MENSTRUAL DYSFUNCTION AND flormonal STATUS IN ATHLETIC WOMEN: A REVIEW

Transcription

1 FERTILITY AND STERILITY Copyright c 1981 The American Fertility Society Vol. 36, No. 6, December 1981 Printed in U.SA. MENSTRUAL DYSFUNCTION AND flormonal STATUS IN ATHLETIC WOMEN: A REVIEW ELIZABETH R. BAKER, M.D. Section of Reproductive Endocrinology and Infertility, Section of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, South Carolina During the past decade, an increasing number of women have begun to participate in strenuous endurance sports. Recent evidence suggests a causal relationship between athletic activity and a higher incidence of delayed menarche and menstrual dysfunction. The American College of Sports Medicine has reported that approximately one-third of competitive female long-distance runners between ages 12 and 45 experience menstrual dysfunction (amenorrhea or oligomenorrhea) for at least brief periods. 1 2 The incidence of menstrual dysfunction has been reported to range from 0% to 50% (Table 1).1' 9 Rougier and Linquette found variable effects of exercise on the menstrual cycle, 4 and Kabisch reported few gynecologic problems in East German athletes. 9 In contrast, Erdelyi3 and Zhanel 8 found that 10% to 12% of women athletes experienced menstrual problems. Of 900 women particiating in the Portland Marathon, 7.9% reported amenorrhea since the onset of training6; however, this report disagreed with the 50% incidence of amenorrhea postulated by Feicht for marathon runners and those running 100 miles per week. 5 The incidence appears to vary. directly with the degree of physical effort and the endurance required. SPORTS AND MENARCHE Some investigators have noted a higher incidence of delayed menarche and subsequent menstrual dysfunction in girls who started intensive athletic training prior to menarche than in those who started after menarche.10'12 In a study of 110 nonathletes, 112 high school and college athletes, and 18 Olympic volleyball candidates, menarche was attained latest in Olympic athletes and earliest in nonathletes.u Erdelyi, however, found no change in the age of menarche of athletes when 691 compared with the general Hungarian population but did find an increase in later menstrual dysfunction in those girls with intensive premenarchial athletic training. 10 Other investigators have not found either of these cases to be true.13 Delayed menarche has also been reported in ballet dancers and occurred at a mean age of 15.4 ± 1.9 years, which was significantly later than in age-matched controls (12.5 ± 1.2 years)14 and significantly later than the mean reported age of menarche in the United States; i.e., 12.9 ± 1.2 years. 15 These dancers, like some young athletes, represent a group who have a significant energy drain occurring early in preadolescence and who are highly motivated to maintain low body weights.16 With this combination of factors, there appears to be a significant delay in puberty and menarche. PREDISPOSING FACTORS Factors predisposing some women runners to secondary amenorrhea may include prior menstrual dysfunction, nulliparity, stress, mileage run per week, weight loss or alteration of body fat percentage (Table 2). Secondary amenorrhea is believed by many to be more common in women who had irregular menses prior to the onset of amenorrhea. 6 Schwartz et al. found that 54.5% of amenorrheic runners had a history of prior menstrual irregularity, compared with 15.5% ofmenstrually regular runners and 13.3% of nonrunners17; however, Erdelyi found no increased incidence of prior menstrual irregularity in athletes, as compared with nonathletes.3 Speroff and Redwine also noted that most runners who became amenorrheic had normal cycles prior to exercising.6

