MEDLINE Abstracts: Polycystic Ovary Syndrome
MEDLINE Abstracts: Polycystic Ovary Syndrome
Kolodziejczyk B, Duleba AJ, Spaczynski RZ, et al
Fertil Steril. 2000 Jun;73(6):1149-1154
Objective: To evaluate the effects of 12 weeks of metformin therapy on hormonal and clinical indices in polycystic ovary syndrome (PCOS). DESIGN: Prospective study.
Setting: University hospital.
Patient(s): Thirty-nine women with PCOS and fasting hyperinsulinemia.
Intervention(S): Twelve weeks of therapy with oral metformin (500 mg three times per day).
Main Outcome Measure(S): Levels of insulin, T, DHEAS, insulin-like growth factor-I (IGF-I), gonadotropins, and sex hormone-binding globulin (SHBG); and clinical symptoms including acne, hirsutism, and length of the menstrual cycle were assessed before and after treatment with metformin.
Result(s): Metformin therapy resulted in a significant decrease in fasting insulin and total T and an increase in SHBG, leading to a decrease in the free T index. In addition, there was a significant decline in mean body mass index, waist-hip ratio, hirsutism, and acne, as well as an improvement in the menstrual cycle. No changes in LH and LH-FSH ratio were observed. Multiple regression analysis demonstrated that the greatest decline of T and free T index in response to metformin was observed among patients with the most pronounced hyperandrogenemia. Subjects with elevated DHEAS differed from those with normal DHEAS in their responses to metformin treatment. Women with high DHEAS exhibited less improvement of menstrual cycle regularity, no change in hirsutism, and an increase in levels of IGF-I after treatment.
Conclusion(s): Metformin treatment of women with PCOS results in a decline of insulin as well as total and bioavailable T, leading to significant improvement of clinical manifestations of hyperandrogenism. Responses to metformin are related to the severity of hyperandrogenemia and to adrenal function.
Unluhizarci K, Kelestimur F, Bayram F, et al
Clin Endocrinol. (Oxf) 1999 Aug;51(2):231-6
Objective: Polycystic ovary syndrome (PCOS) is a form of functional ovarian hyperandrogenism and affects approximately 5-10% of women of reproductive age. Insulin resistance and hyperinsulinaemia appear to be almost universal feature of the polycystic ovary syndrome. Abnormal regulation of cytochrome P450c17alpha causes the exaggerated secretion of ovarian androgens in PCOS. The aim of the present study was to determine whether reduction of insulin levels by metformin would attenuate FSH, LH, 17-Hydroxyprogesterone (17-OHP) and androstenedione hyperresponsiveness to buserelin testing in PCOS women.
Design: The presence of hyperinsulinaemia in 16 women with PCOS was demonstrated by an oral glucose tolerance test (OGTT) and results were compared with 13 healthy women. PCOS women were also evaluated with insulin tolerance test (ITT) for the assessment of insulin sensitivity. FSH, LH, 17-OHP and androstenedione responses to buserelin testing were measured in all the women with PCOS. PCOS patients were given metformin (500 mg, orally, two times daily) for 12 weeks and re-evaluated at the end of the treatment period.
Results: Women with PCOS were hyperinsulinaemic (basal insulin 92.1+/-14.3 vs. 44.0+/-4.0 pmol/l; AUCinsulin 68087.4+/-8862.3 vs. 13075.5+/-1327.6 pmol/lx120 min) compared with healthy women. Metformin therapy improved menstrual disturbances in 25% of the women with PCOS and also resulted in some improvement in insulin sensitivity and reduced basal and post glucose load insulin levels. However, FSH, LH, 17-OHP and androstenedione responses to buserelin testing were unaltered in response to metformin.
Conclusion: It is clear that PCOS is often associated with profound insulin resistance and hyperinsulinaemia. These abnormalities explain the increased prevalence of glucose intolerance in women with PCOS and metformin has beneficial effects on insulin sensitivity in women with PCOS. Amelioration of hyperinsulinaemia has no significant effect on ovarian cytochrome P450c17alpha enzyme activity. However, it can be used in obese women with PCOS as an adjuvant therapy and long term studies should be performed to evaluate the endocrine effects of metformin in women with PCOS.
