it has created for women's health and reproductive function.  Even more significantly, we now know that it is shortsighted for healthcare providers to view Stein-Leventhal/PCOS as simply an ovarian disease or disorder.

Natural Treatments for PCOS can provide profound changes for women suffering from symptoms such as weight gain, excess hair growth, acne, irregular periods and infertility.

Polycystic Ovarian Syndrome (PCOS) is a hormone disorder characterised by the accumulation of what appears to be numerous fluid-filled cysts on the ovaries.

These cysts develop over time as the ova (eggs) fail to mature, then release during the menstrual cycle. This causes multiple immature ova to be visible on ultrasound, which are mistakenly called cysts.

Over the past few years our understanding of how PCOS develops has changed the way this hormone disorder is treated. Natural treatments for PCOS can address the root causes of this difficult condition. Time and time again women are seeing results using a PCOS diet plan, supplements, herbs and lifestyle adjustments. 

Natural Treatments For PCOS

One thing is for certain, making changes to your diet is essential to address the underlying causes such as insulin resistance. You will start to lose excess weight and improve the chances of falling pregnant.

One study found that 11 out of 12 women who had been overweight and not ovulating conceived naturally after losing weight (this study is found in ‘The Natural PCOS Diet e-book’).

As women with PCOS lose weight, hormone levels often start to return to normal. Testosterone levels fall, insulin levels go down, sex hormone binding globulin (SHBG) levels go up and the symptoms of PCOS start to diminish. Women also report significant improvements in the growth of excess hair and skin tone. Weight loss can have a remarkable effect on ovarian function.

Natural Treatments For PCOS Reduce Chance Of Miscarriage

In general, women with high levels of luteinising hormone (LH) in the first half of their menstrual cycle seem to have a greater risk of miscarriage. However, a study found that the rate of miscarriage dropped from 75% to 18% in women with PCOS who changed their diets and lost weight.

As you can see, diet is a major factor when looking at natural treatments for PCOS. 

Herbs and PCOS

Herbs are extremely useful in treating PCOS. Making changes and adding supplements to your diet will help control weight and balance blood sugar, while herbs go a step further, targeting any problems involving hormone balance.

Herbs to consider include:

Chaste tree (Vitex Agnus castus) is one of the most important herbs for PCOS because it helps stimulate and normalise the function of the pituitary gland, which controls the release of luteinising hormone (LH). Chaste tree has been successfully trialled in the treatment of PCOS as well as infertility.

Adrenal tonics such as Rehmannia, Rhodiola, Siberian Ginseng and Withania support the adrenal stress response and help the adrenal glands return to a state of balance.

Peony is another valuable herb as it positively influences low progesterone, reduces elevated androgens (testosterone) and modulates oestrogen and prolactin.

Licorice, especially combined with peony, helps regulate hormones, reduce androgen levels and improve the LH to FSH ratio.

Gymnema is helpful in reducing carbohydrate and sugar cravings. Tribulus helps restore menstrual regularity and regulate ovulation. Blue Cohosh acts as a uterine and ovarian tonic and a pelvic anti-

inflammatory. Saw Palmetto, a traditional male reproductive herb used to control excess

testosterone, offers promising results for hirsuitism.

Milk thistle, rosemary, Bupleurum and Schizandra are excellent liver herbs, aiding in the removal of excess oestrogen.

Recommendations of natural treatments for PCOS including herbs are found in detail in The Natural PCOS Diet .  

Other Natural Treatments for PCOS

Lymphatic drainage may be helpful to reduce congestion. Try massage, skin brushing and exercise such as rebounding.

Try castor oil packs and linseed packs for pain relief. Homoeopathic medicines - your homeopath or naturopath will prescribe

the most appropriate remedy for you. Try natural progesterone cream. The dose depends on your symptoms and

imbalances. Acupuncture is helpful for PCOS, Some acupuncture points are used to

move blood, break up stagnation and stop pain. Aromatherapy can assist and support the reproductive system, and gently

contribute to rebalancing your hormones.

