|Year : 2011 | Volume
| Issue : 2 | Page : 116-125
Effect of metformin combined therapy in patients with polycystic ovary syndrome
Dhanalakshmi Ganesan1, Sumathi Palaniswamy2, Pasupathy Palanisamy3, Babu Shankar Ponnusha3, Ambika Athimoolam3
1 Department of Biochemistry & Biotechnology, Bharathiyar University, Coimbatore, India
2 Department of Biochemistry, Government Arts and Science College for women, Krishnagiri, India
3 Clinical Biochemistry, K. G. Hospital and Post graduate Medical Institute, Coimbatore, Tamil Nadu, India
|Date of Submission||06-Jul-2011|
|Date of Acceptance||17-Aug-2011|
|Date of Web Publication||23-Aug-2011|
Research scholar, Bharathiyar university, Coimbatore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Polycystic ovary syndrome (PCOS) is a common and heterogeneous disorder of women of reproductive age, characterized by hyperandrogenism and chronic anovulation. Metformin may lower the androgen level in follicular fluid, affecting local levels of IGF (Insulin like growth factor)s, and may produce improved ovarian stimulation. Metformin is used in PCOS cases in order to decrease plasma luteinizing hormone (LH), hyperinsulinemia, and ovarian androgen levels. Metformin increases the ovulatory rate, cervical scores and pregnancy rate. This review article focuses on the combined effect of metformin administration in PCOS patients.
Keywords: Hyperinsulinemia, metformin, polycystic ovary syndrome
|How to cite this article:|
Ganesan D, Palaniswamy S, Palanisamy P, Ponnusha BS, Athimoolam A. Effect of metformin combined therapy in patients with polycystic ovary syndrome. Int J Nutr Pharmacol Neurol Dis 2011;1:116-25
|How to cite this URL:|
Ganesan D, Palaniswamy S, Palanisamy P, Ponnusha BS, Athimoolam A. Effect of metformin combined therapy in patients with polycystic ovary syndrome. Int J Nutr Pharmacol Neurol Dis [serial online] 2011 [cited 2019 Dec 8];1:116-25. Available from: http://www.ijnpnd.com/text.asp?2011/1/2/116/84201
| Introduction|| |
The polycystic ovary syndrome (PCOS) is a common endocrine metabolic disorder that occurs in about 7% women of reproductive age. Chronic anovulation, hyperandrogenism, and insulin resistance (IR) are the main characteristics of this multifaceted syndrome. Although currently large, prospective clinical trials evaluating the morbidity and mortality for cardiovascular disease (CVD) in PCOS patients are not available, several investigators ,,,,,,,, reported alterations in intermediate end points for CVD risk in this population. In addition, different factors may coexist in PCOS patients, such as obesity, arterial hypertension, impaired glucose tolerance and/or type 2 diabetes mellitus (DM), hyperinsulinemia, dyslipidemia, and coagulation disorders, which per se could increase the risk for CVD in these subjects.
PCOS is a common hormonal condition in women and is associated with IR, disorders of weight and metabolism, hyperandrogenism, anovulation, infertility, and menstrual irregularities. Its etiology is uncertain, but current theories emphasize genetic and intrauterine origins coupled with environmental factors such as diet and altered lifestyle patterns. Effective treatment of PCOS remains controversial but needs to be based on the main requirements of the patient, depending on whether they are seeking cosmetic improvement, restoration of menstrual function, fertility, weight loss, or amelioration of metabolic changes. In recent years, so-called insulin-sensitizing agents such as metformin have found wide usage in PCOS, based on the relationship between hyperinsulinism and ovarian hyperandrogenism. The introduction of these agents has led to questioning of established therapeutic pathways for ovulation induction, which have been based on clomiphene citrate and gonadotropins such as follicle stimulating hormone (FSH). Much has been written about the value of laparoscopic ovarian drilling whereby diathermy or application of laser surgery to the ovary leads to enhanced ovulation, reduction in testosterone, and increased live birth rates. Although the procedure is less damaging to the ovary than wedge resection, concern has been expressed that adhesions may form that convert an ovulatory infertility into tubal obstruction. Nevertheless, there is widespread use of this procedure by gynecologists who either plan a laparoscopy to perform ovarian drilling or operate on polycystic ovaries that are discovered incidentally at laparoscopic surgery. ,,
PCOS is a common and heterogeneous disorder of women of reproductive age, characterized by hyperandrogenism and chronic anovulation. The pathogenesis of PCOS is still largely unknown, and until now medical care of these subjects has been limited to symptomatic control of cosmetic concerns, menstrual dysfunction, and infertility. Women with the syndrome are frequently insulin resistant, independent of obesity. In this regard, several data support the hypothesis that IR and the associated hyperinsulinemia play a pathogenetic role in PCOS. Insulin has direct effects on ovarian steroidogenesis in vitro, stimulating androgen synthesis in thecal cells. It also decreases synthesis of serum sex hormone binding globulin in the liver, increasing free androgen levels. Furthermore, in vivo studies suggest a potentiation by hyperinsulinemia of adrenocorticotropic hormone (ACTH)-stimulated adrenal androgen secretion. All these effects of insulin may contribute to the androgen excess in women with PCOS. Consistently, decreasing insulin secretion by diazoxide or somatostatin in these subjects has resulted in concurrent reductions of serum androgens.
