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Diurnal Profiles of Testosterone and Pituitary Hormones Suggest Different Mechanisms for Menstrual Disturbances in Endurance Athletes

Departments of Obstetrics and Gynecology (A.R., B.v.S., A.L.H.) and Endocrinology and Diabetology (M.T.), Karolinska Hospital; and Department of Obstetrics and Gynecology (K.C.), Huddinge University Hospital, SE-17176 Stockholm, Sweden

Address all correspondence and requests for reprints to: Anette Rickenlund, M.D., Research Laboratory for Reproductive Health, Department of Obstetrics and Gynecology, C4-U1, Karolinska Hospital, SE-17176 Stockholm, Sweden. E-mail: anette.rickenlund{at}ks.se.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The aim of this study was to evaluate the diurnal pattern of testosterone and pituitary hormones in endurance female athletes with different types of menstrual disorder. Age- and body mass index-matched groups of endurance athletes with amenorrhea (n = 10) and oligomenorrhea (n = 6), regularly cycling athletes (n = 8), and sedentary controls (n = 8) were compared with respect to 24-h hormonal profiles of testosterone, LH, prolactin (PRL), GH, insulin, IGF binding protein 1 (IGFBP-1), and cortisol. The 24-h hormone profiles in amenorrheic athletes were characterized by decreased LH pulsatility and peak amplitude of PRL and increased baseline levels of GH and cortisol. However, oligomenorrheic athletes displayed a significantly different pattern with higher diurnal testosterone secretion than all other groups. Furthermore, LH, PRL, GH, and cortisol secretions were comparable with regularly menstruating subjects. In the combined group of athletes with menstrual disturbances, diurnal secretions of testosterone, LH, and PRL were positively, whereas cortisol was negatively correlated with the number of menstruations the last year. Although this could be explained by a gradual inhibition of the hypothalamic-pituitary-gonadal axis, our results indicate that the symptoms of amenorrhea and oligomenorrhea may reflect two hormonally distinct conditions. Thus, amenorrheic athletes displayed a hormonal pattern in agreement with hypothalamic inhibition due to energy deficiency, whereas oligomenorrheic athletes demonstrated increased diurnal secretion of testosterone, suggesting a different mechanism, e.g. essential hyperandrogenism.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
MENSTRUAL DISTURBANCES IN athletes are usually ascribed to inhibition of the hypothalamic-pituitary-gonadal (HPG) axis resulting in estrogen deficiency (1, 2). Several mechanisms have been hypothesized, i.e. activation of the hypothalamic-pituitary-adrenal axis, increased endorphin release, reduced IGF-I activity and hypoleptinemia (3, 4, 5, 6, 7, 8, 9). Diurnal hormone secretion in athletes studied by Laughlin and Yen (10) showed increased secretion of GH and cortisol, decreased insulin secretion, and increased IGF binding protein 1 (IGFBP-1) in amenorrheic athletes, compared with regularly menstruating athletes and sedentary controls. The authors suggested that these endocrine changes, which all counteract hypoglycemia, are glucoregulatory adaptations to energy deficiency. Waters et al. (11) also showed increased half-life of GH, whereas GH secretion after acute exercise was blunted in amenorrheic athletes. It was explained by a combined reduction in somatostinergic and GH releasing hormone inputs.

We previously identified a hyperandrogenic subgroup of endurance athletes with menstrual disturbances (12). These women had a pathologically increased testosterone/SHBG ratio, increased levels of free testosterone, increased LH/FSH ratio, and significantly reduced SHBG levels, compared with other athletes with and without menstrual disturbances and controls. The hyperandrogenic athletes also had an anabolic body composition with higher bone mineral density and upper/lower fat mass ratio than the other oligo/amenorrheic athletes. Furthermore, the hyperandrogenic athletes had the highest maximal oxygen uptake (VO₂ max). We therefore suggested that essential hyperandrogenism, like the polycystic ovary syndrome, may be a second category of menstrual disorders in athletes that may be unrelated to energy availability.

In the present study, we aimed to evaluate the diurnal endocrine pattern in endurance athletes with different types of menstrual disorder to gain more insight to mechanisms behind menstrual disturbances in athletes. We analyzed the 24-h profiles of testosterone, LH, prolactin (PRL), GH, insulin, IGFBP-1, and cortisol in endurance athletes with amenorrhea or oligomenorrhea, regularly cycling athletes, and sedentary controls.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Female athletes in endurance sports, such as medium- and long-distance running, marathon, orienteering, cross-country skiing, and triathlon, were recruited from universities and high schools specializing in sports and at public sports events and championships all over Sweden. They were healthy, nulliparous, nonsmoking women aged 16–35 yr with body mass index (BMI) 18–24 kg/m². Endurance training criteria were defined as a minimum of 6 h of aerobic weight-bearing training of the legs or a minimum of 70 km of running weekly for a period of at least 6 months. Detailed information about the pattern of menstrual periods during the last year was provided from the athletes’ sport diaries. Amenorrhea was defined as no bleeding for the last 3 months, oligomenorrhea as periods at an interval exceeding 6 wk and not more than nine periods the last year, and regular menstruation as periods with an interval of 22–34 d. No medications, including oral contraceptives and asthma medications, were allowed. Intake of minerals/vitamins or nutritional supplements was accepted. None of the supplements were reported to include anabolic steroids.

