Table 1<\/a> . One important point to recognise in all these studies is the short-term nature of the obser\u00advation period. Insulin is known to promote the ac\u00adtions of LH leading to increased androgen produc\u00adtion from ovarian tissue, and metformin treatment leads to a rapid, if modest, reduction in circulating androgen concentrations in most studies.<\/p>\nIt was noted above that one of the prime fea\u00adtures of PCOS is abnormal primordial-to-primary follicle development, and so far little attention has been paid to these events with any clinical interven\u00adtion in PCOS. However, there is evidence from two studies of protracted metformin treatment,22,23<\/sup> sug\u00adgesting that the number of follicles recruited to grow at this earliest stage may indeed be attenuated by such treatment, which may be related to reduced insulin and\/or androgen drive at the earliest stages of development. This in turn suggests that in order to explore a role for metformin in correcting the over-production of follicles by women with PCOS, the investigations should start only after 6 months treatment or more, not during the first 6 months.<\/p>\nOvulation rates and patients who benefit most
\n<\/strong><\/span><\/em>
\nRestricted to short-term observations as we are, the first three reviews24-26<\/sup> suggest that metformin doubles ovulation rates from low basal levels. On average, one additional ovulation is attained every 5 months with metformin treatment, which is a mod\u00adest benefit in a clinical setting, while it has rarely been shown to increase pregnancy rates.<\/p>\nOne recent randomised study demonstrated that metformin treatment conferred no benefit over and above that of lifestyle modification.27<\/sup> However, more encouraging results, in a relatively lean cohort, were obtained by comparison with the effect of laparo\u00adscopic ovarian diathermy, showing that metformin was at least as effective in terms of achieving preg\u00adnancy within 6 months.28<\/sup><\/p>\nSub-group analysis21<\/sup> and direct investigation29<\/sup> indicate that metformin may be more effective in lean women, with least metabolic disturbance, sug\u00adgesting that the therapy is insufficient to correct the metabolic disturbance induced by obesity in the short-term, at least at current doses. This observa\u00adtion supports the hypothesis that obesity and insu\u00adlin resistance may have independent roles in PCOS.3<\/sup><\/p>\nMetformin as first line fertility treatment?
\n<\/strong><\/span><\/em>
\nIn standard fertility treatment, metformin has been shown to increase the response rate to clomi\u00adphene citrate (the erstwhile first line therapy), lead\u00ading to an increased pregnancy rate in this first line approach.30<\/sup> However, a recent large prospective ran\u00addomised, multicentre trial in Holland31 comparing clomiphene citrate alone or combined with metform\u00adin, has produced strong evidence contradicting the original observations.30<\/sup> It may be anticipated that this will lead to a re-consideration of the general practice, and possible explorations of sub-groups in which the combined therapy may be deemed bene\u00adficial.<\/p>\nAs metformin alone may lead to spontaneous ovulation, particularly in the leaner patient with PCOS, and given that any pregnancy is more likely to be a singleton (in contrast to clomiphene citrate, where we can expect a >10% twinning rate), there is a valid case supporting the use of metformin as first line therapy in women with PCOS. There is no direct evidence to corroborate this concept, but it should be tested prospectively.<\/p>\n
METFORMIN IN ASSISTED CONCEPTION (IVF\/ICSI)<\/strong><\/span><\/p>\nStandard assisted conception treatment involves stimulation of multiple follicular development with exogenous gonadotrophins, and because metform\u00adin appears to improve some aspects of follicular growth, its potential role has been explored in some interesting trials. Though many of the trials lack acceptable levels of control, useful evidence is emerging.<\/p>\n
The main observations in two randomised con\u00adtrol studies32,33<\/sup> indicate that relatively short-term metformin treatment does not influence total folli\u00adcular responses to exogenous FSH, evidenced by numbers of follicles, duration and dose of FSH and numbers of oocytes. This is an important observa\u00adtion, leading us to conclude that short-term modu\u00adlation of the insulin and androgen environment does not affect either the stockpile of follicles awaiting FSH stimulation or the sensitivity of those individu\u00adal follicles to FSH stimulation in terms of growth rate and amount of FSH required to achieve matu\u00adration.<\/p>\nHowever, two end-points deserve further explo\u00adration. The Norwegian group32<\/sup> observed that the lean sub-group showed a statistically increased preg\u00adnancy rate, and the study by Tang et al,33<\/sup> which in\u00adcluded relatively lean patients in the whole study group, showed an unambiguous improvement in pregnancy rate. A large multi-centre study is now addressing this issue and we await the outcome with some anticipation.<\/p>\nIt would appear that the mechanism for any ben\u00adeficial effect is unrelated to changes in FSH sensi\u00adtivity and gross ovarian responses, as these were not influenced by metformin treatment in either study. One potential mechanism of benefit was proposed by Richardson et al,34<\/sup> who showed that the granu\u00adlosa cells, which normally provide the oocyte with essential pyruvate, amino acids and growth factors, displayed altered metabolism in women with PCOS. The altered metabolism displayed reduced break\u00addown of glucose to pyruvate and increased lipolysis, as in other tissues in the insulin resistant state. Con\u00adsequently, the oocyte is exposed to reduced pyru\u00advate (its main source of energy) and increased reac\u00adtive oxygen species and inflammatory products, po\u00adtentially reducing oocyte viability.