The PCOS is defined as the presence of both ovulatory dysfunction and hyperandrogenism. In women with PCOS, oligo- or anovulation manifests itself as irregular cycles with oligo- or amenorrhea. Hyperandrogenism can be identified by physical examination, i.e., the presence of hirsutism, or by laboratory tests that demonstrate an elevated circulating concentration of a major androgen, i.e., free testosterone, total testosterone, and/or androstenedione. A third criterion for the diagnosis of PCOS is to exclude other causes of hyperandrogenism, such as nonclassic adrenal hyperplasia resulting from a 21-hydroxylase defect or an androgen-producing adrenal or ovarian tumor. PCOS occurs in approximately 5-7% of women of reproductive age. This makes PCOS the most common endocrinopathy of women. ,,,,,,,,,,,,
Women with PCOS have both abnormally elevated luteinizing hormone (LH) secretion and hyperinsulinemia as a result of IR. The combination of hypersecretion of LH and insulin causes ovarian androgen overproduction. In turn, ovarian androgen overproduction causes hirsutism and prevents normal ovarian follicle growth, preventing regular ovulation. PCOS can be treated by lowering LH hypersecretion [oral contraceptive pills or gonadotropin releasing hormone (GnRH) agonist analogues] or by reversing the hyperinsulinemia that is caused by IR (weight loss or metformin). An intriguing idea is to use oral contraceptives plus metformin in combination to simultaneously attack the two principal causes of PCOS: hypersecretion of LH and insulin.
Several insulin-sensitizing agents have been demonstrated to improve IR and reduce the circulating insulin levels in women with PCOS. Among these, metformin cloridrate, a biguanide class drug used in patients with type 2 DM, has been recognized to ameliorate IR, hyperinsulinemia, and hyperandrogenism in women with PCOS.
However, to date, there are less data available regarding the effect of metformin administration on the endothelium in PCOS. The aim of the present pilot study was to evaluate the effectiveness of metformin treatment on endothelial structure and function in a group of women with PCOS.
Metformin is currently being used to induce ovulation in women with PCOS. Metformin is an insulin-sensitizing drug originally used in the treatment of diabetes. Metformin "reverses" IR (hyperinsulinemia), thus effectively treating many diabetics.
Up to 40-70% of patients with PCOS have hyperinsulinemia which leads to excess androgen (male hormones) production by the ovaries and increased production of LH by the pituitary. The body tries to compensate for IR by the "over production" of insulin. Increased LH levels cause further elevations in androgens. Clinically, this results in ovulatory irregularities (or anovulation), increased body hair, numerous small ovarian cysts, and a classic "pear-shaped" body appearance (obesity; although not always) and long-term negative health consequences such as diabetes. ,,,,,,,,,,,
Metformin sensitizes the cells to insulin, thus lowering the body's production of insulin and consequently reducing androgen production. Once androgen production has been normalized, ovulation can often resume. Metformin is dosed at 500 mg three times per day and clomid or FSH may be added if ovulation is not established.
Numerous studies indicate that metformin as the sole therapy is often effective in establishing ovulation in PCOS patients. Metformin is not without side effects and nausea is one of the most frequent.
PCOS patients usually have exaggerated responses to medications such as FSH. Given the complexity of the disease, its potential long-term consequences, and difficulty in treating, PCOS patients should seek the advice of a reproductive endocrinologist.
| Metformin : A Novel Drug for Polycystic Ovarian Syndrome|| |
Metformin is a drug that has been used to help control blood glucose levels in people with type 2 diabetes [Figure 1].  Although Glucophage has been used in Europe for over 25 years, it was not available in the US until 1995. The Food and Drug Administration (FDA) has approved metformin only for the treatment of type 2 diabetes. Consequently, some physicians do not have much clinical experience with Glucophage or are reluctant to use it unless the patient has diabetes.
|Figure 1: Summary of a targeted approach to therapy in polycystic ovary syndrome (PCOS) anti-A-antiandrogens, MF-metformin, OCP-oral contraceptive pill|
Click here to view
Metformin appears to work in three ways. First, it decreases the absorption of dietary carbohydrates through the intestines.
