Long-Term consequences of Polycystic Ovary

Syndrome

 

Introduction

 

Stein and Leventhal were the first to recognize an association between the presence of polycystic ovaries and signs of hirsutism amenorrhea (eg, oligomenorrhea,obesity) (1).

Subsequently, after successful wedge resection of the ovaries in women diagnosed with Stein-Leventhal syndrome, menstrual cycles become regular and these patients were able to conceive. Consequently, a primary ovarian defect was thought to be the main culprit, and the disorder come to be known as polycystic ovarian disease. Further, biochemical, clinical and endocrinologic studies have shown an array of underlying abnormalities; hence, the condition is now referred to as polycystic ovary syndrome (PCOS), although it may occur in women without ovarian cysts.

 

PCOS is commonly diagnosed in young women with anovulatory infertility, oligomenorrhea or hyperandrogenic problems such as hirsutism and acne. Although, associated with obesity, the syndrome is also frequently seen in women of normal body habitus.

While most attention has been paid to the management of the presenting complaint (infertility, hirsutism..etc.) it has become clear that the polycystic ovary phenotype is linked to a number of metabolic disturbances, including type II (non-insulin dependent) diabetes and possibly atherosclerotic conditions(2).

 

PCOS is frequently diagnosed by gynecologists and it is therefore important that gynecologists have a good understanding of the long-term implications of the diagnosis.

 

 

Prevalence of PCOS

 

PCOS has been diagnosed with increasing frequency following technological developments in automated hormone assay and in ultrasound. Estimates of the “true” prevalence of the disorder must be made with caution, since there is no overall consensus concerning the diagnostic criteria that must be satisfied in order to make the diagnosis.

 

Most clinical data originates from highly specialized tertiary clinics, which may not reflect the picture in the population at large. However, several attempts have been made to quantify the prevalence of polycystic ovaries in community-based studies (3-5) suggesting that approximately 20% of women of reproductive age demonstrate the ultrasound picture of polycystic ovaries, with half that number having clinical or biochemical signs of anovulation pr androgen excess.

 

PCOS is  a familial condition. Most studies have focused exclusively on white populations. The prevalence of PCOS may be higher in other ethnic groups (6), although further studies are needed.

 

Kousta and colleagues(7) examined the prevalence of PCO, on ultrasonography, among women presenting with infertility. PCO were found in 81(83%) of 98 anovulatory women, 40(53%) of 76 patients who’s partners had sperm dysfunction, 26(50%) of 52 patients with tubal disease and in 28(44%) of 63 patients with unexplained infertility. By comparison, in a central group of 67 parous volunteers, 19(28%) were found to have PCO.

The prevalence of PCO was significantly higher in each of the infertility groups than in controls, and a similar tendency (not significant) was observed among women with unexplained infertility. Ovulatory PCO women with infertility had higher testosterone concentrations in comparison with PCO controls.

It was concluded that the prevalence of PCO among ovulatory women with infertility is higher than that in the normal population suggesting that PCO may, perhaps by virtue of an effect of hyperandrogenemia, contribute to the causes of subfertility in women with regular menses.

 

Pathophysiology of PCOS

 

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, androstendion, and   dehydroepiandrostendione sulfate, may be encountered  in these patients(8). However, significant individual variation exists, and a particular patient might have normal androgen levels.

PCOS also is associated with peripheral insulin resistance and hyperinsulinemia and the degree of both abnormalities is applied by the presence of obesity. Insulin resistance is not due to defects in insulin binding to insulin receptors; rather, it involves postbinding signaling pathways.

The elevated insulin levels may have gonadotropin-augmenting effects on the ovarian function.

 

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 androgen (eg, testosterone, androstendione).

Because of decreased levels of follicle-stimulating hormone(FSH), the ovarian granulose cells are not able to aromatize the androgens to estrogens, leading to decreased estrogen levels and consequent anovulation.

Growth hormone(GH) and insulin-like growth factor-1(IGF-1) also may have an augmenting effect on ovarian function(9,10).

