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Exercise-Associated Amenorrhea

Are Altered Leptin Levels an Early Warning Sign?

Michelle P. Warren, MD
Russalind H. Ramos, MD
Emily M. Bronson

THE PHYSICIAN AND SPORTSMEDICINE - VOL 30 - NO. 10 - OCTOBER 2002


In Brief: Although the exact cause of the female athlete triad (amenorrhea, disordered eating, and osteoporosis) is unknown, recent research implicates leptin, a hormone that is secreted by adipocytes. Leptin may be an important indicator of nutritional status and may also play a role in reproductive function. Physicians who develop a plan for early recognition and treatment of exercise-induced amenorrhea now may prevent the more serious consequences of osteopenia and osteoporosis later.

Women who have exercise-associated amenorrhea are at tremendous risk for developing decreased bone mineral density, bone weakness, and osteoporosis later in life.1,2 Amenorrhea occurring in conjunction with disordered eating and osteoporosis is recognized as the "female athlete triad."3 Because the female athlete triad can decrease physical performance and cause morbidity and mortality, physically active adolescent girls and women who have amenorrhea should be screened for eating disorders and osteopenia.

Defining the Terms

Amenorrhea is the absence or abnormal cessation of menstrual periods and can be classified as primary or secondary. Primary amenorrhea is diagnosed if menstrual bleeding has never occurred by age 14 and the patient has no secondary sex characteristics, or age 16 if secondary sex characteristics are present. Secondary amenorrhea is the absence of menstruation for 3 months if previous menses were regular, or 6 months if previous menses were irregular.4

Oligomenorrhea refers to menses at intervals of 35 days to 6 months. Failure to differentiate between amenorrhea and oligomenorrhea among study subjects has led to confusion in the literature when menstrual dysfunction was not distinguished from other conditions (eg, polycystic ovarian disease) and has been erroneously included in the studies. This review specifically addresses secondary amenorrhea with hypoestrogenemia. Oligomenorrhea and inadequate luteal phases that stem from excessive exercise are beyond the scope of this article.

Those at Risk

The prevalence of exercise-associated menstrual cycle disturbances, such as amenorrhea and oligomenorrhea, varies among athletes (table 1).5-12 Depending on the level of competition and type of athletic discipline, menstrual cycle disturbances occur more commonly among ballet dancers, marathon runners, gymnasts, and figure skaters.

  TABLE 1. Surveys of Prevalence of Amenorrhea and Oligomenorrhea
in Selected Sports


  
ACTIVITY STUDY    NUMBER PERCENT

General Population (Control)
Pettersson et al51,8621.8
Singh69005.0

Weight-Bearing Sports
BalletAbraham et al72979.0
Brooks-Gunn et al85359.0
Feicht et al91286.0-43.0
Glass et al106734.0
 
RunningShangold and Levine1139424.0
Sanborn et al1223726.0

Non-Weight-Bearing Sports
CyclingSanborn et al123312.0
SwimmingSanborn et al1219712.0
 

Many of these women demonstrate patterns of weight loss and dieting behavior. They appear to focus on total calorie and fat intake and, although not severely underweight, they typically have low body mass indices and low percentages of total body fat.13 These individuals also demonstrate diminished production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), probably because of nutritional and metabolic stresses that affect the hypothalamic area that controls the release of pituitary gonadotropins.14

Hidden Origins

Although the exact cause of amenorrhea is unknown, it is widely accepted that the mechanism lies at the hypothalamic level. The normal pulsatile secretion of gonadotropin-releasing hormone (GnRH) originates from the median eminence of the hypothalamus and occurs approximately every 60 to 90 minutes. In amenorrhea, the pulses are completely or partially suppressed. Various GnRH secretion abnormalities are reported, including decreased frequency and amplitude of pulses, sporadic pulses, or an immature pattern seen in puberty (ie, nocturnal entrainment of LH pulses).

The typical diurnal pattern of leptin concentrations found in the normal menstrual cycle is absent in amenorrheic athletes. The relationship between leptin and the integrity of the reproductive axis does not seem to be related to leptin levels per se; rather, it is the absence of a diurnal rhythm that identifies the arrested cyclic reproductive axis (ie, amenorrhea).15

Recent reports suggest, however, that this diurnal rhythm is mediated by food and is eliminated when feeding does not occur.15 In this sense, nutritional deficiencies may lead directly to changes in leptin regulation.