Second, it reduces the production of glucose by the liver. The liver uses the raw material in our food to create a reserve supply of blood sugar. When the body experiences stress, the liver releases the reserve glucose to supply the brain and muscles with an immediate source of energy to cope with the stress. Glucophage suppresses the production of this reserve fuel.
Third, and perhaps most importantly, metformin increases the sensitivity of muscle cells to insulin. Insulin is the hormone that delivers glucose to our cells to be burned as a fuel, or stored. Women with PCOS frequently have "insulin resistance", a condition where excessive amounts of insulin are required in order to get blood glucose moved into cells, where it belongs. Glucophage helps the body to transport glucose with relatively less insulin, thus lowering the insulin levels. Chronically high levels of either glucose or insulin in the blood contribute to obesity, heart disease, infertility, and certain cancers, as well as the development of diabetes.
Metformin is available in three different forms:
- Generic Metformin HCl
- Glucophage (brand name)
- Glucophage XR (brand name)
Glucophage is available in 500 mg, 850 mg, or 1000 mg tablets. The usual dose is 850-1000 mg twice daily. The maximum safe dose is thought to be 850 mg three times daily. To minimize gastrointestinal (GI) upset or diarrhea, it is recommended to start with a low dosage and work your way up to the recommended dose.
Glucophage XR, an extended-release version of Glucophage, allows the patients to take only one dose a day. The slower release of long-acting Glucophage XR may help to reduce stomach upset that may occur with the regular Glucophage or metformin.
Glucophage is chemically identical to generic metformin; thus, using generic metformin is cost-effective.
Metformin is a biguanide derivative with insulin-synthesizing effect. In non-insulin DM cases, it exerts its effect by inhibiting glycogenesis in the liver, decreasing intestinal absorption, and by stimulating peripheral use of glucose. Metformin increases the number of insulin receptors, but does not affect insulin concentration. Thus, it does not lead to hypoglycemia in normoglycemic cases. Metformin is used in PCOS cases in order to decrease plasma LH, hyperinsulinemia, and ovarian androgen levels. Metformin increases the ovulatory rate, cervical scores and pregnancy rate.
Metformin decreases fasting glucose level by decreasing hepatic glucose output. Its use in PCOS patients corrects the response to oral glucose tolerance, thus decreasing insulin level. Cytochrome P450-C17a, which is a key enzyme in androgen synthesis, has an increased activity in PCOS patients due to increased levels of insulin. Metformin decreases the activity of this enzyme, thus increasing the response to ovulation induction.
These observations suggest that insulin-sensitizing agents, such as metformin ortroglitazone, should be tested for the treatment of PCOS. These drugs improve insulin sensitivity by different mechanisms, thus causing a subsequent reduction in plasma insulin levels. Recently, some short-term studies supported this hypothesis, reporting significant reductions of serum androgens in women with PCOS given either metformin or troglitazone. Interestingly, improvements in reproductive abnormalities of these patients have also been reported in some of these studies.
Treatment with the insulin-sensitizing agent, metformin, is effective in many women with PCOS, independent of changes in body weight, in attenuating IR and hyperandrogenemia and in reversing menstrual abnormalities and chronic anovulation. Insulin-sensitizing agents may prove to be an efficacious therapeutic tool in a large subset of subjects with this common disease.
Metformin may lower the androgen level in follicular fluid, affecting local levels of IGFs, and may produce improved ovarian stimulation. Additionally, it leads to a decrease in hyperstimulation risk, number of cycle cancellations, and of multiple pregnancy rates. Metformin is a supportive agent in the management of PCOS patients due to absence of teratogenic effects, lack of use during embryogenesis period, its cost-effectiveness, and tolerable side effects. ,,,,,
| Benefits of Metformin (Glucophage)|| |
Lowering of insulin, testosterone, and glucose levels
Quite a number of studies indicate that Glucophage reduces insulin, testosterone and glucose levels, which in turn reduces acne, hirsutism, abdominal obesity, amenorrhea and other symptoms.
Prevention or delay of onset of diabetes
Glucophage may help to prevent diabetes, according to a study conducted at George Washington University. In this study, 3234 non-diabetics with elevated blood glucose were given metformin, placebo, or lifestyle recommendations. The incidence of diabetes in the metformin group was 31% lesser than in the placebo group.
Restoration of normal menstrual cycle
A number of studies have shown that menstruation can be restored in many women with PCOS. For example, in a study at Jewish Hospital in Cincinnati, 43 women who were not having periods took Glucophage, and 39 of them resumed normal menses. In another study at Jewish Hospital, 11 teenage girls with PCOS were put on metformin and a high-protein, low-carbohydrate diet. Ten of the 11 girls resumed regular periods.