2 692 BAKER TABLE 1. Incidence of Menstrual Dysfunction in Athletes Rougier and Linquette (1962) 4 Variable Zhanel (1971) % Kabisch (1972) 9 0% Erdelyi (1962) 10 10% to 12% Feicht et al. (1978) 5 50% (Marathon runners) Dale et al. (1979) 2 34% (Runners) 23% (Joggers) Sperotf and Redwine (1980) 6 7.9% Baker et al. (1981) 7 39% Prior pregnancy was noted by Dale et al. to provide protection against the development of menstrual dysfunction.1 Only 21% of the multiparous runners developed amenorrhea, whereas 51% of the nulliparous group became amenorrheic. 1 This simple association may not reflect cause and effect. Perhaps hypothalamic maturity, as demonstrated by pregnancy, could decrease the runner's susceptibility to menstrual dysfunction. Age may also influence susceptibility to runningrelated menstrual dysfunction. In our series, the mean age of the amenorrheic runners (24.3 ± 1.3 years) was significantly lower than in those runners with regular menstrual cycles (31.4 ± 1.3 years). 7 Also, the incidence of amenorrhea was higher in those runners less than 30 years of age (66.6%) than in the older group (9.0%).7 These correlations suggest that younger runners may be more prone to develop amenorrhea as a consequence of running. These data support the observation of Speroff and Redwine of the propensity of women runners under age 25 to develop amenorrhea.6 The observation that athletes have a higher incidence of amenorrhea while participating in sports requiring physical effort and endurance suggests the possibility of a stress-related phenomenon The role of stress and energy expenditure is difficult to quantitate; but many amenorrheic runners consider their training to be more intense and stressful than that of their menstrually regular counterparts. Stress may be postulated to result in hypothalamic dysfunction via neurotransmitter alteration, catecholamine depletion, or interference with hypothalamic receptors for the neurotransmitters; however, the precise mechanism by which stress interferes with the hypothalamic-pituitary-gonadal axis has not been clarified. The duration or speed of running may also be a factor in increasing stress and in increasing the incidence of amenorrhea. The longer or faster the women ran, the more menstrual dysfunction they seemed to experience.6 December 1981 Mileage run per week may also affect the menstrual cycle. In two studies 5 19 a striking correlation was noted between amenorrhea and miles run per week. In Feicht's study, 43% were running more than 50 miles per week, and many experienced secondary amenorrhea. 5 Also, in a study involving repeated cycles in an ovulatory 30-year-old distance runner, Shangold et al. found that luteal phase length varied inversely with the average weekly mileage run during the luteal phase and inversely with the total distance run during the first 7 days of the follicular phase. In cycles involving less than 5 miles per week, luteal phase length was normal, whereas in cycles involving greater than 35 miles per week, luteal length was 9 days or less.20 This altered luteal phase length, associated with a normal menstrual interval, may be a potential cause of infertility in long-distance runners. Speroff et al., however, found no correlation between amenorrhea and mileage run, perhaps because their sample included few women running greater than 20 miles per week.6 Ih our study it appeared that in runners, the mileage run per week (10 to 70 miles per week) may not be an important contributing factor in the development of secondary amenorrhea.7 Secondary amenorrhea also can result from excessive weight loss and alteration of the percentage of body fat. According to Frisch and McArthur,21 menarche and the maintenance of menstrual cycles require a critical level of body fat (not merely an absolute weight). This implies that a particular body composition may have an important influence on the reproductive ability of females. Frisch found that at least 17% of the body weight must be in fat for menarche to occur. After age 16, at least 22% of body fat is needed to maintain menstrual cycles. 21 Therefore, one can use weight and height to approximately predict when a woman might develop amenorrhea or might regain menstrual function. 22 Competitive distance runners have the least amount of body fat (7% to 8%) when compared with recreational distance runners (15.2%) and mature nonathletic women (26% to 28%) Speroff and Redwine TABLE 2. Factors Predisposing Female Athletes to Secondary.Amenorrhea 1. Prior menstrual dysfunction or delayed menarche 2. Nulliparity and young age 3. Stress 4. Miles run per week 5. Weight loss 6. Alteration of the percentage of body fat