Excessive exercise may not be the sole cause of disrupted diurnal patterns. Marginal energy intake coupled with high energy expenditure may result in neuroendocrine adaptations to an overall metabolic deficit. For instance, studies14,16 have shown that low LH secretion can be reproduced in normally cycling women with energy deprivation and exercise, but exercise alone does not affect LH secretion.

Other potentially important factors in the pathogenesis of exercise-associated menstrual cycle disturbances include young gynecologic age,17 emotional or psychological stress,18 rapid increase in exercise load,19 low body weight,19 and eating disorders.8

The Many Roles of Leptin

Recent research on the role of leptin20-24 has led to a better understanding of GnRH suppression in exercise-associated amenorrhea. Leptin, a protein product of the obesity (OB) gene, is a circulating hormone synthesized by white adipose tissue and has potent effects on feeding behavior, thermogenesis, and neuroendocrine responses.20 Leptin may be an important indicator of nutritional status and may also mediate reproductive function by responding to an altered metabolic state that is characteristic of individuals who have exercise-associated amenorrhea.

Metabolism. Leptin appears to be regulated by total energy intake and fat stores and correlates with body mass index in humans.22,23 Leptin also regulates the basal metabolic rate and is lowered disproportionately during fasting.23 As a starvation and adiposity signal, leptin binds to the long form of its receptor, localized primarily in the hypothalamus.20,21

Leptin levels may be an especially important indicator of nutritional status. Although amenorrheic subjects in one study25 denied eating disorders, their leptin levels revealed hidden nutritional abnormalities. Results of a screening questionnaire (EAT-26)26 indicated that these subjects had twice the rate of disordered eating behavior and six times the rate bulimic behavior as matched controls. This evidence of chronic disordered eating may explain the abnormal leptin patterns and suppression of GnRH signaling seen in normal weight subjects who have hypothalamic amenorrhea. It also suggests that altered leptin secretion could be an underlying mechanism of hypothalamic amenorrhea.

Consistent observations between normal-weight amenorrheic subjects and undernourished amenorrheic subjects led to further consideration of leptin in the pathogenesis of hypothalamic amenorrhea.15,25,27 Even after patients who have hypothalamic amenorrhea return to normal body weight, alterations in leptin levels are still present.25 Abnormally low levels of leptin are caused primarily by restrictive eating patterns or other subclinical nutritional disturbances such as hypothalamic amenorrhea without obvious caloric deficits.27

The potential mechanism by which leptin links the metabolic and reproductive axes remains unknown. Ahima et al24 proposed that leptin is the signal that informs the brain that energy stores are sufficient to support the high energy demands of reproduction, and leptin may be the major determinant in the timing of puberty.

Neuroendocrine function. In addition to its metabolic function, leptin seems to affect neuroendocrine functions, including the hypothalamic-pituitary-gonadal axis.24 Leptin could significantly mediate reproductive function by responding to the negative energy balance that is characteristic of exercise-associated amenorrhea. Specific signals may communicate low metabolic rates (typical of amenorrheic athletes) to the reproductive axis, possibly via leptin, that influence menstrual cycle disturbances.

Low leptin levels have been reported in amenorrheic women who exercise regularly at high levels.15 One of leptin's major roles is to help the body adjust to energy deprivation via neuroendocrine changes that lead to the cessation of menses. Menstruation does not appear to occur at leptin levels below 1.85 mg/L, although individuals vary considerably.28,29

Animal studies30-34 demonstrate the role of leptin as a metabolic signal to the reproductive axis. Animals that are either leptin deficient (ob/ob mice) or have defective leptin receptors (db/db mice and fa/fa rats) are polyphagic, obese, and infertile.30,31 Exogenous leptin stimulates the reproductive system in ob/ob mice31 and counteracts the inhibitory effects of fasting on gonadotropin secretion in both rats and mice.24,33 Leptin administration also restores GnRH pulses in primates deprived of food.34

Thyroid function. Leptin alterations appear to be directly associated with thyroid hormone changes in the presence of nutritional deficiencies.25 Additional support for the role of leptin in the suppression of GnRH secretion is found in its association with thyroid function and the initiation of puberty. Reports of leptin mutations in humans who show lack of pubertal development and suppression of thyroid-stimulating hormone also support this idea.35 Studies in rats36,37 demonstrate that leptin may regulate adaptation to starvation via prothyrotropin-releasing hormone gene expression at the hypothalamic-pituitary-thyroid axis.