Improved chance of pregnancy
A study of 48 women with PCOS and infertility was conducted at the Baylor College of Medicine. They were first given metformin and 19 of them resumed menses and showed indications of ovulation. But 10 required clomiphene (a fertility drug) in addition to metformin in order to show evidence of ovulation. Twenty of the 48 (42%) women became pregnant. However, 7 of the 20 miscarried.
Reduced risk of miscarriage
Another aspect of PCOS-related infertility is the tendency for repeated miscarriages. A study from the Hospital de Clinicas Caracas in Venezuela looked at 65 women who received Glucophage during their pregnancies versus 31 who did not. The early pregnancy (first trimester) loss rate in the metformin group was 8.8% as compared to a 41.9% loss in the untreated group. Of those women who previously had miscarried, 11.1% of the metformin group miscarried again, while 58.3% of the untreated group again miscarried. ,,,,,,2,,,,
| Risks and Side Effects of Metformin/Glucophage|| |
10-25% of women who take Glucophage just do not feel well. They experience a general malaise, fatigue and occasional achiness that lasts for varying lengths of time. Malaise is a signal for the physician to closely monitor body systems affected by metformin, including liver, kidneys, and GI tract. A blood count should be taken from time to time because metformin can induce B vitamin insufficiencies that can lead to a form of anemia.
About one-third of women on metformin experience GI disturbances, including nausea, occasional vomiting and loose, more frequent bowel movements, or diarrhea. This problem occurs more often after meals rich in fats or sugars. The symptoms lessen over time; so, if the GI upset can be tolerated for a few weeks, it may go away. Starting with a very low dose and gradually increasing it has helped some women.
Vitamin B12 malabsorption
Of patients who take this drug, 10-30% show evidence of reduced vitamin B12 absorption. A substance formed in the stomach called "intrinsic factor" combines with B12 so that it can be transferred into the blood. Metformin interferes with the ability of the cells to absorb this intrinsic factor-vitamin B12 complex.
Over long term, vitamin B12 insufficiency is a significant health risk. B12 is essential for the proper growth and function of every cell in our body. It is required for the synthesis of DNA and for many crucial biochemical functions. There is also a link between B12 insufficiency and CVD.
At least one study raises the concern that even if metformin is withdrawn, the vitamin B12 malabsorption may continue in some people. The apparent cause is continued problems with availability of intrinsic factor, which is required for B12 absorption.
People who take Glucophage tend to have higher homocysteine levels. Women with PCOS also tend to have elevated homocysteine.
Homocysteine is an amino acid in the blood. A normal amount is desirable. But an elevated level means that the metabolic processes are not working properly in the body. Elevated homocysteine is associated with coronary artery disease, heart attack, chronic fatigue, fibromyalgia, cognitive impairment, and cervical cancer.
Vitamin B12, along with vitamin B6 and folic acid (another B vitamin), is responsible for metabolizing homocysteine into less potentially harmful substances. Therefore, when metformin reduces the absorption of vitamin B12, one of the nutrients needed to reduce homocysteine is lost and thus the risk of CVD is reduced. ,,,,,
Elevated homocysteine and pregnancy complications
Pre-eclampsia is a complication of pregnancy characterized by increasing blood pressure and edema. If left untreated, pre-eclampsia can lead to eclampsia, a serious condition that puts the mother and baby at risk. In a study conducted at the Center for Perinatal Studies at Swedish Medical Center in Seattle, a second trimester elevation of homocysteine was associated with a 3.2-fold increased risk of pre-eclampsia.
The Department of Obstetrics and Gynecology, Nijmegen, The Netherlands, reviewed a series of studies on the linkage between elevated homocysteine and early pregnancy loss. They concluded that high homocysteine levels are a risk factor for recurrent early pregnancy loss.
Ovarian follicular fluid contains detectable amounts of homocysteine along with B12, B6, and folic acid. The follicular fluid provides nourishment to the egg by facilitating transport of nutrients from blood plasma. High levels of homocysteine as well as an insufficiency of B vitamins may adversely influence the process of fertilization and early fetal development.
Many women use metformin in their pursuit of a successful pregnancy. However, Glucophage is a category B drug, meaning its safety for use while pregnant has not been established. It is found in breast milk, so it is not advisable to breastfeed while taking Glucophage.
By preventing optimal absorption of vitamin B12 and folic acid, metformin could induce or contribute to megaloblastic anemia. Megaloblastic anemia occurs when the bone marrow does not have enough B vitamins to manufacture red blood cells. The bone marrow then releases immature and dysfunctional red blood cells into the circulation.