 

Hyperinsulinemia also is responsible for dyslipidemia and elevated levels of plasminogen activator inhibitors 1(PAI-1) in patients with PCOS. Elevated PAI-1 levels constitute a risk factor for intravascular thrombosis(11).

Body mass index (BMI) is positively correlated to serum insulin and testosterone levels and is inversely related to sex hormone binding globulin(SHBG) levels(12).

 

Grossly, polycystic ovaries are enlarged bilaterally and have a smooth thickened capsule that is avascular.

On cut section, 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. Upon microscopic examination, luteinized theca cells are seen.

 

Presentation

 

Patients with PCOS present with various symptoms including the following:

*Amenorrhea  *Oligomenorrhea  *Infertility

*Recurrent pregnancy loss  *Hirsutism  *Obesity

*Acne Vulgaris  *Asymptomatic

 

Physical

Physical examination findings are significant for the following:

 

*Hirsutism: patients may have excess body hair in male distribution pattern and acne. In some patients with PCOS virilizing signs such as male-pattern balding or alopecia, increased muscle mass, deepening voice or clitoromegally may be encountered and should prompt the search for other causes of hyperandrogensim.

 

*Obesity: approximately 50% of patients with PCOS are obese.

 

*Acanthosis Nigricans: this is a diffuse velvety-thickening hyperpigmentation of the skin. It may present at the nape of the neck, axillae, area beneath the breasts, intertiginous areas, and exposed areas (eg, elbows, knuckles).

Acanthosis nigricans is thought to be the result of insulin resistance in these patients.

 

 

Other problems to be considered :

 

*Ovarian hyperthecosis

*Congenital adrenal hyperplasia (late-onset)

*Androgen-producing tumors of the ovary and adrenals

*Drugs eg, danazol, androgenic progestin

 

Laboratory Studies

 

·       increased androgen levels in blood (testosterone and androstendione)

·       Increased LH levels, exaggerated surge

·       Increased fasting insulin

·       Increased prolactin

·       Increased estradiol and estrone levels

·       Decreased SHBG levels

 

 

Imaging Studies

 

Ultrasonography is the most sensitive diagnostic study.

The number of cysts found in subcapsular region varies between 8-10 cysts with diameter of 2-8mm.

 

In a study of polycystic ovaries and normal ovaries using three dimensional power Doppler ultrasonography,

Jarvele and colleagues(13) found that the ovaries defined as polycystic (based on finding 8  or more subcapsular follicles of 2-8mm in diameters) were larger than normal ovaries, but they could not find any difference in echogenicity of the stroma between polycystic ovaries and normal ovaries . also, they could not demonstrate that polycystic ovarian stroma was more vascularized than the stroma than the stroma in the normal ovaries.

Recently, Tonard and colleagues(14) modified the definition of polycystic ovaries by adding the presence of  >/=12 follicles measuring 2-9mm in diameter (mean of both ovaries). They also strengthened the hypothesis that the intra-ovarian hyperandrogenism promotes excessive early follicular growth and that further progression can not proceed normally because of hyperinsulinism and/or other metabolic influence linked to obesity.

 

It was observed that the currently used ultrasonographic criteria for the diagnosis of polycystic ovaries do have significant intra-observer and inter-observer variability and as such must be considered subjective and that transvaginal ultrasonography alone may not therefore be a reliable method of diagnosing or excluding PCOS(15)

 

Diagnosis of PCOS

 

 The association of the clinical features of truncal obesity, oligo- or amenorrhea and hirsutism with biochemical evidence of hyperandrogenemia, elevated luteinizing hormone and suppressed sex hormone-binding globulin and characteristic ovarian morphology on ultrasound has formed the basis of the diagnosis of PCOS for some years.

 

However, biochemical abnormalities are seen in women with regular menstrual cycles and normal ovaries on ultrasound but who preset with hirsutism or acne; and women of normal body mass who present with oligomenorrhea will frequently exhibit biochemical and ultrasound signs of PCOS(16,17)

 

The key underlying abnormality that leads to long-term health risk appears to be insulin resistance-hyperinsulinemia in the presence of normoglycemia(18,19)

 

Identification of patients with metabolic complications of PCOS should therefore focus on biochemical criteria to diagnose the syndrome, particularly hyperandrogenemia(20) together with an assessment of fasting glucose and insulin, lipids and triglycerides(21).