3 Vol. 36, No.6 ATHLETIC WOMEN 693 found that menstrual irregularity and secondary amenorrhea were more common in women weighing less than 54.5 kg and 52.3 kg, respectively.6 They also noted that secondary amenorrhea appeared to correlate with the amount of weight lost while running and reported a 17.5% incidence of amenorrhea in those who had lost more than 9 kg.6 Loss of weight involving 10% to 15% of normal weight for height represents about one-third of body fat and may result in amenorrhea Lower initial body weight for height, greater weight loss since the onset of training, and a lower percentage of body fat have been found more often in amenorrheic runners, as compared with runners with regular menses. These findings are supported by Dale et al., who found that runners were 5 to 6 kg below average weight for height, had significantly less body fat, and had lost 5.94% of their body weight since the onset of running.1 However, two other studies noted comparable mean weight and height for amenorrheic and menstrually regular runners.5 7 In many runners, after an initial weight loss, weight will stabilize but body fat will continue to decrease, leading to further alteration in the ratio of lean body mass to body fat. Several mechanisms may be postulated to explain control of menstrual function by the percentage of body fat. Fat cells are a site for aromatization of androgens to estrogens, providing an extragonadal source of estrogen. In thin runners, pituitary sensitivity to luteinizing hormone-releasing hormone may be decreased, resulting in less ovarian stimulation23; or perhaps there is an increase in catecholestrogens in runners with a lowered percentage of body fat, which may inhibit hypothalamic activity The catecholestrogens (2-hydroxyestrogens) are increased in women -with little body fat. As adipose tissue increases, there is a shift in estrogen metabolism towards production of 16-hydroxylated estrogens. Adashi has shown that administration of 2-hydroxyestrone decreases serum luteinizing hormone (LH). 24 Perhaps in the very thin athlete an increased production of catecholestrogens could interfere with LH secretion and in turn contribute to the hypoestrogenic state found in amenorrheic runners. Alteration in the ratio of lean body mass to body fat and degree of weight loss appear to be important factors in the onset of secondary amenorrhea in runners. HORMONAL CHANGES Several studies have evaluated the effects of exercise on the levels of various hormones (Table 3). Jurkowski et al. evaluated acute exercise in 9 regularly menstruating women, ages 20 to 24, and found increased plasma estradiol and progesterone during the luteal phase, but during the follicular phase only estradiol was increased at exhaustion. 26 Dale et al. obtained weekly blood samples from 14 runners (30 miles per week, distance and speed work), 6 joggers (5 to 30 miles per week, slow pace), and 18 nonrunners. Based on serum progesterone, presumptive ovulation occurred in 83% of controls, 67% of joggers, and 50% of runners. In the ovulatory runners, cyclic levels of progesterone and estradiol were found; however, in amenorrheic runners both hormones were low.1 The report of Shangold et al.20 appears at first glance to contradict the progesterone data reported by Jurkowski et al.26; however, they evaluated the more chronic effects of running and found lowered luteal phase progesterone. Later, they evaluated the acute effects of running and noted increased estradiol and increased progesterone. 27 Schwartz et al. found no change in estrone or estradiol with running.17 In our series, plasma estradiol was significantly lower in amenorrheic runners than in menstrually regular runners. 7 Six studies evaluated serum gonadotropins but obtained contradictory results (Table 4). In evaluating luteinizing hormone, Dale et al. found cyclic values in ovulatory runners and low values in amenorrheic runners. 1 Demers et al. 28 also found decreased levels of LH; whereas Jurkowski et al. 26 and Shangold et al found no change in LH with running; and Schwartz et al. found elevated LH values in amenorrheic runners and normal values in regularly menstruating runnersp Shangold et al and Schwartz et al.17 found no effect from running on follicle-stimulating hormone (FSH); however, in amenorrheic runners Dale et al. 1 found lowered FSH values and cyclic values in ovulatory runners. Demers et al. also found decreased FSH a!l_;er running,28 as TABLE 3. Effect of Exercise on Steroid Hormones Study Estradiol Progesterone Jurkowski et al. 26 (acute Increased Increased(luteal phase only) Shangold et al. 20 (chronic No effect Decreased (luteal phase only) Shangold et al. 27 (acute Increased Increased Dale et al.2 (runners) 50% Ovulatory No effect Increased 50% Oligomenorrhea Decreased Decreased Schwart2 et alp No effect