<\/p>\nA second and possibly equally important obser\u00advation is the clear benefit that metformin treatment affords in terms of ovarian hyperstimulation syn\u00addrome (OHSS). This observation is supported by another randomised trial.35<\/sup> Hence there is good clin\u00adical reason to use the drug in these circumstances, because women with PCOS are at increased risk of OHSS, which can be a serious side effect of IVF treatment. This is such a dramatic observation that it may also be instructive of the underlying ovarian abnormality in PCOS, and the role of insulin me\u00adtabolism in vascular development of the ovary and follicles.<\/p>\nMetformin in pregnancy<\/strong><\/span><\/em><\/p>\nLarge observational studies36<\/sup> have suggested that metformin may confer a number of protective ad\u00advantages through pregnancy in women with PCOS by reducing complications such as gestational dia\u00adbetes and even early pregnancy loss. This effect was explored prospectively in a randomised program\u00adme37<\/sup> in which secondary end-point evaluations of late pregnancy problems were abundant in the pla\u00adcebo arm and virtually absent from the metformin arm. Since it has been shown that metformin cross\u00ades the placenta,38<\/sup> care must be exercised to avoid indiscriminate use and any benefits should be ex\u00adplored in a research environment.<\/p>\nMetformin in PCOS: weight loss<\/strong><\/em><\/span><\/p>\nThe high incidence of obesity amongst women with PCOS is an important consideration in man\u00adagement and approaches to treatment. The thiazo\u00adlidinediones tend to increase weight by dint of their mode of action, which is a further argument militat\u00ading against their use in potentially fertile women with PCOS. On the other hand, metformin is generally associated with weight reduction. In terms of meta\u00adbolic and anthropometric effects, current evidence supports a reduction in BMI by around 4% over a few months compared to placebo (representing ~2-\u00ad3 kg reduction) in women with PCOS.39<\/sup> In addition, a role for different doses of metformin has been minimally explored, and where it has been, perhaps more consistent effects upon weight loss can be de\u00adtermined with a higher dose schedule.39<\/sup><\/p>\nSUMMARY
\n<\/strong><\/span>
\nBy and large, these studies suggest that women with PCOS in the fertility clinic may derive benefit and improved safety from treatment with metform\u00adin at all stages. Whilst it is critically important that these studies be confirmed in more extensive trials, it is also important to establish the mechanisms by which the drug confers these benefits. There may be an underlying issue of energy metabolism, but the connections with a number of the observations are tenuous and, in reproductive terms, the link with androgen metabolism may prove to be the critical element.<\/p>\nOverall, the metabolic and reproductive chang\u00ades noted with metformin use in women with PCOS are consistent with its known effect in patients with type 2 diabetes. However, the effects are generally modest and larger trials of longer duration and more comprehensive controls are required.<\/p>\n
It is important to note that metformin is not li\u00adcensed for any of these indications in PCOS and, as shown in the evidence presented above, it is cer\u00adtainly not a ‘cure’ for all reproductive and metabol\u00adic derangements in women with PCOS. Despite this, once established on metformin treatment, women with a history of PCOS are reluctant to discontinue treatment.40<\/sup><\/p>\nIn view of metformin’s generally modest bene\u00adfits in women with PCOS, the relative merits of metformin combined with lifestyle changes, in par\u00adticular exercise, very definitely warrant further ex\u00adamination, and such studies are being developed. It is interesting that both exercise and metformin up-regulate AMP-activated protein kinase activity, a metabolic switch regulating efficient glucose and fatty acid metabolism. It should also be noted that lifestyle intervention was more successful than met\u00adformin alone in reducing risk of diabetes, once again emphasizing the critical role for lifestyle interven\u00adtion.<\/p>\n
Future research: reproduction in women with PCOS<\/strong><\/span><\/em><\/p>\nIn the fertility arena, there is a need for a coor\u00addinated programme of investigations using multi-centre prospective methods. The influence of obe\u00adsity and metformin dose on ovarian function has yet to be explored to the degree that is needed to fully elucidate effects. As the life history of ovarian folli\u00adcular development is so protracted and PCOS ap\u00adpears to be associated with abnormalities from the very beginning, examinations of the effects of treat\u00adment at this level are required. Other potential ar\u00adeas of benefit, including pregnancy complications, should be examined on a large, multi-centre scale.<\/p>\n
There is evidence to support the use of metform\u00adin, in association with other approaches, from the very beginning of treatment of women with PCOS, and this issue should be explored in the research arena.<\/p>\n
CONCLUSION<\/strong><\/span><\/p>\nIn the fertility arena, metformin may prove to be of considerable benefit, but mainly in association with other forms of treatment, and the results of recent studies are generally supportive of its extend\u00aded use, perhaps from the very first stages of treat\u00adment.<\/p>\n
REFERENCES<\/strong><\/span><\/p>\n1. The Rotterdam ESHRE\/ASRM-Sponsored PCOS consensus workshop group, 2004 Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 19: 41-47.
