3 RESULTS 

3.1  Recruitment And Pretreatment Assessments

↓38

A total of 46 women were recruited for the study and underwent the randomization, receiving metformin or placebo. Infertility was the reason for presentation for all patients in the both groups. Table 2 shows that the metformin and placebo groups were matched for age, BMI, testosterone, SHBG, fasting glucose and insulin, haemoglobin A1c, and circulating lipid fractions before treatment. According to Ferriman-Gallwey criteria for hirsutism,13 patients from placebo-treated group and 14 patients from metformin-treated group were hirsute. All women displayed a classical picture of PCOS on vaginal ultrasound scan.

Table 3: Characteristics of the patients randomized to receive placebo or metformin

Parameter

Placebo

Metformin

mean ± SD

mean ± SD

Age (yr)

31.5 ± 5.3

31.7 ± 3.2

BMI (kg/m²)

40.1 ± 5.4

40.3 ± 4.4

Waist/hip ratio

0.84 ± 0.06

0.85 ± 0.07

LH/FSH

1.8 ± 0.7

1.7 ± 0.8

Total T (ng/ml)

2.7 ± 0.6

2.3 ± 0.4

free T (pmol/L)

12.0 ± 8.5

10.7 ± 5.3

SHBG (nmol/L)

29.8 ± 12.7

26.3 ± 10.2

Fasting insulin (μIU/L)

18.5 ± 10.4

21.4 ± 10.1

Fasting glucose (mg/dl)

76.7 ± 7.4

78.1 ± 14.9

Leptin (ng/ml)

41.2 ± 13.1

38.9 ± 12.8

Cholesterol (mg/dl)

218.9 ± 39,6

192.7 ± 40.4

Triglycerides (mg/dl)

153.4 ± 70.3

149.8 ± 64.1

HbA1c ( %)

5.5 ± 0.4

5.6 ± 1.5

3.2 Treatment Compliance

There was no difference in the dropout rates between the placebo group (n=3) and metformin-treated group (n=3).

↓39

All metformin-treated patients experienced mild transient diarrhoea, nausea and headache and one woman has dropped out of the trial due to intolerable gastrointestinal side effects associated with metformin. One patient in the placebo group was excluded from the study because of noncompliance. Another five volunteers did not complete the study for personal reasons. Figure III shows the progress of these patients through the study.

Figure III: Chart of patients progressing through the trial of placebo or metformin treatment.

3.3 Conception During Treatment

One patient in the metformin-treated group became pregnant in the fourteenth week of the treatment and gave a birth in due time. Two spontaneous pregnancies occurred in the placebo-treated group in the twelfth week of the study. One of the pregnancies in the placebo-taking group ended in sponataneous abortion after 7 weeks of gestation. Pregnant patients didn’t complete the study. Their data were not included into statistical analysis. The statistical analysis was conducted with the data of 19 patients in the metformin-treated group and the data of 18 patients in the placebo-treated group who completed the study (see Figure III).

3.4 Anthropometric Assessments

Body Mass Index

↓40

There was a reduction in the mean BMI in both groups although only in the metformin group body mass index and weight decreased significantly (-5.6 kg (metformin, P<0.001) vs. –2.2 kg (placebo, p NS)).  The baseline BMI in the drug-treated group decreased from 40.6 ± 4.2 (kg/m²) to 38.9 ± 4.6kg/m² after 16 weeks. The pretreatment BMI in placebo-taking group was 39.5 ± 5.9 kg/m² and didn’t change after treatment (38.9 ± 5.6 kg/m²).

Table 4: BMI measurements before and after treatment

Placebo

Metformin

n = 18

n = 19

Parameter

Pretreatment

16 wk

P

Pretreatment

16 wk

P

mean ± SD

mean ± SD

mean ± SD

mean ± SD

BMI

39.5 ± 5.9

38.9 ± 5.6

NS

40.6 ± 4.2

38.9 ± 4.6

0.001

Figure IV: Box plot of BMI in women with PCOS before and after metformin treatment.

↓41

Figure V: Box plot of BMI in women with PCOS before and after placebo treatment.

