You are known to have Polycystic Ovary Syndrome and recently married. You wish to become pregnant. You have extensively researched the internet and have come to the conclusion that you should be treated with metformin.

 

My Opinion.

 

I would ensure that you qualify for PCOS diagnosis with at least 2 of the following; US-PCO, symptoms and tests of androgen excess after excluding other causes of androgen excess1,2.

 

Your insulin resistance, ovulation, tubal patency and your partner semen analysis should be tested.  It is important to consider your age and other infertility factors as poorer outcome in older patients may justify IVF.

 

If overweight and insulin resistant; It is important to assess for metabolic syndrome if there is three or more of the following; hypertension ≥130/85mmHg, triglyceride level ≥1.7mmol/L, HDL-cholesterol<1.3mmol/L, abdominal obesity >90cm or fasting glucose ≥6mmol/L3. Hypertension develops later in life.

 

If you are overweight, with waist-circumference>90cm you have cardiovascular risk4.

 

Obesity is associated with anovulation5, pregnancy loss6, pre-eclampsia and gestational diabetes7, response failure to CC8,9, gonadotrophins10,11 and laparoscopic ovarian diathermy-LOS12.

 

Weight loss is first-line therapy. Losing 5% of body-weight can produce pregnancy13. Low-calorie diet reduces weight by 12% in 6/12 and improves reproductive outcome14. Weight loss prior to conception improves live-birth rate in obese women with or without PCOS15.

 

Regular exercise helps long-term weight loss16, but has orthopaedic and cardiovascular limitations in obese women15.

 

Bariatric surgery in morbidly obese may sustain weight loss17. Appetite suppressant Sibutramine18 and intestinal fat absorption-blocker Orlistat19 reduce androgens and insulin resistance independent of weight-loss.

 

If you have normal FSH and not ovulating CC is the first choice to induce ovulation. CC is economical, oral, safe and requires little monitoring20.

 

Your weight, excess-androgen and age predicts treatment success21. Pregnancy rates when BMI>30 are significantly less compared with BMI<3022. CC produces ovulation in 75%–80% of PCOS-patients20,23, but pregnancy is 22% per ovulation and differences are due to CC antiestrogenic effects20,23. Multiple pregnancy is <10% and hyperstimulation is rare.24.

 

Adding hCG mid-cycle does not improve pregnancy rates25. Treatment is usually six ovulatory-cycles24,20 with 50–60% cumulative live-birth rates in six cycles26.

 

Combined CC and metformin as primary therapy to induce ovulation has no beneficial effect27,22. There is; however apparent advantage to adding metformin to CC in women with BMI>35kg/m2 and in those with CC resistance22.

 

Metformin is used to treat diabetes. Metformin reduces gluconeogenesis, increases sensitivity to insulin; consequently reduces hyperinsulinaemia, LH levels, total testosterone, FAI and PAI-1 in overweight women with PCO. It reduces acne and hirsutism. Metformin raises SHBG levels. It induces onset of regular cycles. Adverse effects of the drug include gastro-intestinal disorders, mainly diarrhoea, which improves when the dose is reduced or the drug is taken with meals.

 

In PCOS, metformin lowers fasting insulin level but does not cause significant changes in BMI or waist-to-hip ratio28. It improves oligomenorrhoea but anovulation and menorrhagia persist in many with endometrial hyperplasia risk. Improvement in ovulation is similar to that with weight reduction through life-style modification with no difference between metformin and placebo in weight reduction29.

 

Two RCTs assessed metformin use for ovulation induction in either obese or normal weight women with PCOS indicated that metformin does not increase live birth rates when compared to CC alone27,22. Adding metformin did not reduce miscarriage, which was higher in metformin group22.

 

Metformin treatment during pregnancy may protect against complications30; currently it should be used only in research31. PCOS-women with insulin resistance and taking metformin should stop it if pregnancy occurs22.

 

Use of metformin in PCOS should be restricted to those patients with obesity and insulin resistance32,33.

 

Metformin is also an alternative for patients who manifest excess-androgen. A recent review emphasized use of metformin to improve insulin resistance, type 2 diabetes, dyslipidemia, and cardiovascular alterations in PCOS patients34.

 

Hyperinsulinemia appears to be present in a significant number of PCOS patients. Some believe it is an independent component of obesity35, while others associate insulin resistance in PCOS only with obese patients36. Only 10% of non-obese PCOS patients have insulin resistance37,38.

 

It is important to recognise a past history of teenage syndrome with oligomenorrhoea for at least 2 years following menarche.  Hyperinsulinaemia can lead to premature adrenarche with excess androgens and PCO. Body weight is normal with dyslipidaemia. The marker is a low birth weight as the condition starts in fetal life39,40. Treatment with Metformin returns metabolic parameters to normal and ovulatory menstrual function is initiated41,42.

 

Aromatase inhibitor letrozole does not improve ovulation or pregnancy43.

 

Exogenous gonadotrophins are second possible line of therapy in CC- resistance32. Gonadotrophins induce ovulation and achieve fertilizable follicle but drawbacks are ovarian hyperstimulation and multiple pregnancies which can be reduced with US monitoring and oestradiol measurements44.  No response after six cycles with gonadotrophins signifies resistance.

 

In women with PCOS who failed to conceive despite successful induction of ovulation, IUI may also be considered if there is an associated male factor.

 

Contraceptives combined with metformin; six weeks before stimulation cycle, reduces follicle recruitment and avoid cycle cancellation. Combining GnRH agonists and gonadotrophins improves efficacy.