\n2. Burghen GA, Givens JR, Kitabchi AE, 1980 Correlation of hyperandrogenism with hyperinsulinemia in polycystic ovarian disease. J Clin Endocrinol Metab 50: 113-116.
\n3. Dunaif A, Thomas A, 2001 Current concepts in the polycystic ovary syndrome. Annu Rev Med 52: 401-419.
\n4. Vrbikova J, Cibula D, Dvorakova K, et al, 2004 Insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 89: 2942-2945.
\n5. Holte J, Bergh T, Berne C, Berglund L, Lithell H, 1994 Enhanced early insulin response to glucose in relation to insulin resistance in women with polycystic ovary syndrome and normal glucose tolerance. J Clin Endocrinol Metab 78: 1052-1058.
\n6. Ek I, Arner P, Ryden M, et al, 2002 A unique defect in the regulation of visceral fat cell lipolysis in the polycystic ovary syndrome as an early link to insulin resistance. Diabetes 5: 484-492.
\n7. Kelly CC, Lyall H, Petrie JR, et al, 2001 Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 86: 2453-2455.
\n8. Abbott DH, Dumesic DA, Franks S, 2002 Developmental origin of polycystic ovary syndrome – a hypothesis. J Endocrinol 174: 1-5.
\n9. Cresswell JL, Barker DJ, Osmond C, et al, 1997 Fetal growth, length of gestation, and polycystic ovaries in adult life. Lancet 350: 1131-1135.
\n10. Nestler JE, 1993 Sex Hormone binding globulin: A marker for hyperinsulinaemia or insulin resistance? J Clin Endocrinol Metab 76: 273-274.
\n11. Kelly CJ, Lyall H, Petrie JR, et al, 2002 A specific elevation in tissue plasminogen activator antigen in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 87: 3287-3290.
\n12. Morin-Papunen L, Rautio K, Ruokonen A, et al, 2003 Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 88: 4649-4654.
\n13. Hughesdon PE, 1982 Morphology and morphogenesis of the Stein-Leventhal ovary so called .hyperthecosis.. Obstet Gynecol Surv 37: 59-77.
\n14. Webber LJ, Stubbs S, Stark J, et al, 2003 Formation and early development of follicles in the polycystic ovary. Lancet 362: 1017-1021.
\n15. Maciel GA, Baracat EC, Benda JA, et al, 2004 Stockpiling of transitional and classic primary follicles in ovaries of women with polycystic ovary syndrome. J Clin Endocrinol Metab 89: 5321-5327.
\n16. Jonard S, Dewailly D, 2004 The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest. Hum Reprod Update 10: 107-117.
\n17. White DM, Polson DW, Kiddy D, et al, 1996 Induction of ovulation with low dose gonadotrophins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab 81: 3821-3824.
\n18. Kiddy DS, Hamilton-Fairley D, Bush A, et al, 1992 Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol 36: 105-111.
\n19. Clark AM, Thornley B, Tomlinson L, et al, 1998 Weight loss in obese infertile women results in improvement in the reproductive outcome for all forms of fertility treatment. Hum Reprod 13: 1502-1505.
\n20. Knowler WC, Barrett-Connor E, Fowler SE, et al, 2002 Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346: 393-403.
\n21. Fleming R, Hopkinson ZE, Wallace AM, et al, 2002 Ovarian Function and Metabolic Factors in Women with Oligomenorrhea Treated with Metformin in a Randomized Double Blind Placebo-Controlled Trial. J Clin Endocrinol Metab 87: 569-574.