 

This should identify women with PCOS most at risk of long-term complications of this condition.

 

Genes and PCOS

 

Because of the well-known familial clustering of cases of PCOS recent studies have focused on clinical and molecular genetic studies in an attempt to identify key genes which may be involved in its etiology.

 

 Franks and colleagues(22) found evidence that a polymorphism in the regularity region of CYP11a (encoding P450 cholesterol side chain cleavage, also an important enzyme in the steroidogenic pathway) was associated with and linked to PCOS. When they examined insulin gene (INS) they found, in three separate populations,  that class III alleles in the insulin gene variable number tandem repeat (INS-VNTR)[the minisattilite in the regulatory region of the insulin gene] were associated with PCOS.

 

Also, Michelmore and colleagues(23) showed that the appearance of clinical feature of PCOS was related to insulin resistance and insulin gene VNTR class III alleles.

Siegle and colleagues(24) showed that the INSR gene is a susceptibility gene for PCOS in the population.

 

It seem unlikely that PCOS can be explained on the basis of a single gene disorder although, in a given family, one gene may have a predominant effect.

 

Metabolic consequences of PCOS

 

(1)PCOS and the risk of type II diabetes

 

Insulin plays a major role in PCOS. Insulin resistance and resultant hyperinsulinemia stimulates both the ovary and adrenal to produce androgens.

 

One study has shown that gonadotropin-releasing hormone agonist (GnRHa) therapy suppressed androgens in subjects with PCOS, but no change in insulin resistance was observed(25). When hyperinsulinemia is reduced, however, androgen levels fall (26) indicating that it is insulin that induces hyperandrogenism.

 

Acien and colleagues (27) showed that Insulin, androgen, and body mass index (BMI) are related in women with and without PCOS. Although fasting insulin and glucose levels may be normal in both lean and obese women with PCOS. Women with PCOS manifest an exaggerated serum insulin response to an oral glucose tolerance test (OGTT), as compared with weight-matched controls.

They suggested that three types of disorders are associated with PCOS:

1-simple, hyperinsulinemic, nonhyperandrogenic obesity

2-typical PCOS, probably with hyperactivity of steroidogenic enzymes but without hyperinsulinemia

3-Insulin-resistant PCOS resulting from anomalies in the genes involved in the secretion and action of insulin

 

The latter type is considered to have the highest metabolic, renal and cardiovascular risks.

 

Insulin resistance associated with PCO was reported by Chang and colleagues(28) in 1983. this resistance which is independent of obesity causes hyperinsulinemia(29,30).

Legro and colleague(31) found that more than 50% of obese women with PCOS are insulin resistant compared with age- and weight-matched controls.

 

In a recent study using unselected volunteers, it was shown that obesity increases insulin resistance and the presence of polycystic ovaries appeared to have a strong influence than obesity on insulin resistance(32).

In addition, in women with insulin resistance, the causative defect in insulin secretion is more prevalent and severe in those with a family history of non-insulin-dependent diabetes mellitus(NIDD, type 2)(33).

 

Patients with PCOS were found to be at risk for early onset NIDDM (33-35).

Evidence from small long-term cohort studies, case-control studies and case series, points to a risk of type II diabetes in middle age of 10-20% with a higher rate of impaired glucose tolerance suggesting that further cases of diabetes will develop later(36-38). Increased body mass, particularly truncal obesity, and a strong family history of diabetes both increase the risk of developing type II diabetes in the presence of the polycystic ovary phenotype.

 

The prevalence of polycystic ovaries in premenopausal women presenting with type 2 diabetes mellitus was studied in cross-sectional study by Conn and colleagues(39). They recorded clinical, demographic and anthropometric data in 49 premenopausal women and measured fasting metabolic parameters, reproductive endocrine profile and ovarian dimensions. They found that women with type 2 DM had higher prevalence of PCOS than that reported in general population. Not all women with hyperinsulinemia due to type 2 DM, however, develop PCO suggesting that hyperinslinemia alone is not sufficient for the expression of this ovarian morphology.

