00’1~972X/9’2/7506-1393SO3.00/0 Jwxnal of Clinical Endocrmology and Metabolism Copyright c 1992 by The Endocrine Society

CLINICAL Amenorrhea MICHELLE

REVIEW 40 in Endurance

Vol. 75, No. G Printed in U.S.A.

Runners

P. WARREN

Department of Obstetrics and Gynecology and Medicine, 59th Street, New York, New York 10019

St. Luke’s-Roosevelt

M

ENSTRUAL dysfunction in athletes has been reviewed extensively in the medical literature and had been the subject of several excellent reviews (l-5). This interesting problem which is reversible appears to have multiple causes and originates from an apparent hypothalamic dysfunction. Attempts at understanding the original insult has been confounded by the inability to control for many of the causal variables, few longitudinal studies, and the difficulty of their design. Athletic menstrual dysfunction can be reproduced by extensive physical training but the full fledged hypoestrogenie amenorrhea is not produced by extensive physical training alone in a normal population. Marathon runners are an interesting subset of athletes who appear to have a relatively high incidence of amenorrhea. The training for marathon runners may vary considerably but they generally represent the most intensively trained group of runners. Long distance runners who run more than 70 miles/week are not unusual in the 1990s. The only woman who ran in the 1970 New York City Marathon did not finish whereas 20 yr later in 1990, 5249 women entered and 4500 finished. The prevalence of menstrual dysfunction in runners ranges from 6-43% depending on the definition of the menstrual problem (1). In a study of marathon runners, the incidence was 7% and appears to be more frequent in women who weighed less and were slightly younger. The amenorrheic group was also all nulliparous but this may have been due to the younger age of this group (6). A number of studies have shown however that amenorrhea is directly related to weekly training mileage and it would therefore be reasonable to assume that marathon runners would have the highest incidence of this problem. Glass et al. (6) studied women qualified to compete in the 1984 women’s Olympic trials and reported that 19% had amenorrhea (two or fewer menstrual cycles within the previous year). Whereas many studies show an association between training intensity and reproductive dysfunction, other studies did not find a correlation between the incidence of amenorrhea and the weekly training mileage. Amenorrhea does not appear to increase simply by increasing mileage as suggested. An intriguing associated factor seen with amenorrhea-

Hospital

Center, 428 West

associated athletics is loss of body weight or low weight and/ or body fat. Body fatness as a causal mechanism continues to receive wide publicity in the popular press although numerous cross-sectional studies have established that this factor is probably not causal (7). Twenty-two percent body fat is thought to be necessary for maintenance of regular cycles, but these are seen in athletes with less than 17% body fat. Amenorrheic and eumenorrheic runners have been found to have similar percentages of body fat. Reproductive dysfunction is uncommonly seen in athletes who have a high percent body fat, thus the weight or body fat probably reflects other metabolic parameters (3, 7, 8). Recent research suggests that fat stores are gender specific; depletion of regional fat stores which accumulate in the mature female below the waist may signal inadequate reserves for pregnancy and lactation. This may in turn affect GnRH function. However, amenorrhea and irregular menses becomes increasingly common in athletes with lower percentages of ideal body weight (l-5). Other studies have shown an association between menstrual dysfunction, exercise, and decreasing body weight; certain sports such as swimming and cycling did not show this association (7) and the highest incidence of amenorrhea appears to occur in runners. The focus on body fat and weight in many of these studies has overshadowed other important causal factors. The waters have been further muddied by lack of detailed endocrine studies. Amenorrhea is variously defined as number of cycles per year with no focus on the endocrine profiles. The physiological entity is vaguely described as having low to normal gonadotropins and normal to low estradiol levels. One study reported a 5% incidence of amenorrhea with 51% oligomenorrhea while another showed 50% of competitive runners to be amenorrheic (5). Several studies showed that increasing training induces reproductive dysfunction with 18 of 19 women developing oligomenorrhea when running more than 50 miles/week. Thus, some level of reproductive dysfunction appears to be common in the competitive athlete although a prolonged amenorrhea is uncommon. Demographic studies which attempt to define the amenorrhea seen with endurance running as number of periods per year may inadvertedly include patients with anovulatory syndromes with normal estrogen levels. In fact the heterogeneity of the hormonal profiles found in different studies suggests this is the case. The most prevalent pattern is a

