Ovulation Induction and Controlled Ovarian Stimulation, 2st ed.

10. Insulin Lowering Agents

Roy Homburg1

(1)

Homerton Fertility Centre, Homerton University Hospital, London, UK

Abstract

Polycystic ovary syndrome (PCOS) is associated with about 75 % of all cases of anovulatory infertility. Insulin resistance is frequently associated with PCOS, occurring in 80 % of women with PCOS and central obesity, but also in 30–40 % of lean women with PCOS. As a result of the reduction in insulin sensitivity, hyperinsulinaemia is invoked as a compensatory mechanism and this is of prime importance in the pathophysiology of PCOS as hyperinsulinaemia, which is significantly exacerbated by obesity, is a key factor in the pathogenesis of hyperandrogenism. Weight loss often seems to be an unsurmountable object for the obese patient with PCOS and the alternative possibility of using insulin lowering drugs, particularly metformin, is theoretically attractive. Although metformin as a mono-agent is capable of improving menstrual frequency and restoring ovulation in patients who have oligo-anovulation and PCOS, when used as first line therapy and compared to clomifene (CC), it fairs very poorly. In a large North American randomised controlled trial, CC was found to be superior to metformin as there was a significant difference in the number of clinical pregnancies and live full-term singleton births (22.6 % vs 7.2 %) using CC and metformin respectively. Insulin sensitizers should not be used as first-choice agents for induction of ovulation in women with PCOS and their administration does not appear to decrease the incidence of early pregnancy losses. The combination of metformin and CC is no better than CC alone except perhaps in CC resistant patients. Evidence for a possible role for long-term metformin treatment for the prevention of the long-term sequelae of PCOS is awaited.

Keywords

InsulinPolycystic ovary syndrome PCOSHyperinsulinaemiaHyperandrogenismObeseBody mass indexBMIHirsutismAcneAnovulationInfertilityMultifollicularHyperstimulationWeight lossAndrogenMetforminBiguanideTheca cellsAnovulatory PCOSLHOligomenorrheicOligo-anovulationClomipheneGonadotrophinFSHOestradiolFollicular developmentOvulation inductionIVFIn vitro fertilizationOHSSPregnancyAdolescenceGlitazonesRosiglitazonePioglitazone

Polycystic ovary syndrome (PCOS) is associated with about 75 % of all cases of anovulatory infertility. Insulin resistance is frequently associated with PCOS, occurring in 80 % of women with PCOS and central obesity, but also in 30–40 % of lean women with PCOS. Unlike the insulin resistance associated with diabetes type II, the insulin resistance in women with PCOS is due to a post-receptor defect affecting glucose transport which is unique to women with PCOS. As a result of the reduction in insulin sensitivity, hyperinsulinaemia is invoked as a compensatory mechanism and this is of prime importance in the pathophysiology of PCOS as hyperinsulinaemia, which is significantly exacerbated by obesity, is a key factor in the pathogenesis of hyperandrogenism. In general, the more severe the insulin resistance, the more severe the ovulatory disturbance and the symptoms of hyperandrogenism.

An abnormality of pancreatic beta-cell function has also been described in women with PCOS in whom insulin discharge is exaggerated in response to a glucose load compared with non-PCOS women.

Assessing insulin resistance has not proved to be a rewarding experience. The gold standard is the insulin clamp technique which is extremely cumbersome, complicated and unsuitable for routine use. The performance of an oral glucose tolerance test with the measurement of insulin concentrations under the curve similarly does not lend itself easily to routine practice. Other methods (HOMA, QUICKI), use various combinations of the values of fasting insulin and fasting glucose and are notoriously inaccurate. The ratio of fasting glucose to fasting insulin is probably the most commonly used but suffers from similar inaccuracies [1]. As a routine in every day practice, I do not estimate insulin resistance as this would help me little in the therapeutic decisions. It is fairly safe to assume that overweight and frankly obese women with PCOS suffer from some degree of insulin resistance.

The rate of insulin resistance in all women with PCOS is 50–80 % which means that a very large proportion of cases of anovulation and infertility is associated with hyperinsulinaemia and that the lowering of insulin concentrations can provide a therapeutic pathway.

Figure 10.1 illustrates the ways in which hyperinsulinaemia can cause anovulation and its effect on treatment.

