Metformin 用於多囊性卵巢症候群（Polycystic ovary syndrome；PCOS） @ 快樂小藥師 Im pharmacist nichts glücklich

Metformin不只有用於治療高血糖，也有其他用途，不過臨床上面比較少見，小藥師從Micromedex上面節錄下來給大家做為參考：

簡單解說一下：
多囊性卵巢（Polycystic ovary syndrome；PCOS）會使身體對於胰島素作用鈍化，為了維持身體需求，因應這種狀況，多囊性卵巢患者會分泌過多的胰島素（Insulin），導致血清中三酸甘油脂（Triglyceride）以及膽固醇（Cholesterol）濃度過高、雄性素濃度增加、體重增加、排卵不正常、月經不規則、不易受孕、糖尿病風險增加等問題出現。
此外，可以併用Clomiphene，來提升治療的效果。

在針對626位對胰島素有組抗性的多囊性卵巢症婦女的隨機化，雙盲臨床試驗中，用metformin和clomiphene citrate的合併治療，或者以clomiphene citrate單一用藥比單獨使用metformin更可以顯著增加的新生兒誕生的比率。

Metformin對於有多囊卵巢綜合症(PCOS)的胰島素抗藥性的婦女有恢復月經的周期和排卵功能

Metformin 促進C-reactive protein和代謝綜合症候群的其他特徵。

Metformin與dexamethasone合併可以提升改善激素的水平；至於和pioglitazone的合併則留待被證明

Metformin會不一致的改進對clomiphene citrate有抗藥性的PCOS女性患者的排卵懷孕的比率。

罹患PCOS婦女的處理基本上可以分為幾項原則..

- 雄性激素過多引起的acne或hirsutism:
- 口服避孕藥物
- 抗雄性激素藥物 (cyproterone acetate)
- spironolactone (須使用較大劑量,100-200 mg/day)
- 類固醇製劑,finasteride (2,5 [alpha]-reductase)
- 胰島素抗性: metformin,pioglitazone或rosiglitazone

Polycystic ovary syndrome

a) Overview

FDA Approval: Adult, no; Pediatric, no

Efficacy: Adult, Evidence favors efficacy

Recommendation: Adult, Class IIa

Strength of Evidence: Adult, Category B

See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS

b) Summary:

Combination treatment with metformin and clomiphene citrate or single-agent treatment with clomiphene citrate resulted in significantly improved rates of live births compared to treatment with metformin alone in 626 women with infertility secondary to polycystic ovary syndrome in a randomized, double-blind clinical trial (Legro et al, 2007; Legro et al, 2006)
Metformin restores menstrual cyclicity and ovulatory function among insulin-resistant women with polycystic ovary syndrome (PCOS) (Eisenhardt et al, 2006)
Metformin improves C-reactive protein, and other features of metabolic syndrome
Metformin in combination with dexamethasone improved androgen levels; combination with pioglitazone remains to be substantiated
Metformin has inconsistently improved ovulation pregnancy and abortion rates in women with PCOS resistant to clomiphene citrate

c) Adult:

1) General Information

a) Polycystic ovary syndrome (PCOS) is characterized by menstrual disturbances, anovulation or oligo-ovulation, and hirsutism or acne. In the past, PCOS was treated as a gynecologic disorder; however, available information suggests that PCOS is linked to insulin resistance and hyperinsulinemia. Effects of excess insulin on the ovary and female hormones include thecal hyperplasia, increased androgen secretion, and arrest of follicular development. In the past treatment consisted of oral contraceptives, cyproterone acetate, and clomiphene; however, newer therapies are focusing on insulin sensitizing agents (ie, metformin or troglitazone) which improve the primary defect, insulin resistance and hyperinsulinemia (Hopkinson et al, 1998).