Glycyrrhiza: Licorice root and testosterone

by Paul Bergner

Medical Herbalism 11(3):11-12

Large doses of licorice extract, usually in the form of candy or chewing gum, may cause hypertension and electrolyte imbalances through a well-defined mechanism (de Klerk et al). This effect was seen in an adult female with administration of a simple decoction of licorice root over three months (Bergner). Researchers have recently demonstrated that doses of licorice root extract, delivering the constituent glycyrrhizin in amounts similar to that contained in standard medical doses of the root, rapidly and significantly lowered levels of circulating testosterone in males (Armanini et al.). This effect appears to occur much more rapidly than the previously observed mineral corticoid effects. Similar effects of licorice on testosterone had been suggested previously in animal trials (Sakamoto and Wakabayashi; Takeuchi et al.) and in female subjects with polycystic ovarian syndrome (PCOS) (Takahashi et al; Yaginuma et al).

In the Armanini trial, seven men aged 22-27 years old were given 7 grams daily of a commercial preparation of licorice tablets for a week. The daily dose contained about 0.5 grams (7.14%) of glycyrrhizin, as determined by gas chromatography-mass spectrometry. The tablets appear to be crude licorice root, which reportedly contains between 6-15% glycyrrhizin (Budavari), rather than a concentrate. Table 1 shows the changes is several hormones during an eleven-day period. Testosterone levels fell by

about 40% within four days of licorice administration, returning to normal four days after its withdrawal.

Table 1

Ng/dl                  Day 0         Day 4         Day 7         Day 11

Testosterone             740 +/-216     414 +/-43     484 +/-191     704+/-42

Androstenedione        159 +/-35     140+/-29     177+/-30     170+/-20

17-hydroxy-progesterone     189+/-36     216+/-31     229+/-36     193+/-55

            (Licorice administration was stopped at day 7)

In a 1982 trial, eight anovulatory infertile women with elevated testosterone were investigated for lowering serum testosterone levels and inducing regular ovulation by a formula containing equal parts of peony root (Paeonia lactiflora) and licorice root (Glycyrrhiza glabra). Serum testosterone levels were significantly lowered in seven patients by doses of 5-10 grams of the combination daily for 2-8 weeks. Six of seven patients ovulated regularly and two of six patients conceived (Yaginuma et al.) In a similar trial in 1988, a significant reduction of circulating testosterone occurred in 18 of 20 female subjects with PCOS (Takahashi et al.). Five of the 18 became pregnant. In the above trials, it was not established which plant or plant constituents altered the testosterone levels. In 1991, researchers performed in vitro tests of the effects of several plant constituents from peony and licorice on rat ovary cells, and suggested that glycyrrhetic acid, a metabolite of glycyrrhizin in humans, inhibits the conversion of androstenedione to testosterone. Armanini et al. suggested that glycyrrhizin, or its metabolites, act on the enzymes that convert 17-hydroxy-progesterone to androstenedione, effectively lowering testosterone. 

Glycyrrhiza glabra samples reportedly contain approximately 6-15% glycyrrhizin (Budavari). Therefore the 500 mg daily dose of glycyrrhizin in the trial represents about 3.0 to 8.0 grams of crude plant material. A significant dose of this constituent would be difficult to deliver with standard tincture doses of less than one teaspoon per day. As ô00ö capsules containing about 400 mg of licorice root each, about 8-20 capsules would be expected to deliver a dose of glycyrrhizin comparable to that used in the trial. This would be the equivalent of two-six teaspoons of the powder. Doses of glycyrrhizin on the same order of magnitude as those in the trial could be expected to be delivered from a standard decoction. The standard daily dose in Chinese medicine is 3-12 grams/day, usually as a decoction. This could also result in a dose of glycyrrhizin similar to that in the trial. The German Commission E monograph on licorice prescribes a dose of 5-15 grams of the root per day, which would deliver a dose of 200-600 mg of glycyrrhizin (Blumenthal). (This monograph defines the glycyrrhizin content of licorice at 4% instead of the 6-15% described in the Merck Index.) According to the Merck data, this dose of crude material could deliver 0.3 to 2.3 grams of glycyrrhizin, up to over four times the dose used in the trial.