 

In a recent study Yildiz and colleagues(40) found that first degree relatives with PCOS may be at high risk for diabetes and glucose intolerance. They showed that mothers and sisters of PCOS patients have higher androgen levels than control subjects. They suggested that the high risk of these impairment warrant screening in first degree relatives of patients with PCOS.

 

 

(2)PCOS and risk of cardiovascular disease

 

Coronary heart disease is the largest killer of men and women in the united states. Several researches has linked PCOS with multiple risk factors.

 

To determine if polycystic appearing ovaries (PAO) are associated with differences in risk factors for cardiovascular disease among women with PCOS, Loucks and colleagues (41) studied 63 women with PCOS and 56 non-pcos control. They used transvaginal ultrasound for ovarian appearance with a single venipuncture to measure fasting insulin, lipoproteins, androgens, LH/FSH ratio, anthropomorphic measurements and blood pressure. They found that women with PCOS had higher androgen and fasting insulin levels, a more adverse lipid profile, greater waist-hip and LH/FSH ratio and a larger ovarian volume than controls. Thirty three per cent of cases with PCOS, but only 5% of controls, showed PAO on ultrasound.

PCOS with and without PAO had comparable levels of fasting insulin, lipids, and blood pressure. PCOS with PAO had a higher LH/FSH ratio, increased levels of serum androstendione and testosterone and greater ovarian volume. They concluded that women with PCOS have greater cardiovascular risk than controls and within PCOS cases, the ultrasound appearance of polycystic ovaries dose not appear to further intensify the cardiovascular disease risk profile of these women.

 

Talbott and colleagues (42) evaluated subclinical atherosclerosis among women with PCOS and age-matched control subjects.

A total of 125 white PCOS cases and 142 controls, aged >/=30 years were recruited. They collected baseline sociodemographic data, reproductive hormone levels and cardiovascular risk factors from 1992 to 1994. Follow-up of women was carried out from 1996-1999 where women underwent B-mode ultrasonography of the carotid arteries for the evaluation of carotid intima-media wall thickness (IMT) and the prevalence of plaque. They found a significant difference in the distribution of carotid plaque among PCOS cases compared with controls, where 72% of PCOS cases had a plaque index of >=3 compared with 0,7% of similarly aged controls. They also found a significantly greater mean IMT in PCOS with age >/=45 years than in controls and concluded that life long exposure to an adverse cardiovascular risk profile in women with PCOS may lead to premature atherosclerosis. They explained the association between PCOS-IMT by the weight and fat distribution and associated risk factors.

 

Lakhani and colleagues(43) provided additional evidence of vascular dysfunction in women with PCOS when they found a significant lower compliance in the internal and common carotid arteries in patients with PCOS compared to healthy women.

 

To evaluate the role of insulin resistance, independent of obesity in determining cardiovascular risk among women with PCOS, Mather and colleagues(44) studied 57 patients with clinically defined PCOS and 45 unselected healthy age-matched controls. They found that hyperinsulinemic women with PCOS carried more cardiovascular risk than their normoinsulinemic counterparts who in turn had more risk than control subjects.

 

Goodrazi and colleagues (45) evaluated the impact of insulin resistance and obesity on parameters of cardiovascular risk in 69 patients with PCOS. They found that the most insulin-resistant tertile of patients exhibited higher body mass index (BMI), androgen levels, systolic and diastolic blood pressure, triglyceride levels(TG), and decreased high-density lipoprotein cholesterol (HDL-c) levels. They conclded that insulin resistance, not BMI, was the main determinant of HDL-c and TG levels and systolic blood pressure in PCOS. They also found that both BMI and insulin resistance influenced cardiovascular risk factors in normal women and in contrast to normal women, insulin resistance in PCOS appears to be the primary determinant of abnormal lipids, blood pressure, and androgens. They advised early detection of insulin resistance as well as weight reduction for all patients with PCOS.