2) Abnormal Ovulation

a) In a 12-week, prospective, randomized, placebo-controlled, double-blind, intent-to-treat study among 45 polycystic ovary syndrome (PCOS) women aged 21 to 36 years, metformin 500 milligrams (mg) 3 times daily restored normal menstrual cyclicity in 73% (16 of 22) women compared with 30% (7 of 23) receiving placebo and ovulatory function (67% vs 45%, respectively) (p values not reported). Among metformin-treated patients, there was a close correlation between improved menstrual cycles and insulin resistance (fasting glucose to insulin ratio less than 4.5) (80% with insulin resistance vs 57% without insulin resistance, p less than 0.05). There were no significant changes in fasting glucose, circulating androgen or sex hormone binding globulin (SHBG) concentrations (Eisenhardt et al, 2006).
b) A 16-week course of metformin improved ovulation frequency (as well as some cardiovascular risk factors) in oligomenorrheic women according to a randomized, double-blind, placebo-controlled study (n=92). Subjects were randomized to receive either placebo (n=47) or metformin 850 milligrams (mg) twice daily (n=45; during the first week these women only received metformin once daily). The ovulation frequency assessed by the ratio of luteal phase weeks to observation weeks was significantly higher in the treated group (23%) compared to the placebo group (13%) (p less than 0.01). The time to first ovulation was significantly shorter (24 days) for the treated group compared with the placebo group (42 days) (p less than 0.05). The proportion of patients failing to ovulate was higher among placebo-treated patients (p less than 0.05). The majority of ovulations were characterized by normal progesterone concentrations in both groups. In the intent-to-treat analysis, 8 of 45 women in the metformin group failed to ovulate during treatment compared to 17 of 47 placebo-treated women (p=0.04). One woman conceived within a week of the end of her treatment with metformin. Weight loss was noted in the metformin group whereas weight gain was noted in the placebo group (p less than 0.05). No change in fasting glucose concentrations, fasting insulin, or insulin responses to a glucose challenge were recorded after 14 weeks of metformin or placebo therapy. Metformin-treated women had significantly lower testosterone levels following treatment. Among the metformin-treated subjects, low-density lipoprotein cholesterol tended to decrease and high-density lipoprotein (HDL) cholesterol increased significantly (Fleming et al, 2002).
c) Twelve of 35 (34%) women with polycystic ovary syndrome ovulated spontaneously during treatment with metformin versus 1 of 26 (4%) women treated with placebo; 19 of 21 (90%) women receiving clomiphene and metformin ovulated versus 2 of 25 women treated with clomiphene alone. This study was designed to determine whether reduction of hyperinsulinemia with metformin would increase the ovulatory response to clomiphene. Of 61 women enrolled in the study, 35 and 26 were treated with metformin 500 milligrams (mg) 3 times daily or placebo for 34 days. Treatment with metformin resulted in a significant reduction (p=0.002) in the area under the insulin curve compared to placebo. Forty-six women who failed to ovulate continued to the second phase of the study where clomiphene 50 mg daily was added for 5 days to the previous treatment. This study showed an increase in ovulation in response to metformin alone or metformin plus clomiphene but this study did not address pregnancy or birth rates (Nestler et al, 1998).
d) Of 20 women who had polycystic ovary syndrome (PCOS) and were treated with metformin, 11 (68.8%) had beneficial changes in menstrual patterns but did not have sustained metabolic or hormonal changes (Morin-Papunen et al, 1998). At 4 to 6 months, responders had a significantly (p less than 0.05) lower serum testosterone, free testosterone, free androgen index, and androstenedione concentrations than nonresponders. The mean fasting insulin concentration decreased in all patients. Metformin 500 milligrams (mg) 3 times daily was used for the 4 to 6 month treatment period. Metformin had little lasting effect on hormone concentrations but it did improve the menstrual pattern in up to 70% of women.
e) In an open study (n=22), treatment with metformin for 6 months resulted in return of normal menses in 21 women (95.7%) and pregnancy in 4 women (19%) with polycystic ovary syndrome (PCOS). At baseline, all women underwent an oral glucose tolerance test; luteinizing hormone (LH), follicle stimulating hormone (FSH), free testosterone, and insulin concentrations were also obtained. Patients were treated with metformin 500 milligrams 3 times daily for the remainder of the study. Eight weeks after starting metformin, significant reductions occurred in LH, the LH:FSH ratio, and free testosterone concentrations; in addition, the serum progesterone concentration was within the ovulatory range in 13 women. Women with PCOS also have insulin resistance and hyperinsulinemia which is believed to produce abnormal concentrations of sex hormones, the related symptoms of PCOS, and difficulty conceiving. Larger controlled studies are required to confirm the positive results obtained in this study (Velazquez et al, 1997).

