Effect of Short-Term Diet and Exercise on Hormone Levels and Menses in Obese, Infertile Women
Paul B. Miller, M.D., David A. Forstein, D.O., and Sheena Styles, R.N.
OBJECTIVE: To improve serum metabolic and endocrine measures known to influence fecundity.
STUDY DESIGN: Twelve infertile, obese women were enrolled in a 12-week program of diet and exercise. Subjects underwent baseline testing for estrone (E1), estradiol (E2), testosterone (T), luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), prolactin, fasting leptin, dehydroepiandrosterone sulfate (DHEAS), C-reactive protein (CRP) and total cholesterol. Glucose and insulin levels were measured fasting and 2 hours after a 75-g glucose load. Subjects attended three 1-hour exercise sessions per week and received instructions for a 1,200- to 1,300-kcal/day diet. Serum tests and body mass index (BMI) were remeasured after 12 weeks. Intermenstrual intervals were also recorded. At 24 weeks, subjects rated compliance with diet and exercise. Main outcome measures included change in serum variables, BMI and intermenstrual interval.
RESULTS: BMI, total cholesterol and E1/E2 ratio significantly decreased over 12 weeks (mean difference ± SEM, 2.06±0.51 kg/m2, 25.91±4.33 mg/dL and 0.7±0.22, respectively). No significant differences were noted for all other measures. Ten of the 12 subjects (83%) showed menstrual improvement, with 8 becoming eumenorrheic.
CONCLUSION: Favorable metabolic and menstrual changes are possible in obese, infertile women after 12 weeks of diet and exercise. (J Reprod Med 2008;53:315–319)
Keywords: diet, exercise, fecundity, obesity.
In this prospective, cohort study of
obese, infertile women, favorable
metabolic and menstrual changes
occurred after 12 weeks.
Obesity in the United States, defined as a body mass index (BMI) ≥30 kg/m2, has reached epidemic proportions. Government statistics from 2002 estimated a prevalence of 30% for adults aged 20 years or older.1 An additional 45% are overweight (i.e., BMI 25.0–29.9 kg/m2). This represents a 16% increase over data collected just 10 years earlier. In addition to attendant increased morbidity in areas such as hypertension, diabetes mellitus, cardiovascular disease and cancer, overweight women experience hormonal aberrations manifested as menstrual irregularity and diminished fecundity compared to their peers.
Interventions aimed at increasing fecundity for obese women often include severe, short-term caloric restriction2,3 that requires intensive monitoring and is difficult to sustain.4 Other investigations have studied more modest dieting regimens for longer periods of time5,6 but required participants to postpone further fertility care for a minimum of 6 months. The stringent dietary restrictions and delayed gratification associated with the hiatus from fertility care have led to relatively high study dropout rates. Other weight loss studies have recognized the importance of increased caloric expenditure through exercise, but they have failed to quantify amounts or have simply provided encouragement for exercise.6-8 This is despite established evidence that exercise-induced weight loss preserves lean body mass and has a greater impact on metabolic and hormonal variables that influence fertility.9-11
In an effort to establish a paradigm for weight loss that could easily be integrated into a daily routine, was sustainable and included an educational component that would encourage lifestyle changes, this study was designed for a group of obese, infertile women in the southeastern United States, a geographic area with the highest rate of obesity in the nation.12
Materials and Methods
Study subjects were recruited from the patient roster of the tertiary care, Reproductive Endocrinology practice of the Greenville Hospital System, Greenville, South Carolina. Human subjects approval was provided by our local institutional review committee with all participants providing written informed consent. Women were eligible if they met the following criteria: (1) infertility >12 months’ duration; (2) ovulatory dysfunction; (3) BMI ≥30 kg/m2; (4) normal thyroid-stimulating hormone (TSH) and prolactin levels within 6 months of study onset; and (5) willingness to attend exercise classes 3 times per week. Subjects were excluded if they had any of the following: (1) presence of a medical condition that would compromise participation in an exercise program; (2) hormonal therapy, other than progestins, within 1 month before study initiation; (3) use of insulin sensitizers (e.g., metformin) within 1 month before study initiation; (4) diabetes mellitus; and (5) use of medication that may alter metabolism (e.g., diet pills).