Pugeat M, Ducluzeau PH
Drugs. 1999;58 Suppl 1:41-6; discussion 75-82
Polycystic ovary syndrome (PCOS) is the most common disorder of ovarian function in premenopausal women. PCOS is characterised by chronic anovulation and androgen excess with clinical manifestation of irregular menstrual cycles, hirsutism and/or acne. Insulin resistance with resultant hyperinsulinaemia, irrespective of excess weight or frank obesity, has been reported in patients with PCOS, and, as insulin has a direct effect on ovarian androgen production in vitro, insulin resistance may play a crucial role in the physiopathology of PCOS. Although the molecular mechanism(s) of insulin resistance in PCOS is unclear, excessive insulin-independent serine phosphorylation of the beta subunit of the insulin receptor, as reported in some patients with PCOS, has been put forward as a new mechanism for insulin resistance. Insulin-sensitising agents have recently been investigated for their role in the short term treatment of insulin resistance in PCOS. Controlled studies have shown that metformin administration, by promoting bodyweight loss, can decrease fasting and stimulated plasma insulin levels. However, other studies have shown metformin 500 mg 3 times daily to decrease insulin secretion and to reduce ovarian production of 17alpha-hydroxyprogesterone with recovery of spontaneous or clomifene-induced ovulation, independently of weight loss. These findings suggest a new indication for metformin and present insulin-sensitising agents as a novel approach in the treatment of ovarian hyperandrogenism and abnormal ovulation in PCOS. They also suggest that long term administration of metformin might be helpful in treating insulin resistance, thus reducing risks of type 2 (non-insulin-dependent) diabetes and cardiovascular disease in these patients.
Seale FG, Robinson RD, Neal GS
J Reprod Med. 2000 Jun;45(6):507-510
Background: Infertility is a common manifestation of the polycystic ovary syndrome (PCOS), a condition characterized by chronic anovulation, hyperinsulinemia and hyperandrogenism. Hyperinsulinemia leads to increased ovarian androgen production, resulting in follicular atresia and anovulation. Metformin, a medication that improves insulin sensitivity and decreases serum insulin levels, restores menstrual cyclicity and ovulatory function and may improve fertility rates in women with PCOS. We present three consecutive cases from our clinic that support this premise.
Cases: Three patients were seen in the reproductive endocrinology clinic with documented PCOS, long-standing infertility and clinically diagnosed insulin resistance. The first patient had hyperandrogenic, insulin-resistant acanthosis nigricans syndrome and had been resistant to multiple courses of clomiphene citrate; the second exhibited hypertension, hyperlipidemia and glucose intolerance along with anovulation; and the third presented with poorly controlled type 2 diabetes and a desire to conceive. Each patient received metformin, which led to restoration of menstrual cyclicity and conception in all three cases.
Conclusion: These three patients reflect the heterogeneous nature of PCOS, and treating their underlying insulin resistance with metformin resulted in pregnancy. These findings suggest that metformin may be a useful adjunct for treatment of infertility in patients with PCOS.
la Marca A, Egbe TO, Morgante G, et al
Hum Reprod. 2000 Jan;15(1):21-3
It has recently been proposed that hyperinsulinaemic insulin resistance and increased ovarian cytochrome P-450c17alpha activity, two features of the polycystic ovary syndrome (PCOS), are pathogenetically linked. The aim of the present study was to test the hypothesis of the linkage between hyperinsulinaemia and supranormal activity of cytochrome P-450c17alpha using the human chorionic gonadotrophin (HCG) challenge, which is a more direct ovarian stimulus than gonadotrophin-releasing hormone (GnRH) in detecting modifications in ovarian steroidogenesis. Eleven women with insulin resistance-related PCOS were studied. HCG (10 000 IU) was given i.m., and blood samples were obtained 0, 8, 12, 16 and 24 h thereafter. Next day, metformin was given at a dose of 500 mg three times a day for 30-32 days, at which time the pretreatment study was repeated. Two women ovulated after metformin treatment. The administration of metformin was associated with a decrease in area under the curve for insulin during a 2h, 75g oral glucose tolerance test, in plasma free testosterone concentrations and an increase in plasma sex hormone binding globulin concentration. The plasma 17-hydroxyprogesterone response to HCG was significantly lower after metformin treatment. The present study gives a direct demonstration that metformin leads to a reduction in stimulated ovarian cytochrome P-450c17alpha activity in women with polycystic ovary syndrome.