3) Infertility

a) Clomiphene citrate, either alone or in combination with metformin, resulted in significantly more live births than metformin alone in women with infertility due to polycystic ovary syndrome in a randomized, double-blind clinical trial. Women (n=626) were randomly assigned to treatment for up to 6 cycles with clomiphene citrate 50 milligrams (mg) orally daily for 5 days beginning on day 3 of menses (n=209; mean age, 27.9 +/- 4 years), extended-release metformin with doses gradually titrated to reach a maximum of 1000 mg orally twice daily (n=208; median age, 28.1 +/- 4 years), or a combination of the same doses of clomiphene citrate and extended-release metformin initiated concurrently (n=209; range, 28.3 +/- 4 years). If no or poor response occurred, clomiphene citrate (or matching placebo) was increased by 50 mg daily per cycle, up to a maximum dose of 150 mg daily for 5 days. Patients without recent menses received oral medroxyprogesterone to induce withdrawal bleeding prior to the start of study medication. Regular intercourse every 2 to 3 days was encouraged and patients were required to keep a daily diary of symptoms, vaginal bleeding, and intercourse. Progestin to induce withdrawal bleeding was subsequently administered at the discretion of each principal investigator. The primary endpoint was the rate of live births. The rates of live births were 22.5%, 7.2%, and 26.8% in the clomiphene citrate, metformin, and combination groups, respectively, with significant differences between the clomiphene citrate and metformin groups (p less than 0.001) and the combination and metformin groups (p less than 0.001). Patients with a BMI of less than 30 had a significantly (p less than 0.001) higher rate of live births compared to those women whose BMI was 30 or higher, independent of treatment allocation. Rates of ovulation were significantly higher in the combination arm (60.4%) compared to both the clomiphene citrate (49%; p=0.003) and metformin (29%; p less than 0.001) arms and in the clomiphene citrate arm compared to the metformin arm (p less than 0.001). The rate of women who did not experience ovulation at anytime during the study was significantly higher in the metformin group (44.7%) compared to both the clomiphene citrate group (24.9%; p less than 0.001) and the combination group (16.7%; p less than 0.001). Multiple pregnancies only occurred in the clomiphene citrate group (6% of pregnancies) and the combination group (3.1% of pregnancies), although differences between groups were not significant. The combination arm (5.3%) experienced more serious adverse events, primarily consisting of pregnancy complications, than the metformin arm (1%; p=0.02), while the rate of serious adverse events in the clomiphene citrate arm was 3.3%. The metformin groups experienced more gastrointestinal symptoms while the clomiphene citrate groups experienced more hot flashes and ovulatory symptoms (Legro et al, 2007; Legro et al, 2006).
b) When used in a sequential regimen with clomiphene, metformin was associated with a pregnancy rate of 16.7% in clomiphene-resistant women with polycystic ovary syndrome. Due to patient dropouts, however, the study was inadequately powered to differentiate clinical results from women who received human menotropins (hMG). Thirty women were randomized to receive metformin 500 milligrams (mg) three times daily for 6 months, at which time clomiphene 150 to 200 mg/day was added. After three cycles, ovulation and pregnancy rates were compared to 30 women who had received an hMG regimen for ovulation induction (75 units/ampule; total dosage range from 3 to 44 ampules over 50 cycles among 27 women completing the study). Both groups received subsequent human chorionic gonadotropin. Ovulation occurred at a similar rate among 54 women completing the metformin-clomiphene and hMG regimens (47% and 43%, respectively); 16.7% of those on the metformin-clomiphene regimen and 23.3% of those on hMG successfully conceived. Women on the metformin combination regimen showed a statistically but not clinically significant decrease in body mass index (p less than 0.001) and fasting insulin levels (p less than 0.05) (George et al, 2003).
