title: Metformin in reproductive health, pregnancy and gynaecological cancer: established and emerging indications.
abstract: BACKGROUND
  Metformin is an effective oral anti-hyperglycaemic drug used as first-line medical treatment for type 2 diabetes. It improves systemic hyperglycaemia by reducing hepatic glucose production and enhancing peripheral insulin sensitivity. It also stimulates fat oxidation and reduces fat synthesis and storage. The molecular mechanism of this drug is thought to be secondary to its actions on the mitochondrial respiratory chain.
  
  
  METHODS
  This paper reviews the relevant literature (research articles up to October 2013) on the use of metformin in infertility, polycystic ovary syndrome (PCOS), pregnancy and gynaecological cancers. We present a comprehensive discussion of the evidence supporting the efficacy of metformin in these clinical conditions.
  
  
  RESULTS
  Metformin is used clinically off-label in the management of hirsutism, acne and insulin resistance in PCOS, although the evidence for anti-androgenic effects is inconsistent. Metformin is also used to improve ovulation in women with PCOS both alone and in combination with clomiphene citrate. Trial findings are conflicting but metformin treatment in IVF/ICSI cycles may reduce the risk of ovarian hyperstimulation syndrome and increase live birth rates. Metformin also appears to be effective and safe for the treatment of gestational diabetes mellitus (GDM), particularly for overweight and obese women. Studies have shown that metformin is safe in pregnancy and women with GDM treated with metformin have less weight gain during pregnancy than those treated with insulin. One study with a 2-year follow-up demonstrated that babies born to women treated with metformin also developed less visceral fat, making them less prone to insulin resistance in later life. These findings have sparked interest in the use of metformin for pregnant, obese, non-diabetic women. On-going clinical trials are underway to determine if women treated prophylactically with metformin have a reduced incidence of GDM and demonstrate less weight gain during pregnancy. The hypothesis in these studies is that babies born to obese women on prophylactic metformin will also have better outcomes. Epidemiological studies have linked metformin exposure to a decreased risk of cancer. Pre-clinical experiments report that metformin has a growth-static effect on several cancers, including endometrial cancer, which may be partly due to the effect of metformin on the PI3K/AKT/mTOR signal transduction pathway. A number of on-going early phase clinical trials aim to explore the anti-cancer effects of metformin and investigate its potential as a chemopreventative or adjuvant treatment.
  
  
  CONCLUSIONS
  Obesity is on the rise in developing countries and is strongly linked to several reproductive health problems, including PCOS, GDM and endometrial cancer. Traditional lifestyle measures aimed at weight reduction are challenging to implement and maintain. Metformin may be a valuable alternative to, or adjunct for, modifying the toxic effects of obesity in these populations. This review will appraise the evidence for the use of metformin for the prevention and treatment of adverse health outcomes in obstetrics and gynaecology.
authors.affiliation: Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, Oxford Road, Manchester M13 9WL, UK.
authors.forename: Vanitha N
authors.initials: VN
authors.lastname: Sivalingam
authors.affiliation: Institute of Human Development, Manchester Academic Health Science Centre, University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, Oxford Road, Manchester M13 9WL, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Myers
authors.affiliation: Leeds Centre for Reproductive Medicine, Leeds Teaching Hospitals, Seacroft Hospital, Leeds LS14 6UH, UK.
authors.forename: Susie
authors.initials: S
authors.lastname: Nicholas
authors.affiliation: Leeds Centre for Reproductive Medicine, Leeds Teaching Hospitals, Seacroft Hospital, Leeds LS14 6UH, UK.
authors.forename: Adam H
authors.initials: AH
authors.lastname: Balen
authors.affiliation: Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, Oxford Road, Manchester M13 9WL, UK emma.crosbie@manchester.ac.uk.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Crosbie
mesh_terms: D002996:Clomiphene / Q000627:therapeutic use; D016640:Diabetes, Gestational / Q000188:drug therapy; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000517:prevention & control; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy* / Q000517:prevention & control; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology; D008019:Life Style; D008687:Metformin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D010060:Ovulation / Q000187:drug effects; D010062:Ovulation Induction; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy; D011247:Pregnancy; D011256:Pregnancy Outcome; D018873:Pregnancy Rate; D060728:Reproductive Health
chemical_list: D007004:Hypoglycemic Agents; D002996:Clomiphene; D008687:Metformin
keywords: endometrial cancer; gestational diabetes; metformin; obesity in pregnancy; polycystic ovary syndrome