De Leo V, La Marca A, Orvieto R, et al
J Clin Endocrinol Metab. 2000 Apr;85(4):1598-600
The objective of the present study was to investigate whether metformin affected plasma concentrations of insulin-like growth factor (IGF) I and IGF-binding protein I (IGFBP-I) in polycystic ovary syndrome (PCOS) patients. This was an open study conducted by the Department of Obstetrics and Gynecology at the University of Siena, Italy. Seventeen women with PCOS participated in the study and were administered metformin at a dose of 500 mg three times a day. Treatment was continued for 30-32 days, after which the pretreatment evaluation was repeated. Plasma concentrations of LH, FSH, estradiol, free testosterone, IGF-I, IGFBP-I, sex hormone-binding globulin, and insulin were evaluated. Metformin led to a significant reduction in areas under the insulin curves (9310 +/- 1509 vs. 6520 +/-1108 mU/mL x min; P < 0.05) and was associated with a decrease in plasma free testosterone levels (12.7 +/- 1.7 vs. 10.3 +/- 2 pg/mL; P < 0.05) and an increase in plasma sex hormone-binding globulin concentrations (62 +/- 8 vs. 94 +/- 13 nmol/L; P < 0.05). A nonsignificant increase in plasma IGF-I levels was observed after metformin (276 +/-48 vs. 291 +/- 71 mcg/L), with a significant increase in plasma IGFBP-I levels (0.56 +/- 0.2 vs. 0.98 +/- 0.38 mcg/L; P < 0.05). The IGF-I/IGFBP-I ratio was significantly lower (492.8 +/- 117 vs. 296.9 +/- 82; P < 0.05) at the end of therapy than before treatment. In conclusion, it seems to be appropriate to intervene with an insulin-sensitizing agent such as metformin in an attempt to break the pathogenetic link between hyperinsulinemia and hormonal perturbations in PCOS.
la Marca A, Morgante G, Paglia T, et al
Fertil Steril .1999 Dec;72(6):985-9
Objective: To determine whether the administration of metformin, an insulin-sensitizing agent, is followed by changes in adrenal steroidogenesis in women with polycystic ovary syndrome (PCOS).
Design: Prospective trial.
Setting: Department of Obstetrics and Gynecology, University of Siena, Siena, Italy.
Patient(s): Fourteen women with PCOS.
Intervention(s): Blood samples were obtained before (-15 and 0 minutes) and after (15, 30, 45, and 60 minutes) the administration of ACTH (250 microg). Metformin then was given at a dosage of 500 mg three times a day for 30-32 days, at which time the pretreatment study was repeated.
Main Outcome Measure(s): The adrenal androgen responses to ACTH before and after treatment with metformin.
Result(s): Ovulation occurred in two women (14%) in response to metformin treatment. A significant reduction in basal concentrations of free testosterone and a significant increase in concentrations of sex hormone-binding globulin were observed. The administration of metformin was associated with a significant reduction in the response of 17alpha-hydroxyprogesterone, testosterone, free testosterone, and androstenedione to ACTH. The ratio of 17alpha-hydroxyprogesterone to progesterone, which indicates 17alpha-hydroxylase activity, and the ratio of androstenedione to 17alpha-hydroxyprogesterone, which indicates 17,20-lyase activity, were significantly lower after a month of metformin treatment, indicating a reduction in the activities of these enzymes.
Conclusion(s): The administration of metformin to unselected women with PCOS led to a reduction in the adrenal steroidogenesis response to ACTH. This finding supports the hypothesis that high insulin levels associated with PCOS may cause an increase in plasma levels of adrenal androgens.
