[advanced fertility issues]

Information for TTC Couples...

Written by TTC Couples.

 

Metformin for PCOS & Pregnancy

This page has a simple goal -- to provide journal abstracts regarding metformin use for infertility, specifically PCOS, and abstracts on metformin use during pregnancy. These are very common questions asked by patients, and it is often accompanied by a request

for something the patient can print out for their doctor. You'll notice this page is really bland -- in order to make printing easy! These are from PubMed and your doctor can use the ID numbers to order full copies. You can also go check out PubMed at http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=PubMed.


Metformin for PCOS

Metformin in Pregnancy






Metformin for PCOS



1: J Clin Endocrinol Metab 2000 Aug;85(8):2767-74

Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome.

Pasquali R, Gambineri A, Biscotti D, Vicennati V, Gagliardi L, Colitta D, Fiorini S, Cognigni GE, Filicori M, Morselli-Labate AM

Department of Internal Medicine and Gastroenterology, S Orsola-Malpighi Hospital, Bologna, Italy. rpasqual@almadns.unibo.it

[Medline record in process]

Abdominal obesity and hyperinsulinemia play a key role in the development of the polycystic ovary syndrome (PCOS). Dietary-induced weight loss and the administration of insulin-lowering drugs, such as metformin, are usually followed by improved hyperandrogenism and related clinical abnormalities. This study was carried out to evaluate the effects of combined hypocaloric diet and metformin on body weight, fat distribution, the glucose-insulin system, and hormones in a group of 20 obese PCOS women [body mass index (BMI) > 28 kg/m2] with the abdominal phenotype (waist to hip ratio >0.80), and an appropriate control group of 20 obese women who were comparable for age and pattern of body fat distribution but without PCOS. At baseline, we measured sex hormone, sex hormone-binding globulin (SHBG), and leptin blood concentrations and performed an oral glucose tolerance test and computerized tomography (CT) at the L4-L5 level, to measure sc adipose tissue area (SAT) and visceral adipose tissue area. All women were then given a low-calorie diet (1,200-1,400 kcal/day) alone for one month, after which anthropometric parameters and CT scan were newly measured. While continuing dietary treatment, PCOS women and obese controls were subsequently placed, in a random order, on metformin (850 mg/os, twice daily) (12 and 8, respectively) or placebo (8 and 12, respectively), according to a double-blind design, for the following 6 months. Blood tests and the CT scan were performed in each woman at the end of the study while they were still on treatment. During the treatment period, 3 women of the control group (all treated with placebo) were excluded because of noncompliance; and 2 PCOS women, both treated with metformin, were also excluded because they became pregnant. Therefore, the women cohort available for final statistical analysis included 18 PCOS (10 treated with metformin and 8 with placebo) and 17 control women (8 treated with metformin and 9 with placebo). The treatment was well tolerated. In the PCOS group, metformin therapy improved hirsutism and menstrual cycles significantly more than placebo. Baseline anthropometric and CT parameters were similar in all groups. Hypocaloric dieting for 1 month similarly reduced BMI values and the waist circumference in both PCOS and control groups, without any significant effect on CT scan parameters. In both PCOS and control women, however, metformin treatment reduced body weight and BMI significantly more than placebo. Changes in the waist-to-hip ratio values were similar in PCOS women and controls, regardless of pharmacological treatment. Metformin treatment significantly decreased SAT values in both PCOS and control groups, although only in the latter group were SAT changes significantly greater than those observed during the placebo treatment. On the contrary, visceral adipose tissue area values significantly decreased during metformin treatment in both PCOS and control groups, but only in the former was the effect of metformin treatment significantly higher than that of placebo. Fasting insulin significantly decreased in both PCOS women and controls, regardless of treatment, whereas glucose-stimulated insulin significantly decreased only in PCOS women and controls treated with metformin. Neither metformin or placebo significantly modified the levels of LH, FSH, dehydroepiandrosterone sulphate, and progesterone in any group, whereas testosterone concentrations decreased only in PCOS women treated with metformin. SHBG concentrations remained unchanged in all PCOS women; whereas in the control group, they significantly increased after both metformin and placebo. Leptin levels decreased only during metformin treatment in both PCOS and control groups.

PMID: 10946879, UI: 20401703



2: Fertil Steril 2000 Aug;74(2):394-7

Polycystic ovary syndrome, infertility, familial thrombophilia, familial hypofibrinolysis, recurrent loss of in vitro fertilized embryos, and miscarriage.

Glueck CJ, Awadalla SG, Phillips H, Cameron D, Wang P, Fontaine RN

Cholesterol Center, Jewish Hospital, Cincinnati, Ohio, USA.

[Medline record in process]

Objective: To study reversible determinants of infertility and recurrent loss of transferred embryos after failure of 7 of 10 embryo transfers, 1 live birth, and 2 miscarriages.Design: Measures of thrombophilia, hypofibrinolysis, reproductive hormones, and androgenic steroids before and after metformin therapy.Setting: Outpatient clinical research center.Patient(s): A 32-year-old amenorrheic, infertile woman with polycystic ovary syndrome (PCOS) who had 7 of 10 embryo transfers fail, 1 premature live birth, and 2 miscarriages at 8 and 17 weeks.Intervention(s): Metformin (2.55 g/d) was given to ameliorate the endocrinopathy of PCOS.Main Outcome Measure(s): Coagulation, insulin, reproductive hormones, and androgenic steroids.Result(s): The propositus had thrombophilia (familial protein S deficiency [free protein S 32%; normal >/=65%]). She also had familial hypofibrinolysis with 4G4G polymorphism of the plasminogen activator inhibitor (PAI-1) gene and high PAI-1 activity (PAI-Fx), 42.5 U/mL, normal <21.1. Polycystic ovary syndrome was characterized by amenorrhea, polycystic ovaries, high fasting serum insulin (39 &mgr;U/mL, normal <20), androstenedione (763 ng/dL, normal <250), and testosterone (229 ng/dL, normal <83). After she received metformin for 4 months, PAI-Fx normalized (12.4 U/mL), as did insulin (12 &mgr;U/mL), androstenedione (185 ng/dL), and testosterone (39 ng/dL); weight fell from 109 to 91.3 kg (16%). Conclusion(s): Metformin reversed the endocrinopathy of PCOS. Familial thrombophilia and hypofibrinolysis may lead to thrombosis-mediated uteroplacental vascular insufficiency, failure to achieve pregnancy after embryo transfer, and miscarriage.

PMID: 10927066, UI: 20387192



3: J Reprod Med 2000 Jun;45(6):507-10

Association of metformin and pregnancy in the polycystic ovary syndrome. A report of three cases.

Seale FG 4th, Robinson RD, Neal GS

Department of Obstetrics and Gynecology, San Antonio Uniformed Services Health Education Consortium, Texas, USA. fred_g.seale@sa-chcs.mednet.af.mil

[Medline record in process]

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.

PMID: 10900588, UI: 20357809



4: Fertil Steril 2000 Jun;73(6):1149-54

Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome.

Kolodziejczyk B, Duleba AJ, Spaczynski RZ, Pawelczyk L

Division of Infertility and Reproductive Endocrinology, Department of Gynecology and Obstetrics, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.

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.

Publication Types:
Clinical trial

PMID: 10856473, UI: 20315927



5: Ann N Y Acad Sci 2000;900:203-12

Insulin sensitizers and antiandrogens in the treatment of polycystic ovary syndrome.

Diamanti-Kandarakis E, Zapanti E

1st Department of Internal Medicine, University of Athens Medical School, Greece.

The heterogeneous origin of polycystic ovary syndrome (PCOS) has been demonstrated by several studies. Abnormalities in steroidogenesis and metabolism are present, but the exact link between these two pathologic features remains to be clarified. In clinical practice, more than one therapeutic approach for the treatment of this syndrome has been proposed over the last few decades. Because hyperandrogenism and hyperinsulinemia contribute to a different degree to the phenotype of PCOS, therapeutic efforts have focused on agents that could treat or modify the clinical manifestations of these disorders. Antiandrogens as a sole treatment or combined with oral contraceptives are considered the treatment of choice for the manifestations of hyperandrogenemia, but there is no agreement about their efficacy on the metabolic sequelae of PCOS (insulin resistance, hyperinsulinemia, dislipidemia). Furthermore, the improvement of insulin sensitivity by insulin sensitizers may be of therapeutic value directly and/or indirectly in the management of clinical manifestations of hyperinsulinemia and hyperandrogenemia.

PMID: 10818407, UI: 20278348



6: Chung Hua Fu Chan Ko Tsa Chih 1998 Dec;33(12):731-4

[Role of hyperinsulinemia in pathogenesis of polycystic ovary syndrome and treatment by reduction of insulin secretion].

[Article in Chinese]

Wang A, Li M, Lu C

Naval General Nospital, Beijing.

OBJECTIVE: To investigate the role of insulin in the polycystic ovary syndrome (PCOS) pathogenesis and application of Metformin in the treatment of PCOS. METHODS: Serum androgen, luteinizing hormone (LH) and sex hormone-binding globulin(SHBG) concentration during fasting and serum 17 alpha-hydroxyprogesterone (17-OHP), LH level in response to gonadotropin-releasing hormone agonist (GnRH-a) stimulation were determined. Oral glucose-tolerance tests(OGTT) before and after oral administration of metoformin for 8-12 weeks were performed in 12 obese and 11 lean women with PCOS. RESULTS: After oral administration of metformin for 8-12 weeks, fasting insulin concentration in obese group and area under curve (AUC) after OGTT in lean group decreased significantly. There were significant decrease in basal 17 alpha-hydroprogesterone, androstenedione, testosterone concentration, and increase in serum SHBG concentration in obese and lean groups. Basal LH and the response of serum 17-OHP, LH to GnRHa were not significantly changed. CONCLUSIONS: Hyperinsulinemia may play an important role in hyperandrogenism GnRH-a of PCOS, and metformin may be used in the treatment of PCOS.

