This is a 32 year-old obese female with a history of hypertension, chronic cold urticaria, focal segmental glomerulosclerosis, and polycystic ovarian syndrome who presented for routine follow-up in primary care clinic. The patient was diagnosed with polycystic ovarian syndrome in November 2007. At that time, she presented with irregular menses and dysmenorrhea, at which point pelvic ultrasound revealed polycystic ovaries. The patient was prescribed daily oral contraceptive medication, but was recently advised to discontinue this medication secondary to persistence of irregular menses. Her last menstrual period was 1/3/2008 – 1/10/2008. Her BMI is 30.7 and she had a normal oral glucose tolerance test. The clinical question of whether or not to begin treatment with metformin warranted further discussion:
Polycystic ovarian syndrome (PCOS) affects nearly 5-7 percent of reproductive age women and is characterized by chronic oligo-ovulation or anovulation, androgen excess, insulin resistance, obesity, hirsutism, infertility, and (in some cases) polycystic ovaries (1, 2). These patients are at a markedly increased risk for impaired glucose tolerance, type 2 diabetes, and other metabolic derangements. Metformin, a medication whose major effect is to decrease hepatic glucose production and increase insulin sensitization in peripheral tissues, plays a pivotal role in the treatment armamentarium for PCOS.
The pathophysiology of PCOS is incompletely understood, but is thought to involve multiple interactions among the gonadotropins and androgens, insulin, and the ovaries. Insulin resistance and hyperinsulinemia are central features of PCOS and appear to be responsible for the associations between PCOS and type 2 diabetes, dyslipidemia, hypertension, and other physiological and anatomical cardiovascular maladaptations (3, 4). In brief, there are four concurrent mechanisms of action:
1. Although peripheral tissues such as skeletal muscle and fat are insulin-resistant in this syndrome, insulin actually stimulates the ovarian production of androgens in PCOS.
2. Insulin also stimulates leutenizing hormone production by the anterior pituitary, further driving ovarian stimulation and increasing serum androgen levels.
3. The progressive hyperinsulinemia inhibits hepatic production of sex hormone-binding globulin, a phenomenon that augments circulating free testosterone levels.
4. Finally, insulin inhibits the ovulatory cycle by interfering with gonadotropin secretion, increasing intra-ovarian androgen levels, and directly affecting follicular development.
Inhibiting insulin release with the use of diazoxide or octreotide, improving insulin sensitivity through weight loss, metformin, or thiazolidinediones, and reducing carbohydrate absorption through the use of acarbose have all been shown to lower circulating insulin levels, increase ovulatory frequency or menses, and/or reduce serum testosterone (5). Clearly, the hyperinsulinemia that is so critical to the pathogenesis and natural history of PCOS is a major therapeutic target.
The role of metformin in decreasing the relative risk for progression to type 2 diabetes among patients with impaired glucose tolerance at baseline has been well established (6). Metformin decreases hepatic gluconeogenesis, increases peripheral glucose uptake and utilization, and has an anti-lipolytic effect that decreases fatty acid concentrations (7). In 1996, Nestler and colleagues reported that the administration of metformin to women with PCOS decreased circulating insulin levels and was associated with decreases in ovarian 17,20-lyase activity and the ovarian secretion of androgens (8). However, to date no randomized clinical trials have specifically assessed the effect of metformin on the progression to type 2 diabetes in patients with PCOS. The closest study to accomplish this goal was a 2007 uncontrolled, retrospective analysis of 50 women with PCOS who were treated with metformin for an average of 43 months. The results were very suggestive of a protective effect in this population: none of the participants showed progression to type 2 diabetes, even though 11 of these women (22.0%) had impaired glucose tolerance at baseline (9). Six of the women with impaired glucose tolerance at baseline (55%) had reversion to normal glucose tolerance during the treatment period. Moreover, of the remaining 39 women with normal glucose tolerance at baseline, only 2 (5%) had conversion to impaired glucose tolerance over the 43-month study period, yielding a 1.4% per year annual conversion rate from normal to impaired glucose tolerance. This conversion rate was significantly lower than the 16-19% annual conversion rate reported for women with PCOS who were not taking metformin. In other words, metformin was shown to reduce the annual conversion rate from normal glucose tolerance to impaired glucose tolerance by 11-fold (P = 0.01). Despite being a retrospective analysis of a limited number of patients, this study suggests that long-term treatment with metformin delays or prevents the development of impaired glucose tolerance and type 2 diabetes in the PCOS patient population.