Waist And Hip Circumferences

Table 5: Waist and hip measurements before and after metformin or placebo treatment

Placebo

Metformin

n=18

n=19

Parameter

Pretreatment

16 wk

P

Pretreatment

16 wk

P

mean ± SD

mean ± SD

mean ± SD

mean ± SD

Waist/hip ratio

0,84 ± 0,07

0,84 ± 0,06

NS

0,86 ± 0,06

0,86 ± 0,06

NS

Waist (cm)

108,7 ± 9,0

107,5 ± 10,1

NS

111,4 ± 9,0

108,2 ± 10,1

0,005

Hip (cm)

129,4 ± 12,1

127,8 ± 11,7

0,02

129,5 ± 9,5

125,4 ± 9,8

0,0001

After 16 weeks of metformin or placebo treatment, waist circumstances decreased considerably in the metformin–treated group (111.4 ± 9.0 vs. 108.2 ± 10.1, p<0.005). At the same time, hip circumstances changed significantly in both groups although a more considerable decrease was demonstrated in women treated with metformin (Table 5).

↓42

In spite of significant reduction of body mass index and both waist and hip circumferences in the metformin-treated patients, no changes in the pattern of body fat distribution were seen. The waist-to-hip ratio remained constant in the metformin-treated subjects (0.86 ± 0.06 (pretreatment) vs. 0.86 ± 0.06 (posttreatment) (P=0.53)).

3.5 Endocrine Assessments 

Sex Hormones And SHBG 

Table 6: Sex hormones and SHBG blood concentrations in PCOS women before and after placebo or metformin treatment

Placebo

Metformin

n=18

n=19

Parameter

Pretreatment

16 wk

P

Pretreatment

16 wk

P

mean ± SD

mean ± SD

mean ± SD

mean ± SD

LH/FSH

1.8 ± 0.9

1.78 ± 0.9

NS

1.6 ± 0.8

1.77 ± 0.8

NS

Prolaktin (ng/ml)

8.3 ± 2.8

10.4 ± 5.3

NS

9.9 ± 5.1

8.9 ± 4.4

NS

total testosterone (ng/ml)

2.6 ± 0.7

2.5 ± 1.1

NS

2.1 ± 0.9

2.0 ± 0.6

NS

free testosterone (pmol/L)

11.8 ± 8.7

8.8 ± 3.9

NS

10.3 ± 5.7

9.3 ± 5.6

NS

SHBG (nmol/L)

30.4 ± 12.8

33.6 ± 20.6

NS

26.4 ± 10.1

34.0 ± 16.7

0.04

DHEA-S (µmol/l)

6.0 ± 2.9

5.0 ± 2.3

0,04

6.5 ± 3.0

7.2 ± 2.9

NS

FAI

10.0 ± 4.9

11.1 ± 8.8

NS

8.3 ± 3.5

7.4 ± 4.2

NS

↓43

Total and Free Testosterone

The baseline total and free testosterone concentrations were higher in PCOS women taking placebo compared with those taking metformin: 2.6 ± 0.7 vs. 2.1 ± 0.9 for testosterone (in ng/ml) and 11.8 ± 8.7 vs. 10.3 ± 5.7 for free testosterone (in pmol/L). There was no significant reduction in androgen levels in both groups. Figure VI shows the minimal changes in free testosterone concentrations during the trial.

Figure VI: Box plot of free testosterone levels in women with PCOS before and after metformin or placebo treatment.

↓44

LH/FSH Ratio

Table 6 demonstrates that neither metformin nor placebo treatment significantly modified the LH/FSH ratio, FAI and prolactin parameters.

The LH/FSH ratio remained similar after treatment in the control group: 1.8 ± 0.9 vs. 1.78 ± 0.9 (P=0.81) and increased from 1.6 ± 0.8 to 1.77 ± 0.8 (P=0.28) in the metformin-taking group. The patients with random numbers 18 and 41 in the drug-treated group had higher LH/FSH ratios ( 4.0 for №18 ; 4.4 for №41) and are marked in the box plot as extreme values.

↓45

Figure VII: Box plot of LH/FSH ratio in women with PCOS before and after metformin or placebo treatment.