Publication Types:
Clinical trial
Randomized controlled trial


PMID: 10806662, UI: 20266625



7: J Clin Endocrinol Metab 2000 Apr;85(4):1598-600

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, Morgante G

Department of Obstetrics and Gynecology, University of Siena, Italy. deleo@unisi.it

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.

PMID: 10770203, UI: 20230972



8: Clin Endocrinol (Oxf) 2000 Feb;52(2):243; discussion 244-6

Metformin and ovarian steroidogenesis in PCOS women.

De Leo V, La Marca A, Morgante G

Publication Types:
Comment
Letter

Comments:
Comment on: Clin Endocrinol (Oxf) 1999 Aug;51(2):231-6

PMID: 10671955, UI: 20191686



9: J Clin Endocrinol Metab 2000 Jan;85(1):139-46

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, Tosi F, Perrone F, Caputo M, Zanolin E, Muggeo M

Division of Endocrinology and Metabolic Diseases, University of Verona, Italy. moghetti@iol.it

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.

Publication Types:
Clinical trial
Randomized controlled trial

PMID: 10634377, UI: 20097843



10: Hum Reprod 2000 Jan;15(1):21-3

Published erratum appears in Hum Reprod 2000 Mar;15(3):736 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, Paglia T, Cianci A, De Leo V

Department Obstetrics and Gynaecology, University of Siena, Policlinico Le Scotte, 53100 Siena, Hospital General de Douala, Cameroun and University of Catania, Italy.

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.

Publication Types:
Clinical trial

PMID: 10611182, UI: 20079186



11: Hum Reprod 1999 Dec;14(12):2963-8

Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea.

Pirwany IR, Yates RW, Cameron IT, Fleming R

University Department of Obstetrics and Gynaecology, Glasgow Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, UK.

Hyperinsulinaemic insulin resistance is commonly associated with hyperandrogenaemia, and menstrual dysfunction. The aim of this study was to examine the effects of the insulin sensitizing drug, metformin, on ovarian function, follicular growth, and ovulation rate in obese women with oligomenorrhoea. Twenty obese subjects with oligomenorrhoea [polycystic ovarian syndrome; (PCOS)] were observed longitudinally for 3 weeks prior to and for 8 weeks during treatment with metformin (850 mg twice per day). Fifteen patients completed the study. The frequency of ovulation was significantly higher during treatment than before treatment (P = 0.003). A significant decline in both testosterone and luteinizing hormone concentrations was recorded within 1 week of commencing treatment. Patients with elevated pretreatment testosterone concentrations showed the most marked increase in ovulation rate (P < 0.005), and significant reductions in circulating testosterone from 1.02 to 0.54 ng/ml (P < 0.005) after only 1 week of treatment. However, the sub-group with raised fasting insulin showed less marked changes, and the sub-group with normal testosterone concentrations showed no effect of treatment. Metformin had a rapid effect upon the abnormal ovarian function in hyperandrogenic women with PCOS, correcting the disordered ovarian steroid metabolism and ovulation rate; however, there appeared to be no effect in cases where the circulating androgen concentration was normal.

Publication Types:
Clinical trial

PMID: 10601079, UI: 20069806



12: J Gynecol Obstet Biol Reprod (Paris) 1999 Oct;28(6):510-8

[Diagnosis and treatment of polycystic ovary syndrome].

[Article in French]

Gandar R, Spizzo M, Collin D

Federation de Gynecologie-Obstetrique, Centre Hospitalier, Haguenau.

Obesity, ultrasonic ovarian morphology, serum LH levels and LH/FSH ratio are inconstant symptoms of the polycystic ovary syndrome (PCOS) and are thus no longer essential for diagnosis. PCOS is diagnosed today by the finding of chronic anovulation and hyperandrogenism characterized by a high serum level of "free" testoterone. The other causes of hyperandrogenism, as well as anovulations due to hyperprolactinemia, high levels of FSH and abnormal thyroid function have to be ruled out. PCOS is very often associated with insulin resistance (IR) and hyperinsulinemia (hyper I). From in vitro and vivo studies and treatment of hyper I, it has been shown that the hyper I of PCOS stimulates androgen production. Hyper I of PCOS increases the activity of androgens: by first provoking an important decrease of the sex hormone binding globulin (SHBG) thus increasing the "free", bioactive testosterone level. and then by activating the cytochrome P 450 c 17 alpha enzymatic system that controls androgen production. Subsequent to metformin administration, the reduction of hyper I and androgen serum levels creates a favorable condition for the resumption of ovarian function and clomiphene citrate action. This explains the high percentage of ovulations and pregnancies.

Publication Types:
Review
Review, tutorial

PMID: 10598343, UI: 20066290



13: Fertil Steril 1999 Dec;72(6):985-9

Published erratum appears in Fertil Steril 2000 Apr;73(4):874 Effects of metformin on adrenal steroidogenesis in women with polycystic ovary syndrome.

la Marca A, Morgante G, Paglia T, Ciotta L, Cianci A, De Leo V

Department of Obstetrics and Gynecology, University of Siena, Italy.

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.

Publication Types:
Clinical trial

PMID: 10593368, UI: 20058941



14: Drugs 1999;58 Suppl 1:41-6; discussion 75-82

Insulin resistance, polycystic ovary syndrome and metformin.

Pugeat M, Ducluzeau PH

Clinique Endocrinologique, Hopital de l'Antiquaille and INSERM U329, France. mrichard@cismsun.univ-lyon1.fr

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.

Publication Types:
Review
Review literature

PMID: 10576524, UI: 20041943



15: Hum Reprod 1999 Nov;14(11):2700-3

High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome.

Mitwally MF, Kuscu NK, Yalcinkaya TM

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, School of Medicine, West Virginia University Health Sciences Center, 830 Pennsylvania Avenue, Suite 304, Charleston, WV 25302, USA.

This preliminary report reviews our experience with 18 infertile patients with clomiphene-resistant polycystic ovary syndrome (PCOS). In the first treatment cycle, troglitazone was administered alone. During cycles 2-5, clomiphene was added with increments of 50 mg (up to 200 mg/day) if the previous cycle was anovulatory. Basal body temperature charts and serum progesterone were obtained to confirm ovulation. In a total of 66 treatment cycles, ovulation occurred in 44 (67%) and pregnancy in seven (11%). There were no significant changes in body weight, waist:hip ratio or liver enzymes during treatment. Troglitazone, alone or with clomiphene, induced ovulation in 15 of 18 patients (83%) and seven (39%) of them achieved pregnancy. This is the first report on ovulatory rates in clomiphene-resistant women with PCOS when troglitazone was used alone or with clomiphene. Recently, metformin and clomiphene were successfully used in women with PCOS. However, our patients represent a more resistant population of women with PCOS, with each patient serving as her own historical control by previous resistance to clomiphene. Although the pregnancy rate (39%) was promising for clomiphene-resistant women with polycystic ovary syndrome, it does not seem to have a definite advantage over gonadotrophins.

PMID: 10548604, UI: 20018196



16: Clin Endocrinol (Oxf) 1999 Aug;51(2):231-6

The effects of metformin on insulin resistance and ovarian steroidogenesis in women with polycystic ovary syndrome.

Unluhizarci K, Kelestimur F, Bayram F, Sahin Y, Tutus A

Departments of Endocrinology, Erciyes University School of Medicine, Kayseri, Turkey.

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.

Comments:
Comment in: Clin Endocrinol (Oxf) 2000 Feb;52(2):243; discussion 244-6
Comment in: Clin Endocrinol (Oxf) 2000 Feb;52(2):243-6

PMID: 10468995, UI: 20002377



17: Fertil Steril 1999 Aug;72(2):282-5

Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome.

De Leo V, la Marca A, Ditto A, Morgante G, Cianci A

Department of Obstetrics and Gynecology, University of Siena, Italy. deleo@unisi.it

OBJECTIVE: To evaluate whether pretreatment with metformin improves FSH-induced ovulation in women with clomiphene-resistant polycystic ovary syndrome (PCOS). DESIGN: Randomized prospective trial. SETTING: Department of Obstetrics and Gynecology, University of Siena. PATIENT(S): Twenty women with clomiphene citrate-resistant PCOS. INTERVENTION(S): The women were divided randomly into groups A and B (10 subjects each). Group B received 1,500 mg of metformin for at least a month before a single cycle of FSH stimulation. Group A underwent two cycles of FSH stimulation and then received metformin for a month before undergoing a third cycle. MAIN OUTCOME MEASURE(S): The number of FSH ampules, days of treatment, E2 level on the day of hCG, number of follicles > 15 mm, number of hyperstimulation, and the number of cycles with hCG withheld. RESULT(S): The number of follicles > 15 mm in diameter on the day of hCG administration was significantly lower in cycles performed after metformin treatment. The percentage of cycles with hCG withheld because of excessive follicular development was significantly lower in cycles treated with metformin. Plasma levels of E2 were significantly higher in cycles treated with FSH alone than in those treated with FSH and metformin. CONCLUSION(S): By reducing hyperinsulinism, metformin determines a reduction in intraovarian androgens. This leads to a reduction in E2 levels and favors orderly follicular growth in response to exogenous gonadotropins.

Publication Types:
Clinical trial
Randomized controlled trial

PMID: 10438996, UI: 99367851



18: Endocrinol Metab Clin North Am 1999 Jun;28(2):423-38, viii

Insulin-lowering therapeutic modalities for polycystic ovary syndrome.

Ehrmann DA

Department of Medicine, Pritzker School of Medicine, University of Chicago, Illinois, USA.

This article summarizes the relationship between insulin and androgen excess, with a focus on what is known regarding two related issues in polycystic ovary syndrome: (1) defects in insulin secretion in PCOS and their role in the development of glucose intolerance in this population; and (2) pharmacologic interventions designed to attenuate hyperinsulinemia and its sequelae in PCOS.