c) Metformin treatment before attempted inducement of ovulation by clomiphene citrate (CC) treatment increased the ovulation and pregnancy rates among women with polycystic ovary syndrome (PCOS) who had previously been resistant to CC. In a randomized, double-blind, placebo-controlled trial, women were given placebo or metformin 500 milligrams (mg) 3 times daily for 7 weeks. Women who ovulated in response to metformin or placebo were excluded from further study. Anovulatory participants continued to take metformin or placebo and were given CC 50 mg daily for 5 days. If ovulation occurred, the dose of CC was not changed; with continued anovulation, the dose was increased by 50 mg for the next cycle, to a maximum of 150 mg. The study was considered complete for patients who had 6 ovulatory cycles, became pregnant, or experienced anovulation while receiving 150 mg of CC. Nine of 12 women treated with metformin ovulated (75%), compared to 4 of 15 women in the placebo group (27%). In the metformin group, 6 women conceived (55%); 2 of the pregnancies resulted in spontaneous abortion and the other 4 resulted in delivery of healthy infants. Only 1 woman (7%) from the placebo group became pregnant; she delivered a healthy infant (Vandermolen et al, 2001).
d) Metformin treatment throughout pregnancy reduced the rate of first-trimester spontaneous abortion in women with polycystic ovary syndrome (PCOS) and was not associated with teratogenicity. Twenty-two nondiabetic women who were oligomenorrheic and hyperandrogenemic and who had been taking metformin 1.5 to 2.55 grams per day were enrolled in an open study as they became pregnant. Nineteen women continued taking metformin throughout pregnancy; 3 stopped taking metformin when pregnancy was detected. At the time of publication, there had been 11 normal live births without birth defects, 2 first-trimester spontaneous abortions, and 6 ongoing normal pregnancies (with no fetal defects observable by sonography) of 13 or more weeks' gestation, among the 19 women who continued metformin. Among the 3 women who terminated metformin treatment, there had been 2 live pregnancies (one with patent foramen ovale) and 1 first-trimester spontaneous abortion. Ten of the 19 women who continued therapy had had 22 previous pregnancies while not taking metformin, 16 (73%) resulting in first-trimester spontaneous abortions (Glueck et al, 2001).
e) Metformin improved ovulatory rates, cervical scores, and pregnancy rates in women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS), according to a randomized, double-blind, placebo-controlled study (n=56). Clomiphene citrate resistance was defined as failure to have an ovarian response for three consecutive cycles with concomitant failure of E2 (estradiol) levels to increase following treatment with CC up to 150 milligrams (mg) for 5 days. Interventions consisted of Group I: Two cycles of metformin (850 mg twice daily) and Group II: Placebo therapy (twice daily). Both groups of women received CC (100 mg/day) on cycle days 3-7 of the second cycle. Human chorionic gonadotropin (HCG) 10,000 units was given intramuscularly according to strict criteria. The percentage of insulin-resistant cases decreased significantly after treatment in Group I (before: 53.5%, after: 25.9%; p=0.02) and remained unchanged in Group II (before and after: 50%; p=1.0). In Group I, 92.9% of the patients had more than 1 mature follicle; only 28.5% of patients in Group II had mature follicles (p less than 0.001). Twenty-one patients of Group I (77.7%) had ovulation compared to four patients (14.2%) in Group II (p less than 0.001). Three pregnancies were recorded in Group I, none were recorded in Group II. Although the pregnancy rate was higher in Group I, this difference was not statistically significant, but was considered clinically significant. Other benefits of metformin treatment included decreases in total testosterone, LH level, LH/FSH ratio, insulin resistance, and body mass index. No between-group differences were noted in waist-to-hip ratios, DHEAS level, and fasting insulin levels (Kocak et al, 2002).

