Carl De Crée

Sex steroid metabolism and menstrual irregularities in the exercising female. A review.

SummaryThis article aims to clarify why, and by which mechanisms, exercise may influence the normal menstrual cycle. Therefore, the vast amount of literature on this subject is reviewed and a critical appraisal of the most widespread hypotheses is offered.The strikingly low body mass which frequently accompanies exercise-related menstrual irregularities (ERMI) has led some authors to develop a hypothesis which postulates that a critical percentage of body fat is essential to trigger normal menstruation. The relevance of any reference to anorexia nervosa to support this view lacks consistency: female athletes differ in many ways from patients with anorexia nervosa, not least in their excellent physical status which is essential to deliver first-class performances.ERMI is not identical to the so-called female athlete triad, a complicated pathology that involves ERMI, premature osteoporosis and disordered eating. ERMI itself does not seem to have any substantial pathological effects as long as attention is paid to preventing osteoporosis or stress fractures which may result from prolonged hypo-estrogenaemia. In the female athlete with ERMI who wishes to conceive, the accompanying subfertility may necessitate a response other than a prompt reduction in training intensity, as this is hardly a first choice for any top athlete.During recent years, a number of prospective studies have greatly contributed to our understanding of the complexity of the mechanisms involved in ERMI. Older hypotheses, such as those considering hyperprolactinaemia as the cornerstone of ERMI, have now been firmly rejected. The present hypotheses emphasise the importance of caloric deficiency and limited energy availability, although they still fail to identify the actual mechanism that causes ERMI. There is, however, evidence that ERMI is produced by a disturbance of the hypothalamic gonadotrophin-releasing hormone oscillator. This disturbance is caused by either an insufficient estrogen or progesterone feedback or by an imbalance of local opioid peptide and catecholamine activities mediated by γ-aminobutyric acid (GABA), corticotrophin-releasing hormone and insulin-like growth factor-1.More recent experiments have also linked ERMI with changes in steroid metabolism, in particular, an increasing activity of catecholestrogens possibly leading to enhanced intracerebral noradrenaline (norepinephrine) levels that may interfere with normal gonadotrophin release.This article demonstrates that the outcome of the many studies on ERMI is characterised by much controversy and numerous methodological flaws. The importance and complexity of some recent findings necessitate a comprehensive study which links older and newer findings within a critical perspective.

Influence of exercise and menstrual cycle phase on plasma homocyst(e)ine levels in young women: a prospective study

Plasma total homocysteine (tHcy) has been identified as an independent risk factor for cardiovascular diseases (CVD). The difference in tHcy between the sexes has most often been related to the sex hormones, but also to a higher muscle mass in men. The purpose of this study was to assess the effects of acute exercise, brief exhaustive training, and menstrual cycle phase on circulating plasma tHcy concentrations. Fifteen untrained eumenorrheic women (mean age [±SD]: 18.7±0.4 yr. body fat: 25.8±3.4%, VO2max: 43.8±2.3 ml · kg−1· min−1) volunteered for the present study, which covered two menstrual cycles. During the second cycle the subjects participated in two exhaustive 5‐day training programs on a cycle erg‐ometer: one in the follicular (FPh) and one in the luteal phase (LPh). Pre‐and posttraining plasma tHcy and total estrogen (E) responses were determined in blood samples obtained immediately before, during and immediately after incremental exercise to exhaustion. tHcy levels showed a large between‐subject variation, but differences between FPh and LPh levels were consistent (P=0.063). Mean tHcy levels at rest were 9.44±1.65 μmol/L and 8.93±1.71 μmol/L during the FPh and LPh. respectively. Brief exhaustive training did not elicit any changes in plasma tHcy concentrations. although posttraining LPh E levels were lower (P<0.01). Overall, the differences between FPh and LPh values for tHcy and E were attenuated by training. Acute exercise increased plasma tHcy concentrations (P<0.001). At exhaustion. tHcy levels increased by 17% and 16% during the FPh and LPh. respectively. This was also significantly above tHcy levels at submaximal exercise (P=0.044). After a short period of training tHcy levels did not increase as much during acute exercise as they did before training; however, the increments were still significant (P=0.048). In conclusion, acute exercise in women produces significant increases in plasma tHcy concentrations, whereas brief exhaustive training does not significantly alter plasma tHcy levels. Our findings also suggest that plasma tHcy concentrations are menstrual cycle phase‐dependent and that there is a close association between estrogen status and tHcy levels.