Publication Types:
Review
Review, tutorial

PMID: 10352927, UI: 99281193



19: Endocrinol Metab Clin North Am 1999 Jun;28(2):361-78

Insulin action in the normal and polycystic ovary.</p>

Franks S, Gilling-Smith C, Watson H, Willis D

Department of Reproductive Science and Medicine, Imperial College School of Medicine, St. Mary's Hospital, London, United Kingdom. s.franks@ic.ac.uk

Insulin has a stimulatory effect on steroidogenesis by granulosa cells of normal and polycystic ovaries and interacts with gonadotropins in an additive or, as in the case of LH, a synergistic manner. These actions seem to be mediated specifically by the insulin receptor rather than by cross-reaction with the type I IGF receptor, even in tissue obtained from women with PCOS with biochemical evidence of insulin resistance. The authors suggest that hyperinsulinemia makes a significant contribution to premature arrest of follicle growth, which is characteristic of anovulation in women with PCOS, and that the interaction of insulin with LH is a key element in this process. Insulin may also have a role in amplifying LH-induced androgen production by theca cells, which may help explain the prominence of symptoms of hyperandrogenism in obese subjects with PCOS. The results of recent clinical studies of insulin-sensitizing agents such as metformin and the thiazoladinedione troglitazone in PCOS have provided encouragement that improvement of insulin sensitivity and consequent lowering of circulating insulin levels by these agents may be of therapeutic value in the management of both anovulation and hirsutism.

Publication Types:
Review
Review, tutorial

PMID: 10352923, UI: 99281189



20: Diabet Med 1999 Mar;16(3):179-92

Thiazolidinediones: a new class of antidiabetic drugs.

Day C

Diabetes Research Group, Life and Health Sciences, Aston University, Birmingham, UK.

Thiazolidinediones (TZDs) are a new class of oral antidiabetic agents. They selectively enhance or partially mimic certain actions of insulin, causing a slowly generated antihyperglycaemic effect in Type 2 (noninsulin dependent) diabetic patients. This is often accompanied by a reduction in circulating concentrations of insulin, triglycerides and nonesterified fatty acids. TZDs act additively with other types of oral antidiabetic agents (suphonylureas, metformin and acarbose) and reduce the insulin dosage required in insulin-treated patients. The glucose-lowering effect of TZDs is attributed to increased peripheral glucose disposal and decreased hepatic glucose output. This is achieved substantively by the activation of a specific nuclear receptor - the peroxisome proliferator-activated receptor-gamma (PPARgamma), which increases transcription of certain insulin-sensitive genes. To date one TZD, troglitazone, has been introduced into clinical use (in Japan, USA and UK in 1997). This was suspended after 2 months in the UK pending further investigation of adverse effects on liver function. TZDs have been shown to improve insulin sensitivity in a range of insulin-resistant states including obesity, impaired glucose tolerance (IGT) and polycystic ovary syndrome (PCOS). In Type 2 diabetes, the TZDs offer a new type of oral therapy to reduce insulin resistance and assist glycaemic control.

Publication Types:
Review
Review, academic

PMID: 10227562, UI: 99242101



21: Metabolism 1999 Apr;48(4):511-9

Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome.

Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L

The Cholesterol Center, Jewish Hospital, Cincinnati, OH 45229, USA.

In 43 amenorrheic women with polycystic ovary syndrome (PCOS), 31 (74%) with fasting hyperinsulinemia (> or =20 microU/mL), our aim was to determine whether Metformin (Bristol-Myers Squibb, Princeton, NJ), which reduces hyperinsulinemia, would reverse the endocrinopathy of PCOS, allowing resumption of regular normal menses. A second aim was to assess the effects of weight loss versus other Metformin-induced effects on ovarian function, and to determine if there were different responses to Metformin between those who lost weight and those who did not. A third aim was to assess associations between PCOS, 4G/5G polymorphism in the promoter sequence of the plasminogen activator inhibitor-1 gene (PAI-1 gene), and PAI activity (PAI-Fx). Of the 43 women, 40 (93%) had normal fasting blood glucose and 37 had normal hemoglobin A1C (HgA1C); onlythree (7%) had type 2 diabetes mellitus. Metformin (1.5 to 2.25 g/d) was given for 6.1+/-5.1 months (range, 1.5 to 24), to 16 patients for less than 3 months, to 12 for 3 to 6 months, and to 15 for at least 6 months. On Metformin, 39 of 43 patients (91%) resumed normal menses. The percentage of women resuming normal menses did not differ among treatment duration groups (P<.1) or among dose groups (P>.1). The body mass index (BMI) decreased from 36.4 + 7 Kg/m2 at study entry to 35.1+/-6.7 on Metformin (P=.0008). Of 43 patients, 28 (67%) lost weight (1 to 69 pounds), with nine (21%) losing at least 12 pounds. On Metformin, the median fasting serum insulin decreased from 26 microU/mL to 22 (P=.019), testosterone decreased from 61 ng/dL to 47 (P=.003), and estradiol increased from 41 pg/mL to 71 (P=.0001). Metformin-induced improvements in ovarian function were independent of weight loss (testosterone decrease, P<.002; estradiol increase, P<.0004). The change in response variables on Metformin did not differ (P>.05) between those who lost weight and those who did not, excepting Lp(a), which increased 4 mg/dL in those who lost weight and decreased 9 mg/dL in those who did not (P = .003). The change in response variables on Metformin did not differ among the five quintiles of weight loss, excepting fasting glucose (P<.05), which increased 6 mg/dL in those who lost the least weight on Metformin versus those in the 60th to 80th percentile for weight loss, in whom glucose decreased 33 mg/dL. Although the pretreatment fasting serum insulin was not significantly correlated with testosterone (r=.24, P=.13) or androstenedione (r=.27, P=.09), on Metformin, the change in insulin correlated positively with the change in testosterone (r=.35, P=.047) and with the change in androstenedione (r=.48, P=.01). Patients were more likely than normal controls (83% v 64%, P=.016) to be heterozygous or homozygous for 4G polymorphism of the PAI-1 gene and were also more likely to have high PAI-Fx (> or =22 U/mL, 28% v3%, chi(2)=10.1, P=.001). Metformin reduces the endocrinopathy of PCOS, allowing resumption of normal menses in most (91%) previously amenorrheic women with PCOS.

Publication Types:
Clinical trial
Randomized controlled trial

PMID: 10206447, UI: 99221288



22: Eur J Endocrinol 1999 Jan;140(1):56-61

The treatment of insulin resistance does not improve adrenal cytochrome P450c17alpha enzyme dysregulation in polycystic ovary syndrome.

Unluhizarci K, Kelestimur F, Sahin Y, Bayram F

Department of Endocrinology, Erciyes University School of Medicine, Kayseri, Turkey.

OBJECTIVE: To determine whether metformin. when given to non-diabetic women with polycystic ovary syndrome (PCOS), results in a reduction of insulin resistance and hyperinsulinemia while body weight is maintained. Also we aimed to see whether the reduction in insulin levels attenuates the activity of adrenal P450c17alpha enzyme in patients with PCOS. DESIGN: We investigated the 17-hydroxyprogesterone (17-OHP) and androstenedione responses to ACTH, insulin responses to an oral glucose tolerance test (OGTT) and glucose disposal rate in an insulin tolerance test before and after metformin therapy (500 mg, orally, twice daily, for 12 weeks). METHODS: The presence of hyperinsulinemia in 15 women with PCOS was demonstrated by an OGTT and results were compared with those of 10 healthy women. Insulin sensitivity was measured by the rate of endogenous glucose disposal after i.v. bolus injection of insulin. 17-OHP and androstenedione responses to ACTH were measured in all the women with PCOS and the normal women. RESULTS: Women with PCOS were hyperinsulinemic (102.0+/-13.0 (S.E.M.) VS 46.2+/-4.4 pmol/l) and hyperandrogenemic (free testosterone 15.3+/-1.7 vs 7.9+/-0.6 nmol/l; androstenedione 11.8+/-0.8 vs 8.2+/-0.6 nmol/l) and more hirsute (modified Ferriman-Gallwey score, 17.7+/-1.6 vs 3.0+/-0.3) than healthy women. In addition, women with PCOS had higher 17-OHP and androstenedione responses to ACTH when compared with healthy women. Metformin therapy resulted in some improvement in insulin sensitivity and reduced the basal and post-glucose load insulin levels. But 17-OHP and androstenedione responses to ACTH were unaltered in response to metformin. CONCLUSIONS: PCOS is characterized by hyperactivity of the adrenal P450c17alpha enzyme and insulin resistance. It seems that there is no direct relationship between insulin resistance and adrenal P450c17alpha enzyme dysregulation.

PMID: 10037253, UI: 99154857



23: J Clin Endocrinol Metab 1998 Jul;83(7):2566-8

Decreased serum leptin concentrations during metformin therapy in obese women with polycystic ovary syndrome.

Morin-Papunen LC, Koivunen RM, Tomas C, Ruokonen A, Martikainen HK

Department of Obstetrics and Gynecology, University Hospital of Oulu, Finland.

Previous studies have suggested that metformin is clinically useful in the treatment of polycystic ovary syndrome (PCOS). The aim of this study was to evaluate whether the improvement of ovarian function achieved by metformin therapy is associated with changes in leptin concentrations. Twenty-six obese women with PCOS were treated with 500 mg metformin, x 3 daily, for 2 months; and 12 women continued the therapy for 4-6 months. A significant decrease in the serum leptin level was observed after 2 months of treatment in the whole study group (29.2 +/- 12.7 ng/mL vs. 25.7 +/- 10.9 ng/mL, P = 0.03). In the 12 women treated for 4-6 months, the mean serum leptin concentration decreased after 2 months (38.6 +/- 9.3 ng/mL vs. 30.2 +/- 8.1 ng/mL; P = 0.004) but slightly increased after 4-6 months of treatment (33.4 +/- 15.7 ng/mL; not significant). These results indicate that insulin sensitizing therapy with metformin decreases the leptin concentrations in obese PCOS women.

Publication Types:
Clinical trial
Controlled clinical trial

PMID: 9661644, UI: 98326290



24: Fertil Steril 1998 Apr;69(4):691-6

Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome.

Morin-Papunen LC, Koivunen RM, Ruokonen A, Martikainen HK

Department of Obstetrics and Gynecology, University Central Hospital of Oulu, Finland.

