Current Sports Medicine Reports:
Beyond Hypoestrogenism in Amenorrheic Athletes: Energy Deficiency As a Contributing Factor for Bone Loss
De Souza, Mary Jane PhD*; Williams, Nancy I. ScD
Address *Women's Exercise and Bone Health Laboratory, Faculty of Physical Education and Health, University of Toronto, 55 Harbord Street, Toronto, Ontario M5S 2W6, Canada. E-mail: firstname.lastname@example.org
The etiology of amenorrhea in exercising women is linked to a mismatch between caloric intake and high levels of exercise energy expenditure that results in a chronic energy deficit. This in turn stimulates compensatory mechanisms such as weight loss, metabolic hormone alterations, or energy conservation that subsequently causes a central suppression of reproductive function and concomitant hypoestrogenism. This suppression of reproductive function is associated with stress fractures, loss of bone mineral density, the failure to achieve peak bone mass, osteopenia, and osteoporosis. It has generally been accepted that the chronic hypoestrogenism is the major cause of bone loss in exercising women. However, the effects of food restriction and energy deficiency on bone mineral density likely represents an estrogen-independent mechanism for bone loss that involves some of the metabolic-related hormones altered with exercise-associated amenorrhea. These hormones (IGF-1 and leptin) play an important role in modulating bone turnover and bone mineral density in these women.
Hypothalamic amenorrhea associated with low levels of caloric intake relative to high exercise energy expenditure leads to an energy deficit and subsequent hypoestrogenism that in turn is associated with clinical sequelae that include infertility, disordered eating, stress fractures, osteoporosis, and, as recently reported, a potential increase in the risk of premature cardiovascular disease [1–6]. Among exercising women, a condition describing the interrelated problems of disordered eating, menstrual irregularities, and bone loss, has been termed the female athlete triad . An understanding of the relation between these problems is crucial to understanding the mechanism of bone loss in exercising women, as the mechanical stimulus of weight-bearing exercise in women who are not energy deficient generally has a favorable impact on bone . The prevalence of triad disorders in female athletes ranges from 1% to 66% for menstrual disorders, 2% to 66% for disordered eating, and 6% and 48% for osteoporosis and osteopenia, respectively [8••].
Understanding the mechanism for bone loss in exercising women in the face of a chronic energy deficit is confounded by plausible independent effects of hypoestrogenism and food restriction on bone. It is well known that an energy deficit, here defined as energy intake that is inadequate for exercise energy expenditure, can be a key factor in the modulation of the reproductive axis [9–12] and a cause of decreased exposure of bone to circulating estrogen. However, caloric restriction alone, in the absence of changes in estrogen, has been shown to be an important factor in bone loss [13,14]. Evidence that these factors can both impact bone in women with hypothalamic amenorrhea includes several observations that oral contraceptive use in patients with anorexia or in women with exercise-associated amenorrhea is not associated with complete recovery of bone mineral density (BMD) [15,16]. Similarly, resumption of menses in formerly amenorrheic athletes does not result in complete recovery of BMD, and BMD has been shown to further decline in amenorrheic athletes if left untreated [2,17,18]. Thus, in addition to considering the degree of hypoestrogenism as a contributor of bone loss in women with severe exercise-associated menstrual disturbances, the impact of an energy deficit is also pursued as a potential cause of diminished BMD in this article.
Definitions, and Clinical and Endocrine Presentation of Severe Menstrual Disturbances in Exercising Women
A brief discussion and definition of severe menstrual disturbances, defined as primary or secondary amenorrhea, and oligomenorrhea, in exercising women is presented to correctly identify the specific populations discussed.
Secondary amenorrhea is associated with the most extreme deficiency in estrogen, and the most severe impact on skeletal health relative to other types of menstrual disturbances [5,7]. The definition of amenorrhea in the literature has varied but should be conservatively defined as no menses for a minimum of 3 months in a woman who has previously menstruated . This conservative definition of amenorrhea is used because the literature demonstrates that the risk of bone loss is greatest early after the onset of amenorrhea .