Furthermore, leptin may play a primary role in enabling the body to respond to starvation by shutting down reproduction and returning to a prepubertal state.22 Researchers point to the disproportionate suppression of LH as compared with FSH in patients who have hypothalamic amenorrhea, resembling patterns seen in prepuberty.19 The cause of these patterns is not fully understood.

Hormones and Bone Formation

One of the most disastrous consequences of hypothalamic amenorrhea is the compromise of bone mineral density that leads to osteopenia or, more severely, osteoporosis. Physical activity is important in maintaining bone mass; however, many women tend to exercise excessively, causing hormonal changes that predispose them to a loss of bone mass and an increased risk of fractures.

Previously accepted notions about the primary cause of bone loss in women who have hypothalamic amenorrhea have shifted.38 Researchers traditionally attributed bone loss to estrogen deficiency in women who have hypothalamic amenorrhea and in postmenopausal women. We now understand that undernutrition and its metabolic consequences appear to directly reduce bone turnover39 and, more important, bone formation,40 thereby causing osteopenia. Several other hormones are implicated in the bone remodeling process.

Leptin. A central mechanism involving leptin in the regulation of bone formation was found in mutant mice that lacked circulating leptin.41 Intracerebroventricular infusion of leptin completely rescued their bone phenotype and demonstrated that the hypothalamus may be the central regulator of bone formation and bone remodeling. This regulatory loop is especially significant because diseases of bone remodeling, such as osteopenia and osteoporosis, may also be centrally regulated.41

Moreover, patients who have generalized lipodystrophy (characterized by a nearly complete absence of adipocytes and white fat) exhibit osteosclerosis and accelerated bone growth.42 The role of leptin in bone formation may provide clues about why obese individuals, who often manifest leptin resistance, are protected from bone loss.41,43 Leptin may be a physiologic regulator of bone mass and thus may be an important link between amenorrhea and osteopenia.

Thyroid hormones. The active form of thyroid hormone (triiodothyronine) has been recognized as a potent stimulator of bone turnover,44 and both nutritional status and changes in thyroid metabolism may have a role in the pathogenesis of osteopenia. Thyroid metabolism and nutrition may be important links to the GnRH pulse generator, possibly by a leptin pathway.

Insulin-like growth factor 1 (IGF-1). Recent data suggest that IGF-1, an osteotrophic hormone dependent on nutritional status, is a critical endocrine and paracrine factor in the regulation of bone formation-stimulating osteoblast function and collagen formation.40,45 In a recent study,40 IGF-1 levels were significantly reduced in young women with anorexia nervosa. Short-term administration of recombinant human IGF-1 increases markers of bone turnover in severely osteopenic women who have anorexia nervosa.45 Because it appears to be directly linked to subnormal IGF-1 levels, undernutrition may be a major contributor to the pathogenesis of osteopenia in anorexia nervosa and potentially all forms of hypothalamic amenorrhea, including exercise-associated amenorrhea.

Dehydroepiandrosterone (DHEA). This adrenal steroid plays a role in the stimulation of human osteoblastic cell proliferation through the androgen receptor with alkaline phosphatase production mediated by transforming growth factor-beta.46 Subnormal levels of DHEA have been seen in patients who have anorexia nervosa and may be linked to low bone density.47 Adrenocorticotropic hormone stimulation tests administered to women who had anorexia nervosa increased cortisol and decreased DHEA production.48,49 This finding suggests decreased adrenal 17,20-lyase activity and a more predominant glucocorticoid than androgenic pathway.

A recent study47 on the effects of short-term supplementation of DHEA on bone turnover markers among young patients who had anorexia nervosa suggested that DHEA may both decrease bone resorption and increase bone formation markers. In the same study, IGF-1 levels increased to a physiologic range that strongly correlated with elevation in levels of bone formation markers (eg, bone alkaline phosphatase and osteocalcin).