OBJECTIVE: To determine the clinical, hormonal, and biochemical effects of 4-6 months of metformin therapy in obese patients with polycystic ovary syndrome (PCOS). DESIGN: Prospective study. SETTING: The Gynecological Endocrine Unit of University Central Hospital, Oulu, Finland. PATIENT(S): Twenty obese patients with PCOS. INTERVENTION(S): Patients were treated with 0.5 g of metformin three times daily for 4-6 months. MAIN OUTCOME MEASURE(S): Clinical symptoms, menstrual pattern, and hirsutism, as well as serum concentrations of sex steroids, sex hormone-binding globulin (SHBG), gonadotropins, and lipids were assessed during the treatment. RESULT(S): Eleven women (68.8% of the women with menstrual disturbances) experienced more regular cycles during therapy. No changes in hirsutism, body mass index, or blood pressure occurred. The mean testosterone level was decreased significantly after 2 months of treatment but returned to the starting level by 4-6 months. Free testosterone levels decreased significantly during the treatment. There was no significant change in the levels of other sex steroids or lipids measured at 4-6 months of treatment. CONCLUSION(S): Metformin therapy is well tolerated by the majority of patients and may be clinically useful, especially in obese patients with PCOS and menstrual disturbances.

Publication Types:
Clinical trial

PMID: 9548159, UI: 98207936



25: Eur J Endocrinol 1998 Mar;138(3):269-74

Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome.

Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A

University of Athens Medical School, First Department of Medicine, Laiko Athens General Hospital, Greece.

Evidence suggests that insulin resistance and hyperinsulinaemia are associated with ovarian hyperandrogenism and menstrual irregularities in polycystic ovary syndrome (PCOS). Sixteen obese women with PCOS on a weight-maintaining diet were studied before and after 6 months of therapy with the insulin-sensitizing antidiabetic agent metformin at a dose of 1700 mg per day. Compared with baseline values, glucose utilization was markedly enhanced at 6 months using the two-step euglycaemic-hyperinsulinaemic clamp to measure changes in insulin sensitivity (2.56 +/- 0.32 vs 4.68 +/- 0.49 mg/kg per min, P = 0.0001, when 40 mU insulin/m2 per min was infused, and 6.48 +/- 0.58 vs 9.84 +/- 0.72 mg/kg per min, P = 0.0002, when 400 mU insulin insulin/m2 per min was infused). The improvement in insulin action was accompanied by significant increases in the levels of sex hormone-binding globulin (24.5 +/- 7.2 vs 39.8 +/- 16.2 nmol/l, P = 0.003) and decreases in free testosterone (12.8 +/- 5.8 vs 9.0 +/- 3.0 pmol/l, P = 0.03) and androstenedione (12.9 +/- 5.6 vs 7.3 +/- 1.7 nmol/l, P = 0.003). No significant changes were recorded in body weight. Seven subjects resumed normal menstruation and two cases of spontaneous pregnancy occurred during treatment. Metformin was well tolerated except for one case of flatulence. These results confirm that metformin treatment can lead to improvements in insulin resistance and ovarian hyperandrogenism.

Publication Types:
Clinical trial

Comments:
Comment in: Eur J Endocrinol 1998 Mar;138(3):253-4

PMID: 9539300, UI: 98198706



26: Hum Reprod 1997 Oct;12 Suppl 1:82-7

Weight control and its beneficial effect on fertility in women with obesity and polycystic ovary syndrome.

Pasquali R, Casimirri F, Vicennati V

Department of Internal Medicine and Gastroenterology, St. Orsola-Malpighi Hospital, Alma Mater University, Bologna, Italy.

Obesity may be an important pathogenetic factor involved in the development of hyper-androgenism in women with polycystic ovary syndrome (PCOS). Among several other mechanisms, hyperinsulinaemia plays a fundamental role, due to its gonadotrophic function, which has been demonstrated both in vitro and in vivo. Therefore, not surprisingly, weight loss may be expected to have several beneficial effects upon clinical, endocrinological and metabolic features of obese women presenting both PCOS. In particular, weight loss appears to be associated with a significant improvement in menses abnormalities, ovulation and fertility rates, and with a reduction of hyperandrogenism, hyperinsulinaemia, and altered gonadotrophin pulsatile secretion. The central role of improved insulin concentrations and insulin-resistant state is emphasized by the fact that similar effects can be achieved by both short- and long-term administration of metformin, an insulin-lowering drug which ameliorates peripheral insulin action in non-diabetic insulin resistant states. We therefore recommend weight loss as a first-line therapeutic option in all women with obesity and PCOS.

Publication Types:
Review
Review, tutorial

PMID: 9403324, UI: 98067028



27: J Clin Endocrinol Metab 1997 Dec;82(12):4075-9

Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens.

Nestler JE, Jakubowicz DJ

Department of Internal Medicine, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298, USA. nestler@gems.vcu.edu

It is unknown whether hyperinsulinemia plays a role in the pathogenesis of polycystic ovary syndrome (PCOS) in normal weight or thin women. Evidence indicates that these women are insulin resistant and hyperinsulinemic, and this study was conducted to test the hypothesis that hyperinsulinemia stimulates ovarian cytochrome P450c17 alpha activity in nonobese women with PCOS, thereby increasing serum androgen concentrations. We assessed ovarian P450c17 alpha activity (by measuring the response of 17 alpha-hydroxyprogesterone to a GnRH agonist), fasting serum steroids, and oral glucose tolerance before and after oral administration of either metformin (500 mg) or placebo three times daily for 4-6 weeks in 31 nonobese women with PCOS. In the 19 women given metformin, the mean (+/- SE) area under the serum insulin curve after oral glucose administration decreased from 44 +/- 5 to 24 +/- 3 nmol/L.min (P = 0.003). Basal serum 17 alpha-hydroxyprogesterone decreased from 3.4 +/- 0.3 to 2.5 +/- 0.4 nmol/L (P = 0.05), and GnRH-stimulated peak serum 17 alpha-hydroxyprogesterone decreased from 12.2 +/- 1.6 to 7.5 +/- 0.7 nmol/L (P = 0.005). Serum 17 alpha-hydroxyprogesterone values did not change in the placebo group. In the metformin group, serum free testosterone decreased by 70% from 18.2 +/- 3.1 to 5.5 +/- 0.7 pmol/L (P < 0.001), and serum sex hormone-binding globulin increased from 84 +/- 6 to 134 +/- 15 nmol/L (P = 0.002). None of these values changed in the placebo group. These findings suggest that hyperinsulinemia stimulates ovarian P450c17 alpha activity in nonobese women with PCOS. They also indicate that decreasing serum insulin with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates the hyperandrogenism of these women.

Publication Types:
Clinical trial
Controlled clinical trial

PMID: 9398716, UI: 98060963



28: Obstet Gynecol 1997 Sep;90(3):392-5

Menstrual cyclicity after metformin therapy in polycystic ovary syndrome.

Velazquez E, Acosta A, Mendoza SG

Department of Medicine, Medical Faculty of University of The Andes, Merida, Venezuela.

OBJECTIVE: To assess the effect of insulin-lowering treatment on menstrual cyclicity in polycystic ovary syndrome (PCOS). METHODS: Forty oligoamenorrheic women with PCOS were recruited in a prospective clinical study to receive metformin for a minimum period of 6 months. Twenty-two women completed the study. Serum LH, FSH, free testosterone, and glucose and insulin response to oral glucose load were measured both before and after 8 weeks of metformin treatment. Menstrual cyclicity and serum progesterone levels at the midluteal phase were assessed at the 30th week of metformin treatment. RESULTS: Twenty-one of 22 women had restoration of menstrual cyclicity (95.7%). Four of these women (19%) became pregnant within the 6th and 7th months of treatment. All four of the pregnant women delivered, and the infants were healthy. Thirteen of 15 women who had regular menses demonstrated a serum progesterone level within the ovulatory range (3.1-28 ng/mL). Fasting (P < .001) and the integrated insulin response to the glucose load decreased (P < .001) after 8 weeks of metformin treatment. This was accompanied by significant decreases in serum LH (P < .001) and free testosterone (P < .001) levels and LH/FSH ratio (P < .001). There was a small but significant reduction in body mass index after 8 weeks of metformin treatment (P < .001). CONCLUSION: A 6-month course of metformin may improve menstrual cyclicity and fertility in women with the PCOS. Insulin-sensitizing agents provide a rational approach to the treatment of the metabolic and endocrine abnormalities in PCOS women.

Publication Types:
Clinical trial

PMID: 9277650, UI: 97423708



29: Semin Reprod Endocrinol 1997 May;15(2):111-22

Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications.

Nestler JE

Department of Internal Medicine, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298-0111, USA.

The polycystic ovary syndrome (PCOS) is a prevalent disorder affecting approximately 6% of women of reproductive age, and is characterized by anovulation and hyperandrogenism. It has also become apparent that a frequent feature of women with PCOS is insulin resistance accompanied by compensatory hyperinsulinemia, and increasing evidence suggests that hyperinsulinemia plays an important role in the pathogenesis of PCOS. This article will review (1) evidence indicating that insulin contributes to the hyperandrogenism of PCOS by stimulating ovarian androgen production and decreasing serum sex hormone-binding globulin (SHBG) concentrations; (2) possible direct effects of hyperinsulinemia on folliculogenesis; (3) the relationship between insulin and adrenal androgens in women; and (4) therapeutic and clinical implications of these findings.

Publication Types:
Review
Review, academic

PMID: 9165656, UI: 97308430



30: Metabolism 1997 Apr;46(4):454-7

Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome.

Velazquez EM, Mendoza SG, Wang P, Glueck CJ

University of Los Andes, Merida, Venezuela.

