Obesity and Reproductive Disorders

Obesity, which results from a combination of genetic and environmental factors, is an increasingly prevalent condition in Western society that heightens the risk for reproductive disorders. Lifestyle modifications, including dietary changes and exercise, can go a long way toward restoring ovulation in this patient population.

Overeating and lack of exercise, as well as a more sedentary lifestyle overall, are associated with weight problems in a growing proportion of the population. In 1997, an estimated 33% of US adults were obese;¹ the highest rates were found among women (34%), Hispanics (47%), and African-Americans (49%). Up to 55% of US adults are considered overweight (i.e., above their healthy weight range). Excess weight can be classified more precisely using body mass index (BMI): A BMI of 27 to 29.9 kg per m2 is designated as overweight and a BMI of 30 kg per m2 or higher is termed obese.

Obesity is associated with a host of medical conditions, including diabetes mellitus, osteoarthritis, cardiovascular disease, sleep apnea, breast and uterine cancer, pregnancy complications, and reproductive disorders. Total weight, although important, is not the sole factor in these problems, however; fat distribution is also key. This can be assessed using the waist/hip ratio or, simply, waist circumference.

A disproportionate number of women who seek treatment at infertility centers have a high BMI. For example, among more than 5000 infertile female patients seen at the Reproductive Medicine Unit at the University of Adelaide, Australia, 40% had a BMI exceeding 25 kg per m2 (borderline or overweight), and 17% had a BMI exceeding 30 kg per m2 (obese).² Thus, excess weight appears to have a major impact on reproductive performance, and obesity can compromise reproductive performance in a variety of ways (Table 1). It should be noted that although many obese women are fertile and have children, the overall prevalence of reproductive disorders increases significantly once women reach the overweight and obese ranges. The large number of very overweight, fertile women should not lead practitioners to assume that weight disorders have little impact on reproduction.^3,4

PCOS
Five percent to 10% of all women of reproductive age have polycystic ovary syndrome (PCOS).^3,5 Clinical features of this disorder are listed in Table 2. Although some controversy exists regarding the definition of PCOS, the presence of menstrual abnormalities, hirsutism, obesity, and infertility makes the diagnosis unequivocal. Not all obese women have PCOS, nor are all women with PCOS obese, but the two conditions are closely related.

Initial investigations in patients with suspected PCOS should include a clinical examination and basic laboratory studies. The recommended work-up for these patients, as well as for any obese women with reproductive difficulties, appears in Table 3. It is particularly important to exclude glucose intolerance, through either a fasting blood glucose test or an oral glucose tolerance test.^4,6 Some evidence has suggested that fasting glucose is not entirely reliable in patients with PCOS;⁶ instead, fasting and stimulated serum insulin values may be useful.

Physical Examination
Height, weight, BMI (kg/m2)
Waist circumference
Hair, skin, pigmentation
Purple striae and signs of Cushing’s syndrome

Laboratory Tests
Glucose tolerance
Lipid profile
Androgens (testosterone, free testosterone)
Prolactin and LH
FSH and thyroid hormones
Ovarian ultrasonography (optional)

BMI = body mass index; LH = luteinizing hormone; FSH = follicle-stimulating hormone.

WEIGHT LOSS
Several reports have demonstrated that weight loss helps to regulate the menses in women with obesity and anovulation.^3,4,7 This change is associated with reductions in both plasma androgen levels and miscarriage rates. Studies conducted on women with obesity and PCOS have shown that rigorous dietary manipulation by caloric restriction is extremely effective in restoring menstrual regularity.^8–10 As with all weight-loss programs pursued for any purpose, compliance over the long term remains a major challenge.

Research conducted by Clark and colleagues has suggested that strict calorie counting is not necessary as long as patients exercise and heed dietary advice.^2,11,12 In their studies, more than 90% of obese, oligomenorrheic women experienced a dramatic improvement in menstrual patterns, with a high spontaneous conception rate. Even women whose failure to conceive was unrelated to anovulation (e.g., male factor infertility, tubal blockage) had more success with assisted-reproduction pregnancies following weight loss.¹¹ Surgically induced weight loss via gastric bypass or gastric restrictive procedures (vertical banding, gastroplasty, adjustable gastric banding) has also been shown to restore menstruation and pregnancy, but these operations have very high morbidity rates.¹³

LIFESTYLE MODIFICATION
Several years ago, a group of clinicians at Queen Elizabeth Hospital (Woodville, South Australia) developed the Fertility Fitness© program, which encouraged women to cease all medical treatment for infertility for 6 months while they attended special weekly meetings. At these meetings, the first hour was spent on exercise and the second on a seminar that provided relevant information regarding obesity and reproductive disorders.^2,11,12,14 Exercise regimens were tailored to each woman’s fitness level, and ranged from gentle walking to vigorous aerobic exercise. Exercise sessions were led by a fitness professional who was sensitive to the needs of overweight/obese women. Group seminars-conducted by a dietician, a psychologist, a nurse, and an OB/GYN-dealt with medical and practical aspects of weight loss and its implications for reproduction. After patients participated in weekly meetings for 6 months, appropriate medical infertility treatments were instituted (e.g., ovulation induction with clomiphene citrate).