Free Androgen Index (FAI)

The free androgen index increased from 10.0 ± 4.9 before treatment to 11.1 ± 8.8 after 16 weeks, (P=NS) in placebo-taking women. There were no changes of free androgen index in the metformin treated group (8.3 ± 3.5 to 7.4 ± 4.2, (P=NS)).

↓46

Sex Hormone-Binding Globulin (SHBG)

Placebo treatment did not substantially modify SHBG concentrations in the controls (30,4 ± 12,8 (nmol/L) before study and 33,6 ± 20,6 (nmol/L) after study, P=NS). SHBG levels significantly increased in the metformin-treated group (26,4 ± 10,1 (nmol/L) before study and 34,0 ± 16,7 (nmol/L) after study, P=0,04).

Before treatment, PCOS women taking metformin seem to have slightly lower SHBG levels than women in the placebo-taking group. However, this difference was not significant (26.4 ± 10.1 vs. 30.4 ± 12.8 nmol/L, P=NS).

↓47

Figure VIII: SHBG plasma concentrations in women with PCOS before and after metformin or placebo treatment.

Glycemic Parameters

Table 7: Levels of glucose, insulin, Hb1Ac, leptin and IGF-I levels in PCOS women before and after placebo or metformin treatment.

Placebo

Metformin

n=18

n=19

Parameter

Pretreatment

16 wk

P

Pretreatment

16 wk

P

mean ± SD

mean ± SD

mean ± SD

mean ± SD

Fasting insulin (μIU/mL)

18.3 ± 10.8

26.9 ± 13.8

0.006

21.6 ± 10.0

26.2 ± 12.1

0.04

Fasting glucose (mg/dl)

76.8 ± 7.5

79.2 ± 8.8

NS

78.0 ± 15.3

77.11 ± 11.0

NS

120 min glucose (mg/dl)

109.5 ± 6.8

111.6 ± 5.0

NS

124.2 ± 9.3

119.8 ± 8.4

NS

120 min insulin (μIU/mL)

153.3 ± 26.8

112.8 ± 5.1

NS

138.9 ± 19.9

94.1 ± 14.1

0.01

AUC, insulin (μIU/mL·h)

261.2 ± 50.3

236.6 ± 31.1

NS

262.1 ± 34.0

211.4 ± 20.1

0.03

AUC, glucose ( mmol/L·h)

12.8 ± 0.8

12.9 ± 0.6

NS

14.2 ± 0.7

14.8 ± 0.7

NS

SiM index

0.86 ± 0.8

0.8 ± 0.63

NS

0.64 ±0.5

0.8 ± 0.53

NS

Leptin (ng/ml)

41.4 ± 13.3

43.8 ± 17.0

NS

38.5 ± 13.1

39.6 ± 20.8

NS

IGF-I (ng/ml)

165.6 ± 53.0

175.5 ± 47.1

NS

160.6 ± 84.5

149.1 ± 46.4

NS

Glucose And Insulin

↓48

Before treatment, fasting plasma glucose and insulin concentrations were not significantly different between two groups, however there was a tendency to higher fasting insulin levels in the metformin group.

At baseline, 2 hours post-75-g glucose load values were increased, but not significantly (P=0.2), in the metformin-treated women. Five patients in the metformin-treated group fulfilled ADA criteria for impaired glucose tolerance vs. two patients who took placebo.

After treatment, fasting plasma and 2 hours post-75-g glucose load glucose levels did not change substantially in either group. However, two patients with impaired glucose tolerance (one from the control, other from the metformin group) reverted to normal glucose tolerance.

↓49

Figure IX: Fasting glucose levels in women with PCOS before and after metformin or placebo treatment.

It is interesting that fasting insulin levels increased significantly both in placebo- and metformin-treated patients. The elevation in the placebo-treated group was from 18.3 ± 10.8 (μIU/mL ) to 26.9 ± 13.8 (μIU/mL), P=0.006. The elevation in the metformin-treated group was 21.6 ± 10.0 to 26.2 ± 12.1 (μIU/mL), P=0.04. The box plots demonstrate fasting insulin concentrations in placebo- and metformin-treated women with PCOS before and after treatment.

Figure X: Fasting insulin concentrations in women with PCOS before and after placebo treatment.