Sixteen nondiabetic women with polycystic ovary syndrome (PCOS) aged 18 to 33 years were studied before and after 8 weeks on metformin (1.5 g/d) therapy to assess whether reducing hyperinsulinemia would reduce the levels of the major inhibitor of fibrinolysis, antigenic plasminogen activator inhibitor type 1 (PAI-1). Compared with six normal control women, PCOS women had a higher body mass index (BMI), waist to hip ratio, fasting insulin (Izero), insulin area under the curve during oral glucose tolerance testing (IA), glucose area under the curve during oral glucose tolerance testing (GA), IA/GA ratio, PAI-1, luteinizing hormone (LH) and ratio of LH to follicle-stimulating hormone (FSH), and free testosterone, and lower high-density lipoprotein (HDL) cholesterol (all P < .025). On metformin, BMI decreased 1.3% (P = .04), Izero 43% (P = .002), IA 31% (P = .03), GA 11% (P = .02), PAI-1 16% (P = .01), lipoprotein(a) [Lp(a)] 42% (P = .004), free testosterone 46% (P = .0006), LH 44% (P = .004), and the LH/FSH ratio 41% (P = .0001). On metformin, absolute and percent reductions in Izero correlated with absolute and percent reductions in PAI-1 (r = .60, P = .015 and r = .64, P = .008). On metformin, by stepwise multiple regression, the absolute reduction in Izero was a significant determinant of the absolute reduction in PAI-1 (partial R2 = 35%, P = .02), and the percent reduction in Izero was a significant determinant of the percent reduction in PAI-1 (partial R2 = 52%, P = .003). Metformin decreases Izero in hyperinsulinemic PCOS patients, reverses the hyperinsulinemia-driven endocrinopathy, decreases PAI-1, and decreases Lp(a), and should thus reduce the increased risk of atherothrombosis in PCOS.

PMID: 9109854, UI: 97263982



31: J Clin Endocrinol Metab 1997 Feb;82(2):524-30

Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome.

Ehrmann DA, Cavaghan MK, Imperial J, Sturis J, Rosenfield RL, Polonsky KS

Department of Medicine, University of Chicago, Illinois 60637, USA. dehrmann@medicine.bsd.uchicago.edu

Hyperinsulinemia contributes to the ovarian androgen overproduction and glucose intolerance of polycystic ovary syndrome (PCOS). We sought to determine whether metformin would reduce insulin levels in obese, nondiabetic women with PCOS during a period of weight maintenance and thus attenuate the ovarian steroidogenic response to the GnRH agonist leuprolide. All subjects (n = 14) had an oral glucose tolerance test, a GnRH agonist (leuprolide) test, a frequently sampled iv glucose tolerance test, graded and oscillatory glucose infusions, and a dual energy x-ray absorptiometry scan before and after treatment with metformin (850 mg, orally, three times daily for 12 weeks). With weight maintenance (body mass index: pretreatment, 39.0 +/- 7.7 kg/m2, posttreatment, 39.1 +/- 7.9 kg/m2), oral glucose tolerance, insulin sensitivity (Si; 0.87 +/- 0.82 vs. 0.74 +/- 0.63 x 10(-5) min-1/ pmol.L), and the relationship between Si and first phase insulin secretion (AIRg vs. Si) were not improved by metformin. The insulin secretory response to glucose, administered in both graded and oscillatory fashions, was likewise unaltered in response to metformin. Free testosterone levels remained about 2-fold elevated (pretreatment, 26.6 +/- 12.7 pg/mL; posttreatment, 22.4 +/- 9.8 pg/mL). Both basal and stimulated LH and FSH levels were unaffected by metformin. The mean responses to leuprolide of 17-hydroxyprogesterone (pretreatment, 387 +/- 158 ng/dL; posttreatment, 329 +/- 116 ng/dL) as well as those of the other ovarian secretory products (androstenedione, dehydroepiandrosterone, progesterone, and estradiol) were not attenuated by metformin. We conclude that hyperinsulinemia and androgen excess in obese nondiabetic women with PCOS are not improved by the administration of metformin.

Publication Types:
Clinical trial

PMID: 9024248, UI: 97176709



32: Fertil Steril 1996 May;65(5):946-9

Can metformin reduce insulin resistance in polycystic ovary syndrome?

Acbay O, Gundogdu S

Department of Internal Medicine, Cerrahpasa Medical Faculty of Istanbul University, Turkey.

OBJECTIVE: To examine whether metformin is able to reduce insulin resistance in polycystic ovary syndrome (PCOS). DESIGN: Single-blind study comprising two successive periods of treatment: 8 weeks of placebo and 10 weeks of metformin (orally, 850 mg twice daily). SETTING: Clinic of endocrinology and metabolism of Cerrahpasa Medical Faculty at Istanbul University, Istanbul, Turkey. PATIENTS: Sixteen insulin-resistant women with PCOS. INTERVENTIONS: Insulin sensitivity (with an IV insulin tolerance test), plasma glucose and insulin levels during an oral glucose tolerance test (OGTT), serum androgens, and lipids were measured at baseline and after each treatment period. RESULTS: Insulin sensitivity, the mean fasting serum levels of glucose, insulin, total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total T, free T, androstenedione, DHEAS, and LH:FSH ratio, and the areas under the curve for plasma glucose and insulin during OGTT were not changed by either placebo or metformin treatment. CONCLUSION: Metformin does not decrease insulin resistance in PCOS. This finding suggests that cellular mechanism of insulin resistance in PCOS is different from other common insulin-resistant states such as non-insulin dependent diabetes mellitus and obesity.

PMID: 8612854, UI: 96198848



33: Metabolism 1994 May;43(5):647-54

Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy.

Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ

University of the Andes, Merida, Venezuela.

Using polycystic ovary syndrome (PCOS) as a model of insulin resistance and hyperandrogenism, our specific aim was to assess the effect of Metformin on lipoproteins, sex hormones, gonadotropins, and blood pressure in 26 women with PCOS who were studied at baseline, received Metformin 1.5 g/d for 8 weeks, and were then restudied. None of the women had normal menstrual cycles, 100% had multiple subcapsular follicules by pelvic ultrasound, 90% were hirsute, and 85% had high free testosterone. Comparing post-Metformin versus baseline levels, the Quetelet Index (QI) decreased 1.5% (P = .04) and the waist to hip ratio (WHR) decreased 2.8% (P = .003). After covariance adjusting for changes in the QI and WHR, on Metformin the area under the insulin curve (IA) during oral glucose tolerance testing decreased 35% (P = .04), and the insulin area to glucose area ratio decreased 31% (P = .03). On Metformin, covariance-adjusted systolic blood pressure (SBP) decreased (P = .04) and apo A-1 increased (P = .05). On Metformin, with improvement in insulin sensitivity, there were sharp reductions in covariance-adjusted luteinizing hormone ([LH] P = .0007), total testosterone ([T] P = .0004), free T (P = .0001), androstenedione (P = .002), dehydroepiandrosterone sulfate ([DHEAS] P = .006), and the free androgen index ([FAI] P = .0005), with increments in follicle-stimulating hormone ([FSH] P = .04) and sex hormone-binding globulin ([SHBG] P = .04).

PMID: 8177055, UI: 94231979






Metformin in Pregnancy



1: Fertil Steril 2001 Jan;75(1):46-52

Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study.

Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P.

The Cholesterol Center, Jewish Hospital, Cincinnati, Ohio 45229, USA. glueckch@healthall.com

OBJECTIVE: To determine whether metformin would safely reduce the rate of first-trimester spontaneous abortion without teratogenicity in 19 women with the polycystic ovary syndrome (PCOS). DESIGN: Prospective pilot study. SETTING: Outpatient. PATIENT(S): Twenty-two previously oligoamenorrheic, nondiabetic women with PCOS; 125 women with PCOS who were not currently pregnant and who had > or = 1 previous pregnancy while they were not receiving metformin. INTERVENTION(S): Metformin, 1.5-2.55 g/day, throughout pregnancy. MAIN OUTCOME MEASURE(S): Rates of first-trimester spontaneous abortion and teratogenicity. RESULT(S): Before metformin, 10 women had 22 previous pregnancies with 16 first-trimester spontaneous abortions (73%). While receiving metformin, these 10 women had 6 normal live births (60%), 1 spontaneous abortion (10%), and 3 normal ongoing pregnancies (30%) (all > or = 13 weeks; median gestation, 23 weeks). Among women receiving metformin, including those with live births and normal pregnancy for at least the first trimester, 1 of 10 (10%) had first-trimester spontaneous abortion compared with 73% in 22 previous pregnancies without metformin (P<.002). To date, the 19 women receiving metformin have had no adverse maternal side effects, and no birth defects have occurred; 9 (47%) had normal term live births, 2 (11%) had normal and appropriate for gestational age births (one at 33 and one at 35 weeks), 6 (32%) have ongoing normal pregnancies lasting longer than the first trimester, and 2 (10.5%) had first-trimester spontaneous abortions. Sonography showed normal fetal development without congenital defects in the 6 ongoing pregnancies (median gestation, 23 weeks). Among women who received metformin before conception, reductions in insulin and plasminogen activator inhibitor activity were correlated (r=0.65, P=.04). CONCLUSION(S): Metformin therapy throughout pregnancy in women with PCOS reduces the otherwise high rate of first-trimester spontaneous abortion seen among women not receiving metformin and does not appear to be teratogenic.

Publication Types:
Clinical trial

PMID: 11163815 [PubMed - in process]

1: Fertil Steril 2000 Aug;74(2):394-7

Polycystic ovary syndrome, infertility, familial thrombophilia, familial hypofibrinolysis, recurrent loss of in vitro fertilized embryos, and miscarriage.

Glueck CJ, Awadalla SG, Phillips H, Cameron D, Wang P, Fontaine RN

Cholesterol Center, Jewish Hospital, Cincinnati, Ohio, USA.