Received May 5, 1992. Address correspondence and requests for reprints to: Michelle I’. Warren, M.D., Department of Obstetrics/Gynecology and Medicine, St. Lukes-Roosevelt Hospital Center, 428 West 59th Street, New York, New York 10019.

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WARREN

hypothalamic amenorrhea with altered GnRH pulsatility of both gonadotropins which is often seenwith low gonadotropins, and hypoestrogenism. This is seen in endurance sports such as marathon running or sports where low weights are an advantage, either to enhance performance or esthetic appeal, such as ballet dancing, gymnastics, and figure skating. A high incidence of eating disorders are also seen with endurance training and the hormonal aberrations are similar to that seen in anorexia nervosa (9). Other sport disciplines have been associated with another type of amenorrhea or menstrual irregularity in which the hormonal profile resembles that seen in polycystic ovarian disease. Increased LH levels and LH/FSH ratios, normal estrogen levels, and higher levels of androgens have been reported in runners and swimmers (1). Much emphasis has also been placed on the stressof competition with somestudies showing an association of stressand amenorrhea as measured by psychometric assessmentwhile others have not. Stress-induced menstrual problems may be more likely to produce an anovulatory syndrome; there is a well known secretion of adrenal hormones, including adrenal androgens, with the stressof competition. These changes may be instrumental in the development of anovulation. Thus there is a great need for detailed hormonal evaluation when evaluating reproductive disorders seen with exercise. Other associated factors seen with endurance training include the intensity of training, diet, or energy and nutrition, decreasedbasalmetabolic rate and training before menarche. For reasonsthat are unclear, delayed menarche is associated with a higher incidence of amenorrhea in association with exercise, even if training started well after menarche. Subjects with delayed menarche may have a more sensitive or immature reproductive axis. The nonparous athlete is also at risk suggestingthat a lessrobust hypothalamic-pituitary axis may be more vulnerable. Rats and nonhuman primates show clear evidence of gonadal dysfunction with exercise. The prepubertal state is prolonged by asmuch as 20 days in someanimal experiments and reversed by GnRH administration (8). The insight gathered by animal studies has been hampered by the fact that exerciseinduced reproductive dysfunction is not consistently seenand methods used (swimming, exercisewheels for food) may cause more stressthan in the human situation. Also, a decreasein food intake is often noted making it difficult to control for this variable. Replicating human exercise training with voluntary chronic exercise without stressessuch as swimming, electroshock, and exercising for food has been difficult to implement. Data on monkeys indicate that the primate may be trained to run and increasing caloric intake may reverse the reproductive dysfunction similar to the human situation (10). These experiments suggest that an energy drain may exist with training where endurance training may be associatedwith reproductive dysfunction when caloric intake decreasesand energy output cannot be met. These experiments also suggest that a physiologic paradox exists: a large energy output is not compensated for by increased caloric intake yet weight lossdoes not occur. Thus, training appears to be associatedwith increased caloric effi-