Amenorrhea in exercising women is hypothalamic in origin, presents with severely suppressed levels of circulating gonadotropins and ovarian steroids, and unaltered responsiveness of the pituitary gland and ovaries . Reports of the prevalence of amenorrhea in athletes range from 1% to 66% , and grossly exceed estimates of this condition in sedentary women (2%–5%) . The highest prevalence of athletic amenorrhea is found in sports that emphasize a low body weight such as figure skating, ballet, long-distance running, and gymnastics, but studies have documented menstrual abnormalities in a wide variety of sports .
Primary amenorrhea (delayed menarche)
Primary amenorrhea, or delayed menarche, is defined as the failure to achieve menarche by age 16 . Primary amenorrhea has also been repeatedly reported across a wide range of athletes, but particularly in cross-country running, ballet, and gymnastics . In most adolescents, the timing of menarche is very dependent on hereditary factors. Menarche, however, can also be influenced by other sociocultural factors, including the self-selective nature of participation in some sports, such as gymnastics and ballet, in which selection occurs for specific factors such as small frame or low body weight associated with a later age of maturation. In these adolescents, the later age of menarche is not necessarily associated with an aspect of the sport itself, but rather the type of athlete that excels in that sport. .
Oligomenorrhea is defined by irregular and inconsistent menstrual cycles lasting from 36 to 90 days in length , and represents a menstrual presentation that is difficult to study due to the nature of its inconsistent characteristics. As such, no definitive data exist on the prevalence of this menstrual abnormality in athletes, except to note that cycles of irregular length are often reported in female athletes . The presence of oligomenorrhea has frequently been grouped together with amenorrhea in a number of studies evaluating BMD [23–25]. The ovarian profile of an oligomenorrheic athlete displays erratic, unpredictable, and presumably low E2production as follicles struggle to achieve dominance. Oligomenorrheic cycles may be ovulatory or anovulatory, as the definitive event is the sloughing of the endometrial lining, which can occur in response to increasing E2 levels that are independent of ovulation.
Clinical Presentation and Prevalence of Decreased Bone Mineral Density in Exercising Women with Severe Menstrual Disturbances
Severe menstrual disturbances, defined as primary or secondary amenorrhea, and oligomenorrhea, have been unequivocally associated with decreased BMD in exercising women [1–3,23–25]. Despite the well-documented beneficial effect of weight-bearing exercise on bone, reduced BMD in amenorrheic athletes has been repeatedly reported, particularly in the lumbar spine, which is composed of primarily cancellous bone [1–3,23–27]. BMD can be decreased at multiple sites when amenorrheic athletes are compared with their menstruating counterparts. Although the most severe bone loss has been associated with amenorrhea, irregular menstrual cycles or oligomenorrhea has also been associated with low BMD in athletic women, and thus these less severe menstrual disturbances should not be dismissed clinically [23–27]. One study has reported that oligomenorrheic athletes have a lumbar spine BMD that is only 69% of that observed in an aged-matched cohort of menstruating women . It is important to note that not only is BMD associated with one's current menstrual status, but also one's history of menstrual disturbances, as shown by Drinkwater et al. . The latter point illustrates the cumulative impact of decreased estrogen exposure over many years.
Adolescence represents a critical period of rapid bone accretion toward the attainment of peak bone mass [28,29]. In young adolescents, primary amenorrhea and oligomenorrhea are especially concerning because long-term consequences are likely if their attainment of peak bone mass is compromised and presumably may increase the risk of future fractures from postmenopausal osteoporosis [5,27,30].