[Medline record in process]

Objective: To study reversible determinants of infertility and recurrent loss of transferred embryos after failure of 7 of 10 embryo transfers, 1 live birth, and 2 miscarriages.Design: Measures of thrombophilia, hypofibrinolysis, reproductive hormones, and androgenic steroids before and after metformin therapy.Setting: Outpatient clinical research center.Patient(s): A 32-year-old amenorrheic, infertile woman with polycystic ovary syndrome (PCOS) who had 7 of 10 embryo transfers fail, 1 premature live birth, and 2 miscarriages at 8 and 17 weeks.Intervention(s): Metformin (2.55 g/d) was given to ameliorate the endocrinopathy of PCOS.Main Outcome Measure(s): Coagulation, insulin, reproductive hormones, and androgenic steroids.Result(s): The propositus had thrombophilia (familial protein S deficiency [free protein S 32%; normal >/=65%]). She also had familial hypofibrinolysis with 4G4G polymorphism of the plasminogen activator inhibitor (PAI-1) gene and high PAI-1 activity (PAI-Fx), 42.5 U/mL, normal <21.1. Polycystic ovary syndrome was characterized by amenorrhea, polycystic ovaries, high fasting serum insulin (39 &mgr;U/mL, normal <20), androstenedione (763 ng/dL, normal <250), and testosterone (229 ng/dL, normal <83). After she received metformin for 4 months, PAI-Fx normalized (12.4 U/mL), as did insulin (12 &mgr;U/mL), androstenedione (185 ng/dL), and testosterone (39 ng/dL); weight fell from 109 to 91.3 kg (16%). Conclusion(s): Metformin reversed the endocrinopathy of PCOS. Familial thrombophilia and hypofibrinolysis may lead to thrombosis-mediated uteroplacental vascular insufficiency, failure to achieve pregnancy after embryo transfer, and miscarriage.

PMID: 10927066, UI: 20387192



2: J Reprod Med 2000 Jun;45(6):507-10

Association of metformin and pregnancy in the polycystic ovary syndrome. A report of three cases.

Seale FG 4th, Robinson RD, Neal GS

Department of Obstetrics and Gynecology, San Antonio Uniformed Services Health Education Consortium, Texas, USA. fred_g.seale@sa-chcs.mednet.af.mil

[Medline record in process]

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.

PMID: 10900588, UI: 20357809



3: Ann N Y Acad Sci 2000;900:203-12

Insulin sensitizers and antiandrogens in the treatment of polycystic ovary syndrome.

Diamanti-Kandarakis E, Zapanti E

1st Department of Internal Medicine, University of Athens Medical School, Greece.

The heterogeneous origin of polycystic ovary syndrome (PCOS) has been demonstrated by several studies. Abnormalities in steroidogenesis and metabolism are present, but the exact link between these two pathologic features remains to be clarified. In clinical practice, more than one therapeutic approach for the treatment of this syndrome has been proposed over the last few decades. Because hyperandrogenism and hyperinsulinemia contribute to a different degree to the phenotype of PCOS, therapeutic efforts have focused on agents that could treat or modify the clinical manifestations of these disorders. Antiandrogens as a sole treatment or combined with oral contraceptives are considered the treatment of choice for the manifestations of hyperandrogenemia, but there is no agreement about their efficacy on the metabolic sequelae of PCOS (insulin resistance, hyperinsulinemia, dislipidemia). Furthermore, the improvement of insulin sensitivity by insulin sensitizers may be of therapeutic value directly and/or indirectly in the management of clinical manifestations of hyperinsulinemia and hyperandrogenemia.

PMID: 10818407, UI: 20278348



4: Hum Reprod 1999 Nov;14(11):2700-3

High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome.

Mitwally MF, Kuscu NK, Yalcinkaya TM

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, School of Medicine, West Virginia University Health Sciences Center, 830 Pennsylvania Avenue, Suite 304, Charleston, WV 25302, USA.

This preliminary report reviews our experience with 18 infertile patients with clomiphene-resistant polycystic ovary syndrome (PCOS). In the first treatment cycle, troglitazone was administered alone. During cycles 2-5, clomiphene was added with increments of 50 mg (up to 200 mg/day) if the previous cycle was anovulatory. Basal body temperature charts and serum progesterone were obtained to confirm ovulation. In a total of 66 treatment cycles, ovulation occurred in 44 (67%) and pregnancy in seven (11%). There were no significant changes in body weight, waist:hip ratio or liver enzymes during treatment. Troglitazone, alone or with clomiphene, induced ovulation in 15 of 18 patients (83%) and seven (39%) of them achieved pregnancy. This is the first report on ovulatory rates in clomiphene-resistant women with PCOS when troglitazone was used alone or with clomiphene. Recently, metformin and clomiphene were successfully used in women with PCOS. However, our patients represent a more resistant population of women with PCOS, with each patient serving as her own historical control by previous resistance to clomiphene. Although the pregnancy rate (39%) was promising for clomiphene-resistant women with polycystic ovary syndrome, it does not seem to have a definite advantage over gonadotrophins.

PMID: 10548604, UI: 20018196



5: Diabet Med 1999 Aug;16(8):692-6

Contra-indications to metformin therapy are largely disregarded.

Holstein A, Nahrwold D, Hinze S, Egberts EH

1st Department of Medicine, Klinikum Lippe-Detmold, Germany.

AIMS: To investigate the current metformin treatment practice and in particular to examine the consideration given to its contraindications. METHODS: A cross-sectional analysis of 308 consecutive Type 2 diabetic patients (mean age 66+/-11.3 years) previously treated with metformin on an outpatient basis and admitted to a German general hospital during the period from 1 January 1995 to 31 May 1998 because of acute disease or in order to optimize their diabetes management. All patients underwent a basic investigation comprising a documentation of their medical history, a physical examination, an electrocardiogram, and an extensive laboratory profile; 34% also had acute coronary angiography. RESULTS: On admission to hospital, 73% of the patients were found to have contra-indications, risk factors, or intercurrent illnesses necessitating discontinuation of metformin; 51% of these patients had several of these conditions. As major contra-indications to metformin, renal impairment was present in 19% of all patients, heart failure in 25%, respiratory insufficiency in 6.5%, and hepatic impairment in 1.3%. The risk factors to metformin included advanced coronary heart disease in 51%, atrial fibrillation in 9.8%, chronic alcohol abuse in 3.3%, advanced peripheral vascular disease in 2%, and pregnancy in 0.7%. As intercurrent illnesses, cerebral ischaemia occurred in 9.8% under metformin treatment and malignancies were diagnosed in 6.5%. The patients with contra-indications or requiring caution to metformin were significantly older and had previously been treated with more cardiovascular medication than those without such reservations (P<0.001). CONCLUSIONS: Despite the considerable risk of lactic acidosis in the majority of patients, no cases were observed.

PMID: 10477216, UI: 99404866



6: Fertil Steril 1999 Aug;72(2):282-5

Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome.

De Leo V, la Marca A, Ditto A, Morgante G, Cianci A

Department of Obstetrics and Gynecology, University of Siena, Italy. deleo@unisi.it

OBJECTIVE: To evaluate whether pretreatment with metformin improves FSH-induced ovulation in women with clomiphene-resistant polycystic ovary syndrome (PCOS). DESIGN: Randomized prospective trial. SETTING: Department of Obstetrics and Gynecology, University of Siena. PATIENT(S): Twenty women with clomiphene citrate-resistant PCOS. INTERVENTION(S): The women were divided randomly into groups A and B (10 subjects each). Group B received 1,500 mg of metformin for at least a month before a single cycle of FSH stimulation. Group A underwent two cycles of FSH stimulation and then received metformin for a month before undergoing a third cycle. MAIN OUTCOME MEASURE(S): The number of FSH ampules, days of treatment, E2 level on the day of hCG, number of follicles > 15 mm, number of hyperstimulation, and the number of cycles with hCG withheld. RESULT(S): The number of follicles > 15 mm in diameter on the day of hCG administration was significantly lower in cycles performed after metformin treatment. The percentage of cycles with hCG withheld because of excessive follicular development was significantly lower in cycles treated with metformin. Plasma levels of E2 were significantly higher in cycles treated with FSH alone than in those treated with FSH and metformin. CONCLUSION(S): By reducing hyperinsulinism, metformin determines a reduction in intraovarian androgens. This leads to a reduction in E2 levels and favors orderly follicular growth in response to exogenous gonadotropins.

Publication Types:
Clinical trial
Randomized controlled trial

PMID: 10438996, UI: 99367851



7: Drug Saf 1999 Jul;21(1):7-22

Benefits and risks of transfer from oral agents to insulin in type 2 diabetes mellitus.

Evans A, Krentz AJ

Southampton General Hospital, England.

The treatment of type 2 diabetes mellitus remains controversial. Since most patients are overweight or obese, regimens based on dietary modification and increased physical exercise are logical and safe treatment approaches. However, the long term impact of these interventions is frequently disappointing and pharmacotherapy is therefore required in the majority of patients. Oral antidiabetic agents, principally the sulphonylureas and biguanides, are often only partially effective, even in combination. Insulin is the treatment of choice for certain clinical situations, for example, pregnancy. Often insulin will be a temporary measure. Safety considerations will also point to the preferential use of insulin in other circumstances, for example, in patients with pronounced renal impairment. In addition, a significant proportion of patients with type 2 diabetes mellitus will ultimately require insulin therapy in the long term because of failure of oral agents to provide adequate glycaemic control (i.e. secondary failure). Reservations about insulin therapy in patients with type 2 diabetes mellitus, particularly elderly patients with cardiovascular complications, include hypoglycaemia and bodyweight gain. However, severe hypoglycaemia occurs with considerably lower frequency than in patients with type 1 diabetes mellitus. To date, no clear evidence has emerged implicating exogenous insulin therapy in the promotion of cardiovascular disease. On the contrary, recent clinical and experimental studies suggest anti-atherogenic effects. Insulin therapy can be successful in type 2 diabetes mellitus if patients are carefully selected. Twice daily isophane (neutral protamine Hagedom; NPH) or pre-mixed insulin is used routinely in many centres. The role of combinations of insulin and oral agents remains an area of controversy. Combined therapy with sulphonylureas may be more expensive and clear clinical advantages have not been consistently demonstrated. Bodyweight gain may be lessened by the concomitant use of metformin and troglitazone may improve glycaemic control in obese patients. Procrastination about transfer to insulin is not uncommon. Patient acceptance may be facilitated by a positive attitude from the diabetes care team and discussion of the possibility at a relatively early stage. Adequate support from a multidisciplinary team is important for safe and effective insulin therapy. Even so, in the long term, attainment of glycaemic targets may prove difficult to sustain with present therapeutic strategies.