 

In evaluation of the related risk of PCOS and coronary atherosclerosis, Christian and colleagues(46) measured coronary artery calcium, which is a known marker for plaque, in premenopausal women (ages 30 to 45 years) who suffered from PCOS. Results were then compared with age and weight matched volunteers who did not suffer from PCOS as well as community-dewlling women of similar age from a coronary calcium database. They found that calcified plaques was much more common in women with PCOS compared with the controls and community-dewlling women. Thirty-nine percent of PCOS women had coronary calcium, while only 21% of the controls and 10% of the community-dewlling women had calcified plaque. They noted that PCOS women had significantly higher levels of LDL (‘Bad’) cholesterol and testosterone levels than the other two groups.

Based on their findings they concluded that coronary heart disease is more common with PCOS than in obese and non-obese women of the same age group, moreover, obese women with PCOS are at particular increased risk for developing coronary heart disease.

They advised that women with PCOS should be screened regularly for heart disease risk factors from the time of their initial diagnosis.

 

In a recent study Schachter and colleagues(47) found an association between insulin resistance and hyperinsulinemia in patients with PCOS and elevated plasma homocystein ( a significant risk factor for cardiovascular disease, preeclampsia and recurrent pregnancy loss) regardless of body weight. Their finding may have important implications in the long-term regarding cardiovascular complications associated with insulin-resistance PCOS.

 

 

PCOS and Pregnancy

 

Women diagnosed as having PCOS before pregnancy have increased risk of development of gestational diabetes(GDM) (48,49).

In a retrospective study Mikola and colleagues(50) studied 99 pregnancies in women with PCOS and found an incidence of 20% of GDM in PCOS patients compared with 8.9% in controls. They found that BMI >25 was the greatest predictor for GDM while PCOS remained as another independent predictor.

Glueck and colleagues(51) found that the use of metformin is associated with a 10-fold reduction in gestational diabetes in patients with PCOS.

In a recent study Turhan and colleagues (52) found that the main predictor of GDM is pre-pregnancy BMI>25 while the main predictor of impaired glucose tolerance test(IGT) was PCOS.

However, a retrospective study carried out by Haakova and colleagues(53) comparing the prevalence of GDM in a group of patients with PCOS with a group of healthy weight-matched women did not find differences between PCOS and controls with regard to development of GDM when differences in age and weight in PCOS and healthy women was neglected.

The risk of pregnancy-induced hypertension among patients with PCOS was evaluated and shown to be increased in some studies(54,55). However, other studies showed no relation between PCOS and preeclampsia(50,53)

 

Studies on the association between PCOS and increased rate of abortion and recurrent abortion could not demonstrate any significant relationship with PCOS(56-58).

 

PCOS and Cancer

 

It has been known for many years that sever oligo- and amenorrhoea in the presence of premenopausal levels of estrogen can lead to endometrial hyperplasia and carcinoma(59). Elliott and colleagues (60) reported the development of endometrial adenocarcinoma after diagnosis of PCOS in three premenopausal women, and it was shown that women with PCOS, intervals between menstruations of more than three months may be associated with endometrial hyperplasia(61).

 

Regular induction of a withdrawal bleed with cyclical gestogens is advisable in oligomenorrheic women with PCOS. Those with persistently thickened endometrium when measured by transvaginal ultrasound should be advised to have and endometrial biopsy and/or hysteroscopy to rule out endometrial hyperplasia(62).

 

A recent practice bulletin from the American college of Obstetricians and Gynecologists on the clinical management of PCOS says that there is still no consensus on the optimal progestin duration and frequency of treatment to prevent endometrial carcinoma in women with PCOS(63).

 

Although PCOS is associated with risk factors for endometrial carcinoma, it does not necessarily follow that the incidence or mortality from endometrial cancer is increased (64).

 

The relationship between PCOS and epithelial ovarian cancer risk was studied by Schildkraut and colleagues(65). They analyzed data from a population-based case-control study. Four hundred seventy six subjects with histologically confirmed epithelial ovarian cancer were identified from eight tumor registries of the Surveillance Epidemiology and End Result program. The study included 4081 controls. All subjects and controls were aged 20-54 years. They found that ovarian cancer risk increase 2.5 fold among women with PCOS and they found that a stronger association present among women who never used oral contraceptive. The data presented in this study suggested that the hormonal status of women with PCOS featuring abnormal patterns of gonadotropic secretion (enhanced levels of LH) in lean women may be a mitigating factor for the observed association between PCOS and ovarian cancer.