 The Commission E monograph assertion that daily doses of licorice as a flavoring agent delivering less than 100 mg of glycyrrhizin are safe should be reconsidered until

it is demonstrated that such a dose does not affect testosterone levels. Most reported adverse mineral corticoid effects to licorice are due to consumption or concentrated licorice extracts in candy or in medicines. Such preparations might also present the greatest public risk from testosterone lowering effects.

The above data indicate both potential adverse and therapeutically beneficial effects of licorice. In cases of reproductive dysfunction in males, screening for licorice intake and avoidance of licorice administration may be appropriate. On the other hand, in situations where it would be desirable to lower testosterone levels, such as prostate cancer or male pattern baldness, licorice might be useful. In females, the testosterone-lowering effects of licorice appear to have been helpful in the treatment of PCOS, and might be useful for other expressions of androgenization, such as alopecia, hirsutism, or other effects, including those following menopause. This research reinforces the traditional contraindication of licorice in pregnancy or possible pregnancy, where normal testosterone levels in the male fetus are essential for sexual differentiation and maturation. The recent availability of simple salivary hormone tests for testosterone invites simple investigations on the clinical effects of licorice on various clinical conditions. 

References

AWSUMMMM!

Objectives: The purpose of this article is to educate nurse practitioners about polycystic ovarian syndrome. After reading this article, the nurse practitioner should be able to:

explain the pathogenesis of PCOS identify diagnostic criteria for PCOS describe clinical manifestations associated with PCOS identify appropriate PCOS management principles.

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders in women, affecting 1 in 15 women of childbearing age. It has significant reproductive, metabolic and dermatologic consequences.1

The term PCOS first described the coexistence of amenorrhea, hirsutism, obesity and polycystic ovaries. A great deal of research has been conducted to determine the association among these symptoms.2

PCOS is known as a syndrome, not a disease.3A syndrome is a

symptom complex with no known cause. It is associated with specific characteristics, and it is defined by its consequences.

Women with PCOS are at increased risk for chronic conditions including diabetes, coronary artery disease, hypertension, dyslipidemia, endometrial cancer, infertility and obesity.4PCOS symptoms affect quality of life, leading to a higher frequency of depression and psychosexual morbidity in affected patients.5

PathophysiologyMultiple pathophysiologic mechanisms contribute to PCOS, but a comprehensive explanation is still lacking. Key features of the syndrome are abnormal pituitary function, abnormal steroidogenesis and insulin resistance.6Androstenedione is a steroid hormone produced in the adrenal glands and gonads that is converted to testosterone or estrogen. The enzyme 17-beta hydroxysteroid dehydrogenase is required for conversion to testosterone, and the enzyme aromatase is required for conversion to estrogen.

Studies suggest that ovarian theca cells in women with PCOS are more efficient than normal theca cells at converting the androgenic precursors to testosterone. In women, androstenedione is released into the blood by theca cells that provide androstenedione substrate for estrogen production in the granulosa cells. Theca cells lack aromatase, which is required to make estrogen. Theca cells and granulosa cells work together to form estrogen. Androgens are synthesized by the ovarian theca cells in response to stimulation by luteinizing hormone (LH). LH regulates the androgenic synthesis of theca cells, and follicle-stimulating hormone (FSH) regulates the aromatase activity of granulosa cells, determining the amount of estrogen synthesized from androgenic precursors. When the LH concentration is greater than that of FSH, the ovaries preferentially produce more androgens. Excessive LH secretion relative to FSH was the first laboratory abnormality identified in association with PCOS, but not all patients with PCOS have elevated LH levels.7 pproximately 40% of patients with PCOS