Publication Types:
Review
Review, tutorial

PMID: 10433350, UI: 99360732



8: J Clin Endocrinol Metab 1999 May;84(5):1510-2

Administration of metformin to a diabetic woman with extreme hyperandrogenemia of nontumoral origin: management of infertility and prevention of inadvertent masculinization of a female fetus.

Sarlis NJ, Weil SJ, Nelson LM

Molecular and Cellular Endocrinology Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. njsarlis@box-n.nig.gov

PMID: 10323370, UI: 99254949



9: Eur J Endocrinol 1998 Mar;138(3):269-74

Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome.

Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A

University of Athens Medical School, First Department of Medicine, Laiko Athens General Hospital, Greece.

Evidence suggests that insulin resistance and hyperinsulinaemia are associated with ovarian hyperandrogenism and menstrual irregularities in polycystic ovary syndrome (PCOS). Sixteen obese women with PCOS on a weight-maintaining diet were studied before and after 6 months of therapy with the insulin-sensitizing antidiabetic agent metformin at a dose of 1700 mg per day. Compared with baseline values, glucose utilization was markedly enhanced at 6 months using the two-step euglycaemic-hyperinsulinaemic clamp to measure changes in insulin sensitivity (2.56 +/- 0.32 vs 4.68 +/- 0.49 mg/kg per min, P = 0.0001, when 40 mU insulin/m2 per min was infused, and 6.48 +/- 0.58 vs 9.84 +/- 0.72 mg/kg per min, P = 0.0002, when 400 mU insulin insulin/m2 per min was infused). The improvement in insulin action was accompanied by significant increases in the levels of sex hormone-binding globulin (24.5 +/- 7.2 vs 39.8 +/- 16.2 nmol/l, P = 0.003) and decreases in free testosterone (12.8 +/- 5.8 vs 9.0 +/- 3.0 pmol/l, P = 0.03) and androstenedione (12.9 +/- 5.6 vs 7.3 +/- 1.7 nmol/l, P = 0.003). No significant changes were recorded in body weight. Seven subjects resumed normal menstruation and two cases of spontaneous pregnancy occurred during treatment. Metformin was well tolerated except for one case of flatulence. These results confirm that metformin treatment can lead to improvements in insulin resistance and ovarian hyperandrogenism.

Publication Types:
Clinical trial

Comments:
Comment in: Eur J Endocrinol 1998 Mar;138(3):253-4

PMID: 9539300, UI: 98198706



10: Diabetes Care 1997 Jun;20(6):925-8

Contraindications to metformin therapy in patients with NIDDM.

Sulkin TV, Bosman D, Krentz AJ

Diabetes Resource Centre, Royal South Hants Hospital, Southampton, U.K.

OBJECTIVE: Treatment with metformin is occasionally associated with the development of severe lactic acidosis. However, this is usually observed in patients with major contraindications to the drug. In this study, we aimed to determine the prevalence of conditions currently regarded as either contraindications or cautions to the use of metformin in patients with NIDDM. RESEARCH DESIGN AND METHODS: The case notes of metformin-treated NIDDM patients (mean age 62 years) attending a United Kingdom university hospital diabetes clinic over a 3-month period were reviewed according to criteria reflecting a pragmatic view of current prescribing recommendations. RESULTS: Of 89 consecutive patients whose notes could be evaluated in detail, only 41 (46%) had no contraindications or cautions to metformin whatsoever. Concomitant chronic disorders associated with a potentially increased risk of hyperlactatemia were renal impairment (n = 2; plasma creatinine concentrations 1.7 and 2.3 mg/dl, respectively), cardiac failure (n = 2), and chronic liver disease (n = 2). Other potentially relevant disorders included ischemic heart disease (n = 20), clinical proteinuria (n = 14), peripheral vascular disease (n = 22), and pulmonary disease (n = 7). Multiple conditions (i.e., two, three, or four) were present in eight, five, and one patient(s), respectively. CONCLUSIONS: More than half the patients in our series had concomitant conditions or complications conventionally regarded as cautions or contraindications to metformin; approximately 10% had a multiplicity of such conditions. Regular surveillance is necessary to detect the development of complications such as renal impairment. Vigilance is also required in view of the increased risk of major intercurrent illnesses, which may independently disturb lactate metabolism in patients with NIDDM. Metformin should be withdrawn promptly under such circumstances.

PMID: 9167101, UI: 97309686



11: Metabolism 1994 May;43(5):647-54

Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy.

Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ

University of the Andes, Merida, Venezuela.

Using polycystic ovary syndrome (PCOS) as a model of insulin resistance and hyperandrogenism, our specific aim was to assess the effect of Metformin on lipoproteins, sex hormones, gonadotropins, and blood pressure in 26 women with PCOS who were studied at baseline, received Metformin 1.5 g/d for 8 weeks, and were then restudied. None of the women had normal menstrual cycles, 100% had multiple subcapsular follicules by pelvic ultrasound, 90% were hirsute, and 85% had high free testosterone. Comparing post-Metformin versus baseline levels, the Quetelet Index (QI) decreased 1.5% (P = .04) and the waist to hip ratio (WHR) decreased 2.8% (P = .003). After covariance adjusting for changes in the QI and WHR, on Metformin the area under the insulin curve (IA) during oral glucose tolerance testing decreased 35% (P = .04), and the insulin area to glucose area ratio decreased 31% (P = .03). On Metformin, covariance-adjusted systolic blood pressure (SBP) decreased (P = .04) and apo A-1 increased (P = .05). On Metformin, with improvement in insulin sensitivity, there were sharp reductions in covariance-adjusted luteinizing hormone ([LH] P = .0007), total testosterone ([T] P = .0004), free T (P = .0001), androstenedione (P = .002), dehydroepiandrosterone sulfate ([DHEAS] P = .006), and the free androgen index ([FAI] P = .0005), with increments in follicle-stimulating hormone ([FSH] P = .04) and sex hormone-binding globulin ([SHBG] P = .04).

PMID: 8177055, UI: 94231979



12: Teratology 1994 Apr;49(4):260-6

Effects of the biguanide class of oral hypoglycemic agents on mouse embryogenesis.

Denno KM, Sadler TW

Department of Cell Biology and Anatomy, School of Medicine, University of North Carolina at Chapel Hill 27599.

The incidence of birth defects among offspring of mothers with non-insulin dependent diabetes mellitus (NIDDM) is 2-3-fold higher than among infants of non diabetics. Since mothers with NIDDM are frequently given oral hypoglycemic agents, including sulphonylureas and biguanides, to control their disease and since these agents have been associated with the occurrence of congenital malformations in humans and animals, the embryotoxic effects of the most commonly employed biguanides, metformin and phenformin, were evaluated in whole embryo culture. Neurulating mouse embryos were exposed to therapeutic concentrations (metformin 500-2,550 mg per day; phenformin 50-400 mg per day, respectively) of the compounds for 24-48 h. Concentrations of metformin in culture ranged from 0.15 to 1.8 mg/ml and phenformin from 2.5 x 10(-5) to 0.4 mg/ml. Cultures were terminated and scored for gross morphological alterations and total protein content. Metformin produced no alterations in embryonic growth and no major malformations. Approximately 10% of all embryos exposed to metformin regardless of dose, exhibited open cranial neuropores after 24 h of culture. However, this anomaly appeared to represent a delay in closure as opposed to an overt defect, since no embryos exposed to the highest concentration of the drug and cultured for 48 h showed open neural tubes. In contrast, phenformin produced dose dependent changes in incidence of malformations, protein content, and embryolethality. Malformations included neural tube closure defects, craniofacial hypoplasia, and reduction in size of the first and second visceral arches. Doses above 0.1 mg/ml produced embryolethality and all embryos were killed at the 0.4 mg/ml concentration.

PMID: 8073364, UI: 94353326



13: Diabet Med 1992 Jan-Feb;9(1):30-7

The influence of hypoglycaemic agents on the growth and metabolism of human endothelial cells.

Petty RG, Pearson JD

Section of Vascular Biology, M.R.C. Clinical Research Centre, Harrow, UK.

Using human umbilical vein endothelial cells, and human microvascular endothelial cells from omental and subcutaneous fat obtained at laparotomy, we studied the effects of sulphonylureas and the biguanide metformin on endothelial cell proliferation, prostacyclin production, ecto-5'-nucleotidase activity, and von Willebrand factor release. Each drug produced a concentration-dependent proliferation of umbilical vein but not of microvascular endothelial cells. The stimulation of umbilical vein endothelial cell proliferation by sulphonylureas, but not by metformin, was serum- and insulin-dependent. Sulphonylureas and metformin had no effect on the proliferation of human dermal fibroblasts, smooth muscle cells derived from the umbilical artery, or 3T3 cells, until concentrations greater than 100 fold those found in vivo were reached, when there was inhibition of proliferation. These agents had no effect on prostacyclin or von Willebrand factor production, or on ecto-5'-nucleotidase activity, until high concentrations were used, at levels which also inhibited proliferation. The results suggest that the sulphonylureas and metformin, may, at concentrations found in vivo, induce changes in the turnover of endothelial cells from large vessels, but not of microvascular endothelial cells.

PMID: 1551307, UI: 92200863



14: CMAJ 1991 Dec 15;145(12):1571-81

Non-insulin-dependent (type II) diabetes mellitus.

Rodger W

Lawson Diabetes Centre, St. Joseph's Health Centre, London, Ont.