Metformin is increasingly being used to treat the metabolic derangements of PCOS despite the fact that treatment decisions have so far been guided by the results of randomized controlled trials of populations without the polycystic ovarian syndrome. There is limited evidence on the long-term role of metformin for the treatment of insulin insensitivity, few studies on the efficacy of metformin in ameliorating signs of androgen excess (e.g. hirsutism), and conflicting data on how improvement of insulin sensitivity and fertility compares when metformin is used alone or in combination with existing hormonal therapies. Yet despite the current ambiguity on its role, the American Association of Clinical Endocrinologists recommends that metformin be considered as the initial intervention for most women (particularly those who are overweight or obese) with PCOS. On the other hand, other organizations, like the Androgen Excess Society, are more stringent in their recommendations and point out that therapy should not be mandated until well-designed randomized controlled trials have demonstrated efficacy in this population.
As for this patient, a 32 year-old overweight woman with established polycystic ovarian disease and metrorrhagia refractory to oral contraceptive medication, therapy with metformin should be recommended. Whereas oral contraceptive medication aims to correct ovulatory cycling, metformin functions to help rectify the fundamental metabolic imbalance of PCOS. If she decides to pursue pregnancy, metformin can be safely continued in the first trimester and, although recently published studies have found metformin to be inferior to clomiphine for ovulation induction, metformin has proven efficacy in this regard (10). In conjunction with a comprehensive nutrition management program, metformin will likely help the patient lose weight, improve her ovulatory cycling, and diminish her risk for developing type 2 diabetes.
References:
1. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and longer-term health risk related to polycystic ovary syndrome PCOS. Hum Reprod 2004:19:41-7.
2. Knochenhauer ES, Key TJ et al. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 1998; 83:3078.
3. Paradisi G, Steinberg HO, Hempfling A, et al. Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation 2001; 103: 1410-5.
4. Lilloja S, Mott Dm, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus: prospective studies of Pima Indians. N Engl J Med 1993; 329:1988-92.
5. Nestler, JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med 2008; 358:47-54.
6. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393-403.
7. Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334:574.
8. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17alpha activity and serum free testosterone after reduction in insulin secretion in polycystic ovary syndrome. N Engl J Med 1996; 335:617-23.
9. Sharma St, Wickham EP III, Nestler JE. Changes in glucose tolerance with metformin treatment in polycystic ovary syndrome: a retrospective analysis. Endocr Pract 2007; 13:373-9.
10. Legro RS, Barnhart HX, Shlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356:551-556.
Polycystic ovarian syndrome (PCOS) affects nearly 5-7 percent of reproductive age women and is characterized by chronic oligo-ovulation or anovulation, androgen excess, insulin resistance, obesity, hirsutism, infertility, and (in some cases) polycystic ovaries (1, 2). These patients are at a markedly increased risk for impaired glucose tolerance, type 2 diabetes, and other metabolic derangements. Metformin, a medication whose major effect is to decrease hepatic glucose production and increase insulin sensitization in peripheral tissues, plays a pivotal role in the treatment armamentarium for PCOS.
The pathophysiology of PCOS is incompletely understood, but is thought to involve multiple interactions among the gonadotropins and androgens, insulin, and the ovaries. Insulin resistance and hyperinsulinemia are central features of PCOS and appear to be responsible for the associations between PCOS and type 2 diabetes, dyslipidemia, hypertension, and other physiological and anatomical cardiovascular maladaptations (3, 4). In brief, there are four concurrent mechanisms of action:
1. Although peripheral tissues such as skeletal muscle and fat are insulin-resistant in this syndrome, insulin actually stimulates the ovarian production of androgens in PCOS.
2. Insulin also stimulates leutenizing hormone production by the anterior pituitary, further driving ovarian stimulation and increasing serum androgen levels.
3. The progressive hyperinsulinemia inhibits hepatic production of sex hormone-binding globulin, a phenomenon that augments circulating free testosterone levels.
4. Finally, insulin inhibits the ovulatory cycle by interfering with gonadotropin secretion, increasing intra-ovarian androgen levels, and directly affecting follicular development.
Inhibiting insulin release with the use of diazoxide or octreotide, improving insulin sensitivity through weight loss, metformin, or thiazolidinediones, and reducing carbohydrate absorption through the use of acarbose have all been shown to lower circulating insulin levels, increase ovulatory frequency or menses, and/or reduce serum testosterone (5). Clearly, the hyperinsulinemia that is so critical to the pathogenesis and natural history of PCOS is a major therapeutic target.