A319194_2_En_10_Fig1_HTML.jpg

Figure 10.1

The importance of hyperinsulinaemia in the genesis and treatment of anovulation

A large majority of women who have PCOS and hyperinsulinaemia are obese [12]. Obesity, in women with PCOS, exacerbates insulin resistance and its associated clinical sequelae as central obesity and body mass index (BMI) are major determinants of insulin resistance, hyperinsulinaemia and hyperandrogenaemia. Insulin stimulates LH and ovarian androgen secretion and decreases SHBG concentrations therefore increasing the circulation of more, free, biologically active testosterone [3]. Now that obesity is reaching epidemic proportions in some countries, we tend to see more expression of the stigmata of PCOS; hirsutism, acne, anovulation and infertility.

Ovulation induction therapy is negatively influenced by obesity and hyperinsulinism in women with PCOS. More gonadotrophins are required to achieve ovulation in insulin resistant women [45]. Obese women being treated with low dose therapy have inferior pregnancy and miscarriage rates [6]. Both obese [7] and insulin resistant [5] women with PCOS, even on low dose FSH stimulation, have a much greater tendency to a multifollicular response and thus a relatively high cycle cancellation rate in order to avoid hyperstimulation.

At least, in the short term, the deleterious effects of hyperinsulinaemia in these patients are reversible. This may be achieved by weight loss in the obese and with insulin lowering medications. An additional bonus is that in the long-term, prevention of the metabolic syndrome in PCOS patients by maintenance of a normal body weight and lifestyle changes seems to be an effective measure although the use of insulin lowering drugs for this purpose is still awaiting confirmation.

10.1 Weight Loss

The combination of PCOS, hyperinsulinaemia and obesity exacerbates the expression and severity of symptoms of PCOS, including the prevalence of anovulation. However, loss of weight can reverse this process by inducing a reduction of insulin and androgen concentrations and an increase in sex hormone binding globulin, thus improving ovarian function [810].

This correction of the hormonal profile is reflected by significant improvement in the severity of the symptoms, whether they are hirsutism and acne, ovulatory dysfunction and infertility or features of the metabolic syndrome. A reduction of 5–10 % in body weight improves hirsutism in 40–50 % of patients within 6 months of weight reduction [9]. For obese women with PCOS, a loss of just 5–10 % of body weight is also enough to restore reproductive function in 55–100 % within 6 months of weight reduction [810].

Weight loss has the undoubted advantages of being effective and cheap with no side effects and should be the first line of treatment in obese women with any of the symptoms associated with PCOS and should be applied, in particular, for those wishing to conceive. Clinics dedicated to life-style changes are the best source of advice. It is no longer acceptable to send the subject away for 3 months and tell her to return when she has lost weight!

10.2 Metformin

The importance of decreasing the level of hyperinsulinaemia to improve results of treatment for PCOS, regardless of which of the presenting symptoms is the target, has become obvious [1112]. Weight loss often seems to be an unsurmountable object for the obese patient with PCOS and the alternative possibility of using insulin lowering drugs (particularly metformin) has recently undergone a thorough examination.

Metformin is an oral biguanide, well established for the treatment of hyperglycaemia, that does not cause hypoglycaemia in normoglycaemic patients. It reduces insulin resistance and secretion and also seems to have a direct action on ovarian theca cells to decrease androgen production [13]. The sum total of its actions is a decrease in insulin levels and a lowering of circulating total and free androgen levels with a resulting improvement of the clinical sequelae of hyperandrogenism.

Metformin is taken orally in a dose of 1,500–2,500 mg. About 15–20 % of patients may suffer from gastro-intestinal side effects, some of which may be avoided or lessened by a graduated starting dose. The indications for giving metformin to women with anovulatory PCOS have become progressively wider as it seems to be difficult to predict which individuals will respond well with this medication [12]. The fact that metformin has been shown to have a direct action on ovarian cells in-vitro decreasing androgen production [13] and the difficulties of accurately measuring insulin sensitivity in all PCOS patients, has encouraged ‘blanket’ treatment with metformin to all PCOS patients in many centers. The wisdom of this strategy has not been ratified or, as noted by Harbourne et al. [14] in a critical review of the literature in 2003, clinical practice is ahead of the evidence. Today, we have the evidence and the initial enthusiasm for the use of metformin, particularly for ovulation induction, has been curtailed by the publication of a number of randomised controlled trials.