Decreased BMD in athletes is associated with an increased risk of stress fractures, nontraumatic fracture, fractures of the hip and spine, and an increased risk of associated injuries [5,31–33]. Specifically, studies of BMD in amenorrheic athletes show values equivalent to that observed in postmenopausal women, and likely accounts for the high rate of stress fractures observed in these young women [5,31–33]. Fracture risk, however, has not been clearly established in relation to BMD in this population. Other significant findings regarding BMD and amenorrhea are that the duration of amenorrhea is inversely related to BMD, and the risk of bone loss is greatest early after the onset of amenorrhea , underscoring the importance of effective and early intervention strategies. Especially in young adolescent athletes, clinicians are well advised to encourage nutritional intervention as soon as the problem is identified. As shown in Figure 1, the low BMD experienced by amenorrheic athletes is likely irreversible because resumption of menses offers very minimal improvements in BMD, permanently compromising the attainment of peak BMD in young athletes [2,17,18]. Even the administration of oral contraceptives and other hormonal replacement strategies fail to significantly improve BMD in amenorrheic athletes [15,34,35]. For example, Keen and Drinkwater  determined that after 6 to 10 years of normal menses or oral contraceptive therapy, lumbar spine BMD remained only 85% of that in athletes who had a history of regular menses. Thus, factors other than hypoestrogenism alone likely account for the diminished BMD in athletes with severe menstrual disturbances.
In athletes, bone loss more frequently meets the clinical criterion of osteopenia, not osteoporosis . Osteopenia is clinically defined as a T-score at any region of interest which is 1 to 2.5 standard deviations (-1.0 to -2.5) below the mean of that observed in young adults . Osteoporosis is clinically defined as a T-score in any region that is more than 2.5 standard deviations below the mean achieved in young adults. Where osteopenia is associated with a 100% increase in the risk of fracture in postmenopausal women osteoporosis represents an even greater risk of fractures . The prevalence of osteopenia in amenorrheic athletes is estimated to range from 1.4% to 50% [1,5,23–27]. The prevalence of osteoporosis is lower [23,38].
The International Society of Clinical Densitometry (ISCD) has recently recommended the use of a different set of clinical criteria that may be more appropriate in premenopausal women [39,40]. Specifically, they recommend the use of a Z-score, rather than a T-score, which represents comparison with aged-matched peers, in conjunction with secondary risk factors should be used [39,40]. These secondary risk factors include glucocorticoid therapy, hypogonadism, hyperparathyroidism, or an increased risk for fracture. The recommendation clearly states that BMD alone should not be used to define a diagnosis of osteoporosis in premenopausal women. Of significance, the ISCD has noted that all premenopausal women with low BMD should be evaluated for clinical and subclinical ovulatory disturbances.
Relationship of Bone Mineral Density to Hypoestrogenism and Energy Deficit
The following section addresses the interrelationships between energy deficit and the physiologic consequences of hypoestrogenism on the skeletal system.
Etiology of exercise-associated amenorrhea
During times of a chronic energy deficit, a shift in metabolic fuels occurs that repartitions energy away from the costly processes of reproduction and toward the essential processes of cellular, locomotive, and other life-sustaining metabolic functions . With respect to exercising women, eloquent short-term experiments by Loucks et al.  and Loucks and Thuma  manipulating both dietary intake and energy expenditure have demonstrated a relationship between energy status and luteinizing hormone (LH) pulsatility. Support for a causal relationship between energy status and menstrual cyclicity was provided by Williams et al. [11,12] who demonstrated that amenorrhea in exercising monkeys could be reversed by increasing food intake without any moderation in daily exercise training volume. Resumption of ovulation in the amenorrheic monkeys exhibited a dose-response relationship with energy availability, such that monkeys that ate more calories recovered ovulatory function more quickly than the monkeys that ate fewer calories. The additional observation in this study that changes in circulating total T3 was correlated with both the induction and reversal of amenorrhea lends support to the idea that the suppression of reproductive function is linked with adaptive mechanisms to reduce energy expenditure [11,12] in the face of inadequate caloric intake. Additional evidence for the relationship between energy availability and exercise-associated menstrual disturbances is found in cross-sectional studies of metabolic hormones and substrates that illustrate adaptive changes similar to that observed during episodes of chronic undernutrition [42–44]. These studies in amenorrheic athletes, combined with studies exposing metabolic endocrine signs of an energy deficit in exercising women with subtle menstrual disturbances such as luteal phase defects and anovulation  provide strong evidence that a hypometabolic state exists commensurate with exercise-associated menstrual disturbances. This hypometabolic state includes reductions in resting metabolic rate, total T3, leptin, insulin, glucose, IGF-1, and IGFBP-3 and elevations in IGFBP-1, ghrelin, growth hormone, and cortisol [42–44]. Changes in some of these metabolic hormones are documented to play a role in altered bone turnover that can contribute to bone loss, particularly a decrease in IGF-1 and leptin [46••].