JCE & M. 1992 Vol75.No6

ciency and may represent an adaptive syndrome. Initial studies examining energy balance are conflicting. A number of studies have found resting metabolic rate increasesduring exercisetraining program (with an increasein dietary intake) and others have shown no effect of training on resting metabolic rate; Others have speculated that dietary and intense exercise deplete energy stores stimulating the body to increasefood efficiency (11). How these adaptive changes tie in with reproductive dysfunction is unclear. The well documented decreases in GnRH pulses suggest that the GnRH pulse generator may be affected by metabolic fuels. Someexperiments suggestthis: starvation induced a blocking of the estrous cycle in the Syrian Hamster and is reversed by glucose added to drinking water (8). Interestingly, the estrous blocking effect of starvation is more rapid in lean hamsters. Drugs which inhibit glycosis and fatty acid oxidation in normal hamsters can also block the estrous cycle (8). Interest has centered insulin as a mediator of fuel availability, particularly as it influences amino acid substancesnecessary for the synthesis of the neurotransmitters norepinephrine and serotonin which influence GnRH pulses. Further work in this area is needed. Another pathway which has stimulated studies in the animal model is the possible effect of activation of the hypothalamic pituitary adrenal axis on the GnRH pulse generator. CRF decreasesLH pulses in the rhesus monkey and in rats. ACTH and cortisol levels are elevated during exercise with disturbances of rhythms of both ACTH and cortisol in amenorrheic runners. These effects may be a side effect of the activation of CRF which may be the factor which directly suppressesGnRH. The stress of chronic exercise or competition may be the initiating factor which induces reproductive dysfunction. Alternatively, this type of amenorrhea may be different from that seen with an energy drain or may be superimposedon it. Another puzzling factor hasbeen the associationof athletic amenorrhea and eating disorders. This has been seenparticularly in runners often in association with major affective disorders (9). This issuemust be examined in more depth as some evidence exists that food restriction may activate the hypothalamic-pituitary adrenal axis. This association presents an interesting hypothesis, a common denominator for both the cortisol elevations and the suppressedgonadotropin pulsatility seenwith athletically induced amenorrhea asboth are seenwith eating disorders. A history of an eating disorder also appears to increase susceptibility to the development of a reproductive abnormality during intense athletic activity. A recent cross-sectionalstudy of endurance runners, who were well matched for age, body fat, weight, and training, showed significant differences in basal metabolic rate between amenorrheic and eumenorrheic runners, with the former showing a significantly higher score on scalesof restrictive eating disorders (12). The diagnosisof an eating disorder will generally be missed unless specifically searched for as there is a strong pattern of denial and a standardized scale or a diagnostic interview must be obtained. Thus more work is needed in this area as well. There are basically three types of reproductive dysfunction

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CLINICAL seen with endurance running. Delayed menarche or primary amenorrhea, secondary amenorrhea, and more subtle cycle phase abnormalities including prolonged follicular phases and abnormal luteal function which is associated with altered LH pulsatility (13) (Fig. 1). Although delayed menarche has been thought to be related to premenarcheal training, there is a considerable genetic component and a number of studies have shown that runners who develop secondary amenorrhea have a high incidence of delayed menarche even though training did not occur until well after adolescence. Those factors which led to delayed menarche, which may include genetic factors, may thus render the reproductive system vulnerable to the effects of exercise training in later life. Endurance running, which encourages a low weight with high caloric expenditure, is associated with delayed menarche. Some studies suggest that girls with this physique may MEAL

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be socialized into intense athletic training. The full blown hypoestrogenic secondary amenorrhea has been difficult, if impossible, to reproduce in the human with exercise training alone. In one study, which attempted to induce the dysfunction by endurance running in normal women, the cycle abnormalities observed were more frequent with weight loss (14) (Fig. 2). Reproductive dysfunction may occur with exercise training alone, however, but these abnormalities are usually subtle and will present as irregular cycles with prolonged follicular phases or inadequate luteal phases. The amenorrhea seen with exercise training is multifactorial and may include in its genesis low weight or weight loss, inadequate caloric intake to meet energy requirements (energy drain), stress, genetic predisposition, and hypothalamic-pituitary-ovarian susceptibility as reflected in the high incidence of delayed menarche and in nulliparous women. The weight loss is usually from a normal to underweight level with athletes who are lo-12% below ideal at greatest risk. Some individuals may remain euestrogenic whereas others progress to hypoestrogenism. Although training mileage appears to have some relationship to the amenorrhea, the correlation has been extremely variable. Acute exercise training may cause changes in hormone levels including elevations in PRL, androgens, and P-endorphins, but these changes have not been related to the menstrual dysfunction (l-5). Menstrual cycle dysfunction is very common and may present as prolonged follicular phases, anovulatory cycles, or most commonly inadequate luteal phases (Fig. 3). These disorders may be the earliest forms of reproductive dysfunction in the spectrum of abnormalities with the severe hypoestrogenic amenorrhea at the other end. These subtle abnormalities have been reproduced in the human and monkey under experimental conditions with running. Regularly ClWtROL m-I--It-