These recent developments could redirect the focus of treatment toward correcting metabolic abnormalities and androgen deficiencies that affect bone formation and, thereby, decrease the risk of osteopenia and osteoporosis.

Clinical Presentation

Women with prolonged exercise-associated menstrual cycle disturbances report irregular or absent periods. These patients are usually near or below ideal body weight and participate in sports that have some advantage to low weight, such as distance running, gymnastics, figure skating, or ballet. Many of these patients manifest disordered eating patterns and obsessive avoidance of high-calorie or high-fat foods.

Physical examination is usually normal, although hypoestrogenemia with vaginal atrophy may be present on pelvic exam. Laboratory tests reveal low gonadotropin levels with disproportionately lowered concentrations of LH. Thyroid tests are usually normal. Osteopenia or osteoporosis may be found on a bone density scan if the problem is prolonged, although in some sports, such as gymnastics, bone density is preserved despite the presence of amenorrhea. Athletes also have a high risk of stress fractures, and data from ballet dancers show that abnormal eating patterns are highly prevalent in dancers who have fractures (figure 1).50

Responsive Treatment

Until the mechanisms are more clearly understood, treatment aims to improve diet, maintain a positive energy balance, enhance weight gain, and perhaps decrease the level of exercise. If nonpharmacologic measures are not successful, hormone replacement may be used as a last resort; however, its use is controversial. Patients also need education about the risk of developing osteopenia and osteoporosis. By understanding more about the role of leptin, we are further able to modify intervention to prevent osteopenia and osteoporosis.

Decreasing the level of exercise is often difficult, especially among highly competitive athletes. Exercise load, diet (including calcium intake), and fluctuations in weight should all be discussed with the patient. Competitive athletes who may have little sun exposure and poor diets should be advised to supplement their vitamin D intake. Often these patients are resistant to changing restrictive eating patterns; therefore, nutritional and/or psychiatric counseling may be necessary. Weight gain is particularly important in managing these patients.

If no weight gain occurs in 3 months, a patient may be given progesterone to see if she will have menstrual bleeding on withdrawal. The patient may not respond to a progesterone challenge if she is hypoestrogenemic, although some patients, particularly as they near recovery, will experience menses. If the patient does not experience menses when progesterone is withdrawn, oral contraceptives may be used as a last resort, but this use is controversial.

In addition, patients should have a bone density measurement. We are not convinced that oral contraceptives are helpful, but one randomized trial51 showed benefit for bone density among women who had hypothalamic amenorrhea. A controlled trial52 documented a significant increase in spinal bone density among active women with menstrual cycle disturbances who were treated with cyclic medroxyprogesterone acetate, although another study51 noted a lack of effect. Although estrogen therapy and weight gain may not fully restore bone mineral density in patients recovering from hypothalamic amenorrhea, bone mass can likely be preserved with restoration of menses.

Patients who have primary amenorrhea need to be carefully monitored. After ruling out other causes, clinicians should determine if a growth spurt occurred without weight gain. This commonly occurs among certain athletes (eg, gymnasts, swimmers, figure skaters, and ballet dancers) and constitutes a relative weight loss. Bone age should be measured with a radiograph of the wrist, and oral contraceptives or hormone replacement should only be used when growth is complete or adequate. Otherwise, therapeutic modalities are the same.

Unraveling New Mysteries

Our current, preliminary understanding of the roles that leptin plays in metabolism and neuroendocrine regulation is mainly derived from animal studies. Although studies of the association between leptin levels and various disease states in humans exist, future studies should evaluate the direct effect of leptin in humans. As only future protocols can explore, leptin may have far greater roles than have been realized.

References

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Dr Warren is an endocrinologist and a professor of obstetrics and gynecology, Dr Ramos is an associate researcher, and Ms Bronson is a research associate in the Center for Menopause, Hormonal Disorders, and Women's Health at Columbia-Presbyterian Medical Center in New York City. Address correspondence to Michelle P. Warren, MD, Columbia University, PH 16-20, 622 W 168th St, New York, NY 10032; email to [email protected].

Disclosure information: Dr Warren is a Wyeth-Ayerst Professor of Woman's Health. Dr Ramos and Ms Bronson disclose no significant relationship with any manufacturer of any commercial product mentioned in this article. No drug is mentioned in this article for an unlabeled use.


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