Non-insulin-dependent (type II) diabetes mellitus is an inherited metabolic disorder characterized by hyperglycemia with resistance to ketosis. The onset is usually after age 40 years. Patients are variably symptomatic and frequently obese, hyperlipidemic and hypertensive. Clinical, pathological and biochemical evidence suggests that the disease is caused by a combined defect of insulin secretion and insulin resistance. Goals in the treatment of hyperglycemia, dyslipidemia and hypertension should be appropriate to the patient's age, the status of diabetic complications and the safety of the regimen. Nonpharmacologic management includes meal planning to achieve a suitable weight, such that carbohydrates supply 50% to 60% of the daily energy intake, with limitation of saturated fats, cholesterol and salt when indicated, and physical activity appropriate to the patient's age and cardiovascular status. Follow-up should include regular visits with the physician, access to diabetes education, self-monitoring of the blood or urine glucose level and laboratory-based measurement of the plasma levels of glucose and glycated hemoglobin. If unacceptably high plasma glucose levels (e.g., 8 mmol/L or more before meals) persist the use of orally given hypoglycemic agents (a sulfonylurea agent or metformin or both) is indicated. Temporary insulin therapy may be needed during intercurrent illness, surgery or pregnancy. Long-term insulin therapy is recommended in patients with continuing symptoms or hyperglycemia despite treatment with diet modification and orally given hypoglycemic agents. The risk of pancreatitis may be reduced by treating severe hypertriglyceridemia (fasting serum level greater than 10 mmol/L) and atherosclerotic disease through dietary and, if necessary, pharmacologic management of dyslipidemia. Antihypertensive agents are available that have fewer adverse metabolic effects than thiazides and beta-adrenergic receptor blockers. New drugs are being developed that will enhance effective insulin secretion and action and inhibit the progress of complications.

Publication Types:
Review
Review, academic

PMID: 1742694, UI: 92076346



15: Trop Doct 1990 Jan;20(1):4-10

Practical management of diabetes in the tropics.

Gill G

Arrowe Park Hospital, Wirral, Merseyside, UK.

Publication Types:
Review
Review, tutorial

PMID: 2407010, UI: 90163004



16: Ann Biol Clin (Paris) 1987;45(2):202-6

[Anti-activator inhibitors of plasminogen].

[Article in French]

Juhan-Vague I, Alessi MC, Aillaud MF

Plasminogen Activator Inhibitors (PA Inhibitor) have recently been identified in plasma. They are directed against t-PA and Urokinase. Two PA Inhibitors have been described: PA Inhibitor 1 from endothelial cells, hepatocytes and platelets and PA Inhibitor 2 from placenta. Enzymatic assays have been developed. They show that plasma levels of PA Inhibitor are very low under normal conditions, but a considerable increase (X10 or 20) is found in several pathological conditions (thrombo embolic disease, atherosclerosis, thrombotic risk factors (obesity, hypertriglyceridemia, diabetes) inflammatory syndrome, post operative period for PA Inhibitor 1, and in some physiological conditions (pregnancy for PA Inhibitor 2). These results plead for a pathogenic role of PA Inhibitor 1 in the development of thrombosis. Pharmacological products able to decrease the plasma level of PA Inhibitor are as yet scarce. Stanozolol, an anabolic steroid, some biguanides such as Metformin possess this property.

PMID: 3113299, UI: 87296902



17: Diabetes Res Clin Pract 1985-86 Feb;1(5):281-7

The management of non-insulin-dependent diabetes during pregnancy.

Coetzee EJ, Jackson WP

We propose a rational regimen for management of non-insulin-dependent pregnant diabetics (NIDD), using appropriately constituted calorie-restricted diets with the oral agents metformin and glibenclamide as may be necessary, with rapid recourse to insulin if the latter do not produce excellent control of blood glucose. Using this regimen between June 1974 and December 1983 we have managed 423 new diabetics (ND, diagnosed during pregnancy) with a perinatal mortality (PNM) of 14 per 1000 and 268 established diabetics (known diabetics, KD) with a PNM of 70/1000 (57/1000 since 1978). A further 80 NIDDs were 'untreated', i.e., not seen by us until near term; these suffered a PNM of 313/1000. Side-effects of the drugs have been few and mild, they are not teratogenic; 'starvation ketosis' does not occur; neonatal hypoglycaemia is preventable by using continuous insulin infusion during delivery. We suggest that the regimen outlined here is acceptable to the patients, is safe, gives excellent results and furthermore teaches the diabetic mother proper dietary control and combats lifelong obesity. It should be useful especially in developing countries in which pregnant, overweight NIDDs are common. Precise control of the blood glucose is essential.

PMID: 3939118, UI: 86246951



18: S Afr Med J 1984 Apr 21;65(16):635-7

Oral hypoglycaemics in the first trimester and fetal outcome.

Coetzee EJ, Jackson WP

During a 5 1/2-year period we saw 171 pregnant women with established non-insulin-dependent diabetes; 78 patients received oral hypoglycaemic drugs during the 1st trimester and 93 did not. The outcome of pregnancy in these two groups is compared. Only two major congenital anomalies were seen in the tablet-taking group and the number of abortions (4) was not excessive. The perinatal mortality (PNM) rate was initially high after large doses of chlorpropamide or metformin had been given during the 1st trimester, but this was clearly related to inadequate diabetic control in later pregnancy. Among the last 50 of the total of 75 viable infants whose mothers received oral drugs early in pregnancy, the PNM rate was 40/1 000. We conclude that modern oral hypoglycaemic drugs are safe and useful, not only during later pregnancy but also during the 1st trimester, provided excellent control of blood glucose levels is achieved.

PMID: 6369573, UI: 84172551



19: S Afr Med J 1980 Nov 15;58(20):795-802

Pregnancy in established non-insulin-dependent diabetics. A five-and-a-half year study at Groote Schuur Hospital.

Coetzee EJ, Jackson WP

During a 5 1/2-year period we have seen 171 pregnant women with established insulin-independent diabetes. Eleven of them booked late and received virtually no treatment. The remaining 160 patients were managed primarily by regulating diet; when this failed metformin or glibenclamide therapy was instituted. Insulin was used when diet and oral drugs failed. Diabetic control was considered adequate if fasting blood glucose levels remained below 5,5 mmol/l and post-prandial levels were below 6,7 mmol/l. Twenty-five per cent of patients were well controlled on diet only during the duration of their pregnancies, with 1 perinatal death. Glibenclamide and metformin appear to be safe drugs during pregnancy when properly used. The overall perinatal mortality rate was 78/1 000; 42/1 000 since January 1978, as compared with 364/1 000 in the 'untreated' group. Only 18 babies were large (> 4 000 g), respiratory distress rarely occurred and hyaline membrane disease was virtually absent. Hypoglycaemia of the neonate was seldom a problem, but was most frequently related to the use of glibenclamide. Neonatal hypoglycaemia may be abolished if patients receiving tablets or insulin are given continuous, intravenous low-dose insulin 24 hours before planned delivery. The prevalence of major abnormalities was as least double that among infants of non-diabetic mothers.

PMID: 6777880, UI: 81079162



20: S Afr Med J 1979 Dec 22;56(26):1113-4

Side-effects of metformin.

Jackson WP, Coetzee EJ

Publication Types:
Letter

PMID: 550448, UI: 80258969



21: S Afr Med J 1979 Sep 1;56(12):467-75

Diabetes newly diagnosed during pregnancy: A 4-year study at Groote Schuur Hospital.

Coetzee EJ, Jackson WP

As a result of active screening for gestational diabetes of the population attending various antenatal clinics in the Cape Peninsula, 127 patients with a repeatedly diabetic glucose tolerance test (GTT) were discovered; in many the GTT was grossly abnormal. The most useful screening factor was repeated glycosuria. Because they had booked late, 22 patients received virtually no treatment, and 1 patient aborted. Treatment of the remaining 104 patients was achieved principally by regulating diet, but when this failed metformin or glibenclamide therapy was instituted. Insulin was used when diet and oral drugs failed. Diabetic control was considered adequate if fasting blood glucose levels remained below 5,5 mmol/l and if postprandial levels were below 7 mmol/l. Most patients (67) were well controlled on a strict dietary regimen, and there were no perinatal deaths in this group. Glibenclamide and metformin, judging from this small series, appear to be safe for use in gestational diabetics. The overall perinatal mortality in treated patients was 10/1 000 as compared with an effective perinatal mortality of 145/1 000 in the 'untreated' group. Neonatal morbidity was similar to that in other reported series. Hypoglycaemia was seldom a problem and 79% of birth weights were between the 10th and the 90th percentiles.

PMID: 121638, UI: 80258873



22: Diabetologia 1979 Apr;16(4):241-5

Metformin in management of pregnant insulin-independent diabetics.

Coetzee EJ, Jackson WP

Sixty pregnant "maturity-onset" (insulin-independent), established and gestational, diabetics were treated with Metformin in the second and third trimester after dietary treatment had failed. The incidence of Metformin failure was 53.8% in the established diabetics and 28.6% in the "gestational" diabetics. The 27 Metformin failures were transferred to other therapy, leaving for further analysis 33 patients who received Metformin up till delivery. Two neonatal deaths occurred in this group (1 congenital abnormality and 1 preterm infant) giving a perinatal mortality of 61/1000. This compares with a perinatal mortality of 103/1000 in the Metformin failure group and 105/1000 in a group of insulin-dependent diabetics treated during the same period. Apart from a high incidence of neonatal jaundice requiring phototherapy the infant morbidity in the Metformin group was low. The mothers of 3 infants with congenital abnormalities had received Metformin only during the last trimester of their pregnancy.

PMID: 428695, UI: 79149107



23: Practitioner 1975 Nov;215(1289):644-52

The management of pregnancy in diabetes mellitus.

Brearley BF

A personal series of 100 consecutive diabetic pregnancies of over 28 weeks' gestation in 78 mothers during the period from January 1961 to June 1973, is described. There were 92 live births (including two pairs of twins) and 10 foetal deaths (9.8 per cent). The findings show that in diabetic pregnancies good results can be obtained by meticulous control and carefully coordinated obstetric and paediatric care.

PMID: 1202478, UI: 76078212



24: Q J Med 1974 Apr;43(170):339-57

Mild familial diabetes with dominant inheritance.

Tattersall RB

PMID: 4212169, UI: 74304593



25: Br Med J 1972 Jul 15;3(819):163-5

Diabetes mellitus--refractory obesity.

PMID: 5064737, UI: 72225112



26: Br Med J 1971 Jul 3;3(765):29-30

Adverse reactions to oral antidiabetic agents.

Harris EL

PMID: 5091891, UI: 71234313


Buy Ovacue Fertility Monitor

FertilAid