Polycystic ovary syndrome (PCOS) is a prevalent endocrinological disorder characterized by anovulation, hyperandrogenism, and infertility, significantly impacting women of reproductive age. This syndrome, affecting approximately 4% to 12% of women, is a leading cause of infertility. Metformin, traditionally used to manage Type 2 diabetes, has emerged as a valuable tool in PCOS management, addressing insulin resistance and associated hormonal imbalances. This article delves into the appropriate metformin dosage for PCOS, its mechanisms of action, benefits, potential side effects, and overall role in managing this complex condition.
Understanding PCOS
PCOS is characterized by a combination of oligomenorrhea or anovulation with hyperandrogenism. This neuroendocrine abnormality may be caused by elevated luteinizing hormone (LH) levels and more frequent pulses of LH secretion. Women with hyperandrogenism also have increased insulin resistance (IR), which manifests as increased body mass index (BMI), increased waist-to-hip ratio or, in severe cases, acanthosis nigricans. The combination of severe insulin resistance and LH stimulation results in increased ovarian secretion of testosterone, leading to the virilizing features of PCOS. The syndrome should be suspected in women with hirsutism, irregular menstruation, or infertility. Traditional treatment involves the use of clomiphene therapy and weight loss for sub-fertility, and combination oral contraceptives plus spironolactone for hirsutism.
The clinical characteristics of PCOS include menstrual irregularity with associated anovulatory infertility and hyperandrogenism. Over time, it became obvious that the syndrome was quite heterogeneous with a wide clinical spectrum. It is considered a syndrome, not a disease. A significant association between the level of insulin and testosterone was observed in PCOS. It was obvious that IR is a popular feature of the disorder and is not relevant to obesity. Approximately 50%-70% of PCOS women have IR, which has a critical role in PCOS pathogenesis.
PCOS has a significant negative effect on the body's physiology and metabolism because it can develop into a metabolic syndrome (MS) with IR, hyperinsulinemia, hypertension, dyslipidemia, and abdominal obesity. Women with polycystic ovaries have been proven to have a high incidence of spontaneous abortions in the first trimester (25%-73%). It is noted that 81% of women with frequent fetal loss have defects in LH secretion, and among those with recurrent miscarriages, both with and without PCOS elevated androgen levels have been reported. One of the most common metabolic abnormalities in PCOS patients is IR (71%) followed by obesity (52%) and dyslipidemia (46.3%), with an incidence of 31.5% for MS.
Metformin: Mechanism of Action and Benefits in PCOS
Metformin, also called dimethyl biguanide, is an oral antidiabetic drug. It helps restore insulin response in the body, and also it decreases the amount of liver glucose production that the intestines or stomach can absorb. The benefits of metformin on insulin sensitivity have been shown in women with PCOS who are not DM.
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Metformin's principal clinical function is to inhibit the production of hepatic glucose, increasing insulin sensitivity in peripheral tissues and decreasing intestinal glucose uptake. Metformin also results in the reduction of fasting serum insulin (thus the risk of hypoglycemia is minimal) by about 40% and leads to a reduction in the mean weight by 5.8%. Additionally, it inhibits mitochondrial respiratory chain complex I (mitochondrial stress) by interfering with cellular respiration, which imitates a cell starvation condition by decreasing intracellular ATP. The activation of AMPK also results in a reduction in the activity of acetyl-CoA carboxylase (ACC) which in turn reduces oxidation of fatty acids and suppresses lipogenic enzymes. Suppression of fatty acid oxidation results in decreased hypertriglyceridemia, thus reducing the availability of energy for gluconeogenesis. This is linked with increased clearance of very low-density lipoprotein (VLDL) and decreased synthesis.
Many studies showed that metformin, when used to treat PCOS, significantly reduced serum androgen levels, improved insulin sensitivity, restored menstrual cyclicity, and was successful in triggering ovulation. As a result, metformin may be useful in treating PCOS-related infertility. The use of metformin is related to ovulation and increased menstrual cyclicity, in women with PCOS.
Metformin can improve insulin sensitivity, lower insulin levels, and address insulin resistance in PCOS. It may also reduce serum androgen levels, help regulate menstrual cycles, and stimulate ovulation. While metformin can aid with infertility by helping women with PCOS conceive, it is not the first choice for those having difficulty getting pregnant. In such cases, medications like letrozole or clomiphene are usually more effective.
Recommended Metformin Dosage for PCOS
According to the Prescriber’s Digital Reference (PDR), a typical dose of metformin for PCOS is 500 mg by mouth three times a day. However, doses may range from 500 mg per day to 3,000 mg per day. The dosage provided above is for metformin’s immediate-release (IR) formulation. There is also a once-daily extended-release (ER) formulation of metformin, which may be prescribed for patients who experience stomach problems with the immediate-release (IR) formulation-or for various other reasons.