 

Further investigations with regard to the association between PCOS and ovarian cancer are awaited.

 

Studies examining the relationship between PCOS and breast carcinoma have not always identified a significant increased risk(66).

 

 

 

Strategies for reduction of risk

 

(1)Exercise  and weight control

The impact of exercise and reduction in body mass by hypocaloric dieting on ovarian function in PCOS is well characterized. Adoption of simple methods for reduction of body fat and improvement in physical fitness will result in resumption of ovulation and increase in fertility in a high proportion of anovulatory obese PCOS women (67).

 

The demonstration that improvement in diet and exercise in obese young women with PCOS is accompanied by normalization in glucose metabolism suggests that life style alteration will reduce the likelihood of developing type II diabetes later in life (68).

 

There is no clear evidence of an effect of diet or exercise on the long-term health of women with PCOS who have normal body habitus, although it seems prudent to advise such patients to maintain their body weight within the normal range.

 

(2) Drug therapy

 

The demonstration of the long-term health consequences of PCOS has been accompanied by renewed interest in the use of drugs, particularly “insulin-sensitizing agents” such as metiformin and troglitazone to reduce insulin resistance and thereby reduce the risk of developing diabetes and other metabolic sequelae.

 

Anxieties concerning adverse effects of troglitazone on hepatic function have led to its withdrawal in UK.

 

 

 

PCOS and Metformin

 

Oral antidiabetic agents are usually used by internists and endocrinologists to treat NDDM, but for the past decade, the drugs have become familiar in gynecologic practice.

Metformin was the first drug used for alleviation of the symptoms of PCOS. Its major action is suppression of glucose output, but it also improves insulin’s action without affecting its secretion. Various studies with metformin have evaluated the changes in both insulin and androgen levels. Some report that the drug is effective while others report no benefit. For example, Valezquez and colleagues (69) found a decrease in androgen level accompanied with weight loss in patients treated with metformin, suggesting that the effect may be primarily due to weight loss rather than the drug itself. In another study, similar results… i.e. no apparent drug effect… were found when weight loss only was compared with weight loss and metformin therapy(70).

Acbay and Gundogdu (71) reported that insulin resistance and associated metabolic and hormonal abnormalities did not improve in patients with PCOS who were given metformin 10 weeks. BMI did not change during the therapy, so these patients did not have the beneficial effect of weight loss.

 

 Metformin reduces the resistance and dyslipidemia when given to patients with NIDDM. These findings suggest that the mechanism for insulin resistance in PCOS is different from that in NIDDM. In a 12-week trial of metformin in 14 obese nondiabetic women with PCOS , no improvement in hyperinsulinemia and androgen excess was noted(72). In addition in vitro study showed that metformin had no effect on insulin-stimulated theca cell androgen production(73).

 

However, there are studies that report good results with metformin therapy in women with PCOS. One randomized placebo-controlled trial showed that metformin therapy administered for 4-8 weeks resulted in decreased levels of insulin, 17-OHP, and free testosterone levels and increased SHBG levels, without a change in BMI(74).

 

Reduction of serum insulin levels also decreased ovarian cytochrome P450, 17 alpha activity, which is responsible for exaggerated serum 17-OHP response in patients with PCOS(75,76).

In another placebo-controlled study, metformin improved hyperinsulinemia and reduced androgen levels in nonobese women with PCOS within 4-6 weeks(77). No change was seen in the control group, and the authors concluded that reduction of insulin with metformin decreased P450, 17alpha activity and thus ameliorated hyperandrogenism. But on the contrary, in another study, metformin administration did not decrease adrenal androgen secretion(78). Subjects with elevated adrenal androgens had less improvement of  menstrual cycle irregularity, and no change in hirsutism was noted with metformin treatment of 12 weeks duration(79).

