The evidence supporting these recommendations and current clinical practice [ 1 , 2 ] are mainly provided from short term studies and meta-analysis designed from 3 up to 12 months [ 9 , 10 ]. Long-term studies are very limited [ 3 , 9 , 11 , 12 ].
The longest 10 year-retrospective study demonstrated that metformin treatment of overweight-obese women with PCOS resulted in reduction and stabilization of weight, improvements of menstrual function and androgen profile and in low conversion rate to diabetes [ 13 ]. Given the lack of long term data, it is not known whether metformin should be considered as a symptomatic or as a curative therapy.
It is also not clear for how long metformin should be prescribed or whether there is any treatment legacy effects after its suspension. Prior to inclusion, short-term ST group had been treated with metformin for 1 year 1. The rationale behind selecting the treatment time in ST and LT groups was based on previous observations that the most meaningful effect of metformin has been demonstrated within first year of treatment, while during the following years of treatment the improved outcomes remained stable [ 13 ].
Out of patients treated with metformin after a year at the outpatients Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, 77 were eligible for enrolment into ST group, 23 agreed to participate. Out of patients, who had been treated with metformin for over 3 years, 38 were eligible for enrolment in the LT group, 21 agreed to participate, all of them were included. The study was ongoing between March and December After inclusion, all women discontinued metformin for 6 months.
The stable LSI was advised throughout the observation period. Pregnancy was not specifically restricted. The entry data for the body weight, menstrual frequency and androgens at the beginning of metformin treatment were collected for all participants from the medical records.
At baseline and after 6 months of follow up, all patients underwent history check-up and standard anthropometric measurements: height, weight, waist circumference, blood pressure BP. A fasting blood was drawn for determination of glucose, insulin, luteinizing hormone LH , follicle-stimulating hormone FSH , androstenedione, total and free testosterone followed by a standard 75 g oral glucose tolerance test OGTT.
After 3 months of withdrawal from metformin all women came for a safety check-up visit to determine glucose homeostasis with standard OGTT.
Body weight was measured with body weight scale to the nearest 1 kg. BMI was calculated as the weight in kilograms divided by square of height in meters.
Waist circumference was measured in a standing position midway between the lower costal margin and the iliac crest. Impaired glucose tolerance IGT was identified by 2 h glucose levels between 7. Intra-assay coefficient of variation CV for androstenedione ranges from 5. Since normal BP and fasting plasma glucose within normal reference range were inclusion criteria, participants were categorized as having metabolic syndrome based only on waist circumference and dyslipidemia.
Menstrual regularity was defined as number of bleeds per 6 months using self reported menstrual intervals based on a dairy review. The instrument is a shortened and revised version of the original item TFEQ [ 20 ]. The translation of the Slovenian version had been back translated by a native English speaker and evaluated as required. The questionnaire measures three different aspects of eating behavior: cognitive restraint CR referring to conscious restriction of food intake in order to control body weight or to promote weight loss, uncontrolled eating UE referring to tendency to eat more than usual due to a loss of control over intake accompanied by subjective feelings of hunger, and emotional eating EE referring to inability to resist emotional cues.
Responses to each of the 18 items are given a score between 1 and 4 and item scores are summed up into scale scores for CR, UE, and EE [ 16 , 20 ]. Nonparametric Mann—Whitney was used to compare the distribution of continuous variables between different groups, while nonparametric Wilcoxon signed-rank test was used to compare continuous variables for related samples.
Based on average weight increase after metformin withdrawal, we were able to detect differences in weight change of 3. Four patients were lost due to drop out: two of them from ST group became pregnant, one from each group were excluded due to protocol violation. Prior the inclusion, the weight reduction was not significant in either group women from ST group lost 3 kg from 95 There was no statistically significant difference between the groups in the response to metformin treatment regarding weight reduction.
Metformin treatment increased menstrual bleeding from 4. Free testosterone and androstenedione decreased during ST metformin intervention 8. Total testosterone 2 to 0. During follow up, three patients one in ST group, two in LT group complained over poor weight control.
After they completed the study protocol, they immediately asked for re-introduction of metformin. Waist circumference did not significantly increase in either group 6 months after metformin suspension Tables 2 and 3.
At the end of observation period there was no statistically significant difference in anthropometric parameters between the groups Table 1. There were no statistically significant difference between both groups at the end of the follow up period Table 1. Five patients 2 from ST group and 3 from LT group complained over irregular menstrual cycle.
After they completed the study protocol, they immediately asked for metformin treatment. At 3-month safety check-up, none of the participants developed diabetes mellitus, therefore all patients continued with the study. After 6 months, none of them developed IGT or impaired basal glycemia or diabetes mellitus. After 6 months, additionally one woman in ST group and two women in LT group developed metabolic syndrome due to increase of serum triglyceride.
Values of assessed hormones remained stable over the study period in both groups with borderline increase of androstenedione in LT group 6. After cessation of metformin UE in the ST group increased from In LT group CR decreased from There were no significant changes in other measured aspects of eating behavior or between ST and LT groups Tables 1 , 2 and 3.
In LT users withdrawal resulted in changed eating behavior and menstrual irregularity. By contrast, waist circumference, IR, glucose homeostasis and the androgen profile, except borderline increase in androstenedione in LT group, remained stable implying some metabolic and endocrine treatment legacy of metformin in 6 month follow up.