↓50

Figure XI: Fasting insulin concentrations in women with PCOS before and after metformin treatment.

2 hours post 75 g glucose load insulin concentrations declined significantly after 16 weeks of metformin treatment (138.9 ± 19.9 (μIU/mL) (pretreatment) vs. 94.1 ± 14.1 (μIU/mL) (posttreatment), P=0.01). The control group also revealed a decrease of 2 hours post 75 g glucose load insulin levels (153.3 ± 26.8 (μIU/mL) (pretreatment) vs. 112.8 ± 5.1 (μIU/mL) (posttreatment)) but P value did not achieve statistical significance (P=0.2).

Figure XII: 2-hours postprandial insulin concentrations in women with PCOS before and after metformin or placebo treatment.

Area Under The Curve (Glucose And Insulin)

↓51

The integrated glucose response to the glucose load, AUC glucose, did not change in either group. AUC glucose was 12.8 ± 0.8 mmol/mL/h before treatment and 12.9 ± 0.6 mmol/mL/h after treatment, P=NS in the control group. In the metformin-treated group AUC glucose was 14.2 ± 0.7 mmol/mL/h before treatment and 14.8 ± 0.7 mmol/mL/h after treatment, P= NS.

Integrated insulin response, AUC insulin, decreased in the both groups. The decrease was from 262.1 ± 34.0 (μIU/mL·h) to 211.4 ± 20.1 (μIU/mL·h), P=0,03 for the drug-treated group. AUC insulin changed in the placebo-taking group 261.2 ± 50.3 (μIU/mL·h) vs. 236.6 ± 31.1(μIU/mL·h), but P value did not reach a significant rate.

Figure XIII: Area Under The Curve insulin (AUC insulin) in metformin-treated women with PCOS before and after treatment.

↓52

Figure XIV. Area Under The Curve insulin in placebo-treated women with PCOS before and after treatment

Leptin

There were no differences in baseline leptin concentrations between PCOS women and controls. In spite of significant weight reduction in the metformin-treated group, leptin levels did not decline. Moreover, a slight increase (38.5 ± 13.1 (pretreatment) vs. 39.6 ± 20.8 (posttreatment) ng/ml in the metformin and 41.4 ± 13.3 (pretreatment) vs. 43.8 ± 17.0 (posttreatment) ng/ml in the placebo-treated group ) was shown in both groups, but this change was not significant.

IGF–I

IGF-I levels in the metformin-treated group demonstrated a tendency to decline (160.6 ± 84.5 (ng/ml) (pretreatment) vs. 149.1 ± 46.4 (ng/ml) (posttreatment), P= NS), difference came to –11,5 ng/ml. IGF-I levels demonstrated a tendency to augment in the control group (165.6 ± 53.0 (ng/ml) vs. 175.5 ± 47.1 (ng/ml), P=NS, difference was +9.9 ng/ml).

↓53

Figure XV. IGF-I plasma concentrations in women with PCOS before and after metformin or placebo treatment

Cholesterol And Triglycerids

Table 8: Serum cholesterol and triglycerids concentrations in placebo- and metformin-treated women with PCOS before and after treatment.

Placebo

Metformin

n=18

n=19

Parameter

Pretreatment

16 wk

P

Pretreatment

16 wk

P

mean ± SD

mean ± SD

mean ± SD

mean ± SD

Total cholesterol (mg/dl)

216.7 ± 39.1

206.4 ± 32.7

NS

191.2 ± 40.1

196.8 ± 42.2

NS

HDL (mg/dl)

54.3 ± 14.2

52.6 ± 10.1

NS

47.3 ± 8.4

51.0 ± 10.1

0.07

LDL (mg/dl)

132.1± 28.6

123.4 ± 24.5

NS

114.2 ± 36.9

116.3 ± 38.5

NS

Triglycerides (mg/dl)

152.2 ± 71.1

159.4 ± 80.1

NS

149.0 ± 65.3

148.1 ± 58.2

NS

Table 8 shows that control women revealed higher baseline concentrations of total cholesterol compared to the metformin-treated group but this difference was not significant. Triglycerides, cholesterol and lipoprotein concentrations was in the upper bound of the normal range according to National Cholesterol Education Programme guidelines [ total cholesterol 200 mg/dl; LDL-C 130 mg/dl; HDL-C <35 mg/dl;

↓54

TTG >200 mg/dl] in both groups. There was no significant reduction in these parameters after treatment. Total cholesterol levels didn’t change in the metformin-treated group (191.2 ± 40.1 (pretreatment) vs. 196.8 ± 42.2 (posttreatment) mg/dl, PS=NS). Total cholesterol levels in the placebo-treated group were 216.7 ± 39.1 (pretreatment) vs. 206.4 ± 32.7 (posttreatment), P=NS.