Here I will present the best available evidence for the treatment with metformin for anovulatory infertility and examine the proposal of administration throughout pregnancy.

10.3 Restoration of Ovulation

10.3.1 Metformin Alone

There are now a large number of studies published on the effect of metformin in a dose of 1,500–2,550 mg/day in women with PCOS. The majority of these studies have demonstrated an improvement in insulin concentrations, insulin sensitivity, and serum androgen concentrations accompanied by decreased LH and increased SHBG concentrations [15]. The restoration of regular menstrual cycles by metformin has been reported in the majority of published series with the reinstatement of ovulation [1115]. Fleming et al. [12], in a randomized placebo-controlled trial, demonstrated a significantly increased frequency of ovulation with metformin (850 mg, twice a day) compared to placebo in a group of 92 oligomenorrheic women with PCOS.

However, although metformin as a mono-agent is capable of improving menstrual frequency and restoring ovulation in patients who have oligo-anovulation and PCOS, when used as first line therapy and compared to CC, it fairs very poorly. In a large North American randomised controlled trial, CC was found to be superior to metformin as there was a significant difference in the number of clinical pregnancies and live full-term singleton births (22.6 % vs 7.2 %) when using CC [16] . Another large studies came to a similar conclusion [17]. A placebo controlled study did not show any benefit of metformin in inducing ovulation in obese women with PCOS [18]. A meta-analysis examining the use of metformin for ovulation induction in women with PCOS concluded that it could not be recommended for this indication [19]. An ESHRE-ASRM consensus meeting therefore concluded that insulin sensitizers should not be used as first-choice agents for induction of ovulation in women with PCOS, while their administration does not appear to decrease the incidence of early pregnancy losses [20].

10.3.2 Metformin + Clomiphene

In a Dutch multicentre study, there was no advantage found when CC alone was compared with a combination of CC and metformin [21]. Despite this, metformin may be useful for women with clomifene resistance and this combination is worth trying before proceeding to the much more expensive low-dose gonadotrophin therapy [2223].

10.3.3 Metformin + Low-Dose FSH

When women with clomiphene resistant PCOS are administered FSH following pretreatment with metformin for 1 month they develop significantly less large follicles, produce less oestradiol and have fewer cycles cancelled due to excessive follicular development. The reduction of insulin concentrations induced by metformin seems to favour a more orderly follicular growth in response to exogenous gonadotrophins for ovulation induction [24].

10.3.4 Metformin in IVF

Early evidence suggested that when metformin was used preceding and in conjunction with gonadotrophin stimulation in protocols for in vitro fertilization, there was an improvement in the outcome in normal weight women with PCOS [25]. However, this possible benefit is still debated although a reduction in the incidence of OHSS with the use of metformin now seems to be well established. It is very possible that subtle treatment with metformin will not have a substantial effect on the results of IVF in which large doses of gonadotrophins are administered to achieve ovarian stimulation.

10.3.5 Metformin During Pregnancy

Metformin seems to be safe when continued into pregnancy as no increase in congenital abnormalities; teratogenicity or adverse effects on infant development have been recorded. However, no advantage seems to be gained by pursuing this strategy as it helped neither the miscarriage rate, (confirming earlier data), nor the obstetric complications [26].

10.4 The Treatment of PCOS in Adolescence

The treatment of PCOS in adolescence with metformin is a vexing subject for which no one has an answer at the moment. The theoretical advantages are plain to see as metformin, in addition to improving the disturbing unaesthetic symptoms and regulating ovulation, should also improve the insulinaemic and androgenic status of the teenager which, again theoretically, should improve her chances of having ovulatory cycles when the age for a desired pregnancy arrives. However, there is next to no data to back this up. Many questions still remain [27]. Will metformin truly prevent long-term sequelae? Will the long-term administration of metformin prove to be as safe as the reassuring short-term data that we presently have available suggest? How troublesome will the side effects be and, finally, is it justified to subject a teenager to a possible 20 years of preventative treatment?

10.5 Other Insulin Lowering Drugs

The glitazones, notably rosiglitazone and pioglitazone, which also lower insulin concentrations, have been investigated. They did not show any notable superiority over metformin. Rosiglitazone has since been withdrawn from the market due to undesirable side effects while pioglitazone has produced unwelcome weight gain. Neither is recommended for ovulation induction for PCOS. Further, d-chiro-inositol, which is also is said to have the property of lowering insulin concentrations, has been investigated but has proved disappointing and withdrawn in most countries for this indication.