Caloric restriction, weight loss, and skeletal health
Crash dieting, weight cycling, and disordered eating, including cognitive dietary restraint, are known to result in clinical sequelae, including menstrual cycle disturbances, decreased bone mass and fractures, and increased risk of osteoporosis [13,23,47–49]. Further, weight loss, calorie restriction, and restrained eating have all been associated with bone loss in humans [13,23,47–51]. In humans, a 10% decrease in body weight has been shown to result in a 1% to 2% loss in BMD [50,51]. This risk is exacerbated in low weight women. A significant percentage of premenopausal women, especially exercising women, utilize food restriction and exercise in their attempts to lose weight.
Beyond hypoestrogenism: bone loss in exercising women with an energy deficiency
Despite the known association between caloric restriction, weight loss, and skeletal health, it has generally been accepted that chronic hypoestrogenism is the major cause of bone loss in exercising women . During episodes of hypoestrogenism, osteoclasts are activated by circulating cytokines, thus promoting increased bone resorption . The physiologic evidence for the role of estrogen in bone mineralization has been reviewed elsewhere . Indeed, estrogen plays an important role in promoting bone mass in adolescents and young adults and in maintaining bone mass in adult women.
The effects of caloric restriction on BMD may be mediated by endocrine factors that may include an estrogen-dependent pathway, but may also include an estrogen-independent pathway that involves some of the metabolic-related hormones that are altered in exercising women with severe menstrual disturbances and that impact bone turnover. Because an energy deficit is a key factor in the modulation of the reproductive axis [9–12], our knowledge of the mechanism for bone loss with a chronic energy deficit is confounded by plausible independent roles of hypoestrogenism and caloric restriction on bone. Evidence that these factors can both impact bone includes several observations that oral contraceptive use in hypothalamic amenorrhea associated with anorexia, exercise or other functional hypothalamic causes is not associated with complete BMD recovery [15,16,18]. Similarly, recovery of menses in formerly amenorrheic athletes does not result in complete recovery of BMD and BMD has been shown to further decline in amenorrheic athletes if left untreated [3,17,18]. Other evidence in support of this concept is that eumenorrheic athletes are in some instances, reported to also display decreased BMD. Cobb et al.  observed osteopenia in 26% of regularly menstruating exercising women who met criteria for subclinical disordered eating, perhaps secondary to some degree of energy deficit-induced metabolic endocrine changes. Previous investigators concluding that hypoestrogenism contributes substantially to bone loss in premenopausal women most likely neglected to consider the potential for an additional and independent impact of calorie restriction on bone.