Moghetti P, Castello R, Negri C, et al
J Clin Endocrinol Metab. 2000 Jan;85(1):139-46
In the last few years some studies assessed the effects of attenuation of hyperinsulinemia and insulin resistance, obtained by insulin sensitizing agents, in women with polycystic ovary syndrome (PCOS), suggesting potential scope for these drugs in treating the whole spectrum of reproductive, endocrine, and metabolic abnormalities found in such subjects. However, the results of these studies, mostly uncontrolled and short-term, are still inconclusive, and there is no long-term follow-up. In the present study, 23 PCOS subjects [mean (+/- SE) body mass index 30.0+/-1.1 kg/m2] were randomly assigned to double-blind treatment with metformin (500 mg tid) or placebo for 6 months, while maintaining their usual eating habits. Before and after treatment, menstrual history, endocrine and metabolic profiles, serum 17-hydroxyprogesterone response to GnRH-agonist testing, and insulin sensitivity measured by the glucose clamp technique were assessed. Eighteen of these women, as well as 14 additional PCOS patients, were subsequently given metformin in an open trial for 11.0+/-1.3 months (range 4-26), to assess long-term effects of treatment and baseline predictors of metformin efficacy on reproductive abnormalities. After metformin treatment, mean frequency of menstruation improved (P = 0.002), due to striking amelioration of menstrual abnormalities in about 50% of subjects. Women given metformin showed reduced plasma insulin (at fasting: P = 0.057; during the clamp studies: P<0.01) and increased insulin sensitivity (P<0.05). Concurrently, ovarian hyperandrogenism was attenuated, as indicated by significant reductions in serum free testosterone (P<0.05) and in the 17-hydroxyprogesterone response to GnRH-agonist testing (P<0.05). No changes were found in the placebo group. Only comparable minor changes in body mass index were found both in the metformin group and in the placebo group. In the open, long-term trial 17 women (54.8%) showed striking improvements of their menstrual abnormalities and were considered as responders. Logistic regression analysis of baseline characteristics in responders and nonresponders showed that plasma insulin, serum androstenedione, and menstrual history were independent predictors of the treatment's clinical efficacy. In 10 subjects whose menses proved regular after treatment, the great majority of cycles became ovulatory (32 out of 39 assessed, 79%). In conclusion, in women with PCOS metformin treatment reduced hyperinsulinemia and hyperandrogenemia, independently of changes in body weight. In a large number of subjects these changes were associated with striking, sustained improvements in menstrual abnormalities and resumption of ovulation. Higher plasma insulin, lower serum androstenedione, and less severe menstrual abnormalities are baseline predictors of clinical response to metformin.
MEDLINE Abstracts: Polycystic Ovary Syndrome
Metformin Therapy Decreases Hyperandrogenism and Hyperinsulinemia in Women With Polycystic Ovary Syndrome
Kolodziejczyk B, Duleba AJ, Spaczynski RZ, et al
Fertil Steril. 2000 Jun;73(6):1149-1154
Objective: To evaluate the effects of 12 weeks of metformin therapy on hormonal and clinical indices in polycystic ovary syndrome (PCOS). DESIGN: Prospective study.
Setting: University hospital.
Patient(s): Thirty-nine women with PCOS and fasting hyperinsulinemia.
Intervention(S): Twelve weeks of therapy with oral metformin (500 mg three times per day).
Main Outcome Measure(S): Levels of insulin, T, DHEAS, insulin-like growth factor-I (IGF-I), gonadotropins, and sex hormone-binding globulin (SHBG); and clinical symptoms including acne, hirsutism, and length of the menstrual cycle were assessed before and after treatment with metformin.
Result(s): Metformin therapy resulted in a significant decrease in fasting insulin and total T and an increase in SHBG, leading to a decrease in the free T index. In addition, there was a significant decline in mean body mass index, waist-hip ratio, hirsutism, and acne, as well as an improvement in the menstrual cycle. No changes in LH and LH-FSH ratio were observed. Multiple regression analysis demonstrated that the greatest decline of T and free T index in response to metformin was observed among patients with the most pronounced hyperandrogenemia. Subjects with elevated DHEAS differed from those with normal DHEAS in their responses to metformin treatment. Women with high DHEAS exhibited less improvement of menstrual cycle regularity, no change in hirsutism, and an increase in levels of IGF-I after treatment.
Conclusion(s): Metformin treatment of women with PCOS results in a decline of insulin as well as total and bioavailable T, leading to significant improvement of clinical manifestations of hyperandrogenism. Responses to metformin are related to the severity of hyperandrogenemia and to adrenal function.
The Effects of Metformin on Insulin Resistance and Ovarian Steroidogenesis in Women With Polycystic Ovary Syndrome
Unluhizarci K, Kelestimur F, Bayram F, et al
Clin Endocrinol. (Oxf) 1999 Aug;51(2):231-6
Objective: Polycystic ovary syndrome (PCOS) is a form of functional ovarian hyperandrogenism and affects approximately 5-10% of women of reproductive age. Insulin resistance and hyperinsulinaemia appear to be almost universal feature of the polycystic ovary syndrome. Abnormal regulation of cytochrome P450c17alpha causes the exaggerated secretion of ovarian androgens in PCOS. The aim of the present study was to determine whether reduction of insulin levels by metformin would attenuate FSH, LH, 17-Hydroxyprogesterone (17-OHP) and androstenedione hyperresponsiveness to buserelin testing in PCOS women.