To the best of our knowledge, this is the first study that compared consequences of metformin withdrawal on clinical, metabolic and endocrine parameters in ST and LT prior users. The amount of weight change was associated with adherence, with highly adherent patients experiencing 3. Your doctor can order a laboratory test of your vitamin B12 levels.
Hair loss or alopecia is becoming more common in women. PCOS may cause hair loss. Vitamin B12 deficiency prevents hair follicles from receiving oxygenated blood, leading to hair loss. Taking metformin for a long time can cause Vitamin B12 deficiency. If you are losing your hair or your hair is thinning, ask your doctor to test your vitamin B12 and iron levels.
Current recommendations do not support a need to discontinue metformin before a CT scan using contrast in persons with mild to moderate renal failure. If you have severe kidney impairment, you may need to discontinue metformin for the hours before the test. Your health care team will provide instructions. Metformin has been shown to improve total cholesterol, lower LDL cholesterol, the lousy or bad cholesterol and lower triglycerides fats in the blood.
Your doctor will check your kidney function before prescribing metformin. Your doctor will test your estimated glomerular filtration rate GFR.
GFR measures how effective are your kidneys in removing waste and excess fluids from your body. Metformin is contraindicated in severe reduction in GFR. Your dose depends on your. Your doctor will prescribe a lower dose and slowly increase the dose until it reaches mgmg daily. Take metformin as prescribed by your doctor. If you only take one dose, it is preferable to take it at night after your meal to decrease side effects such as nausea, bloating, or diarrhea. If you are taking 2 doses, take it after meals.
Metformin is not addictive. Diabetes is a progressive chronic condition and when metformin is no longer effective at lowering blood glucose, another medication may be added, or you may be taken off metformin completely. Metformin is excreted in the saliva causing changes in taste. Some people taking metformin report a metallic taste in their mouths. After some time, this aftertaste will disappear.
Possible side effects of metformin include nausea, vomiting, stomach pain, diarrhoea and loss of appetite. As metformin can stimulate fertility, if you're considering using it for PCOS and not trying to get pregnant, make sure you use suitable contraception if you're sexually active.
Letrozole is sometimes used to stimulate ovulation instead of clomifene. This medicine can also be used for treating breast cancer.
Use of letrozole for fertility treatment is "off-label". This means that the medicine's manufacturer has not applied for a licence for it to be used to treat PCOS. In other words, although letrozole is licensed for treating breast cancer, it does not have a license for treating PCOS. Doctors sometimes use an unlicensed medicine if they think it's likely to be effective and the benefits of treatment outweigh any associated risks.
Find out more about unlicensed and off-label use of medicines. If you're unable to get pregnant despite taking oral medicines, a different type of medicine called gonadotrophins may be recommended. These are given by injection. There's a higher risk that they may overstimulate your ovaries and lead to multiple pregnancies. Medicines to control excessive hair growth hirsutism and hair loss alopecia include:. If you have ongoing digestive issues, your healthcare provider may switch you to the extended-release version of metformin, which is gentler on the digestive system and better tolerated.
Metformin should be taken with food to minimize side effects. However, you should avoid eating sugary and processed foods, as they can worsen the digestive side effects of the medication. Long-term use and high doses of metformin increase the likelihood of vitamin B12 deficiency. A lack of vitamin B12 can cause mood changes, memory loss, and damage to the nervous system. While taking this drug, you should supplement your diet with vitamin B12 and have your levels checked annually.
Elevated serum homocysteine and urinary methylmalonic acid MMA levels, the gold standard in assessing B12 status, also indicate a B12 deficiency. The most serious side effect of metformin is lactic acidosis, a potentially life-threatening condition caused by the buildup of lactic acid in the blood. This can occur if too much metformin accumulates in the blood due to overdose or chronic or acute kidney problems. If you have serious kidney problems, you shouldn't take metformin.
Drinking alcohol while on metformin, and especially binge drinking, can increase your risk of lactic acidosis. Some medications can also increase the risk, including:. Symptoms of lactic acidosis include:. You can prevent lactic acidosis by:. If you develop symptoms of lactic acidosis, get medical attention right away. There is no natural substitute for metformin. However, there are natural ways to improve your insulin sensitivity in other ways.
The most important things are eating a healthy diet and getting regular physical activity. N-acetyl cysteine is an antioxidant that was shown in one randomized controlled trial to work as well as metformin for reducing insulin resistance and cholesterol in people with PCOS. Myo-inositol was found to restore ovulation, resulting in more pregnancies than metformin. Myo-inositol has also been shown to improve insulin and other metabolic aspects of PCOS.
Regular menstrual cycles usually return within about six months in women with PCOS taking metformin. Some studies have shown that women without PCOS may benefit from using metformin for infertility.
Sign up for our Health Tip of the Day newsletter, and receive daily tips that will help you live your healthiest life. American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: Guide to the best practices in the evaluation and treatment of polycystic ovary syndrome - part 2. Endocr Pract. Off-label drug use in the treatment of polycystic ovary syndrome. Fertil Steril. Metformin use in practice: compliance with guidelines for patients with diabetes and preserved renal function.
Clin Diabetes. The clinical application of metformin in children and adolescents: A short update. Acta Biomed.
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