have normal LH:FSH ratios.8The ratio of LH to FSH is partly determined by the frequency of hypothalamic gonadotropin-releasing hormone (GnRH) stimulation. Increased pulse frequency of GnRH increases the LH:FSH ratio, and decreased pulse frequency reduces the ratio. Women with PCOS appear to have increased LH pulse frequency, indicating an increased pulse frequency of GnRH. It is unclear whether this is due to an intrinsic abnormality in the GnRH pulse generator or is caused by low levels of progesterone from infrequent ovulatory events. The low circulating progestin levels in women with PCOS may cause a rise in the pulse frequency of GnRH, increasing levels of LH and of ovarian androgens.7Polycystic ovaries have two to six times more follicles than healthy ovaries.5In anovulatory women with PCOS, the antral follicle stops growing at the stage just before the emergence of a dominant follicle. Excessive stimulation of follicular cells by insulin, LH or both is related to follicular arrest. Arrested follicles show signs of premature luteinization. Androgen excess results in excessive growth of small ovarian follicles and inhibition of the follicular maturation and development of the dominant follicle, resulting in the polycystic appearance of the ovary. Polycystic ovaries also have a thickened thecal layer that secretes excessive androgens.5Insulin influences the pathogenesis of hyperandrogenemia in PCOS. Insulin enhances the androgen production of theca cells by working synergistically with LH. It also inhibits hepatic synthesis of sex hormone-binding globulin (SHBG), the main protein that binds to testosterone. This increases the bioavailability of testosterone. Women with PCOS often have hyperinsulinemia, which elevates free testosterone concentration.7Insulin may act directly on the hypothalamus or pituitary gland - or both - to regulate gonadotropin release.9Hyperinsulinemia causes the pituitary gland to hypersecrete LH, which results in anovulation and thickening of the ovarian theca. This leads to higher androgen levels, specifically testosterone. Elevated testosterone may cause many of the symptoms associated with PCOS.8 The ovarian enzymatic activity involved in the synthesis of

testosterone precursors is most likely the main cause for increased testosterone levels. Elevated LH levels, together with hyperinsulinemia, lead to an increase in androgen production by ovarian theca cells.9The pathogenesis of PCOS suggests that it is a complex multigenic disorder. Both genetic and environmental factors are implicated in causation.5The popular understanding is that PCOS is the result of intrinsic ovarian genetic traits that interact with other congenital or environmental factors to cause dysregulation of steroidogenesis.6Diagnostic criteria are outlined in Table 1.

Clinical Manifestations

PCOS is usually identified as a disorder of ovarian androgen excess and is not diagnosed without evidence of clinical or biochemical hyperandrogenism. Clinical features of hyperandrogenism reflect a subjective assessment of manifestations of excessive androgen activity. Common features associated with PCOS include hirsutism, acne and androgenic alopecia.

Hirsutism is the most common of these symptoms, manifesting in about 60% of women with PCOS.3 The most common sites are the upper lip, chin, chest, lower abdomen and inner thighs. Degrees of hirsutism vary depending on ethnicity. It is important to obtain a medication history because many drugs cause hirsutism.

Acne occurs in 15% to 25% of women with PCOS. Androgenic alopecia is more common in older women, affecting approximately 5% of women with PCOS.3,5 Approximately 60% to 80% of patients diagnosed with PCOS have elevated serum androgen levels. Biochemically, hyperandrogenemia is most commonly assessed by measuring total testosterone and sex hormone-binding protein (SHBP), followed by calculation of free serum testosterone. Although radioimmunoassays to directly measure free testosterone are available, they are

considered unreliable.5 The mass action equation to calculate free serum testosterone is considered the method of choice, assuming reliable assays are used. The majority of abnormal values are in the form of free testosterone.5