 

Metformin does not primarily act on insulin, but reduction of insulin levels is a secondary effect following reduced gluconeogensis. In a study conducted in women with PCOS, metformin for 6 months was compared with ethinyl estradiol(35micrograms)-cyproterone acetate(25mg) oral contraceptive pills(80). Although similar results were obtained in both groups for hyperandrogenism, metformin decreased fasting free fatty acids and insulin concentrations and improved oxidative glucose utilization.

Reduction in the release of fatty acids from the adipose tissue helped to reduce hyperinsulinemia by blocking the competition of fatty acids with glucose for oxidation in the skeletal muscle.

 

Why metformin is successful in some studies and not in other is a concern, however, obesity, variation in the dose, genetic background and duration of therapy may be major factors in

patient’s response. It may take 4-6 months to improve menstrual cyclicity and ovulation rates when metformin is used as a single agent. Patients should be aware of this time interval to avoid expecting a positive result too soon.

Side effects encountered during the therapy include nausea, abdominal discomfort, diarrhea, and anorexia. Blood glucose levels of patients who use metformin decrease without a hypoglycemic risk.

Major contraindications to metformin include organic or functional renal failure with serum creatinine level higher than 1.4ng/dl, alcoholism, hepatic disease, and chronic cardiopulmonary dysfunction.

 

Metformin for ovulation induction in PCOS

 

Metformin has been used as an adjuvant agent for ovulation induction in women with PCOS. When used alone, 40%(19/48) of patients in one study resumed regular cycles and ovulation (81). Addition of clomiphene citrate(cc) to nonresponders increased ovulation rate to 67%. The combination of metformin and cc seems to be synergistic, but metformin alone was also effective as an inducer in this study.

In another study, a 28.25 ovulation rate and 4.2% pregnancy rate were achieved with cc in 24 women with PCOS(82). But when metformin was added to the induced cycles, ovulation and pregnancy rates increased to 57.9% and 65.2% respectively. The mean time to achieve conception was 4.3 months. The most striking results of this study is the high pregnancy rate.

In a 2 double-blind, placebo-controlled studies, pretreatment with metformin in cc-resistant patients with PCOS improved ovulation rates(83,84).

Vandermolen and colleagues (83) used 500 mg metformin 3 times daily for 7 weeks in the study group and then both study and controlled groups received 50mg cc for 5 days. In anovulatory patients, the cc dose was increased by 50mg for the next cycle. Patients were given this regimen for up to 6 cycles to achieve either ovulation or pregnancy or both. Ovulation and pregnancy rates were significantly higher in the study group (ovulation rates: 75% vs. 7.7%; pregnancy rates: 55% vs. 7%). Although fasting serum insulin and glucose: insulin ratio did not change during the treatment, the authors related higher response to the insulin-sensitizing effect of metformin.

Kocak and colleagues (84) compared metformin with placebo before induction with cc in their study. They used 850mg metformin twice daily during the first cycle and then added 100mg cc for the subsequent cycle. In addition to a significant decrease in total testosterone, LH levels, LH/FSH ratio, insulin resistance, and mean BMI in the study group, the ovulation rate was significantly higher in the study group than in the control group (77% vs. 14%). The pregnancy rate did not differ significantly, but the total number of pregnancies in the metformin group was significantly higher. The authors hypothesized that metformin could alter follicular steriodogensis. But the factor responsible for higher ovarian androgen production in these patients is actually hyperinsulinemia, which activates IGF-1 receptors in theca cells  and augments androgen production, not insulin resistance.

In addition to the ways in which metformin was used in these studies, it has been used in conjunction with  gonadotropins for ovulation induction. Yarali and colleagues (85) did not observe an improvement in either insulin sensitivity or ovarian response in cc-resistant PCOS patients when pretreated with metformin 850 mg twice daily and then induced with recombinant FSH. Although, insulin sensitivity did not change during the 6-week metformin trial, the investigators noticed  an increase in spontaneous ovulation rate. Metformin treatment did not affect ovarian response with rFSH. The dose and treatment period might be the limiting factors in this study.

