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Cited by 635Ovarian function and disordersDiabetes, Cardiovascular Risks, and LipoproteinsAdipokines, Inflammation, and Metabolic Diseases

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, Renato, Gambineri, Alessandra, Biscotti, Domenico, Vicennati, Valentina, Gagliardi, Lorenza, Colitta, Donatella, Fiorini, Stefania, Cognigni, Graciela Estela +2 more·2000·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jcem.85.8.6738
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Abstract

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 (1200–1400 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. In summary, this study shows that, in PCOS women with abdominal obesity, long-term treatment with metformin added to hypocaloric diet induced, in comparison with placebo, a greater reduction of body weight and abdominal fat, particularly the visceral depots, and a more consistent decrease of serum insulin, testosterone, and leptin concentrations. These changes were associated with a more significant improvement of hirsutism and menses abnormalities. Moreover, the effects on body weight, insulin, and leptin were similar to those observed in the group of comparable abdominally obese controls, in whom, however, a more pronounced reduction of sc fat in the abdominal region and an increase of SHBG concentrations were found. These findings, therefore, indicate that hyperinsulinemia and abdominal obesity may have complementary effects in the pathogenesis of PCOS.

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Crossref · 10.1210/jcem.85.8.6738

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  • Body composition as assessed by computed tomography at L4-5 was provided in two of nine studies comparing lifestyle plus metformin with lifestyle plus placebo.

    “Body composition as assessed by computed tomography(CT)atL4-5wasprovided in two (Pasquali et al. , 2000; Gambineri et al. , 2006) of nine studies comparing lifestyle + metformin with lifestyle + placebo.”

    From Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis (2015) · cites this paper as Pasquali et al. , 2000

  • Two participants on lifestyle plus metformin (16%, 2/12) in Pasquali et al. (2000) became pregnant and were excluded, and two pregnancies (18%, 2/11) occurred on lifestyle plus placebo in Hoeger et al. (2004).

    “Two participants on lifestyle + metformin [16% (2/12)] in one study (Pasquali et al. , 2000) who became pregnant were excluded and two pregnancies [18% (2/11)] occurred on lifestyle + placebo in another study (Hoeger et al. , 2004).”

    From Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis (2015) · cites this paper as Pasquali et al. , 2000

  • Insulin resistance was assessed in five of nine studies comparing lifestyle plus metformin with lifestyle plus placebo.

    “Insulin resistance was assessed in five of nine studies comparing lifestyle + metformin with lifestyle + placebo (Pasquali et al. , 2000; Hoeger et al. , 2004; Gambineri et al. , 2006; Ladson et al. , 2011a, b).”

    From Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis (2015) · cites this paper as Pasquali et al. , 2000

  • Lifestyle plus metformin compared with lifestyle plus placebo was associated with lower subcutaneous adipose tissue on CT scan (mean difference -92.49 cm2, 95% CI -164.14 to -20.84, P=0.01).

    “27 100.0%-92.49 [-164.14,-20.84]”

    From Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis (2015) · cites this paper as Pasquali et al., 2000

  • Two studies were designed as randomized controlled studies but comprised two intervention groups and were used as comparative studies.

    “Two were designed as randomized controlled studies (RCTs) but comprised two intervention groups, respectively, and were used as comparative studies [38,39].”

    From Weight management interventions in women with and without PCOS: a systematic review (2017) · cites this paper as [38]

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Authors
Pasquali, R., Gambineri, A., Biscotti, D., Vicennati, V., Gagliardi, L., Colitta, D., Fiorini, S., Cognigni, G. E., Filicori, M., & Morselli-Labate, A. M.
Affiliations
  • IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
  • Department of Obstetric and Gynecology, Reproductive Endocrinology Center (G.E.C., M.F.), University of Bologna, 40138 Bologna, Italy
  • University of Bologna (IT)
  • Endocrine Unit (R.P., A.G., D.B., V.V., L.G., D.C., S.F., A.M.M.-L.), Department of Internal Medicine and Gastroenterology, S. Orsola-Malpighi Hospital
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2000-08-01
Volume
85
Issue
8
Pages
2767-2774
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jcem.85.8.6738
OpenAlex
W2021450389
Semantic Scholar
10a3b38be42fe7f9b622bc8f835115a223f088dd
Cited by
635
References
45
Citations by year
2026: 5 · 2025: 1 · 2024: 7 · 2023: 10 · 2022: 9 · 2021: 19 · 2020: 8 · 2019: 19 · 2018: 14 · 2017: 50 · 2016: 21 · 2015: 43 · 2014: 18 · 2013: 24 · 2012: 16
FWCI
35.15
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
polycystic ovary syndrome, metformin, hypocaloric diet, abdominal obesity, body composition, visceral adipose tissue, subcutaneous adipose tissue, hyperandrogenism, insulin resistance, hyperinsulinemia, sex hormone-binding globulin, leptin, hirsutism, menstrual cycle, weight loss, women's health, oral glucose tolerance
MeSH terms
Abdomen, Adipose Tissue, Adult, Androgens, Body Composition, Combined Modality Therapy, Diet, Reducing, Double-Blind Method, Estradiol, Female, Follicle Stimulating Hormone, Humans, Hypoglycemic Agents, Insulin, Luteinizing Hormone, Metformin, Obesity, Placebos, Polycystic Ovary Syndrome, Progesterone, Sex Hormone-Binding Globulin, Viscera, Leptin

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