4-hydroxycatecholestrogen metabolism responses to exercise and training: Possible implications for menstrual cycle irregularities and breast cancer

OBJECTIVE To investigate the behavior of C4-substituted estrogens, the so-called catecholestrogens, in response to acute exercise and training. The 4-hydroxyestrogens are known to have both a strong estrogenic potency and affinity for catechol-O-methyltransferase (COMT), the enzyme that deactivates catecholamines. DESIGN A prospective trial covering three menstrual cycles: a control cycle, a moderate training cycle, and a heavy training cycle. PARTICIPANT(S) Six untrained, healthy, eumenorrheic women (mean pretraining maximum oxygen uptake: 40.9 +/- 4.9 mL/kg per minute, body fat: 27.9% +/- 3.6%) volunteered for this study. INTERVENTION(S) An incremental exercise test to exhaustion on a cycle ergometer, in the follicular and luteal phases, before and after a brief but exhaustive training program. MAIN OUTCOME MEASURE(S) Hormone measurements included follicular and luteal phase plasma E2, LH, catecholamines, PRL, total unconjugated and conjugated estrogens, total 4-hydroxyestrogens (4-OHE), and 4-hydroxyestrogen-monomethylethers (4-MeOE). RESULT(S) Pretraining baseline 4-OHE levels were significantly higher in the luteal phase (66 +/- 9 pg/mL; mean +/- SEM) than in the follicular phase (51 +/- 7 pg/mL). Pretraining and post-training baseline 4-MeOE values were below minimal detection limits (< 35 pg/mL). During incremental exercise, catecholamines, PRL, E2, unconjugated and conjugated estrogens, 4-OHE, and 4-MeOE always increased (the increases in 4-OHE during exercise were more pronounced before training, contrary to the 4-MeOE being most increased after training). The baseline 4-MeOE:4-OHE ratio (a measure of catecholestrogen activity) significantly increased with progressive training. CONCLUSION(S) Because 4-OHE have been shown to be able to control the hypothalamic gonadotropin oscillator and to stimulate the luteolytic prostaglandin PGF2 alpha, the acute exercise-induced increases of 4-OHE and their positive correlation with lactate levels may indicate a key process in the pathogenesis of exercise-associated menstrual irregularities. In addition, 4-OHE, when insufficiently O-methylated, are known to be capable of raising mutagenic superoxide free radicals and causing DNA damage that may lead to breast cancer. The results of the present study also may be of significance for the apparent protective effects of sports participation against cancer of the breast.

Endogenous opioid peptides in the control of the normal menstrual cycle and their possible role in athletic menstrual irregularities

The remarkable morphinic capacities of endogenous opioid peptides give these agents particular and interesting properties. They can be found on different locations throughout the human body, where they bind to specific receptors. By means of various agonists and antagonists it was shown that endogenous opioids possibly play a prominent role in the control of hypophyseal secretions. The menstrual cycle is thought to represent one of the most important phenomena in which these agents are involved. In the presence of a steroid-sufficient environment (that is to say, in the luteal phase) beta-endorphin exerts a tonic inhibition on the secretion of GnRH and thereby on the LH-release. Moreover, the regulation of prolactin is probably under the control of endorphins interfering via dopamine (PIF). It becomes possible to explain a number of menstrual dysfunctions in this manner. The increased plasma concentrations of beta-endorphin, which are found after physical exercise, give rise to speculations as to their involvement in the frequently appearing menstrual irregularity in women athletes. The hypothesis proposing prolactin as being entirely responsible for these phenomena is unconvincing. We believe that endogenous opioid peptides could have a possible inhibitory effect on the GnRH-LH-axis. At this moment, methodological inaccuracies and differences of various studies make it very difficult to arrive at any firm conclusion.