 

Ovulation induction by LOS-diathermy is an option45 in CC-resistant or excess LH or if laparoscopic assessment of pelvis is required or if you live too far for monitoring required during gonadotrophin therapy. Because of inherent risks of surgery and lack of long-term evidence from RCTs, LOS cannot be recommended46. Adjuvant therapy CC or FSH will be required in 50% of LOS-treated women47.

 

RCTs comparing LOS with gonadotrophins for CC-resistant PCOS showed similar ongoing pregnancy rate and live birth rate48,49,47; but multiple pregnancy rates were significantly higher in gonadotrophin compared with LOS.

 

Treating CC-resistant PCOS by LOS resulted in reduced costs50,51. In addition to laparoscopic complications; ovarian adhesions as late complication are common52.

 

In principle, anovulation is not an indication for IVF. IVF is used when weight reduction, CC, gonadotrophins, LOD and metformin have failed32. After failure of weight reduction, anti-oestrogen or LOS, it may be argued that gonadotrophin should be omitted and replaced by ovarian stimulation and IVF53. Risk of multiple pregnancies is markedly reduced in IVF with single-ET54,55. PCOS associated with tubal damage, severe endometriosis, PGD and male infertility indicate IVF. Women with PCOS undergoing IVF had more cycle cancellation56.

 

Use of metformin in IVF improves viable pregnancy rates and reduces incidence of ovarian OHSS57. PCOS does not intervene in embryo implantation as IVF success is similar in patients with or without PCOS.

 

It is important to assess endometrium with biopsy to exclude cancer after long exposure of unopposed oestrogen58.

 

Folate supplementation; smoking, alcohol and caffeine cessation are recommended.

References

 

1 The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004a:81; 19–25.

2 The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004b:19; 41–47.

3 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001: 285; 2486-2497.

4 Pouliot M, Després J, Lemieux S et al. Waist circumference and abdominal sagittal diameter: best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women. Am J Cardiol 1994: 73; 460-468.

5 Pasquali R, Pelusi C, Genghini S et al. Obesity and reproductive disorders in women. Hum Reprod Update 2003:9; 359–372.

6 Froen J, Arnestad M, Frey K et al. Risk factors for sudden intrauterine unexplained death: epidemiologic characteristics of singleton cases in Oslo, Norway, 1986–1995. Am J Obstet Gynecol 2001:184; 694–702.

7 Boomsma C, Eijkemans M, Hughes E et al. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update 2006:12; 673–683.

8 Imani B, Eijkemans M, Te Velde E et al. Predictors of patients remaining anovulatory during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab 1998:83; 2361–2365.

9 Imani B, Eijkemans M, Te Velde E et al. Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab 1999:84; 1617–1622.

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11 Balen A, Platteau P, Andersen A et al. The influence of body weight on response to ovulation induction with gonadotrophins in 335 women with World Health Organization group II anovulatory infertility. BJOG 2006:113; 1195–1202.

12 Gjonnaess H. Ovarian electrocautery in the treatment of women with polycystic ovary syndrome (PCOS). Factors affecting the results. Acta Obstet Gynecol Scand 1994:73; 407–412.

13 Kiddy D, Hamilton-Fairley D, Bush A et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 1992:36; 105–111.

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17 Escobar-Morreale H, Botella-Carretero J, varez-Blasco F et al. The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J Clin Endocrinol Metab 2005:90; 6364–6369.

18 Sabuncu T, Harma M, Harma M et al. Sibutramine has a positive effect on clinical and metabolic parameters in obese patients with polycystic ovary syndrome. Fertil Steril 2003:80; 1199–1204.

19 Jayagopal V, Kilpatrick E, Holding S et al. Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome. J Clin Endocrinol Metab 2005:90; 729–733.

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22 Legro R, Barnhart H, Schlaff W et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007a:356; 551–566.

23 Messinis IE. Ovulation induction: a mini review. Hum Reprod. 2005:20; 2688–2697.

24 Eijkemans M, Imani B, Mulders A et al. High singletons live birth rate following classical ovulation induction in normogonadotrophic anovulatory infertility (WHO 2). Hum Reprod. 2003:18; 2357–2362.

25 Kosmas I, Tatsioni A, Fatemi H et al. Human chorionic gonadotropin administration vs. luteinizing monitoring for intrauterine insemination timing, after administration of clomiphene citrate: a meta-analysis. Fertil Steril 2007; 87:607–612.

26 Kousta E, White D, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod Update 1997:3; 359–365.

27 Moll E, Bossuyt P, Korevaar J et al. 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. BMJ

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28 Lord J, Flight I, Norman R. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane Database Syst Rev 2003; CD003053.

29 Tang T, Glanville J, Hayden C et al. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study. Hum Reprod 2006a:21; 80–89.

30 Vanky E, Salvesen K, Heimstad R et al. Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study. Hum Reprod 2004:19; 1734–1740.

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36 Holte J, Bergh T, Berne C et al. Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1995: 80; 2586–2593.

37 Meirow D, Yossepowitch O, Rosler A et al. Insulin resistant and non-resistant polycystic ovary syndrome represent two clinical and endocrinological subgroups. Hum Reprod. 1995: 10; 1951–1956.

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42 Ibanez L, Valls C, Ferrer A et al.  Sensitization to insulin induces ovulation in nonobese adolescents with anovulatory hyperandrogenism. J Clin Endocrinol Metab 2001: 86; 3595- 3598.

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