4 694 BAKER TABLE 4. Effect of Exercise on Gonadotropins Study LH FSH Jurkowski et al. 26 (acute No effect Increased (follicuexercise lar phase only) Shangold et al. 20 (chronic? Slight de- No effect crease in Shangold et al. 27 (acute surge No effect No effect Dale et al. 2 (runners) 50% Ovulatory No effect No effect 50% Oligomenorrheic Decreased Decreased Schwartz et al. 17 Ovulatory runners No effect No effect Amenorrheic Increased No effect Demers et al. 28 Decreased Decreased opposed to Jurkowski et al., 26 who noted increased follicular FSH values. In women runners, plasma testosterone varied from normal in three studies 7' 17' 27 to increased (but still within the normal female range) in two studies.1 28 Two other androgens, dehydroepiandrosterone (DHA) and androstenedione, may be altered by running; however, DHA in runners has been measured only in one study. 7 In two studies, androstenedione levels were normal in runners as compared with controls. 7' 17 The role of androgens in exercise is unclear. Perhaps a higher testosterone level in runners, as reported by some investigators, may be important in maintaining a greater muscle to body weight ratio. 29 In exercise, androgens may be important in muscle fiber repair and hypertrophy by enhancing protein synthesis. Testosterone also enhances the ability of muscle fibers to synthesize and store glycogen, an important muscle energy substrate.29 In women runners possible mechanisms for higher androgen levels may be either increased production by the ovary or adrenal gland in response to stress or other stimuli, decreased aromatization of androgens to estrogeh because of decreased peripheral fat tissue, or decreased hepatic clearance secondary to reduced hepatic blood flow. 30 Demers found a threefold increase in norepinephrine and epinephrine and speculated that adrenergic stimulation may enhance testosterone secretion.28 Elevated androgens could result in menstrual dysfunction directly through a feedback effect on the hypothalamus or indirectly through a decrease in peripherally produced estrogen, 1 which may be necessary to "prime" the hypothalamic-pituitary axis during the early follicular phase of the normal menstrual cycle. Prolactin has been reported to increase in response to exercise31; however, levels obtained at 1 hour and at 16 hours after running were nor- December 1981 mal.20 In a later study evaluating the acute effects of running, Shangold found that prolactin levels measured within one minute after running were dramatically increased.27 One could speculate that perhaps a borderline hyperprolactinemia could result from chronic long-distance running and, as a result, be a factor in running-associated menstrual dysfunction. However, if estrogen metabolism is shifted in favor of catecholestrogens, which cause a decrease in gonadotropins until hypoestrogenic hypogonadotropic amenorrhea results, prolactin levels could remain low because of the effect of catecholestrogens on dopamine receptors. 24 Supporting evidence comes from one study that reported a fourfold increase in dopamine immediately after a 42-km run.28 Another factor in the onset of running-associated amenorrhea could be altered levels of prostaglandins. An average increase of 200% in 6-keto PGF 1,. (a prostaglandin metabolite), of 160% in PGF 2,., and of 140% in PGE2 has been reported in four female runners immediately following a 42- km race.28 OTHER SPORTS Women participating in other strenuous endurance sports such as tennis, rowing, skiing, fencing, volleyball, and gymnastics and in ballet or modem dance may also experience a higher incidence of amenorrhea or oligomenorrhea Many of these women also have a low percentage of body fat, early intensive training, a prior history of menstrual irregularity or delayed menarche, and increased stress. REVERSIBILITY