All subjects underwent phlebotomy within 1 week prior to starting the active phase of diet and exercise in the study. Samples were collected by venipuncture during the follicular phase of the menstrual cycle if subjects were menstruating or at random for women who were amenorrheic. Samples were centrifuged at 3,200 rpm for 10 minutes with freezing of serum at -70°C for later analysis. Samples for glucose and insulin testing were drawn after fasting and 2 hours after a 75-g oral glucose load. Height was measured without shoes to the nearest centimeter using a wall-mounted stadiometer (HR-100, Tanita Corporation, Tokyo, Japan). Weight was measured to the nearest 0.1 kg using a digital floor scale (BWB-800, Tanita Corporation). BMI was calculated by dividing weight (in kilograms) by height squared (in meters). Participants reported their intermenstrual intervals over the preceding 6 months with later categorization as follows: oligomenorrhea (cycle interval >35 days; n= 1); irregular menses (cycle intervals discrepant by >5 days; n=3); amenorrhea (>90 days without menses; n=8). All amenorrheic subjects received an intramuscular injection of 150 mg of progesterone in oil within 24 hours of their initial phlebotomy to induce withdrawal menstrual bleeding.
All subjects attended a 1-hour informational session at study onset during which they received detailed nutritional counseling, an outline of the study schedule and contact information for the principal investigator, research nurse, nutritionist and fitness instructor. All participants were instructed in a 1,200–1,500-kcal/day diet (carbohydrates 40%, protein 28%, fat 32%) individualized and supervised by a nutritionist. Subjects were encouraged to contact any or all of the research team 7 days per week with questions.
The 12-week active phase of the study included 1-hour fitness sessions every Monday, Wednesday, and Friday from 6 AM to 7 AM at our institution’s fitness and rehabilitation center. Fitness sessions consisted of 20–30 minutes of lightly supervised aerobic exercise (e.g., treadmill, cycling) followed by 30–40 minutes of formal group strength training under the direct supervision of a certified fitness instructor. Intensity of fitness sessions was gradually increased over the course of the 12-week phase. In addition to scheduled sessions, subjects were encouraged to exercise independently throughout the week with recording of total exercise time in a weekly log book.
Once-weekly educational sessions were held Mondays from 7 AM to 8 AM on topics germane to women, obesity and infertility (e.g., polycystic ovaries, stress reduction, reproductive technologies). Sessions were videotaped and made available to participants who were unable to attend at the normal times. In addition, weight was measured before each education session and recorded in the log books. Each attendee was given the opportunity to speak with the nutritionist after every educational session. At the end of the 12-week active phase of the study, repeat blood sampling was performed with freezing of serum for later batched analysis with samples drawn at baseline. Anthropometric measurements also were repeated and recorded with a report of menstrual frequency. Regarding the latter, any movement in the following progression was considered improvement: amenorrhea —> oligomenorrhea —> eumenorrhea.
Twelve weeks after the end of the active phase, subjects were given a questionnaire during a personal interview with the study nurse (S.S.) in which they were asked to categorize their dietary and exercise compliance. Dietary compliance was rated by quartiles (<25%, 25–50%, 51–75% and >75%), whereas amount of exercise per week was grouped as follows: <2 hours, 2–3.9 hours, 4–5.9 hours, 6–7.9 hours or ≥8 hours. Information for both active and follow-up phases was obtained. Moreover, although it was not a primary outcome of the study, subjects were asked whether they were actively trying to conceive, and if so, whether they were successful.
Serum levels of estrone (E1) were measured by radioimmunoassay (Nichols Institute, San Juan Capistrano, California). Serum levels of estradiol (E2), testosterone (T), thyrotropin and dehydroepiandrosterone sulfate (DHEAS) were measured by solid-phase, competitive chemiluminescent enzyme immunoassay (IMMULYTE 2000 Analyzer, Diagnostic Products Corporation, Los Angeles, California). Follicle-stimulating hormone (FSH) and insulin were measured by solid-phase, 2-site chemiluminescent immunometric assay, while LH and prolactin were analyzed via immunometric assay (IMMULYTE 2000 Analyzer). Serum glucose and cholesterol levels were analyzed via colorimetric enzymatic analysis (Ortho-Clinical Diagnostics, Inc., Rochester, New York). Leptin was measured with commercially available radioimmunoassay kits (Millipore Corporation, Billerica, Massachusetts) with sensitivity 0.5 ng/mL and interassay and intraassay coefficients of variation are 4.92% and 4.5%, respectively. C-reactive protein (CRP) was measured by particle enhanced immunonephelometry (Dade Behring, Inc., Deerfield, Illinois).
Results of testing at baseline and week 12 were compared using paired t tests.
Of the 12 women who enrolled in the study, 2 never attended exercise and educational classes, while a third participant dropped out after 2 weeks. None of these women had significant changes in any measured variables but were included in this intention-to-treat analysis. Another woman had a baseline thyrotropin level of 11.9 mU/mL (normal 0.3–5.6 mU/mL) that was undetected until after the active phase of the study was completed due to freezing and batching of samples; this was despite a normal thyrotropin level 5 months before study onset. With regard to conception, 9 of the 10 women who attended sessions reported actively trying to conceive over the 12-week follow-up period.