Before attributing anovulation to PCOS, consider any form of functional hypothalamic amenorrhea that may be caused by extreme dietary restrictions or exercise. Chronic anovulation is associated with unopposed estrogen stimulation of the endometrium, which can result in endometrial hyperplasia or carcinoma. PCOS is also the most common cause of infertility due to anovulation and often the primary reason a patient seeks medical advice.5Polycystic ovaries detected by transvaginal ultrasonography may be detected in approximately 75% of women diagnosed with PCOS.3Polycystic ovaries are identified when at least one ovary is greater than 10 mL or has 12 or more follicles measuring 2 mm to 9 mm in diameter, according to transvaginal ultrasound. Transabdominal ultrasonography with measurement of ovarian volume is only appropriate for adolescent girls because determining the number of follicles via transabdominal ultrasonography is much less reliable in women, especially when they are obese.

Measurement of anti-Müllerian hormone secreted by granulosa cells of developing follicles is emerging as an alternative to ultrasonography because values do not closely correlate with the number of antral follicles. This assay is not valid for women older than 35, but it may be helpful when ultrasonography is inappropriate or unavailable.5 The finding of polycystic ovarian morphology on ultrasound is not unique to the clinical disorder of PCOS. This morphology has been documented in association with other disorders - as well as in 16% to 25% of apparently healthy women with regular cycles.10

Approximately 10% to 30% of women diagnosed with PCOS do not have polycystic ovaries on ultrasound, and the definition of the diagnostic features for polycystic ovaries by ultrasound is controversial.3Other clinical features of PCOS include obesity,

insulin resistance, hyperinsulinism, gonadotropic abnormalities, increased LH levels and increased LH:FSH ratio. These findings are not universally present and are not considered part of the diagnostic criteria for PCOS.3

Obesity is present in at least 30% of women with PCOS, and in some studies the prevalence is as high as 75%.7PCOS is characterized by an increase in waist circumference (greater than 35 inches), typically known as central obesity. This type of obesity is generally related to insulin resistance, glucose intolerance, dyslipidemia and decreased sex hormone-binding globulin, which increases circulating free testosterone.

Acanthosis nigricans, a hyperpigmentation of the skin, is common in patients who are insulin resistant. It often appears on the nape of the neck, the axilla and the area between the breasts.9

Fasting insulin and glucose levels are often normal in women with PCOS. However, they may have an exaggerated serum insulin response to oral glucose tolerance tests (OGTT). They may also exhibit elevated LH levels, low to normal FSH levels, and an LH:FSH ratio of 2:1 or higher. Patients can present with a range of symptoms and laboratory abnormalities. This underscores the importance of first excluding any other possible diagnoses associated with similar symptoms and laboratory values. A thorough family history, past medical history and focused physical exam are necessary to detect any signs of hyperandrogenism.8

Treatment of Androgen Excess

Manifestations of hyperandrogenemia are a common complaint in women with PCOS, due to elevated levels of free testosterone. Hepatic production of sex hormone-binding

globulin is inhibited by hyperinsulinemia, which increases unbound testosterone. Hirsutism can be treated with electrolysis or laser treatments; other methods (e.g., waxing, shaving) are often used, but they do not provide permanent hair removal.

Generally, OCs are considered first-line pharmacologic therapy for hirsutism and acne. In some cases, an oral antibiotic or a dermatologist-directed therapy is necessary. Estrogen suppresses LH secretion, decreasing ovarian androgen production. Estrogen increases hepatic production of sex hormone-binding globulin, decreasing the amount of free testosterone. Higher androgenic progestins may counteract those effects and have a negative effect on insulin; therefore, OC choice should be based on progestin component. Antiandrogens can be used alone or in combination with oral contraception to decrease the effects of androgen excess. Spironolactone (Aldactone) has antiandrogenic effects when administered in doses of 100 mg to 200 mg daily. Finasteride is a competitive inhibitor of the enzyme that converts testosterone to dihydrotestosterone, but studies show it is suboptimal for the treatment of hirsutism. Eflornithine (Vaniqa) is a topical treatment for facial hirsutism.12 Antiandrogens and OCs are often used to treat androgen excess. A starting dose of 30 mcg to 35 mcg of ethinyl estradiol combined with a progestin is recommended. If the patient is not satisfied after 4 to 6 months, a spironolactone may be added. When OCs are contraindicated, spironolactone may be used alone. Endometrial protection is necessary with intermittent progestin or metformin (Glucophage). An alternate form of contraception is necessary because spironolactone may cause abnormal development of external genitalia in male fetuses.15