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FIG. 1. Different patterns of LH pulsatility (mean + SE) in eumenorrheic controls, eumenorrheic athletes, and amenorrheic athletes. Plasma LH concentrations were obtained every 20 min for 24 h. Adapted from Ref. 13.

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FIG. 2. Three sequential cycles in a woman who began as sedentary (control cycle) and was running nearly 10 miles/day by cycle 2. Urinary hormone concentrations show probable luteal phase shortening in cycle 1 and loss of estradiol and LH surges in cycle 2 (8).

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WARREN

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JCE & M - 1992 Vol75.No6

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3. Menstrual cycle phases in 12 consecutive cycles and daily miles run. The entire bar represents cycle length and the cross-hatched area luteal length in days. Daily mileage is shown in the line graph at the bottom (17).

FIG.

menstruating athletes may show a shortened luteal phase and anovulation. Two thirds of women training for marathons showed abnormalities with one third having anovulatory cycles and another third short luteal phase despite regular menses. Interestingly, luteal phases are shorter and progesterone levels lower even in recreational athletes (2). The clinical consequences of reproductive dysfunction in endurance running have included fractures, particularly stress fractures, osteoporosis, and infertility as well as some reversal of the beneficial change in plasma lipoprotein levels. It is generally thought that the fractures may be due to a chronic hypoestrogenism, although progesterone deficiencies associated with inadequate luteal phases has also been implicated (3). There is also evidence that reproductive dysfunction (delayed menarche, amenorrhea) may affect the immature skeleton in unusual ways. Studies in ballet dancers have suggested that delayed menarche is related to scoliosis and stress fractures (15). Scoliosis is more common in young swimmers but the incidence in runners has not been examined. Endurance running appears to be associated with an increased risk of fractures, particularly stress fractures. This may be indirectly related to the hypoestrogenism and a relative osteopenia with overuse syndromes. Runners with menstrual disorders report stress fractures more frequently. This is particularly surprising as exercise is known to improve density of bone, particularly bone stressed by weight-bearing exercise. However, amenorrheic hypoestrogenic ballet dancers do not show a normal response to the stress of overuse in the metatarsal of the foot; in fact their bone is less dense than normals (Fig. 4). This data suggests that the skeleton may be vulnerable in the hypoestrogenic adolescent and lack the normal physiological response to stress which strengthens exercised bone. These issues need to be examined in the young runner. The exact mechanism by which physical stress is translated into bone mass is unknown although may involve electrophysical effects on the osteoblast or other

nD vs aD weight adjusted

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4. Foot hone mineral densities in normal and amenorrheic subjects. Groups are divided into dancers and nondancers. Significance determined by analysis of variance. P < 0.05. St&pled bar, Mean of all values. Two-way analysis of variance shows a significant effect of amenorrhea on bone mineral density even when controlling for age but was eliminated by controlling for weight. *, Multiple comparisons show that amenorrheic dancers differ from normal dancers even when controlling for age and weight. ** , Normal dancers were higher than both amenorrheic groups when controlling for age. Interaction eliminated when controlling for age but not weight (16). FIG.

chemical and humeral (hormonal) processes. The osteoblast has recently been found to have estrogen receptors and the mechanism of bone remodeling may involve this hormone. Estrogen may act directly on a receptor to stimulate skeletal remodeling by influencing osteoblastic secretions which in turn influence extracellular matrix and mineralization. Our studies suggest that the process of translating mechanical stress into bone is hormonally dependent in premenopausal women as it does not occur normally in the absence of estrogen secretion even with normal calcium intake (16). Alternatively, the amenorrhea associated with exercise may involve nutritional factors and may not be a pure hypogonadal model as seen in the menopause. Thus, the factors which are causal in the development of the amenorrhea may be involved in the genesis of the osteopenia. Many unanswered questions remain on the pathogenesis of endurance running. Research on these factors with detailed medical and hormonal studies are needed.