Although anemia is not common among people taking metformin, it remains a risk for those whose B12 and folic acid levels were already low when metformin therapy was started.
Liver or kidney problems
If there are liver or kidney problems of any kind, metformin could pose a problem because it alters liver function and is excreted through the kidneys. A healthy liver and kidneys will improve the outcome with metformin. Liver and kidney function should be assessed before starting metformin and rechecked at least once a year while taking it. A blood chemistry screen and a complete blood count would tell the physician how well the patient's system is doing with this drug.
The patient may be at risk for health problems or symptoms if metformin is taken in addition to other medications. The more drugs the patient takes, and the higher the dosage, the greater the probability that there will be some kind of interaction between the drugs or some unexpected effect from the combined drugs. The effect of combined drugs also depends on the state of the patient's health, their genetic uniqueness, and their diet and lifestyle. The doctor has to be consulted always if any medication is added or changed, or if there is development of any symptom.
Metformin may contribute to male pattern hair loss at the temples and top of head. Although there is nothing in the medical literature to support this linkage, some women have reported that hair loss became worse with metformin.
About 3 of every 100,000 people who take metformin develop a medical emergency called "lactic acidosis". Lactic acid is a metabolic byproduct that can become toxic if it builds up faster than it is neutralized. Lactic acidosis is most likely to occur in people who with diabetes, kidney or liver disease, multiple medications, dehydration, or severe chronic stress.
Lactic acidosis can gradually build up. Symptoms to watch for include a need to breathe deeply and more rapidly, a slow, irregular pulse, a feeling of weakness, muscle pain, sleepiness, and a sense of feeling very sick. Treatment requires intravenous administration of sodium bicarbonate. The doctor has to be consulted or a visit to the hospital emergency room is a must if these symptoms are present.
Bile is produced by the liver, stored in the gallbladder, and secreted into the intestines in order to absorb fats into the bloodstream. One possible reason for the GI problems is that metformin reduces normal reabsorption of bile from the intestines back into the bloodstream, which causes elevated bile salt concentrations in the colon. Most studies suggest that colonic bile salts cause free radical damage to DNA and may contribute to colon cancer.
In addition, bile acids may stimulate cells in the colon to produce leukotriene B4 (LTB4), a highly inflammatory substance. LTB4 would be a contributor to any intestinal inflammatory condition. Products of bacterial action on bile salts may lead to intestinal cell damage and absorption of "foreign" molecules such as food or bacteria particles into the bloodstream, possibly causing allergies and other immune responses.
Moreover, many PCOS women switch to a high-protein diet. If the protein consists of beef and other meats, bile acid concentration in the intestines increases. A diet high in meats is also linked to a higher risk of colon cancer.
In about 25% of women, Glucophage causes side effects which may include abdominal discomfort, cramping, diarrhea and nausea. The side effects may be severe enough to make the woman stop the Glucophage medication. We are not aware of any serious complications resulting from Glucophage treatment.
Another oral medication used for diabetes called Troglitazone has been associated with liver failure and death in rare cases. This has been publicized on television shows, in newspapers, etc. These problems have not been associated with the use of metformin for PCOS.
The most common side effects of metformin are diarrhea, nausea or vomiting, flatulence, indigestion, and abdominal discomfort. In one clinical trial of metformin at a dose of 2250 mg daily, diarrhea was reported in 53% of the patients taking metformin and 12% of patients taking placebo. In the same study, nausea or vomiting was reported in 26% of those taking metformin and 8% of those taking placebo. However, only about 5% of patients discontinued the medication because of side effects.
A rare problem caused by metformin is lactic acidosis, which is fatal in as many as 30-50% of cases. Metformin is excreted by the kidney and the risk of metformin-induced lactic acidosis is increased when patients have renal insufficiency (creatinine > 1.4 mg/dl). Before initiating metformin treatment, it should be ensured that serum creatinine level is <1.4 mg/dl. In addition, women with conditions that increase the risk of lactic acidosis, such as congestive heart failure or sepsis, should not be prescribed metformin. Other contraindications to the use of metformin are concurrent liver disease and a previous history of lactic acidosis. Metformin therapy should be temporarily suspended for all major surgical procedures that entail restriction of fluid intake. Metformin should not be restarted until normal fluid intake has resumed and renal function has been shown to be normal. ,,,
| Treatment Process for Taking Metformin|| |
Laboratory (blood) tests that are sometimes done before starting metformin
LH, FSH, estradiol, 5-dehydroepiandrosterone (DHEAS), testosterone, 17-hydroxypregesterone (17-OHP), prolactin, thyroid stimulating hormone (TSH), kidney function tests [blood urea nitrogen (BUN), creatinine] and liver function tests [aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH)].