References

1.

Legro RS, Finegood D, Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1998;83:2694–8.PubMed

2.

Carmina E, Lobo RA. Polycystic ovary syndrome: arguably the most common endocrinopathy is associated with significant morbidity in women. J Clin Endocrinol Metab. 1999;84:1897–9.PubMedCrossRef

3.

Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LA. The insulin-related ovarian regulatory system in health and disease. Endoc Rev. 1999;20:535–82.CrossRef

4.

Homburg R. Adverse effect of luteinizing hormone on fertility: fact or fantasy. Baillieres Clin Obstet Gynaecol. 1996;12:555.CrossRef

5.

Dale O, Tanbo T, Haug E, Abyholm T. The impact of insulin resistance on the outcome of ovulation induction with low-dose FSH in women with polycystic ovary syndrome. Hum Reprod. 1998;13:567–70.PubMedCrossRef

6.

Hamilton-Fairley D, Kiddy D, Watson H, et al. Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary treated with low dose gonadotrophin. Br J Obstet Gynaecol. 1992;99:128–31.PubMedCrossRef

7.

White DM, Polson DW, Kiddy D, et al. Induction of ovulation with low-dose gonadotrophins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab. 1996;81:3821–4.PubMed

8.

Kiddy DS, 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;36:105–11.CrossRef

9.

Pasquali R, Antenucci D, Casmirri F, et al. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J Clin Endocrinol Metab. 1989;68:173–9.PubMedCrossRef

10.

Clark AM, Ledger W, Galletly C, et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod. 1995;10:2705–12.PubMedCrossRef

11.

Velazquez EM, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol. 1997;90:392–5.PubMedCrossRef

12.

Fleming R, Hopkinson ZE, Wallace AM, et al. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab. 2002;87:569–74.PubMedCrossRef

13.

Mansfield R, Galea R, Brincat M, et al. Metformin has direct effects on human ovarian steroidogenesis. Fertil Steril. 2003;79:956–62.PubMedCrossRef

14.

Harbourne L, Fleming R, Lyall H, et al. Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome. Lancet. 2003;361:1894–901.CrossRef

15.

Nestler JE, Stovall D, Akhter N, et al. Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril. 2002;77:209–15.PubMedCrossRef

16.

Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551–66.PubMedCrossRef

17.

Zain MM, Jamaluddin R, Ibrahim A, Norman R. Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction, achievement of pregnancy, and live birth in Asian women with polycystic ovary syndrome: a randomized controlled trial. Fertil Steril. 2009;91:514–21.PubMedCrossRef

18.

Tang T, Glanville J, Hayden CJ, White D, Barth JH, Balen AH. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study. Hum Reprod. 2006;21:80–9.PubMedCrossRef

19.

Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2010;20(1):CD003053.

20.

Thessaloniki ESHRE/ASRM- sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23:462–77.CrossRef

21.

Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. 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. 2006;332:1485–8.CrossRef

22.

Vandermolen DT, Ratts VS, Evans WS, et al. Metformin increases the ovulatory rate and pregnancy rate with clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001;75:310–5.PubMedCrossRef

23.

George SS, George K, Irwin C, et al. Sequential treatment of metformin and clomiphene citrate in clomiphene resistant women with polycystic ovary syndrome: a randomized, controlled trial. Hum Reprod. 2003;18:299–304.PubMedCrossRef

24.

De Leo V, la Marca A, Ditto A, et al. Effects of metformin on gonadotropin-induced ovulation women with polycystic ovary syndrome. Fertil Steril. 1999;72:282–5.PubMedCrossRef

25.

Kjotrod SB, von During V, Carlsen SM. Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome: a prospective, randomized, double-blind study. Hum Reprod. 2004;19:1315–22.PubMedCrossRef

26.

Vanky E, Stridsklev S, Heimstad R, et al. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J Clin Endocrinol Metab. 2010;95:E448–55.PubMedCrossRef

27.

Homburg R. Polycystic ovary syndrome in adolescence – a therapeutic conundrum. Hum Reprod. 2004;19:1039–42.