Word count: 2845



Word count: 2845

Amenorrhea: Influence of Endogenous Opioids

Mack T. Ruffin IV

Department of Family Practice

University of Michigan Medical School

Ann Arbor, Michigan 48109-0708

USA

The first reports of the effect of exercise on women did not document evidence of significant menstrual dysfunction. It was not until the late 1970s and early 1980s, reports of exercise-induced amenorrhea began to appear. Subsequent studies have shown that 3 to 80% of exercising women experience amenorrhea or menstrual irregularities, compared to 5% of nonexercising women. The wide range reflects the variety of research methodologies used and the definition of secondary amenorrhea considered. Today, exercise-induced amenorrhea is a health problem with significant sequelae for all physically active women.

Numerous theories have been developed to explain the relationship between exercise and amenorrhea, but each theory lacks a unique association to exercise. Subsets of women with normal menstrual function can be found who have similar characteristics to amenorrheic athletes, such as diet, body composition, levels of stress and reproductive maturity. The uniqueness of amenorrheic athletes appears to be the intense level of exercise or physical activity. A scientifically sound explanation for exercise-induced amenorrhea linking the physiologic changes of exercise to the resulting amenorrhea has not been clearly established. The association appears multifactorial, but the influence of endogenous opioids may hold the key to establishing a sound explanation of the relationship between exercise and the others factors which result in amenorrhea. This chapter focuses on the relationship of endogenous opioids to exercise-induced amenorrhea.

Endogenous Opioids: Historical Aspects

Endogenous opioids were first described in 1975 and can now be divided into three types: encephalon, endorphin, and dynorphin. Initially the endogenous opioids were studied in relation to pain sensation and management; later research examined their association to stress. Recent evidence suggests that the endogenous opioids are linked to appetite, thermoregulation, lipolysis, and reproduction. Many of these functions are associated with endurance exercise suggesting a possible relationship between exercise and the level of endogenous opioids via multiple stimuli.

The secretion of endorphin is linked with the secretion of anterior pituitary hormones [prolactin, growth hormone, corticotrophin (adrenocorticotrophic hormone or ACTH)]. Both ACTH and endorphin are synthesized in the pituitary from a common precursor, pro-opiocortin. B-Lipotropic hormone, the immediate precursor to endorphins, is secreted in response to the same stimuli as ACTH and endorphin. Therefore, ACTH, as well as growth hormone and prolactin, need to be observed in concert with B-endorphin and B-lipotropic hormone in evaluating the response to exercise. The mechanism for stimulating secretion of endorphin or other hormones during periods of stress or exercise is still unanswered.

Physiology of Menstruation and the Relationship of Opioids

In the normal menstrual cycle, gonadotrophin-releasing hormone (GnRH) is secreted by the hypothalamus in pulses lasting several minutes that occur every one to three hours. The frequency of pulsations of the secretions of GnRH are fast in early in the menstrual cycle when there is a low estrogen environment in the body. This results in the stimulation of the pituitary to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in a rapid pulsatile manner. FSH stimulates ovarian follicular growth and maturation and the synthesis of estrogen by the follicles. As the estrogen level increases, FSH secretion is inhibited and LH surge is facilitated, resulting in ovulation.

Following the LH surge, the corpus luteum then secretes progesterone which appears to down regulate GnRH pulse frequency and slow LH pulse frequency during the normal luteal phase or later stages of the menstrual cycle. The feedback appears to be coupled to endogenous opiate pathways at the level of the hypothalamic pulse generator for GnRH located in the mediobasal hypothalamus. If fertilization does not occur, the corpus luteum involutes and progesterone levels fall. The resulting low estrogen environment causes fast pulsatile secretion of GnRH, FSH, and LH leading to the next menstrual cycle.