References 1. Neinstein LS. 1985 Menstrual dysfunction in pathophysiologic states [Clinical Review]. West J Med. 143:476-484. 2. Prior JC. 1987 Physical exercise and the neuroendocrine control of reproduction. Ballaire’s Clin Endocrinol Metab. 1:299-317. 3. Highet R. 1989 Athletic amenorrhea: an update on aetiology, complications, and management. Sports Med. 7:82-108. 4. Keizer HA, Rogol AD. 1990 Physical exercise and menstrual cycle alterations: what are the mechanisms? Sports Med. 10:218-235. 5. DeSouza MJ, Metzger DA. 1991 Reproductive dysfunction in amenorrheic athletes and anorexic patients: a review. Med Sci Sports Exert. 23:995-1007. 6. Glass AR, Deuster PA, Kyle SB, Yahiro JA, Vigersky RA, Schoomaker EB. 1987 Amenorrhea in Olympic marathon runners. Fertil Steril. 48:740-744. 7. Sanborn CF, Albrecht BH, Wagner WW. 1987 Athletic amenorrhea: lack of association with body fat. Med Sci Sports Exert.

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CLINICAL 19:207-211. 8. Bronson FH, Manning JM. 1991 The energetic regulation of ovulation: a realistic role for body fat. Biol Reprod. 44:945-950. 9. Gadpaille WJ, Sanborn CF, Wagner WW. 1987 Athletic amenorrhea, major affective disorders, and eating disorders. Am J Psychiatry. 144:939-942. 10. Cameron JL, Nosbisch C, Helmreich DL, Parfitt DB. 1990 Reversal of exercise-induced amenorrhea in female cynololgus monkeys. Prog of the 72nd Meeting of the Endocrine Sot. 285. 11, Wilmore JH, Wambsgans KC, Brenner M, Broeder CE, Paijmans I, Volpe JA, Wilmore KM. 1992 Where energy conservation in amenorrheic compared with eumenorrheic distance runners? J Appl Physiol. 72:15-22. 12. Myerson M, Gutin B, Warren Ml’, et al. 1991 Resting metabolic rate and energy balance in amenorrheic and eumenorrheic runners. Med Sci Sports Exert. 23:15-22.

REVIEW 13. Loucks AB, Mortola JF, Girton L, Yen SSC. 1989 Alterations in the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes in athletic women. J Clin Endocrinol Metab. 68:402-411. 14. Bullen BA, Skrinar GS, Beitins IZ, von Mering G, Turnbull BA, McArthur JW. 1985 Induction of menstrual disorders by strenuous exercise in untrained women. N Engl J Med. 312:1349-1353. 15. Warren Ml’, Brooks-Gunn J, Hamilton LH, Warren LF, Hamilton WG. 1986 Scoliosis and fractures in young ballet dancers. N Engl J Med. 314:1348-1353. 16. Warren MP, Brooks-Gunn J, Fox RP, Lancelot C, Newman D, Hamilton WG. 1991 Lack of bone accretion and amenorrhea: evidence for a relative osteopenia in weight-bearing bones. J Clin Endocrinol Metab. 72:847-853. 17. Prior JC, Ho Yuen B, Clement P, Bowie L, Thomas J. 1982 Reversible luteal phase changes and infertility associated with marathon training. Lancet. 11:269-270.

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Clinical review 40: Amenorrhea in endurance runners.

00’1~972X/9’2/7506-1393SO3.00/0 Jwxnal of Clinical Endocrmology and Metabolism Copyright c 1992 by The Endocrine Society CLINICAL Amenorrhea MICHELLE...
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