At the same time, circulating HDL concentrations in the metformin-treated group showed a trend to rise (47.3 ± 8.4 (pretreatment) vs. 51.0 ± 10.1(posttreatment) mg/dl), however P value=0.07 did not achieve statistical significance.

Figure XVI. HDL-cholesterol concentrations in women with PCOS before and after metformin or placebo treatment.

3.6 Menstrual Cycle

↓55

At the baseline, six (31.5 %) of the 19 women who took metformin had amenorrhea, eight (42.0 %) had oligomenorrhea and five (26.3%) patients had a regular menstrual cycle. In the placebo- treated group, four (22.2%) of the 18 women had amenorrhea, twelve (66.6%) women had chronic oligomenorrhea and two (11.1%) had a regular menstrual cycle before trial.

After metformin treatment, in two of six patients with amenorrhea, the cycle returned to normal, in one woman the cycle became oligomenorrheic and three patients remained amenorrheic. In three of eight oligomenorrheic women, the cycle became regular. There were 11 patients with a regular cycle after 16 weeks of metformin treatment.

Table 9: Menstrual cycle in metformin-treated women with PCOS before and after treatment, n=19

0 week

16 weeks

Amenorrhea

6

3

Oligomenorrhea

8

5

Regular cycle

5

11

↓56

After placebo treatment, one of four amenorrheic patients became oligomenorrheic and three patients remained amenorrheic. In six of twelve oligomenorrheic women, the cycle turned normal. There were 9 patients with a regular cycle after 16 weeks of placebo treatment.

Table 10: Menstrual cycle in placebo-treated women with PCOS before and after treatment, n=18

0 week

16 weeks

Amenorrhea

4

3

Oligomenorrhea

12

6

Regular cycle

2

9

Figure XVII. Menstrual cycle in women with PCOS before metformin or placebo treatment.

↓57

Figure XVIII. Menstrual cycle in women with PCOS after metformin or placebo treatment.

Table 11: Menstrual cycle in amenorrheic patients with PCOS treated with placebo or metformin.

Metformin-treated group

Placebo-treated group

0 week

6 amenorrhea

4 amenorrhea

2 regular cycle

16 weeks

1 oligomenorrhea

1 oligomenorrhea

3 amenorrhea

3 amenorrhea

Metformin-treated patients were divided into two groups according to menstrual changes: responders (n=7) and nonresponders (n=7). Baseline characteristics of responders and nonresponders were compared to identify any predictors of clinical response to metformin treatment. Women with regular cycle were excluded from analysis.

↓58

Table 12: Main baseline characteristics of metformin-treated patients divided into responders and nonresponders according to efficacy of treatment of menstrual disturbances

 

RESPONDERS

n=7

NONRESPONDERS

n=7

P

BMI

41.5±4.2

38.4±3.1

NS

total testosterone (ng/ml)

1.9±0.6

2.5±1.1

NS

SHBG(nmol/L)

21.7±4.7

26.0±11.3

NS

FAI

8.9±3.2

10.0±3.4

NS

DHEAS(µmol/l)

8.6±3.1

4.4±1.3

0.005

fasting insulin(μIU/mL)

18.5±4.8

28.2±11.5

0.06

RESPONDERS

n=7

NONRESPONDERS

n=7

fasting glucose(mg/dl)

75.6±11.2

83.3±20.9

NS

AUC insulin (μIU/mL·h)

218,9±83.1

370.8±170.2

0.05

SIM index

0.58±0.23

0.41±0.27

NS

Analysis of baseline features showed that the responders had significantly lower insulin levels in response to oGTT (AUC insulin) and significantly higher DHEAS levels. Fasting insulin levels tended to be lower in responders. There was no difference in BMI, total testosterone and SHBG concentrations.