Some doctors do fasting blood sugar and fasting insulin levels in order to calculate a fasting glucose to insulin ratio. This is a measure of IR, which is present in some women with PCOD.
When to have intercourse
- Patients need to be counseled regarding possibility of ovulation occurring and need for regular intercourse (about every 2-3 days) in order to maximize the chances for pregnancy.
- Women should keep menstrual calendars, recording days of menstrual bleeding and intercourse.
Treat polycystic ovarian syndrome with Glucophage/metformin alone
Metformin dosing and protocol
Metformin is taken in a dose that the woman can tolerate. Most people can tolerate 500 mg three times daily, if they build up to that dose gradually [Figure 1].
We start metformin at 500 mg once daily, increase to 500 mg twice a day after 1 week, then to 500 mg three times daily after another week.
- If the three times daily dose cannot be tolerated due to side effects, we remain on the twice-daily dose.
- The most effective dose of Glucophage for PCOS is generally 500 mg three times daily.
Add clomiphene to metformin treatment regimen
If the metformin does not result in ovulation and regular periods, the next step often followed is adding clomiphene to the regimen [Figure 2]. 
|Figure 2: A cost-effective and evidence-based approach to the anovulatory woman with PCOS, seeking to become pregnant|
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- Treatment with Clomid and Metformin Together for PCOS
Other treatment options
If the combination of metformin and clomiphene does not result in ovulation, then we move on to other options.  We usually proceed with one of the following treatments to achieve pregnancy:
- Injectable FSH hormone for PCOS treatment
- IVF treatment for PCOS
- Femara (letrozole) for PCOS treatment
Combined therapy with clomiphene citrate and letrazole
Adding metformin to clomiphene citrate in clomiphene-resistant PCOS patients increases ovulatory response. However, because of anti-estrogenic effects of clomiphene, it may be associated with lower pregnancy rate, offsetting the ovulation rate benefit. Letrozole is an aromatase inhibitor which induces ovulation without anti-estrogenic effects.
Studies have been conducted to compare the combined effects of metformin-clomiphene citrate and metformin-letrozole on ovulation and better pregnancy rate in South Indian women patients with PCOS. All patients between the age of 27 and 37 years who attended an infertility clinic with a suspicion of PCOS (specifically complaining of infertility, menstrual dysfunction or dermatological problems) were included in the study.
The population consisted of 2000 subjects (female population) and was divided into four groups. From them, 400 patients who were screened and found to be ideal for the study were selected. The groupings were as follows: treatment of PCOS patients with metformin-clomiphene citrate drugs (PCOS-MC; n = 100); treatment of PCOS patients with metformin-letrozole drugs (PCOS-ML; n = 100); untreated PCOS patients (UTPCOS; n = 100); and control subjects selected from normal healthy female patients (C; n = 100) [Figure 3]. 
|Figure 3: Demographic changes in normal women, PCOS women, PCOS women treated with metformin– clomiphene citrate and metformin– letrozole|
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The average mean levels of body weight, body mass index (BMI), hirsutism, menstrual status in control, untreated PCOS patients and in patients treated with metformin-clomiphene citrate and metformin-letrozole subjects are presented in [Table 1]. 
|Table 1: Biophysical changes in normal women, PCOS women, PCOS women treated with metformin– clomiphene citrate and metformin– letrozole|
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[Table 2]  shows that there was a significant increase in the blood glucose level,total cholestrol,and triglycerides in treated PCOS subjects as compared to control and untreated PCOS subjects,but the levels of glucose, cholestrol and triglycerides were significantly (P<0.001)decreased in metformin-letrozole group compared to metformin-clomiphene citrate group and untreated PCOS subjects, but the levels of glucose, cholesterol and triglycerides were significantly (P < 0.001) decreased in metformin-letrozole group compared to metformin-clomiphene citrate group and untreated PCOS subjects. There is no statistical significance in the level of cholestrol in both PCOS groups (treated and untreated) as compared to the control group.
|Table 2: Biochemical and hormonal changes in normal women, PCOS women, PCOS women treated with metformin– clomiphene citrate and metformin– letrozole|
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The secondary outcome of the ovulatory induction of the present study is presented in [Table 3].  Ovulation occurred in 32 patients (64%) of metformin-letrozole group and in 16 patients (32%) of metformin-clomiphene citrate group, which showed a statistically significant difference (P < 0.05).