Hypothalamic dysfunction appears to be the central abnormality found in women with exercise-related menstrual abnormalities. Several studies have demonstrated low LH, FSH and estradiol levels with normal to increased pituitary and ovarian responses to exogenous GnRH in amenorrheic athletes.(2,10) Some female athletes have been found to maintain a slow LH pulse frequency that is independent of progesterone.(9) In addition, slow LH pulse frequency has been found in amenorrheic athletes(17) and acute exercise has an inhibitory effect on LH pulsatile release at the hypothalamic level in eumenorrheic (women with normal menstrual cycles) runners.(6,7) Thus the change in LH pulse frequency appears to represent an effect of exercise rather than amenorrheic state.

Several studies have shown that an elevation of endogenous opioids will suppress the pulsation of LH and FSH, resulting in amenorrhea. For example, Stubbs et al.(15) showed that the intravenous infusion of encephalon analog leads to a 100-fold increases in serum levels, and significantly reduces LH and FSH levels. Wardlaw et al.(19) demonstrated that ovarian steroids regulate the production of hypothalamic endorphins and their release into hypophysical portal blood monkeys. However, Sforzo et al.(14) showed that endurance exercise increases peripheral B-endorphin levels with no probable supraspinal action in the rat brain, but did alter opioid receptors in the brain. This raised the important issue of relying on peripheral blood measurements of hormones and opioids to determine action in the brain. Overall conclusions about the association between peripheral changes in opioids and central endocrine function have not been resolved in animals or humans.

Naloxone (an opioid antagonist) has been shown to lead to stimulation of LH release during midfollicular and luteal phases of the menstrual cycle and the blunting of endogenous opioid effects in animals(16,20) and humans.(11,12) In patients with amenorrhea-galactorrhea, naloxone was found to induce LH responses that were abnormal to the patients' endocrine state.(3) In addition, naloxone infusions in women using oral contraceptives produce changes in serum LH and prolactin levels consistent with continuous hypothalamic elevations of opioids.(5)

Other studies(11,18) have shown the presence of cyclic variation of plasma B-endorphin in healthy subjects, indicating a possible role in the neurochemical mechanisms of gonadotrophin release. The cyclic levels of B-endorphin are constant during follicular and luteal phase, with increases in the preovulatory period. Petraglia et al.(11) found this preovulatory increases absent in anovulatory women and present in the same women when ovulation was induced. Finally, studies have shown that hirsute women(8) and women with polycystic ovarian disease(1) have higher B-endorphin levels which correlate with the degree of obesity above ideal body weight.

In summary, these studies suggest that endogenous opioids are involved in the regulation and control of the menstrual cycle. Many of the details of this regulation still remain to be determined.

Endogenous Opioids: Relationship to Exercise

The association of exercise with changes in the endogenous opioid levels has been reviewed in several studies (for review(13)). Exercise produces a 2- to 5-fold rise in endorphins levels. The extent of increase in beta-endorphins is directly related to the degree of anaerobic activity and the degree of lactate concentration. Women who regularly exercise have a higher baseline level of endorphins compared to women not engaged in regular exercise. Opioids play some hemodynamic role during exercise in the heat, it appears that opioid mediated reduction in the perceived stress of exercise is through an increase in the individual's thermal tolerance. The acute mood changes associated with various forms of physical activity appear to be mediated through endogenous opioid changes.

Animal data has found that acute exercise activates the opioid system mainly through the increased release of beta-endorphin. With daily exercise, the production of beta-endorphin increases and exceeds the elevated release in the hypophysis and adrenals. However, studies on rats have found that exercise-induced enhancement of peripheral beta-endorphin probably does not have a supraspinal action. Thus, the peripheral changes noted in humans may not effect the central nervous system. In fact, encephalins poorly penetrate the blood-brain barrier and beta-endorphin is rapidly degraded after entry into the brain or cerebrospinal fluid. There are, however, several alternative routes for peripheral opioids to act on the central nervous system. These routes include action on vascular receptors, release of second messengers to affect the brain, or mediation of seemingly central nervous effects via peripheral mechanisms.

Several studies have evaluated the response on endogenous opioids in women who exercise, as well as the possible association of exercise to menstrual dysfunction. Before evaluating the outcomes of these studies or others to come, the study participant selection criteria, level of training, amount of exercise, method of measuring the exercise, and measurement techniques for the hormones must be critically evaluated.