Treatment of Insulin Resistance

Hyperinsulinemia plays a primary role in the pathogenesis of PCOS. Women with PCOS have increased rates of obesity,

type 2 diabetes, impaired glucose tolerance and dyslipidemia. In addition to the metabolic risks, hyperinsulinemia contributes to hyperandrogenemia by decreasing hepatic production of SHBG and increasing free testosterone levels. Insulin also binds to ovarian theca cells to stimulate testosterone production and may act to enhance LH-stimulated testosterone by the ovary. Insulin-lowering therapy improves insulin resistance and regulates menstrual activity. It may also influence body weight and lipid metabolism.12Metformin and the thiazolidinediones (TZDs) are the two most common pharmacologic approaches to hyperinsulinemia. Metformin is a biguanide used in the treatment of type 2 diabetes. It is an antihyperglycemic agent that decreases hepatic glucose production, improves glucose utilization in peripheral tissue, reduces intestinal glucose uptake and decreases lipolysis. Some research suggests that it also acts directly to reduce ovarian steroidogenesis. In women with PCOS, metformin therapy can increase ovulation rates, decrease body mass index or waist-to-hip ratio and decrease fasting insulin and testosterone levels.

Some researchers have suggested using OCs together with metformin to minimize the unwanted side effects of oral contraception. OCs work well for hyperandrogenic symptoms and menstrual cycle regulation, but they may worsen insulin sensitivity and occasionally cause a small increase in weight. The addition of metformin produces a modest improvement in insulin sensitivity.12 ZDs such as pioglitazone (Actos) and rosiglitazone (Avandia) are other treatments for type 2 diabetes. These are insulin sensitizers believed to improve the action of insulin in the liver, skeletal muscle and adipose tissue. They may have a direct effect on the ovary by decreasing testosterone and estradiol production. Troglitazone (Rezulin) was removed from the market because it was associated with severe idiosyncratic hepatotoxicity. The FDA now recommends liver function tests prior to TZD therapy and occasionally during therapy.12Pioglitazone and rosiglitazone improve insulin

sensitivity, hyperandrogenemia and menstrual cycles, but they can cause weight gain. TZDs have been studied less than metformin but appear to produce clinical improvements; they are not recommended in women with PCOS who are not diabetic.15Insulin sensitizing agents are associated with reduced serum androgen evels and gonadotropins and improvement in serum lipids nd in prothrombotic factor.16This therapy has lso been associated with a decrease in hirsutism and acne, regulation of menses and an improvement of ovulation nd fertility. Notable improvements in all these parameters ave also been described after a change in lifestyle approach, articularly in the presence of obesity. Lifestyle interventions hould therefore be combined with insulin sensitizers when obesity is present.16In women with PCOS, oral contraception is more effective than insulin sensitizing agents in improving menstrual pattern and reducing serum androgen levels.17Metformin is more effective in reducing fasting insulin levels and not increasing triglyceride levels.17Limited evidence supports the preferential use of insulin sensitizing agents or OCs in the treatment of hirsutism or acne, or in preventing the development of diabetes, cardiovascular disease or endometrial cancer.

A combination therapy is often needed to achieve optimal results, but no specific combination of medications is recommended for all patients diagnosed with PCOS. Each woman has different needs and goals. Encourage lifestyle modifications before any pharmacologic treatment when obesity is present. All studies show that weight oss improves endocrine and metabolic abnormalities and hat ovulation and fertility may be restored.16