Participants lost an average of 10.2 kg. Ovulation was restored in 60 of 67 previously anovulatory women; among them, 52 achieved a pregnancy (18 spontaneously) and 45 had live births. The miscarriage rate dropped from 75% before the study to 18% during the study. Based on these results, investigators concluded that most overweight women with infertility could expect to become pregnant after participating in an organized 6-month regimen of gentle weight loss.^2,11

The program was also highly cost-effective: Before entering the program, the 67 participants underwent fertility treatments that cost a total of $550,000 and resulted in 2 live births; after the program and subsequent treatment (total cost, $210,000), there were 45 live births.

INSULIN RESISTANCE
Improvements in insulin resistance induced by weight loss and/or exercise have important implications for restoring reproductive function.^15,16 Calorie restriction has been shown to reduce insulin resistance and lower circulating androgen levels.¹⁵ Because of insulin’s adverse effect on the ovary and ovulation, it is thought that lowering serum insulin levels reduces androgen production and thereby promotes ovulation. Even women who do not lose much weight but who become more fit through exercise can reduce their insulin resistance. For example, one study showed that obese women with PCOS who responded to a lifestyle modification program (dietary changes and exercise) experienced an 11% reduction in central body fat, a 71% improvement in insulin sensitivity index, a 33% drop in fasting insulin levels, and a 39% reduction in luteinizing hormone levels.¹⁶ Ovulation was restored in many cases. Anecdotal evidence suggests that, unlike the short-term results from calorie-restriction diets that have been popular in the past, long-term weight loss continues with such a regimen.

CONCLUSION
All health programs should emphasize weight loss and exercise for overweight women. This will improve menstrual regularity, reduce infertility, and prepare women for a less hazardous pregnancy. In addition, the potential for long-term complications such as diabetes mellitus and cardiovascular disease will be reduced. It is tempting for both physicians and patients to resort immediately to medical treatment such as ovulation induction with gonadotropins or clomiphene citrate or even in vitro fertilization, but these measures do not confer long-term benefits to women when they are in their 50s and 60s. Although many medical insurance programs do not provide reimbursement for weight loss measures, women’s health programs should recognize the cardinal importance of weight in reproductive function and pressure regulatory bodies to provide financial means for women to participate in weight loss regimens before undergoing any other treatment for menstrual irregularities or infertility.

References:

REFERENCES
1. Legato MJ. Gender-specific aspects of obesity. Int J Fertil Womens Med. 1997; 42:184–197.
2. 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;10:2705–2712.
3. Friedman CI, Kim MH. Obesity and its effect on reproductive function. Clin Obstet Gynecol. 1985;28:645–663.
4. Norman RJ, Clark AM. Obesity and reproductive disorders. Reprod Fertil Dev. 1998;10:55–63.
5. Dunaif A. Polycystic ovary syndrome. Curr Ther Endocrinol Metab. 1994;5: 222–229.
6. 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;83:2694–2698.
7. Mitchell GW, Rogers J. The influence of weight reduction on amenorrhea in obese women. N Engl J Med. 1953;249:835–837.
8. Bates GW, Whitworth NS. Effect of body weight reduction on plasma androgens in obese, infertile women. Fertil Steril. 1982;38:406–409.
9. Kiddy DS, Hamilton Fairley D, Seppala M, et al. Diet-induced changes in sex hormone binding globulin and free testosterone in women with normal or polycystic ovaries: correlation with serum insulin and insulin-like growth factor-I. Clin Endocrinol (Oxf). 1989;31:757–763.
10. 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: 105–111.
11. Clark AM, Thornley B, Tomlinson L, et al. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod. 1998;13:1502–1505.
12. Galletly C, Clark A, Tomlinson L, Blaney F. Improved pregnancy rates for obese, infertile women following a group treatment program: an open pilot study. Gen Hosp Psychiatry. 1996;18:192–195.
13. Bilenka B, Ben Shlomo I, Cozacov C, et al. Fertility, miscarriage and pregnancy after vertical banded gastroplasty operation for morbid obesity. Acta Obstet Gynecol Scand. 1995;74:42–44.
14. Galletly C, Clark A, Tomlinson L, Blaney F. A group program for obese, infertile women: weight loss and improved psychological health. J Psychosom Obstet Gynaecol. 1996;17:125–128.
15. Dunaif A. Insulin resistance in polycystic ovarian syndrome. Ann NY Acad Science. 1993;687:60–64.
16. Huber-Buchholz M, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab. 1999;84:1470–1474.

Robert J. Norman, MD, is a Professor and Head of the Reproductive Medicine Unit, Department of Obstetrics and Gynaecology, University of Adelaide and Queen Elizabeth Hospital, Woodville, South Australia, Australia.

Originally published in The Female Patient -- November, 2000
© Copyright, 2000 Quadrant Publishing, All Rights Reserved. Reprints are not allowed without the expressed written consent of Quadrant Publishing.