The studies to this point involve limited numbers of women and thus firm conclusions may be premature. However, these preliminary studies do demonstrate increased endorphin and lipotropic hormone production in response to exercise, which can lead to suppression of LH and FSH pulsations.

The study participants are the key to all of the studies and the interpretation of the outcomes. In studies of menstrual function, exercise, and endogenous opioids, women need to be grouped according to level of activity, menstrual function, duration of present level of activity, and previous menstrual function (e.g. pregnancy, estrogen uses, menstrual irregularities), with objectives measures used to define each group. Of the current studies, the general trend is to describe in subjective terms the participants' menstrual characteristics. Only Bullen et al.(4) uses an objective measure in classifying menstrual cycle by determining presence of ovulation by confirmed diphasic temperature patterns and luteal phase plasma progesterone concentrations above 5 ug.L-1. This type of objective assessment should be the standard to avoid misclassification of participants or nonhomogenous groups with respect to menstrual function.

The level of training of participants prior to study has been described in most studies, but only general terms were used (athlete, sedentary). The use of such general classification reduces the studies' specificity.

The level of exercise used to evaluate the acute response of endogenous opioids has been measured by graded exercise test, running events, bicycle ergometer test or at rest. Of these four tests, the graded exercise and bicycle ergometer tests were the most controlled and provide the most reliable and valid results. Further studies must adhere to this type of documented level of activity within a controlled environment.

It is extremely difficult to measure serum hormones or endogenous opioids, while maintaining validity and reliability. All the hormones being followed can be influenced by many factors that can affect the accuracy of the measurement. In addition, the measurement of opioid peptides involves the use of complex bioassays or radioimmunoassay (RIA) technique. RIA involves the use of specific antiserum for the opioid of interest as well as other hormones. The technique has excellent reliability and validity if strict adherence to protocol for procedure is maintained. In addition, the calculations must consider cross reactivity between B-lipotrophin and B-endorphin by knowing percentage of cross reactivity or by separating the two by cation-exchange liquid chromatography.

Finally the human studies may have a limited contribution to explaining the role of endorphins in menstrual function and exercise, since all of these studies rely on peripheral measurements, but are not likely to accurately reflect brain levels. Currently, this is the only acceptable form of assessing opioid activities.

Conclusion

The attractiveness of the endogenous opioid theory lies in its unique association to exercise, especially in the endurance sports. In the past, theories linking exercise and amenorrhea have been expounded frequently, but they have not associated the dysfunction uniquely with exercise. A number of large groups of women can be identified with decreased body weight and lean body mass, who are under severe stress and nutritional deficits, but who still maintain normal menstrual cycles and fertility (e.g. the refugees of the developing countries or victims of severe starvation). Exercise appears to stimulate endogenous opioids more significantly than any other single stimulus (pain, hunger for temperature, for example). These changes in endogenous opioid levels or receptors appear to disrupt or alter the hypothalamic and pituitary control of a woman's menstrual cycle. However, many of the details concerning the relationship between exercise, endogenous opioids and menstrual function are missing. A partial list of the missing details are:

• What are the baseline levels of endogenous opioids?

• How do endogenous opioid levels correlate with activity at baseline settings?

• What is the correlation of baseline measurements with other hormones (LH, FSH, GnRH, prolactin, estrogen, progesterone) and menstrual function in large numbers of women?

• What are the long term effects of acute elevations of endogenous opioids?

• What is the interaction between ovarian hormones and endogenous opioids?

• What are the levels of endogenous opioids in women with menstrual dysfunction not related to exercise, such as hypothalamic, psychogenic, hyperprolactinemia, etc.?

• Does naloxone block the stimulus of exercise to increase endogenous opioids and maintain normal menstrual function?

• What is the association between serum endogenous opioid levels and central nervous system levels?

A more clear understanding of the relationship between the endogenous opioids, exercise and menstrual changes could lead to a more thorough and accurate evaluation of the amenorrheic athlete, as well as a more effective and acceptable treatment regimens.

References

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