4) Effects on Serum Markers

a) Low-dose dexamethasone added to metformin improved androgen levels in women with polycystic ovary syndrome (PCOS). A 26-week randomized, double-blind, placebo-controlled trial was conducted in which 38 women, aged 28.6 +/- 5.4 years, with PCOS (verified by ultrasonography) received either placebo (n=20) or dexamethasone 0.25 milligrams (mg) (n=18) daily. All patients received metformin 850 mg daily for one week, twice daily during the next week, and thrice daily thereafter. After 26 weeks of therapy, testosterone serum level was significantly reduced in both groups, however, a greater reduction was seen with the dexamethasone plus metformin regimen (-38%; -1.25 +/- 1.13 nanomoles/liters (nmol/L)) compared to metformin alone (-11%; -1.33 +/- 0.79, p less than 0.05). Free testosterone index was reduced by 46% with combination therapy and increased 4% on metformin monotherapy after 26 weeks of therapy. Likewise, compared to baseline, combination therapy reduced androstenedione (-28%) and dehydroepiandrosterone sulfate (DHEA-S) (-30%) serum levels to a greater extent than metformin monotherapy (androstenedione -7%, p less than 0.05; DHEA-S +16%, p less than 0.001). Changes in body mass index, fasting glucose, insulin C-peptide, and serum lipids were not significantly different between groups (Vanky et al, 2004).
b) Non-obese patients rather than obese patients with polycystic ovary disease (PCOS) responded to metformin therapy. Women (aged 17 to 32) with PCOS were randomized to receive placebo (n=14) or metformin 1.5 grams daily (n=15) for 6 months in a double-blind fashion. Women were stratified according to body weight with obese defined as body mass index (BMI) exceeding 30 kilograms/square meter (kg/m(2)). Fasting serum insulin decreased from 12.1 +/- 2.4 microunits/milliliter (mcU/mL) to 6.3 +/- 0.6 mcU/mL in non-obese patients receiving metformin (n=7; p less than 0.03). While obese patients receiving metformin (n=8) did not show a significant decrease: 22.6 +/- 4.1 mcU/mL compared to 21.1 +/- 3.3 mcU/mL. Placebo treated women did not have a significant change in serum insulin concentrations compared to baseline. Compared to baseline, non-obese patients had significant decreases in serum total testosterone (38%), free testosterone (58%), and androstenedione (30%) concentrations, while obese patients had a significant decrease in free testosterone (47%) and an increase in sex hormone binding globulin (21%) (Maciel et al, 2004).
c) Metformin therapy significantly decreased serum C-reactive protein (CRP) levels in obese and non-obese women with polycystic ovary syndrome (PCOS). In an open-label study, 20 non-obese (body mass index (BMI) less than or equal to 25 kilograms/square meter (kg/m(2)) and 32 obese (BMI greater than or equal to 27 kg/m(2)) women with PCOS were randomized to receive either metformin 500 milligrams (mg) twice daily for 3 months then to 1 gram twice daily for the next 3 months or ethinyl estradiol 35 micrograms (mcg) plus cyproterone acetate 2 mg (EE-CA) for 21 days every month followed by 7 days of placebo for a total of 6 months. Results are reported in mean +/- standard error of the mean (SEM). At baseline, serum CRP was significantly higher in obese (4.08 +/- 0.53 mg/liter (L)) compared to non-obese (1.31 +/- 0.28 mg/L, p less than 0.001) women. At 6 months, serum CRP levels decreased significantly compared to baseline in both obese and non-obese women treated with metformin (3.08 +/- 0.7 mg/L versus 1.52 +/- 0.26 mg/L, p less than 0.01). Serum CRP levels increased significantly from baseline in all women treated with EE-CA (2.91 +/- 0.68 mg/L versus 4.58 +/- 0.84 mg/L, p less than 0.001) (Morin-Papunen et al, 2003).
d) Limited evidence from a small nonrandomized, observational study suggested combined metformin-pioglitazone therapy may improve signs of PCOS. In a prospective, open label, single center case series, 13 women who had inadequately responded to metformin (850 milligrams (mg) three times daily) were given pioglitazone 45 mg/day. Results from 11 women were evaluated after chronic therapy (median 10 months), and compared to results obtained on metformin alone. Statistically significant improvements were noted in measures of androgenicity, glucose and lipid abnormalities. Further well-designed, large scale investigation is needed to clarify the role of managing PCOS symptoms with a metformin-thiazolidinedione combination (Glueck et al, 2003b).
e) In a nonrandomized subgroup analysis, metformin plus diet improved abnormalities of metabolic syndrome in women with polycystic ovary syndrome. One-hundred thirty-eight consecutively enrolled women with PCOS were given metformin 2.55 grams/day and a reduced calorie diet for 6 to 8 months. Among these women, 46% (n=64) had metabolic syndrome based on National Institutes of Health's Adult Treatment Panel III (ATP III). Interim subgroup results in women completing an average of 6 months of treatment included changes to mean values as follows: reduced triglycerides, total cholesterol, and low-density lipoprotein cholesterol (p less than 0.0001, p=0.0001, and p=0.011, respectively); reduced systolic (SBP) and diastolic (DBP) blood pressures (p=0.0007 and p=0.0002, respectively); 25.2% decrease in insulin levels (p less than 0.0001); and 4.7% weight loss (p less than 0.0001). Significant effects were achieved as early as 2 months of initiating treatment, with exception of high density cholesterol level, which was significantly increased (p=0.013) only at the 6-month follow-up. When analyzed separately, women with baseline abnormalities showed similar improvements and variably achieved clinical goals for individual parameters (Glueck et al, 2003a).