BMI and total cholesterol significantly decreased over the 12-week active study period (mean difference ± SEM; 2.06±0.51 kg/m2 [p<0.001] and 25.91 ±4.33 mg/dL [p<0.0001], respectively; Table I). The E1:E2 ratio also decreased significantly (1.8±0.3 baseline, 1.1±0.13 at 12 weeks). No significant differences were noted for the following measures: E1, E2, T, LH, FSH, thyrotropin, prolactin, DHEAS, CRP, fasting and 2-hour insulin, fasting glucose and fasting glucose/insulin ratio. Downward trends were noted for fasting leptin (mean difference 4.32±2.00 ng/mL, p=0.056) and 2-hour glucose (mean difference 11.22±5.41 mg/dL, p=0.07).
Ten of the 12 subjects (83%) showed menstrual improvement with 8 becoming eumenorrheic after the 12-week active phase. All were in the group who regularly attended sessions. Results of dietary and exercise compliance are shown in Figure 1. Two women who began the study amenorrheic conceived within the 12-week follow-up period: 1 spontaneously and 1 using low-dose letrozole.
The results of this pilot study provide reassurance to motivated individuals who hope to affect their fecundity over a relatively short period. Prior investigations focused on 6-month trials of diet and exercise, typically emphasizing the former with little structured guidance for the latter.2,6 Available evidence suggests that a synergistic, 2-pronged approach to improving fitness, rather than weight loss per se, would be advantageous for reducing body fat, increasing lean body mass and improving insulin sensitivity.10,11 Our study successfully combined these 2 elements in a more compacted period of 12 weeks with success noted in areas of BMI and total cholesterol despite the small sample size. Fecundity was not an intended outcome measure for this study, although the few conceptions that did occur were encouraging.
The significant decrease in the E1:E2 ratio reflects the complex relationship between abdominal obesity and the so-called intracrinology of adipose tissue.13 While E1 declined to a small degree and E2 increased slightly, the enzymatic activity of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) subtypes involved in the interconversion of E1 and E2 obviously changed. While type 1 17beta-HSD catalyzes the conversion of E1 to E2 and type 2 catalyzes the conversion of E2 to E1, it is uncertain which subtype was most affected by diet and exercise in our study.14 Furthermore, it is pure speculation as to which adipose compartment (i.e., visceral or subcutaneous) contributed most to this enzymatic shift. However, the E1:E2 ratio moved in a more normal direction away from the E1-dominant ratio seen typically in women with polycystic ovaries. Further studies analyzing levels of enzyme activity or expression in adipose tissue samples taken before and after lifestyle intervention such as this would provide the most useful information about the exact mechanisms at play.
As is true for any ongoing program of weight loss, compliance was a major weakness in our study. Encouraging numbers of hours were spent exercising during the active phase of the study with the majority of women exercising well beyond the thrice-weekly sessions. Similarly, dietary compliance was self-rated at ≥50% for most women in the first 12 weeks. Despite this early success, maintenance of both routines throughout the 12-week follow-up period declined dramatically, perhaps due to the loss of a group environment—the psychological aspects of which were key to past investigations.6,15 Our initial dropout rate of 25% (3/12) significantly weakened our power to detect any meaningful statistical changes but was not unexpected based on past reports with rates of 23–38%.6,16 An additional weakness was our reliance on patient recall to judge compliance, although exercise reports during the active phase closely corresponded to regular attendance patterns for the morning sessions (data not shown).
Refinement of our program should emphasize measures to increase compliance and accountability in a group setting. Our participation may have been hampered by the time of day that classes were held or by the relatively modest population density of our surrounding area. In some cases, subjects drove 30 minutes to reach our exercise facility. In a larger, urban area, proximity of the central facility to patient homes may greatly improve participation. Less frequently scheduled meetings are another alternative, although the rapidity of weight loss would invariably suffer. In terms of data collected, more sensitive measures of body fat (e.g., dual-energy x-ray absorptiometry) would likely provide more information than anthropometric measures such as BMI about the impact on fitness.
From the Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Greenville Hospital System, Greenville, South Carolina.
Supported by a grant from the Greenville Hospital System, Department of Obstetrics and Gynecology.
Presented at the 61st Annual Meeting of the American Society for Reproductive Medicine, Montreal, Canada, October 19, 2005.
Address correspondence to: Paul B. Miller, M.D., Division of Reproductive Endocrinology and Infertility, University Medical Group, 890 West Faris Road, Suite 470, Greenville, SC 29605 (email@example.com).
Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.
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