The monitoring of the menstrual status of female athletes by salivary steroid determination and ultrasonography.

SummaryThis study was designed to evaluate whether traditional plasma hormone determinations can be adequately replaced by measurements of salivary hormones. Eleven young sportswomen with menstrual irregularities attributed to strenuous physical exercise participated in this study. Mean body weight expressed as a percentage of ideal body weight was 92%, SD 4%. Their mean weekly training distance was 35 km, SD 15. Basal plasma endocrinological measurements revealed a hypo-oestrogenic status (mean plasma oestradiol values: 22pg-ml−1, SD 8.8), and a deficient luteal phase (mean plasma progesterone: 2.9 ng · ml−1, SD 2.1). Preexercise salivary sex steroids were low. Salivary progesterone levels were 39.3 pg · ml−1, SD 9.5 (normal ranges in saliva: 25–60 pg· ml−1), salivary oestrone (E1) was 12.2 pg · ml−1, SD 2.3 (normal ranges in saliva: 7.5–25 pg·ml−1), and salivary oestradiol (E2) < 1.9 pg · ml−1, SD 1.1 (normally 1.0–10.0 pg · ml−1). After a 21-km run, all salivary steroids appeared to increase. Mean salivary testosterone levels increased by 15.2% and salivary progesterone by 14.8%. Mean salivary oestrogens also increased (E1: + 13.9%; E2: +21.1%). These findings confirm the results of earlier studies which found higher post-exercise plasma sex steroid levels. Since salivary measurements are believed to reflect non-protein-bound, thus free steroid levels, the results obtained by these techniques may provide a more realistic picture of the hormonal effects of physical exercise. In future, more accurate, cost-effective and easier techniques for salivary measurements may offer additional advantages.

Exercise-induced changes in enzymatic O-methylation of catecholestrogens by erythrocytes of eumenorrheic women.

The present study was designed to assess the effects of acute exercise and short-term intensive training on catechol-O-methyltransferase (COMT) activity. COMT inactivates catecholamines and converts primary catecholestrogens (CE) into their O-methylated form yielding the 2- (2-MeOE) and 4-methoxyestrogens (4-MeOE). Blood samples were obtained from 15 previously untrained eumenorrheic women (mean +/- SE, VO2max: 43.8 mL x kg-1 x min-1 +/- 0.6) before and after a 5-d intensive training period, at rest and during incremental exercise. COMT activity was determined in the erythrocytes (RBC-COMT) after incubation of blood lysate with primary CE. The formation of both 2- and 4-MeOE was significantly higher (P < 0.05) during the luteal (LPh) than during the follicular phase (FPh). The amount of 2-MeOE formed (FPh: 4.2 +/- 0.2%; LPh: 4.9 +/- 0.2%) was significantly greater than the produced amount of 4-MeOE (FPh: 1.4 +/- 0.1%; LPh: 1.5 +/- 0.1%) (P < 0.05). Both before and after training, incremental exercise did not significantly alter RBC-COMT activity although we observed a trend for RBC-COMT activity increasing proportionally with the exercise intensity. After a brief period of exhaustive training, during rest the formation of 2-MeOE (FPh: +16.7%, LPh: +15.7%) and 4-MeOE (FPh: +28.6%; LPh: +40%) was significantly (P < 0.05) increased. The results of the present study are consistent with earlier findings reporting increased plasma concentrations of O-methylated CE following training. It is concluded that RBC-COMT activity is increased by brief intensive training, but not by acute exercise. We speculate that an increase in COMT-catalyzed O-methylation of CE may indicate that less COMT is available to deactivate norepinephrine.