Design: The presence of hyperinsulinaemia in 16 women with PCOS was demonstrated by an oral glucose tolerance test (OGTT) and results were compared with 13 healthy women. PCOS women were also evaluated with insulin tolerance test (ITT) for the assessment of insulin sensitivity. FSH, LH, 17-OHP and androstenedione responses to buserelin testing were measured in all the women with PCOS. PCOS patients were given metformin (500 mg, orally, two times daily) for 12 weeks and re-evaluated at the end of the treatment period.
Results: Women with PCOS were hyperinsulinaemic (basal insulin 92.1+/-14.3 vs. 44.0+/-4.0 pmol/l; AUCinsulin 68087.4+/-8862.3 vs. 13075.5+/-1327.6 pmol/lx120 min) compared with healthy women. Metformin therapy improved menstrual disturbances in 25% of the women with PCOS and also resulted in some improvement in insulin sensitivity and reduced basal and post glucose load insulin levels. However, FSH, LH, 17-OHP and androstenedione responses to buserelin testing were unaltered in response to metformin.
Conclusion: It is clear that PCOS is often associated with profound insulin resistance and hyperinsulinaemia. These abnormalities explain the increased prevalence of glucose intolerance in women with PCOS and metformin has beneficial effects on insulin sensitivity in women with PCOS. Amelioration of hyperinsulinaemia has no significant effect on ovarian cytochrome P450c17alpha enzyme activity. However, it can be used in obese women with PCOS as an adjuvant therapy and long term studies should be performed to evaluate the endocrine effects of metformin in women with PCOS.
Insulin Resistance, Polycystic Ovary Syndrome and Metformin
Pugeat M, Ducluzeau PH
Drugs. 1999;58 Suppl 1:41-6; discussion 75-82
Polycystic ovary syndrome (PCOS) is the most common disorder of ovarian function in premenopausal women. PCOS is characterised by chronic anovulation and androgen excess with clinical manifestation of irregular menstrual cycles, hirsutism and/or acne. Insulin resistance with resultant hyperinsulinaemia, irrespective of excess weight or frank obesity, has been reported in patients with PCOS, and, as insulin has a direct effect on ovarian androgen production in vitro, insulin resistance may play a crucial role in the physiopathology of PCOS. Although the molecular mechanism(s) of insulin resistance in PCOS is unclear, excessive insulin-independent serine phosphorylation of the beta subunit of the insulin receptor, as reported in some patients with PCOS, has been put forward as a new mechanism for insulin resistance. Insulin-sensitising agents have recently been investigated for their role in the short term treatment of insulin resistance in PCOS. Controlled studies have shown that metformin administration, by promoting bodyweight loss, can decrease fasting and stimulated plasma insulin levels. However, other studies have shown metformin 500 mg 3 times daily to decrease insulin secretion and to reduce ovarian production of 17alpha-hydroxyprogesterone with recovery of spontaneous or clomifene-induced ovulation, independently of weight loss. These findings suggest a new indication for metformin and present insulin-sensitising agents as a novel approach in the treatment of ovarian hyperandrogenism and abnormal ovulation in PCOS. They also suggest that long term administration of metformin might be helpful in treating insulin resistance, thus reducing risks of type 2 (non-insulin-dependent) diabetes and cardiovascular disease in these patients.
Association of Metformin and Pregnancy in the Polycystic Ovary Syndrome: A Report of Three Cases
Seale FG, Robinson RD, Neal GS
J Reprod Med. 2000 Jun;45(6):507-510
Background: Infertility is a common manifestation of the polycystic ovary syndrome (PCOS), a condition characterized by chronic anovulation, hyperinsulinemia and hyperandrogenism. Hyperinsulinemia leads to increased ovarian androgen production, resulting in follicular atresia and anovulation. Metformin, a medication that improves insulin sensitivity and decreases serum insulin levels, restores menstrual cyclicity and ovulatory function and may improve fertility rates in women with PCOS. We present three consecutive cases from our clinic that support this premise.