The general recommended dose of metformin for PCOS is 500 mg three times daily. However, healthcare providers often start with a lower dose to help the body adjust to the medication and minimize side effects. This gradual approach allows patients to build up to the recommended dose of 500 mg three times a day. It’s important to note that the exact dose may vary based on individual needs and responses to the medication.
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Doses ranging from 500 to 3000 mg/day are used and the most common dosage regimens are about 500 mg three times daily or 850 mg twice daily.
A study examined different dose regimes in polycystic ovary syndrome (PCOS):
- A: 500 mg twice a day (1000 mg)
- B: 500 mg three times a day (1500 mg)
- C: 850 mg twice a day (1700 mg)
The authors concluded that "… results from our study seem to indicate that the effects of metformin treatment in PCOS are independent of the administered dose. Different anthropometrical and metabolic characteristics do not give grounds for an adjustment of the dose of the drug. Hence, since metformin efficacy in PCOS seems not to be dose related, while side effects are, low dosages should be preferred in the clinical practice."
Titration of Metformin
Titration schedules for metformin with women with side effects should have a slower titration to a target dose of 1g twice daily of metformin.
Slow route (in women with side effects) as:
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- Week 1 - 250mg once a day
- Week 2 - 250mg twice a day
- Week 3 - 250mg three times a day
- Week 4 - 500mg twice a day
- Week 5 - 500mg three times a day
- Week 6 - 1g twice a day
Important Considerations
- Individualized Treatment: The exact metformin dose may vary based on individual needs and responses to the medication.
- Gastrointestinal Side Effects: Because of the gastrointestinal side effects of metformin, the usual starting dosage is 500 mg taken with the largest meal of the day. If tolerated, the dosage is gradually increased to 500 mg with each meal.
- Weight Loss: Metformin also is effective in achieving weight loss in women with PCOS. It potentiates the low-calorie diets typically used to achieve the BMI of 20 to 25 kg per m2 that is necessary for the return of ovulation. The weight loss action of metformin appears to be caused by the reduction in insulin resistance as well as by appetite suppression.
- Menstrual Regularity and Ovulation: The effects of metformin on menstrual function and infertility may be caused by decreased insulin resistance and lowered testosterone levels. Four to six months of therapy are thought to be necessary for ovulation to commence. In studies of women who were treated for at least six months report that more than 90 percent of women resumed regular menstruation.
- Combination Therapy: Using clomiphene and metformin together can be beneficial for the women with polycystic ovarian syndrome. If the combination of metformin and clomiphene does not result in ovulation then we move on to other options.
Side Effects and Precautions
The most common side effects of metformin therapy are related to the stomach and intestines and include nausea, vomiting, diarrhea, gas, indigestion, and stomach discomfort. Serious side effects may also occur, requiring emergency or urgent medical care.
About one fourth of women taking metformin have gastrointestinal side effects such as abdominal discomfort, diarrhea and nausea. 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. In studies, about 5 percent of patients discontinued metformin therapy because of side effects, but more than one half of patients reported diarrhea, and one fourth experienced other gastrointestinal upsets.
A rare but potentially serious side effect is lactic acidosis in patients with renal insufficiency.
- Take metformin exactly as directed by your healthcare provider.
- Take metformin with meals.
- Follow any dietary, exercise, and lifestyle recommendations your healthcare professional provides, especially if obesity is a medical concern.
- Avoid drinking alcohol during the use of metformin.
- Ask your healthcare provider about checking your blood sugar levels, as metformin lowers blood sugar.
- For the liquid form of metformin, use a medicine-measuring device to ensure accurate dosing.
- If you miss a metformin dose, take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and return to your regular dosing schedule.
Metformin and Pregnancy
Metformin seems to be safe in pregnancy, while customary advice is to avoid it once pregnancy occurs. Treatment with metformin should be stopped once pregnancy is confirmed, whether used as a first-line treatment or in women who are clomifene-resistant, as it is not authorized for use in pregnancy. However, there is no evidence of metformin teratogenicity in animal or human fetuses. For instance, pregnant women with type 2 diabetes mellitus who were treated with metformin showed no rise. There was evidence that supported that metformin can reduce miscarriage rates. In a retrospective study that included many women with polycystic ovaries, metformin was proven to reduce spontaneous miscarriages in the first trimester; the reduction in the risk of gestational diabetes in women with PCOS has also been shown in metformin therapy.