 

On contrary, Stadtmauer and coworkers (86) reported improvement in IVF and pregnancy rates in cc-resistant PCOS patients pretreated with metformin. The protocol in their study was administration of 1000-1500mg metformin daily for 1 cycle before induction with gonadotropins . Fertilization and clinical pregnancy rates were higher in patients who received metformin. Although metformin was used for a shorter period (1 cycle). In this study, the author observed a better response when metformin was used in combination with rFSH.

 

These studies support the use of metfromin as an adjunctive  treatment in cc-resistant PCOS patients. Treatment period and dosage may vary, but the usual dosage is 500mg twice or single 850mg for normal-weight subjects and 500 mg 3 times daily or 850g twice daily for subjects. Maximum dosage should not exceed 3g/day.

 

 

(3) Surgery

 

Anovulation associated with PCOS has long been known to be amenable to surgical treatment.

A long-term cohort study up to 20 years after laparoscopic ovarian electrocautery has shown persistence of ovulation and normalization of serum androgens and SHBG over many years in over 60% of subjects (87). Insulin resistance and serum lipids were not assessed, but women with PCOS treated with ovarian diathermy for reproductive reasons might obtain long-term benefit over and above resumption of ovulation and menses.

 

The long term benefits of ovarian drilling, including alterations in endocrine profile, have recently been confirmed (88).

 

The effectiveness  and safety of laparoscopic ovarian drilling with ovulation induction for subfertile women with Clomiphene resistant PCOS was reviewed  in fifteen trials; six were randomized(89). All trials were assessed for quality criteria. The main studied outcomes were ovulation and pregnancy rates, miscarriage rate, multiple pregnancy rate, and incidence of overstimulation and ovarian hyperstimulation syndrome rates were a secondary outcomes.

The ongoing pregnancy rate following ovarian drilling compared with gonadotropins differed according to the length of follow-up. Overall, the pooled OR(all studies) was not statistically significant (OR 1.27,  95% CI 0.77,1.98).

Multiple pregnancy rates were reduced in the ovarian drilling arms of the four trials where there was a direct comparison with gonadotropins (OR 0.16, 95%CI 0.03,0.98).

There was no difference in miscarriage rates in the drilling group when compared with gonadotropins in these trials (OR 0.61, 95%CI 0.17,2.16).

It was concluded that there is insufficient evidence of a difference in cumulative ongoing pregnancy rates between laparoscopic ovarian drilling after 6-12 months follow-up and 3-6 cycles of ovulation induction with gonadotropins as a primary treatment for subfertile women anovulation and PCOS. Multiple pregnancy rates are considered reduced in those women who conceive following laparoscopic ovarian drilling

 

Should we screen young PCOS patients for long-term health risk?

 

Epidemiological and experimental studies suggest that young women with PCOS are at increased risk of developing type II diabetes and disorders secondary to hyperlipidemia, when compared with women who do not have COS(90), however, evidence that these metabolic complications lead to an increased risk of early death is lacking.

 

A retrospective cohort study has shown an increased prevalence of non-fatal cardiovascular disease and cardiovascular disease risk factors among women with PCOS(91).

In order to encourage compliance with a regimen of diet and exercise designed to maintain a normal body habitus, it seems reasonable to offer measurement of glucose in a fasting blood sample, along with measurement of lipids and triglycerides.

A 75gram oral glucose tolerance test with measurement of glucose at o and 2hours (with consideration of including measurement of insulin concentrations) should be performed if fasting glucose is elevated at the time of diagnosis and may be advisable even if fasting glucose is normal(92).

This advice is particularly relevant for obese patients with PCOS (body mass index greater than 30 for white group) and if there is a family history of diabetes or heart disease.

However, adverse lipid profiles are seen even in thin women with PCOS, and non-obese women with PCOS might also benefit from this information (18,35,90)

 

Women with PCOS who are found to have abnormal glucose tolerance, hyperinsulinemia or an adverse lipid profile should be referred appropriately for further advice and management.

 

Acknowledgment

I would like to thank Dr. Hardiman P, Department Obstetrics and Gynecology , Royal Free and University College Medical school.

And Dr Antoni Duleba MD, Yale Education for their replies to me.

 

References

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