Cases: Three patients were seen in the reproductive endocrinology clinic with documented PCOS, long-standing infertility and clinically diagnosed insulin resistance. The first patient had hyperandrogenic, insulin-resistant acanthosis nigricans syndrome and had been resistant to multiple courses of clomiphene citrate; the second exhibited hypertension, hyperlipidemia and glucose intolerance along with anovulation; and the third presented with poorly controlled type 2 diabetes and a desire to conceive. Each patient received metformin, which led to restoration of menstrual cyclicity and conception in all three cases.
Conclusion: These three patients reflect the heterogeneous nature of PCOS, and treating their underlying insulin resistance with metformin resulted in pregnancy. These findings suggest that metformin may be a useful adjunct for treatment of infertility in patients with PCOS.
Metformin Treatment Reduces Ovarian Cytochrome P-450c17alpha Response to Human Chorionic Gonadotrophin in Women With Insulin Resistance-Related Polycystic Ovary Syndrome
la Marca A, Egbe TO, Morgante G, et al
Hum Reprod. 2000 Jan;15(1):21-3
It has recently been proposed that hyperinsulinaemic insulin resistance and increased ovarian cytochrome P-450c17alpha activity, two features of the polycystic ovary syndrome (PCOS), are pathogenetically linked. The aim of the present study was to test the hypothesis of the linkage between hyperinsulinaemia and supranormal activity of cytochrome P-450c17alpha using the human chorionic gonadotrophin (HCG) challenge, which is a more direct ovarian stimulus than gonadotrophin-releasing hormone (GnRH) in detecting modifications in ovarian steroidogenesis. Eleven women with insulin resistance-related PCOS were studied. HCG (10 000 IU) was given i.m., and blood samples were obtained 0, 8, 12, 16 and 24 h thereafter. Next day, metformin was given at a dose of 500 mg three times a day for 30-32 days, at which time the pretreatment study was repeated. Two women ovulated after metformin treatment. The administration of metformin was associated with a decrease in area under the curve for insulin during a 2h, 75g oral glucose tolerance test, in plasma free testosterone concentrations and an increase in plasma sex hormone binding globulin concentration. The plasma 17-hydroxyprogesterone response to HCG was significantly lower after metformin treatment. The present study gives a direct demonstration that metformin leads to a reduction in stimulated ovarian cytochrome P-450c17alpha activity in women with polycystic ovary syndrome.
Effect of Metformin on Insulin-Like Growth Factor (IGF) I And IGF-Binding Protein I in Polycystic Ovary Syndrome
De Leo V, La Marca A, Orvieto R, et al
J Clin Endocrinol Metab. 2000 Apr;85(4):1598-600
The objective of the present study was to investigate whether metformin affected plasma concentrations of insulin-like growth factor (IGF) I and IGF-binding protein I (IGFBP-I) in polycystic ovary syndrome (PCOS) patients. This was an open study conducted by the Department of Obstetrics and Gynecology at the University of Siena, Italy. Seventeen women with PCOS participated in the study and were administered metformin at a dose of 500 mg three times a day. Treatment was continued for 30-32 days, after which the pretreatment evaluation was repeated. Plasma concentrations of LH, FSH, estradiol, free testosterone, IGF-I, IGFBP-I, sex hormone-binding globulin, and insulin were evaluated. Metformin led to a significant reduction in areas under the insulin curves (9310 +/- 1509 vs. 6520 +/-1108 mU/mL x min; P < 0.05) and was associated with a decrease in plasma free testosterone levels (12.7 +/- 1.7 vs. 10.3 +/- 2 pg/mL; P < 0.05) and an increase in plasma sex hormone-binding globulin concentrations (62 +/- 8 vs. 94 +/- 13 nmol/L; P < 0.05). A nonsignificant increase in plasma IGF-I levels was observed after metformin (276 +/-48 vs. 291 +/- 71 mcg/L), with a significant increase in plasma IGFBP-I levels (0.56 +/- 0.2 vs. 0.98 +/- 0.38 mcg/L; P < 0.05). The IGF-I/IGFBP-I ratio was significantly lower (492.8 +/- 117 vs. 296.9 +/- 82; P < 0.05) at the end of therapy than before treatment. In conclusion, it seems to be appropriate to intervene with an insulin-sensitizing agent such as metformin in an attempt to break the pathogenetic link between hyperinsulinemia and hormonal perturbations in PCOS.