3.7 Subgroup Analysis

An additional aspect of this study was an analysis of the group treated with metformin. The patients were divided into two groups according to the body mass index. The commonly accepted definition of morbid obesity is a body mass index greater than 37 (Fleming et al., 2002). Responses were examined according to the BMI lying to either side of this value. The subgroup analysis was conducted to find out, first, if an initial body mass could be a predictor for successful treatment with metformin. Second, if hazards of morbid obesity have an influence on clinical and biochemical outcomes of metformin treatment.

↓59

Table 13 demonstrates the results of the study for the weight-matched groups.

Endocrine And Metabolic Parameters

Table 13: Endocrine and metabolic parameters in women with PCOS before and after metformin treatment.
Subgroup analysis

Obesity

BMI < 37

Obesity

BMI > 37

n=7

n=12

Parameter

Pretreatment

16 wk

P

Pretreatment

16 wk

P

mean ± SD

mean ± SD

mean ± SD

mean ± SD

BMI (kg/m²)

36.8 ± 0.8

34.9 ± 1.4

0.01

43.4 ± 3.3

41.9 ± 3.8

0.01

LH/FSH

1.57 ± 0.7

1.77 ± 0.4

NS

1.63 ± 1.3

1.76 ± 1.0

NS

Prolactin (ng/ml)

9.7 ± 4.3

9.2 ± 4.3

NS

10.0 ± 5.9

8.75 ± 4.6

NS

total testosterone (ng/ml)

2.1 ± 0.7

2.1 ± 0.6

NS

2.1 ± 1.1

2.0 ± 0.5

NS

free testosterone (pmol/L)

9.2 ± 4.8

10.6 ± 6.7

NS

11.1 ± 6.4

8.4 ± 4.7

NS

SHBG (nmol/L)

23.0 ± 6.8

30.4 ± 13.1

0.05

28.9 ± 11.5

36.5 ± 19.1

NS

FAI

9.9 ± 4.2

8.0 ± 3.9

NS

7.0 ± 2.3

7.0 ± 4.5

NS

Fasting insulin (μIU/L)

25.1 ± 10.6

24.3 ± 9.7

NS

19.1 ± 9.3

27.7 ± 13.9

0.01

Fasting glucose (mg/dl)

73.3 ± 13.7

72.9 ± 8.7

NS

81.3 ± 16.0

80.2 ± 11.9

NS

AUC, insulin (μIU/L·h)

344.0± 183.2

220.7± 102.2

0.02

202.5 ± 82.3

204.6 ± 80.3

NS

AUC, glucose( mmol/L·h)

13.9 ± 2.2

14.4 ± 2.4

NS

14.5 ± 4.1

15.2 ± 3.6

NS

SiM index

0.54 ± 0.38

0.76 ± 0.44

0.02

0.7 ±0.56

0.82 ± 0.6

NS

Leptin (ng/ml)

28.6±9.4

26.8±13.1

NS

45.6 ± 10.5

49.0 ± 20.7

NS

IGF-I (ng/ml)

193.4±124.6

158.2 ±49.6

NS

136.8±22.1

142.4±45.1

NS

Obesity

BMI < 37

Obesity

BMI > 37

n=7

n=12

Parameter

Pretreatment

16 wk

P

Pretreatment

16 wk

P

mean ± SD

mean ± SD

mean ± SD

mean ± SD

Triglycerides (mg/dl)

172.6 ± 74.6

170.3± 70.7

NS

131.6 ± 54.7

132.0 ± 43.8

NS

HbA1c ( %)

5.0 ± 2.06

5.5 ± 0.38

NS

6.0 ± 0.6

5.6 ± 0.2

0.03

↓60

There was no significant difference in pretreatment levels of total testosterone, SHBG and cholesterol among these groups. Leptin levels were significantly higher in more

obese patients ( 45.6 ± 10.5 (women with BMI<37) vs. 28.6±9.4 (women with BMI >37)).

However, it is interesting that women with BMI<37 have higher AUC insulin levels and fasting insulin levels (P<0.04) than patients with BMI>37.