The role of metformin in decreasing the relative risk for progression to type 2 diabetes among patients with impaired glucose tolerance at baseline has been well established (6). Metformin decreases hepatic gluconeogenesis, increases peripheral glucose uptake and utilization, and has an anti-lipolytic effect that decreases fatty acid concentrations (7). In 1996, Nestler and colleagues reported that the administration of metformin to women with PCOS decreased circulating insulin levels and was associated with decreases in ovarian 17,20-lyase activity and the ovarian secretion of androgens (8). However, to date no randomized clinical trials have specifically assessed the effect of metformin on the progression to type 2 diabetes in patients with PCOS. The closest study to accomplish this goal was a 2007 uncontrolled, retrospective analysis of 50 women with PCOS who were treated with metformin for an average of 43 months. The results were very suggestive of a protective effect in this population: none of the participants showed progression to type 2 diabetes, even though 11 of these women (22.0%) had impaired glucose tolerance at baseline (9). Six of the women with impaired glucose tolerance at baseline (55%) had reversion to normal glucose tolerance during the treatment period. Moreover, of the remaining 39 women with normal glucose tolerance at baseline, only 2 (5%) had conversion to impaired glucose tolerance over the 43-month study period, yielding a 1.4% per year annual conversion rate from normal to impaired glucose tolerance. This conversion rate was significantly lower than the 16-19% annual conversion rate reported for women with PCOS who were not taking metformin. In other words, metformin was shown to reduce the annual conversion rate from normal glucose tolerance to impaired glucose tolerance by 11-fold (P = 0.01). Despite being a retrospective analysis of a limited number of patients, this study suggests that long-term treatment with metformin delays or prevents the development of impaired glucose tolerance and type 2 diabetes in the PCOS patient population.
Metformin is increasingly being used to treat the metabolic derangements of PCOS despite the fact that treatment decisions have so far been guided by the results of randomized controlled trials of populations without the polycystic ovarian syndrome. There is limited evidence on the long-term role of metformin for the treatment of insulin insensitivity, few studies on the efficacy of metformin in ameliorating signs of androgen excess (e.g. hirsutism), and conflicting data on how improvement of insulin sensitivity and fertility compares when metformin is used alone or in combination with existing hormonal therapies. Yet despite the current ambiguity on its role, the American Association of Clinical Endocrinologists recommends that metformin be considered as the initial intervention for most women (particularly those who are overweight or obese) with PCOS. On the other hand, other organizations, like the Androgen Excess Society, are more stringent in their recommendations and point out that therapy should not be mandated until well-designed randomized controlled trials have demonstrated efficacy in this population.
As for this patient, a 32 year-old overweight woman with established polycystic ovarian disease and metrorrhagia refractory to oral contraceptive medication, therapy with metformin should be recommended. Whereas oral contraceptive medication aims to correct ovulatory cycling, metformin functions to help rectify the fundamental metabolic imbalance of PCOS. If she decides to pursue pregnancy, metformin can be safely continued in the first trimester and, although recently published studies have found metformin to be inferior to clomiphine for ovulation induction, metformin has proven efficacy in this regard (10). In conjunction with a comprehensive nutrition management program, metformin will likely help the patient lose weight, improve her ovulatory cycling, and diminish her risk for developing type 2 diabetes.
References:
1. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and longer-term health risk related to polycystic ovary syndrome PCOS. Hum Reprod 2004:19:41-7.
2. Knochenhauer ES, Key TJ et al. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 1998; 83:3078.
3. Paradisi G, Steinberg HO, Hempfling A, et al. Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation 2001; 103: 1410-5.
4. Lilloja S, Mott Dm, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus: prospective studies of Pima Indians. N Engl J Med 1993; 329:1988-92.
5. Nestler, JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med 2008; 358:47-54.
6. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393-403.
7. Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334:574.
8. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17alpha activity and serum free testosterone after reduction in insulin secretion in polycystic ovary syndrome. N Engl J Med 1996; 335:617-23.
9. Sharma St, Wickham EP III, Nestler JE. Changes in glucose tolerance with metformin treatment in polycystic ovary syndrome: a retrospective analysis. Endocr Pract 2007; 13:373-9.
10. Legro RS, Barnhart HX, Shlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356:551-556.
3 comments:
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