\n22. Fleming R, Harborne L, MacLaughlin DT, et al, 2005 Metformin reduces serum mullerian-inhibiting substance levels in women with polycystic ovary syndrome after protracted treatment. Fertil Steril 83: 130-136.
\n23. Piltonen T, Morin-Papunen L, Koivunen R, Perheentupa A, Ruokonen A, Tapanainen JS, 2005 Serum anti-Mullerian hormone levels remain high until late reproductive age and decrease during metformin therapy in women with polycystic ovary syndrome. Hum Reprod 20: 1820-1826.
\n24. Harborne L, Fleming R, Lyall H, et al, 2003 Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome. Lancet 361: 1894-1901.
\n25. Lord JM, Flight IH, Norman RJ, 2003 Metformin in polycystic ovary syndrome: systematic review and metaanalysis. BMJ 327: 951-953.
\n26. Costello MF, Eden JA, 2003 A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome. Fertil Steril 79: 1-13.
\n27. Tang T, Glanville J, Hayden CJ, White D, Barth JH, Balen AH, 2006 Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study. Hum Reprod 21: 80-89.
\n28. Palomba S, Orio Jr, Nardo LG, et al, 2004 Metformin administration versus laparoscopic ovarian diathermy in clomiphene citrate-resistant women with polycystic ovary syndrome: a prospective parallel randomized double-blind placebo-controlled trial. J Clin Endocrinol Metab 89: 4801-4809.
\n29. Maciel GA, Soares Junior JM, Alves da Motta EL, Abi Haidar M, de Lima GR, Baracat EC, 2004 Nonobese women with polycystic ovary syndrome respond better than obese women to treatment with metformin. Fer-til Steril 81: 355-360.
\n30. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R, 1998 Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 338: 1876-1880.
\n31. Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F, 2006. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. Br Med J 332: 1485.
\n32. Kjotrod SB, von During V, Carlsen SM, 2004 Metformin treatment before IVF\/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study. Hum Reprod 19: 1315-1322.
\n33. Tang T, Glanville J, Orsi N, Barth JH, Balen AH, 2006 The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod 21: 1416-1425.
\n34. Richardson MC, Cameron IT, Simonis CD, et al, 2005 Insulin and human chorionic gonadotropin cause a shift in the balance of sterol regulatory element-binding protein (SREBP) isoforms toward the SREBP-1c isoform in cultures of human granulosa cells. J Clin Endocrinol Metab 90: 3738-3746.
\n35. Onalan G, Pabuccu R, Goktolga U, Ceyhan T, Bagis T, Cincik M, 2005 Metformin treatment in patients with polycystic ovary syndrome undergoing in vitro fertilization: a prospective randomized trial. Fertil Steril 84: 798-801.
\n36. Glueck CJ, Goldenberg N, Wang P, et al, 2004 Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy. Hum Reprod 19: 510-521.
\n37. Vanky E, Salvesen KA, Heimstad R, et al, 2004 Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study. Hum Reprod 19: 1734-1740.
\n38. Vanky E, Zahlsen K, Spigset O, Carlsen SM, 2005 Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril 83: 1575-1578.
\n39. Harborne LR, Sattar N, Norman JE, Fleming R, 2005 Metformin and weight loss in obese women with polycystic ovary syndrome: comparison of doses. J Clin Endocrinol Metab 90: 4593-4598.
\n40. Muth S, Norman J, Sattar N, Fleming R, 2004 Women with polycystic ovary syndrome (PCOS) often undergo protracted treatment with metformin and are disinclined to stop: indications for a change in licensing arrangements? Hum Reprod 19: 2718-2720.<\/p>\n<\/div>\n","protected":false},"excerpt":{"rendered":"
Richard Fleming<\/p>\n
Download PDF<\/a><\/div>\nInsulin resistance is an important “upstream” driver for reproductive and metabolic abnormalities in women with Polycystic Ovary Syndrome (PCOS). This theoretical background is now supported by substantial evidence for treating women with PCOS with insulin sensitising agents such as metformin or the thiazolidinediones…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[37,2,7],"tags":[560,561,562,563,235],"class_list":["post-1151","post","type-post","status-publish","format-standard","hentry","category-volume-5-issue-3","category-journal-articles","category-volume-5","tag-insulin-sensitising-agents","tag-insulin-sensitivity","tag-metformin","tag-ovulation","tag-pcos"],"_links":{"self":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts\/1151","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/comments?post=1151"}],"version-history":[{"count":4,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts\/1151\/revisions"}],"predecessor-version":[{"id":12999,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts\/1151\/revisions\/12999"}],"wp:attachment":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/media?parent=1151"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/categories?post=1151"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/tags?post=1151"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}