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After 16 weeks of metformin treatment AUC insulin and SHBG concentrations changed significantly only in leaner PCOS women. SHBG concentrations increased from 23.0 ± 6.8 to 30.4 ± 13.1 nmol/L , P=0.05. Area Under the Curve (insulin) decreased from 344.0± 183.2 to 220.7± 102.2 μIU/L, P=0.02.

Fasting insulin levels increased significantly after 16 weeks of metformin treatment in more obese women with BMI>37 (19.1 ± 9.3 (pretreatment) vs. 27.7 ± 13.9 (posttreatment) μIU/L, P=0.01). Fasting insulin levels did not change in the metformin-treated patients with BMI<37.

Free androgen index (FAI) showed a tendency to decrease in the leaner subgroup (9.9 ± 4.2 (pretreatment) vs.  8.0 ± 3.9 (posttreatment)) but P value did not achieve statistical significance.

Menstrual Cycle

↓62

Before treatment, three of seven women with BMI<37 had amenorrhea, two had oligomenorrhea and two patients had a regular menstrual cycle. In the group of patients with BMI>37, three of twelve women had amenorrhea, six women had chronic oligomenorrhea and three patients had a regular menstrual cycle.

Table 14 demonstrates changes in menstrual history in patients with PCOS after metformin treatment.

Table 14: Menstrual cycle in women with PCOS before and after metformin treatment, subgroup analysis

BMI<37

n=7

BMI>37

n=12

0 week

16 weeks

0 week

16 weeks

Amenorrhea

3

1

3

2

Oligomenorrhea

2

3

6

2

Regular cycle

2

3

3

8

3.8 Correlation Analysis

↓63

The correlation analysis was undertaken to reveal a relationship between several clinical and metabolic parameters, such as BMI, leptin, insulin, SHBG and lipids.

Leptin

Leptin level correlated strongly with Body Mass Index in women with PCOS (r=0.53, P<0.001). No significant correlation was found between serum leptin concentrations and insulin.

↓64

Figure XIX. Correlation between BMI and leptin concentrations in women with PCOS, r=0.53; n=46

Insulin

AUC insulin significantly correlated with free androgen index (r=0.38; P<0.01).

Figure XX. Correlation between Free Androgen Index (FAI) and AUC insulin, n=46

↓65

A significant inverse correlation between fasting insulin and HDL cholesterol levels

was demonstrated (r=-0.37, P<0.02).

Figure XXI. Correlation between HDL total cholesterol and fasting insulin
in women with PCOS, n=46

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A significant positive correlation between 2-hours insulin and total cholesterol (r=0.5; P<0.002) was shown.

Figure XXII. Correlation between total cholesterol and 2 hour insulin
in women with PCOS, n=46

3.9 Menstrual Cycle

There was a strong correlation between menstrual dysfunction and insulin resistance in the whole group. As one can see in the table 13, eight of ten (80%) patients with amenorrhea fulfilled criteria for insulin resistance (Insulin sensitivity index (SiM)<1). Eighteen of twenty (80%) oligomenorrheic women had insulin resistance as well. There were three of seven (42.8%) patients with regular cycle who fulfilled criteria for insulin resistance.

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Table 15: Menstrual disfunction and insulin resistance.

 

Amenorrhea n=10

Oligomenorrhea n=20

Regular Cycle n=7

 

mean±SD

mean±SD

mean±SD

Insulin Sensitivity Index (SiM)

0.54±0.31

0.57±0.3

1.4±1.1

 

8 of 10 (80%)

18 of 20 (80%)

3 of 7 (42.8%)

IGF-I

After 16 weeks of metformin treatment changes in IGF-I level correlated with changes in AUC insulin (r=0.56, P<0.01).

Figure XXIII. Correlation between changes in IGF-I levels and AUC insulin in the  
metformin-treated group, n=19

↓68

Changes in IGF-I level showed a tendency to correlate with changes in HDL-cholesterol concentrations (r=-0.59; P<0.008) in the metformin-treated group.

Figure XXIV. Correlation between changes in IGF-I and HDL cholesterol levels in the
metformin-treated group, n=19


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