The effects of caloric restriction may independently affect bone through energy deficit-induced decreases in bone trophic factors, such as IGF-1 and leptin, or through micronutrient deficiencies of calcium, for example [14,46••,53–55]. Recent studies have utilized biochemical markers of bone turnover to assess the effects of an energy deficit on bone in exercising women with severe menstrual disturbances. Unlike the mechanism of bone loss in postmenopausal women, Zanker and Swaine  have shown that markers of bone formation (N-terminal pro-peptide of type 1 collagen [P1NP]) are suppressed in amenorrheic athletes, whereas markers of bone resorption (deoxypyridinoline [DPD]) are unchanged. Thus, unlike the postmenopausal, estrogen-deficient woman who exhibits increased bone resorption, the amenorrheic athlete does not. Figure 2 demonstrates the proposed mechanism of bone loss in amenorrheic athletes. Zanker and Swaine  also demonstrated that the lowest levels of the bone formation markers were observed in the amenorrheic athletes with the lowest total T3 and IGF-1. In the literature on anorexia, an energy-deficit model somewhat similar to amenorrheic athletes, but likely more severe, has demonstrated interesting observations that also support an energy-deficit–induced mechanism of bone loss [56,57]. Again unlike the amenorrheic athlete, patients with anorexia nervosa have both suppressed bone formation markers, but also increased bone resorption markers with a similar metabolic endocrine profile of amenorrheic athletes, but of greater magnitude of changes. During refeeding, recovering anorexic women exhibit a rapid increase in bone formation, followed by a more gradual decrease in bone resorption. Given the recent data published by Ihle and Loucks [58••], this is likely attributable to the estrogen deficiency requiring a longer intervention period of nutritional recovery for bone resorption to decrease, whereas early in the initial stages of refeeding, some of the metabolic endocrine disturbances are normalized.
Recently, Ihle and Loucks [58••] have eloquently demonstrated an intriguing relationship between varying levels of an energy deficit and markers of bone turnover in exercising women that significantly help to clarify the aforementioned relationships. A dose-response relationship between bone markers and reproductive and metabolic hormones was observed, such that at moderate volumes of energy restriction, markers of bone formation (osteocalcin, and C-terminal pro-peptide of type 1 collagen were suppressed, whereas severe volumes of energy restriction were required before bone resorption (N-terminal telopeptide) was increased. The increase in bone resorption was not observed, however, until a severe degree of energy restriction was imposed and was associated with a suppression of serum estrogen by 18% [58••]. The markers of bone formation, on the other hand, were decreased in a manner very similar to that observed for several metabolic hormones, including T3, insulin, and IGF-1, in conditions of a moderate degree of energy restriction [58••]. Figure 3 depicts these relationships. These data demonstrate a plausible estrogen-independent pathway whereby bone turnover, and specifically bone formation, is suppressed, and thus may contribute to decreased BMD in athletes experiencing a chronic energy deficiency. These findings may explain why reductions in BMD might be expected in eumenorrheic women with subtle and less severe menstrual disturbances secondary to an energy deficit, with or without weight loss, who also have slight metabolic hormone alterations indicative of a moderate energy deficit, but do not have severe reductions in estrogen.
Energy deficiency in female athletes and active women can give rise to hypoestrogenism and is associated with skeletal demineralization. Severe menstrual disturbances are a serious medical condition that signals concern for premature bone loss or the failure to achieve peak bone mass. The etiology of menstrual disturbances is causally linked to an energy deficit with a characteristic hypometabolic profile that includes alterations in bone trophic factors that may contribute to bone loss. Thus far, definitive experiments in exercising women with menstrual disturbances tease out the differential effects of hypoestrogenism and energy deficiency have not been conducted. However, studies revealing differences in the balance between bone formation and bone resorption in models of postmenopausal women who are hypoestrogenic but presumably not energy deficient and amenorrheic athletes who are both hypoestrogenic and energy deficient point to the plausible addition of energy deficiency to the mechanism of bone loss in these women. In addition, studies reporting otherwise unexplained compromised bone density in exercising women with normal menstrual cyclicity lend support to this idea. Expanding our understanding of the role of energy deficiency in bone loss associated with menstrual disturbances is important for designing optimal strategies for prevention and reversal of bone loss in exercising women, since a stronger emphasis on adequate nutrition, regardless of menstrual status, would be appropriate.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance, •• Of major importance
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© 2005 American College of Sports Medicine