Effects of Metformin on Adrenal Steroidogenesis in Women With Polycystic Ovary Syndrome
la Marca A, Morgante G, Paglia T, et al
Fertil Steril .1999 Dec;72(6):985-9
Objective: To determine whether the administration of metformin, an insulin-sensitizing agent, is followed by changes in adrenal steroidogenesis in women with polycystic ovary syndrome (PCOS).
Design: Prospective trial.
Setting: Department of Obstetrics and Gynecology, University of Siena, Siena, Italy.
Patient(s): Fourteen women with PCOS.
Intervention(s): Blood samples were obtained before (-15 and 0 minutes) and after (15, 30, 45, and 60 minutes) the administration of ACTH (250 microg). Metformin then was given at a dosage of 500 mg three times a day for 30-32 days, at which time the pretreatment study was repeated.
Main Outcome Measure(s): The adrenal androgen responses to ACTH before and after treatment with metformin.
Result(s): Ovulation occurred in two women (14%) in response to metformin treatment. A significant reduction in basal concentrations of free testosterone and a significant increase in concentrations of sex hormone-binding globulin were observed. The administration of metformin was associated with a significant reduction in the response of 17alpha-hydroxyprogesterone, testosterone, free testosterone, and androstenedione to ACTH. The ratio of 17alpha-hydroxyprogesterone to progesterone, which indicates 17alpha-hydroxylase activity, and the ratio of androstenedione to 17alpha-hydroxyprogesterone, which indicates 17,20-lyase activity, were significantly lower after a month of metformin treatment, indicating a reduction in the activities of these enzymes.
Conclusion(s): The administration of metformin to unselected women with PCOS led to a reduction in the adrenal steroidogenesis response to ACTH. This finding supports the hypothesis that high insulin levels associated with PCOS may cause an increase in plasma levels of adrenal androgens.
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
Moghetti P, Castello R, Negri C, et al
J Clin Endocrinol Metab. 2000 Jan;85(1):139-46
In the last few years some studies assessed the effects of attenuation of hyperinsulinemia and insulin resistance, obtained by insulin sensitizing agents, in women with polycystic ovary syndrome (PCOS), suggesting potential scope for these drugs in treating the whole spectrum of reproductive, endocrine, and metabolic abnormalities found in such subjects. However, the results of these studies, mostly uncontrolled and short-term, are still inconclusive, and there is no long-term follow-up. In the present study, 23 PCOS subjects [mean (+/- SE) body mass index 30.0+/-1.1 kg/m2] were randomly assigned to double-blind treatment with metformin (500 mg tid) or placebo for 6 months, while maintaining their usual eating habits. Before and after treatment, menstrual history, endocrine and metabolic profiles, serum 17-hydroxyprogesterone response to GnRH-agonist testing, and insulin sensitivity measured by the glucose clamp technique were assessed. Eighteen of these women, as well as 14 additional PCOS patients, were subsequently given metformin in an open trial for 11.0+/-1.3 months (range 4-26), to assess long-term effects of treatment and baseline predictors of metformin efficacy on reproductive abnormalities. After metformin treatment, mean frequency of menstruation improved (P = 0.002), due to striking amelioration of menstrual abnormalities in about 50% of subjects. Women given metformin showed reduced plasma insulin (at fasting: P = 0.057; during the clamp studies: P<0.01) and increased insulin sensitivity (P<0.05). Concurrently, ovarian hyperandrogenism was attenuated, as indicated by significant reductions in serum free testosterone (P<0.05) and in the 17-hydroxyprogesterone response to GnRH-agonist testing (P<0.05). No changes were found in the placebo group. Only comparable minor changes in body mass index were found both in the metformin group and in the placebo group. In the open, long-term trial 17 women (54.8%) showed striking improvements of their menstrual abnormalities and were considered as responders. Logistic regression analysis of baseline characteristics in responders and nonresponders showed that plasma insulin, serum androstenedione, and menstrual history were independent predictors of the treatment's clinical efficacy. In 10 subjects whose menses proved regular after treatment, the great majority of cycles became ovulatory (32 out of 39 assessed, 79%). In conclusion, in women with PCOS metformin treatment reduced hyperinsulinemia and hyperandrogenemia, independently of changes in body weight. In a large number of subjects these changes were associated with striking, sustained improvements in menstrual abnormalities and resumption of ovulation. Higher plasma insulin, lower serum androstenedione, and less severe menstrual abnormalities are baseline predictors of clinical response to metformin.
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