|Table 3: The outcome of ovulatory induction with metformin– clomiphene citrate and metformin– letrozole|
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Studies concluded that the ovulatory rate is higher on treatment with metformin-letrozole compared with metformin-clomiphene citrate. A non-significant increase in pregnancy rate was observed in metformin-letrozole group. Miscarriage rate and multiple pregnancy rates were comparable in both the groups. Aromatase inhibitors are effective for ovulation induction or augmentation of ovulation. Also, administration of them in early follicular phase could be safe for ovulation induction. ,,,,
| Conclusions|| |
Metformin is an insulin-sensitizing drug. There seems to be a connection between insulin and the reproductive hormones. While no one is quite sure exactly how the two connect, it seems that increased insulin levels lead to increased levels of androgens, also known as the male hormones. High androgen levels lead to PCOS symptoms and problems with ovulation. Many women with PCOS have IR. IR is when the body's cells stop reacting to normal levels of insulin. They become less sensitive, or resistant. As a result, the body thinks that there is not enough insulin in the system, which triggers the production of more insulin than it really needs. In this study has reported the combined metformin treatment to improve hirsutism, induce ovulation and normalize menstrual cycle.
| References|| |
|1.||Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: A randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 2000;85:139-46. |
|2.||Pirwany IR, Yates RW, Cameron IT, Fleming R. Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea. Hum Reprod 1999;14:2963-8. |
|3.||Morin-Papunen LC, Koivunen RM, Tomas C, Ruokonen A, Martikainen HK. Decreased serum leptin concentrations during metformin therapy in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998;83:2566-8. |
|4.||Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647-54. |
|5.||Pasquali R, Gambineri A, Biscotti D. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. AM J Clin Endocrinol Metab 2000;85:2767-74. |
|6.||Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A. Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur J Endocrinol 1998;138:269-74. |
|7.||Morin-Papunen LC, Koivunen RM, Ruokonen A, Martikainen HK. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril 1998;69:691-6. |
|8.||Norman RJ. Editorial: Metformin-Comparison with Other Therapies in Ovulation Induction in Polycystic Ovary Syndrome. J Clin Endocrinol Metab 2004;89:4797-800. |
|9.||Dhanalakshmi G, Sumathi P, Pasupathi P, Ganadeban M. Comparison of Metforminclomiphine citrate and Metformin - Letrozole effect on pregnancy rate in infertile PCOS south Indian women. Int J Boil Med Res 2011;2:490-6. |
|10.||Guzick DS, Wing R, Smith D, Berga SL, Winters SJ. Endocrine consequences of weight loss in obese hyperandrogenic, anovulatory women. Fertil Steril 1994;61:598-604. |
|11.||Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: Role of insulin sensitivity and luteinising hormone. J Clin Endocrinol Metab 1999;84:1470-7. |
|12.||Clark AM, Ledger W, Galletly C, Tomlinson L, Blaney F, Wang X, et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod 1995;10:2705-12. |
|13.||Clark AM, Thornley B, Tomlinson L, Galletley C, Norman RJ. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod 1998;13:1502- 5. |
|14.||Royal College of Obstetrics and Gynaecology. Long-term consequences of polycystic ovary syndrome. London: RCOG; 2003. (Clinical Green Top Guideline No 33.) |
|15.||Harborne LR, Fleming R. A randomized study comparing dose of metformin in obese women with polycystic ovary syndrome. Fertil Steril 2002;78:S34. |
|16.||Coetzee EJ, Jackson WP. Oral hypoglycaemics in the first trimester and fetal outcome. S Afr Med J 1984;65:635-7. |
|17.||Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, Nestler JE. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:524-9. |
|18.||Sagle M, Bishop K, Ridley N, Alexander FM, Michel M, Bonney RC, et al. Recurrent early miscarriage and polycystic ovaries. BMJ 1998;297:1027-8. |
|19.||Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: A pilot study. Fertil Steril 2001;75:46-52. |
|20.||Heard MJ, Pierce A, Carson SA, Buster JE. Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome. Fertil Steril 2002;77:524-9. |
|21.||Glueck CJ, Wang P, Kobayashi S, Phillips H, Sieve-Smith L. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril 2002;77:520-5. |
|22.||NICE, 2003. Available from: http://www.nice.org.uk/pdf/Fertility_Algorithm_2nd_consultation.pdf. |
|23.||Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: A randomised, double-blind, placebo controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 2000;85:139-46. |
