Randomized Controlled Trial of Preconception Interventions in Infertile Women With Polycystic Ovary Syndrome

Legro RS; Dodson WC; Kris-Etherton PM; Kunselman AR; Stetter CM; Williams NI; Gnatuk CL; Estes SJ; Fleming J; Allison KC; Sarwer DB; Coutifaris C; Dokras A

doi:10.1210/jc.2015-2778

Reproductive Endocrinology · Ovulation Physiology

Randomized Controlled Trial of Preconception Interventions in Infertile Women With Polycystic Ovary Syndrome

Legro RS, Dodson WC, Kris-Etherton PM, Kunselman AR, Stetter CM, Williams NI, Gnatuk CL, Estes SJ, Fleming J, Allison KC, Sarwer DB, Coutifaris C, Dokras A

Published November 2015 The Journal of clinical endocrinology and metabolism, 100(11), 4048-58

DOI 10.1210/jc.2015-2778 PMID 26401593 PMC PMC4702450

RRM Academy Synopsis

Weight loss improved ovulation in overweight and obese women with PCOS

In a randomized trial of 149 overweight or obese women with PCOS, weight loss improved ovulation and avoided metabolic worsening seen with pills. Ovulation followed 67 out of 100 treatment cycles with pills plus a lifestyle program and 46 out of 100 with pills alone. Live births did not differ significantly. PCOS is also called PMOS (Polyendocrine Metabolic Ovarian Syndrome).

Key Findings

Weight change averaged -6.2% with Lifestyle and -6.4% with Combined (95% CIs -7.4 to -5.0 and -7.6 to -5.2). Both differed from baseline and oral contraceptive pills (OCP; both P < .001).
Metabolic syndrome rose from baseline within OCP (OR 2.47; 95% CI 1.42-4.27). No change was detected within Combined (OR 0.72; 95% CI 0.44-1.17) or Lifestyle (OR 1.18; 95% CI 0.63-2.19).
Ovulation followed 71 of 154 OCP treatment cycles (46.1%), 82 of 136 Lifestyle cycles (60.3%) and 94 of 140 Combined cycles (67.1%). Versus OCP: Lifestyle P = 0.06, Combined P = 0.002.
Live births occurred in 5 of 49 OCP participants, 13 of 50 Lifestyle participants (26%) and 12 of 50 Combined participants (24%). Groups did not differ significantly (P = .13).
Diarrhea or fatty stools (steatorrhea) occurred in 0 of 49 OCP, 6 of 50 Lifestyle and 12 of 50 Combined participants (P < .05 versus OCP). The paper reports no congenital anomalies.

Interpretation

The trial was randomized and open-label. Analysis followed intention to treat, with women analyzed in their assigned groups. Women aged 18 to 40 with PCOS, infertility, and a body mass index of 27 to 42 took part. Male partners had to meet sperm concentration and motility criteria. Lifestyle combined calorie restriction, meal replacements, and more activity. Lifestyle also included a weight loss medication for women with a body mass index of 30 or more. Combined added oral contraceptive pills. Four cycles of ovulation medication with timed intercourse followed. Live birth was the main outcome. The authors note the trial was underpowered to detect a difference between Lifestyle and Combined.

RRM Context

RRM looks for the root cause of ovulation problems and works with the body's own cycle, so the metabolic side of PCOS matters. Insulin sensitivity improved in both weight loss groups, while the OCP group took a suppressive medication. The authors say that oral ovulation drugs do not address the metabolic problems underneath.

Our editorial summary of this paper, not the article's abstract.

Abstract

Context

Lifestyle modification is recommended in women with polycystic ovary syndrome (PCOS) prior to conception but there are few randomized trials to support its implementation or benefit.

Objective

This study aimed to determine the relative efficacy of preconception intervention on reproductive and metabolic abnormalities in overweight/obese women with PCOS.

Design, Setting, and Participants

This was a randomized controlled trial of preconception and infertility treatment at Academic Health Centers in women with infertility due to PCOS, age 18-40 y and body mass index 27-42 kg/m(2).

Intervention

Women were randomly assigned to receive either 16 weeks of 1) continuous oral contraceptive pills (OCPs) (ethinyl estradiol 20 mcg/1 mg norethindrone acetate) ("OCP"); 2) lifestyle modification consisting of caloric restriction with meal replacements, weight loss medication (either sibutramine, or orlistat), and increased physical activity to promote a 7% weight loss ("Lifestyle"); or 3) combined treatment with both OCP and lifestyle modification ("Combined"). After preconception intervention, women underwent standardized ovulation induction with clomiphene citrate and timed intercourse for four cycles. Pregnancies were followed with trimester visits until delivery.

Main Outcome Measures

Weight, ovulation, and live birth were measured.

Results

We consented 216 and randomly assigned 149 women (Lifestyle: n = 50; OCP: n = 49; Combined: n = 50). We achieved significant weight loss with both Lifestyle (mean weight loss, -6.2%; 95% confidence interval (CI), -7.4--5.0; and Combined (mean weight loss, -6.4%; 95% CI, -7.6--5.2) compared with baseline and OCP (both P < .001). There was a significant increase in the prevalence of metabolic syndrome at the end of preconception treatment compared with baseline within OCP (odds ratio [OR, 2.47; 95% CI, 1.42-4.27) whereas no change in metabolic syndrome was detected in the Lifestyle (OR, 1.18; 95% CI, 0.63-2.19) or Combined (OR, 0.72; 95% CI, 0.44-1.17) groups. Cumulative ovulation rates were superior after weight loss: OCP, 46%; Lifestyle, 60%; and Combined, 67% (P < .05). Live birth rates were OCP, 12%; Lifestyle, 26%; and Combined, 24% (P = .13).

Conclusions

A preconception weight loss intervention eliminates the adverse metabolic oral contraceptive effects and, compared with oral contraceptive pretreatment, leads to higher ovulation rates.

Topics

Reproductive Endocrinology › Ovulation Physiology › Anovulation · Lifestyle and Environment › Nutrition and Metabolic Health › Body Weight and Composition · Therapeutics › Hormonal Agents › Estrogen Preparations

Richard S Legro, William C Dodson, Penny M Kris-Etherton, Allen R Kunselman, Christy M Stetter, Nancy I Williams, Carol L Gnatuk, Stephanie J Estes, Jennifer Fleming, Kelly C Allison, David B Sarwer, Christos Coutifaris, Anuja Dokras

Rick Legro, Dick Legro, Rich Legro, R Legro, Bill Dodson, Will Dodson, Billy Dodson, W Dodson, P Kris-Etherton, A Kunselman, C Stetter, N Williams, C Gnatuk, S Estes, Jen Fleming, Jenny Fleming, J Fleming, K Allison, Dave Sarwer, D Sarwer, C Coutifaris, A Dokras

PMID 26401593 26401593 DOI 10.1210/jc.2015-2778 10.1210/jc.2015-2778 Legro et al. 2015, Legro 2015

Randomized Controlled Trial of Preconception Interventions in Infertile Women With Polycystic Ovary Syndrome

Weight loss improved ovulation in overweight and obese women with PCOS

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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