Exercise-associated menstrual dysfunction is probably reversible; however, this reversibility has not been completely proven. The following observations suggest that secondary amenorrhea related to exercise is temporary: (1) when training is interrupted, long-distance runners and ballet dancers resume menses often without change in weight14; (2) when training decreases below some critical level, amenorrhea frequently resolves20; (3) resolution of amenorrhea in rowers occurs after the close of the rowing season 10; and (4) normal reproductive functions are found in young girl swimmers 10 years after discontinuing strenuous training.32

5 Vol. 36, No. 6 ATHLETIC WOMEN 695 CLINICAL MANAGEMENT The clinical management of amenorrheic athletes seeking pregnancy is often quite difficult. Many physicians question whether these athletes are physically or nutritionally capable of carrying a pregnancy. If the athlete insists on attempting pregnancy, the first approach should include a decrease in the amount of exercise. Should this reduction in activity fail, or should the athlete be unwilling to decrease her exercise, pharmacologic induction of ovulation may be considered. However, the responsiveness of amenorrheic athletes to ovulation-inducing medications has not been thoroughly investigated in the literature. In our experience and in the literature, prolactin is elevated acutely with exercise but returns to normal levels within 1 hour after exercise Bromocriptine would be the initial drug of choice, since daily exposure to very high prolactin levels (up to 100 ng/ml), even for brief periods, may adversely affect ovarian function. If, after several months of therapy, the athlete does not respond, ovulation induction with human menopausal gonadotropins plus human chorionic gonadotropin (hmg-hcg) could be utilized; however, this regimen has the disadvantages of hyperstimulation, multiple births, and great expense. Gonadotropin-releasing hormone (GnRH or LHRH), or one of its agonists, may be useful in ovulation induction; however, a recent paper by Casper and Yen33 demonstrated concomitant release of LH and prolactin after the administration of a potent and long-acting LHRH-agonist. This concomitant release of prolactin and LH may result in ovulation inhibition or in the induction of luteolysis.33.s5 Clomiphene could be tried, but the amenorrheic athletes might not respond, since their serum estradiol levels are extremely low. 7 SUMMARY Since women have become more involved in physical fitness and competitive endurance sports, the incidence of menstrual dysfunction has increased. Long-distance running and other sports may lead to alterations in gonadotropins, androgens, estrogens, progesterone, or prolactin, which in some women may directly or indirectly result in amenorrhea or infertility. The effects of running and strenuous exercise on the menstrual cycle and reproductive hormones remain controversial. Reported incidences of menstrual dysfunction vary widely, and many factors have been implicated in the onset of this problem. Exercise- associated menstrual dysfunction seems to occur more frequently in nulliparous athletes, in athletes with delayed menarche, and in athletes with low body fat. It is important to realize that disruption of the menstrual cycle, ranging from mild changes in flow to amenorrhea, is a relatively common problem for the female athlete engaged in strenuous endurance sports. Yet no evidence exists at present to indicate conclusively that this menstrual dysfunction is harmful to the female athlete's reproductive system. Acknowledgments. I thank Dr. Rajesh S. Mathur and Dr. H. Oliver Williamson for clinical discussion during preparation of this manuscript and Mrs. Lucy DiGiuseppe for her excellent editorial assistance. REFERENCES 1. Dale E,, Gerlach DH, Wilhite AL: Menstrual dysfunction in distance runners. Obstet Gynecol 54:47, Dale E, Gerlach DH, Martin DE, Alexander CR: Physical fitness profiles and reproductive physiology of the female distance runner. Physician Sportsmed 7:83, Erdelyi GJ: Effects of exercise on the menstrual cycle. Physician Sportsmed 4:79, Rougier G, Linquette Y: Menstruation and physical exercise. Presse Medicate 70:1921, Feicht CB, Johnson TS, Martin BJ, Sparkes KE, Wagner WW: Secondary amenorrhea in athletes. Lancet 2:1145, Speroff L, Redwine DB: Exercise and menstrual function. Physician Sportsmed 8:42, Baker ER, Mathur RS, Kirk RF, Williamson HO: Female runners and secondary amenorrhea: correlation with age, parity, mileage, and plasma hormonal and sex-hormonebinding globulin concentrations. Fertil Steril 36:183, Zhanel K: Fencing in relation to menstrual cycle and gestation. J Sports Phys Fitness 11:120, Kabisch D: Congress of Hungarian Society of Sports Physicians, 1972, p 92. Cited by Erdelyi Erdelyi GJ: Gynecological survey of female athletes: AMA Proceedings of the Second National Conference on the Medical Aspects of Sports, November, J Sportsmed 2:174, Malina RM, Spirduso W, Tate C, Baylor AM: Age at menarche and selected menstrual characteristics in athletes at different competitive levels and in different sports. Med Sci Sports 10:218, Prokop L: On the question of overtraining. Sportarzt Kongress Frankfurt Am Main, 1953, Deutscher Sporta.rtzebund. Cited by Erdelyi Astrand P, Eriksson B, Nylander I, Engstrom L, Karlberg P, Saltin B, Thoren C: Girl swimmers. Acta Paediatrica Scand Suppl 147:33, Warren MP: The effects of exercise on pubertal progression and reproductive function in girls. J Clin Endocrinol Metab 51:1150, Frisch RE, Revelle R: Height and weight at menarche and a hypothesis of menarche. Arch Dis Child 46:695, 1971

6 696 BAKER 16. Frisch RE, Wyshak G, Vincent L: Delayed menarche and amenorrhea in ballet dancers. N Engl J Med 303:17, Schwartz B, Rebar RW, Yen SSC: Amenorrhea and long distance running (Abstr). Fertil Steril 34:306, Harris DV: Secondary amenorrhea linked to stress. Physician Sportsmed 6:24, Foreman K: Seattle Pacific College, Seattle, Washington, Cited by Dale et aj.l 20. Shangold M, Freeman R, Thysen B, Gatz M: The relationship between long distance running, plasma progesterone and luteal phase length. Fertil Steril 31:130, Frisch RE, McArthur JW: Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science 185:949, Trussell J, Frisch RE: Menarche and fatness: re-examination of the critical body composition hypothesis. Science 200:1506, Wentz AC: Body weight and amenorrhea. Obstet Gynecol 56:482, Adashi EY, Rakoff J, Divers W, Fishman J, Yen SSC: The effect of acutely administered 2-hydroxyestrone on the release of gonadotropins and prolactin before and after estrogen priming in hypogonadal women. Obstet Gynecol Surv 35:363, Fishman J, Boyar RM, Hellman L: Influence of body weight on estradiol metabolism in young women. J Clin Endocrinol Metab 41:989, 1975 ~ 26. Jurkowski JE, Jones NL, Walker WC, Younglai EV, Sutton JR: Ovarian hormonal responses to exercise. J Appl Physiol 44:109, 1978 December Shangold M, Gatz ML, Thysen B: Acute effects of exercise on plasma concentrations of prolactin and testosterone in recreational women runners. Fertil Steril 35:699, Demers LM, Harrison TS, Halbert DR, Santen RJ: Cited by Grunby P: Increasing numbers of physical changes found in nation's runners (Medical News). JAMA 245: 547, Sutton JR, Coleman MJ, Casey J, Lazarus L: Androgen responses during physical exercise. Br Med J 1:520, Dessypris A, Knoppasalmi K, Adlercreutz H: Plasma cortisol, testosterone, androstenedione and luteinizing hormone (LH) in a noncompetitive marathon run. J Steroid Biochem 7:33, Williams R: The adenohypophysis. In Textbook of Endocrinology. Philadelphia, W. B. Saunders Co., 1974, p Eriksson BO, Engstrom L, Karlberg P, Lundin A, Saltin B, Thoren C: Long-term effect of previous swimtraining in girls: a 10-year follow up on the "girl swimmers." Acta Paediatr Scand 67:285, Casper RF, Yen SSC: Simultaneous pulsatile release of prolactin and luteinizing hormone induced by luteinizing hormone-releasing factor agonist. J Clin Endocrinol Metab 52:934, Nillius SJ, Bergquist C, Wide L: Inhibition of ovulation in women by chronic treatment with a stimulatory LRH analogue-a new approach to birth control? Contraception 17:537, Casper RF, Yen SSC: Induction ofluteolysis in the human by a long-acting analogue of luteinizing hormone-releasing factor. Science 205:408, 1979 Received June 1, Reprint requests: Elizabeth R. Baker, M.D., Department of Obstetrics and Gynecology, The Milton S. Hershey Medical Center, 500 University Drive, Hershey, Pennsylvania