補充另外一位醫師寫的資料：

在治療所謂「胰島素抗性」方面，最近有人主張使用一些治療糖尿病的藥物，也可以得到很好的效果，例如Metformin與Troglitazone。通常在使用這些藥物二至三個月之後，就可見療效，包括體重減輕，脫髮減少，面部與身體的毛髮生長速度減慢，月經正常，回復排卵生育能力等。

Troglitazone(Rezulin)，是一種thiazolidinedione的衍生物，可以經由細胞核接受器peroxisome proliferator activated receptors(PPARs)影響脂肪酸的代謝，使其不與葡萄糖競爭氧化代謝，而使局部細胞組織對胰島素的抗拒力降低，達到降低血糖與的效果，也同時減少代償性的高胰島素血症的發生率。
副作用包括：頭痛(11%)，疼痛(10%)，無力(6%)，暈眩(6%)與噁心(6%)。

Metformin(即glaucophage)是一種biguanide的降血糖藥物，主要作用在藉由無氧葡萄糖代謝路徑，將腸道中的葡萄糖轉變成乳酸，減少葡萄糖的吸收，並減少肝臟中葡萄糖的製造，同時也增加組織對胰島素的敏感度，幫助胰島素清除過多的血糖，並且有降低三酸甘油酯與膽固醇的效用。在卵巢方面，Metformin可以降低卵巢中細胞色素P450c17-α的活性，改善男性素過高的情形。
副作用：約有百分之二十至三十的人會有上腹灼熱感，腹瀉，食慾不振等。有非常少數(1/100000 patient-years)的人會發生「乳酸血症」(lactic acidosis)，對於腎臟功能不佳者，如「肌酸酐大於1.5」或「肌酸酐清除小於60%」者，應該非常謹慎使用。

以上這兩種藥物，是否能夠於懷孕中使用？目前並無足夠的人體證據證實其會導致胎兒畸形，目前美國FDA將其歸諸於Class B的分類中，認為並不會影響懷孕的安全。