|24.||Fleming R, Hopkinson ZE, Wallace AM, Greer IA, Sattar N. Ovarian function and metabolic factors in women with oligomenorrhoea treated with metformin in a randomised double blind placebo-controlled trial. J Clin Endocrinol Metab 2002;87:569-74. |
|25.||De Leo V, la Marca A, Ditto A, Morgante G, Cianci A. Effects of metformin on gonadotrophin-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 1999;72:282-5. |
|26.||Yarali H, Yildiz BO, Demirol A, Zeyneloglu HB, Yigit N, Bukulmez O, et al. Co-administration of metformin during rFSH treatment in patients with clomiphene citrate-resistant polycystic ovarian syndrome: A prospective randomised trial. Hum Reprod 2004;19:41-7. |
|27.||Kumari AS, Haq A, Jayasundaram R, Abdel-Wareth LO, Al Haija SA, Alvares M. Metformin monotherapy in lean women with polycystic ovary syndrome. Reprod Biomed Online 2005;10:100-4. |
|28.||Ertunc D, Tok EC, Aktas A, Erdal EM, Dilek S. Theimportance of IRS-1 Gly972 Argpolymorphism in evaluating the response to metformin treatment in polycystic ovary syndrome. Hum Reprod 2005;20:1207-12. |
|29.||De Leo V, la Marca A, Petraglia F. Insulin-loweringagents in the management of polycystic ovary syndrome. Endocr Rev 2003;24:633- 67. |
|30.||Ganie MA, Khurana ML, Eunice M, Gupta N, Gulati M, Dwivedi SN, et al. Comparison of efficacy ofspironolactone with metformin in the management ofpolycystic ovary syndrome: An open-labeled study. J ClinEndocrinol Metab 2004;89:2756-62. |
|31.||Mansfield R, Galea R, Brincat M, Hole D, Mason H. Metformin has direct effects on human ovarian steroidogenesis. Fertil Steril 2003;79:956-62. |
|32.||Harborne LR, Sattar N, Norman JE, Fleming R. Metformin and weight loss in obese women with polycystic ovary syndrome: Comparison of doses. J Clin Endocrinol Metab 2005;90:4593-8. |
|33.||Arslanian SA, Lewy V, Danadian K, Saad R. Metformintherapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance: Amelioration of exaggerated adrenal response to adrenocorticotropin with reduction of insulinemia/insulin resistance. J Clin Endocrinol Metab 2002;87:1555-9. |
|34.||Gambineri A, Pelusi C, Genghini S, Morselli-Labate AM, Cacciari M, Pagotto U, et al. Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2004;60:241-9. |
|35.||Wang HS, Chard T. IGFs and IGF-binding proteins in the regulation of human ovarian and endometrial function. J Endocrinol 1999;161:1-13. |
|36.||Genazzani AD, Battaglia C, Malavasi B, Strucchi C, Tortolani F, Gamba O. Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Fertil Steril 2004;81:114-9. |
|37.||Kashyap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome. Hum Reprod 2004;19:2474-83. |
|38.||Weerakiet S, Tingthanatikul Y, Sophonsritsuk A, Choktanasiri W, Wansumrith S, Rojanasakul A. Efficacy of metformin on ovulation induction in Asian women with polycystic ovary syndrome. Gynecol Endocrinol 2004;19:202-7. |
|39.||Palomba S, Orio F Jr, Falbo A, Manguso F, Russo T, Cascella T, et al. Prospective parallel randomized double-blind double dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in non-obese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:4068-74. |
|40.||Dunaif A. Insulin resistance in women with polycystic ovary syndrome. Fertil Steril 2006;86 (Suppl 1):S13-4. |
|41.||Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A. Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur J Endocrinol 1998;138:269-74. |
|42.||Dor J, Seidman DS, Ben-Shlomo I, Levran D, Karasik A, Mashiach S. The prognostic importance of the number of oocytes retrieved and estradiol levels in poor and normal responders in in vitro fertilization (IVF) treatment. J Assist Reprod Genet 1992;9:228-32. |
|43.||Dunaif A. Insulin resistance and ovarian hyper androgenism. Endocrinologist 1992;2:248-60. |
|44.||Fisher SA, Reid RL, Van Vugt DA, Casper RF. A randomized double-blind comparison of the eVects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril 2002;78:280-5. |
|45.||Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001;75:305-9. |
|46.||Al-Fozan H, Al-Khadouri M, Tan SL, Tulandi T. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril 2004;82:1561-3. |
|47.||Carmina E, Azziz R. Diagnosis, phenotype, and prevalence of polycystic ovary syndrome. Fertil Steril 2006;86:S7-8. |
|48.||Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19-25. |
|49.||Bayar U, Basaran M, Kiran S, Coskun A, Gezer S. Use of an aromatase inhibitor in patients with polycystic ovary syndrome: A prospective randomized trial. Fertil Steril 2006;86:1447-51. |
|50.||Harborne L, Fleming R, Lyall H, Norman J, Sattar N. Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome. Lancet 2003;361:1894-901. |
|51.||Evanthia DK, Charikleia D, Eleni KA, Frangiskos NE. Metformin: An old medication of new fashion: Evolving newmolecular mechanism and clinical implications in polycysticovary syndrome. Eur J Endocrinol 2010;162:193-212. |
|52.||Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril 2001;75:669-73. |
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]