A control group of inactive women was recruited from universities and high schools and hospital staff at Karolinska Hospital. They were screened using the same inclusion criteria as for the athletes, except that the amount of training was restricted to 1 h of light aerobic training a week. The local committee for medical ethics approved the study protocol, and all women gave their informed consent to participate.

Four groups of women characterized on the basis of endurance training and menstrual status and matched for age and BMI were studied: 10 amenorrheic athletes (AM), six oligomenorrheic (OM), eight regularly menstruating athletes (RM), and eight sedentary regularly menstruating controls (CTR).

Experimental design

All women were examined in the morning, starting at 0730 h at the Women’s Health, Clinical Research Unit at the Department of Obstetrics and Gynecology, Karolinska Hospital. Body weight, height, and blood pressure were recorded, and general health conditions were controlled. Subjects with irregular menstruation underwent gynecological examination and assessment of the degree of menstrual disturbance.

Investigation of diurnal profiles started at 0800 h after an overnight fast. Menstruating subjects were studied during the early follicular phase of the menstrual cycle (d 1–5). Continuous sampling from an antecubital vein via heparin-coated PVS tubing (Durascan Medical Products ApS, Odense, Denmark) was effected by means of a portable, battery-charged excentric pump (Carmeda, Stockholm, Sweden). Venous blood samples were obtained every 20 min for 24 h. The withdrawal rate was 8–10 ml/h, and approximately 3 ml were collected in each 20-min period. Blood samples were centrifuged and sera were stored at -20C until assayed.

The sampling technique allowed free movements within the hospital ward. During daytime the women were instructed to change the reservoir tubes every 20 min, whereas experienced staff changed the tubes during the night. The period of sleep was recorded and most subjects slept between 2300 and 0700 h. Subjects received standard meals composed by a nutritionist. Breakfast was served at 0800 h, 600 kcal; light snack meal at 1030 h, 200 kcal; lunch at 1300 h, 750 kcal; light snack meal at 1530 h, 200 kcal; dinner at 1800 h, 700 kcal; and evening meal at 2100 h, 250 kcal. The total amount of 2700 kcal (nutrient composition of 52% carbohydrate, 17% protein, and 32% fat) was based on energy needs for women with a corresponding weight and energy expenditure (13). One of the sedentary controls was served vegetarian meals with equal caloric and nutrient composition. Each meal was consumed within 30 min.

VO₂ max was determined while the subjects ran on a motor-driven treadmill (Cardionics AB, Stockholm, Sweden), using the leveling-off criterion (14). VO₂ max was determined by sampling expired air in Douglas bags. The oxygen and carbon dioxide contents were measured with an analyzer (Beckman, Fullerton, CA).

Body composition [bone mineral areal density (BMD), g/cm²], lean body mass (LBM) and fat mass was determined by dual energy x-ray absorptiometry by using Lunar Model DPX-L equipment (Lunar Radiation, Madison, WI).

Assays

Serum concentrations of testosterone were determined with RIA in untreated serum, using commercial kits obtained from Diagnostic Products Corp. (H; Coat-a-Count testosterone; Los Angeles, CA) according to the manufacturers’ protocols.

Serum concentrations of LH, PRL, GH, and cortisol were determined by time-resolved fluorescence immunoassay using commercial kits obtained from Wallac OY, Turku, Finland (AutoDELFIA). The concentrations of LH was expressed as units per liter of the second LH international reference preparation 80/552. The concentrations of PRL and GH were expressed as micrograms per liter of the third PRL IRP 84/500 and World Health Organization first international GH reference preparation 80/505, respectively. Cortisol was expressed as nanomoles per liter. Serum insulin was determined by RIA, using a commercial kit obtained from Pharmacia Diagnostics (Uppsala, Sweden) and expressed as picomoles per liter of the World Health Organization international reference preparation 66/304. Serum concentrations of IGFBP-1 were determined by RIA as described by Póvoa et al. (15). The IGFBP-2 and IGFBP-3 cross-reactivity were less than 0.5% and 0.05%, respectively.

Detection limits and within and between assay coefficients of variation were for testosterone 0.1 nmol/liter, 6.0 and 10.0%; LH 0.05 U/liter, 1.7 and 2.0%; PRL 0.04 µg/liter, 1.9 and 3.2%; GH 0.012 µg/liter, 2.0 and 3.3%; cortisol 15 nmol/liter, 1.1 and 2.9%; insulin 2 mIU/liter, 5.4 and 6.4%; and IGFBP-1 3 µg/liter, 3.0 and 10.0%, respectively.

Analysis of 24-h profiles

Analysis of the diurnal profile hormones was performed using a computerized pulsatile profile and smoothed baseline diurnal pattern analysis program, the Pulsar program developed by Merriam and Wachter (16). The program identifies the peaks and smoothed baseline using the assay SD as a scale factor. The cut-off parameters G₁ to G₅ for detecting the peaks were set to 2.5, 1.5, 1, 0.75, and 0.5 times the intraassay SD for accepting peaks of 1, 2, 3, 4, and 5 points wideness, respectively. Peak splitting period was set to 1.5. The following four Pulsar parameters were used for further statistical analysis: area under curve (AUC x 24 h), baseline mean, number of peaks, and mean peak amplitude for 24 h. For testosterone, number of peaks were not analyzed because the concentration of this hormone was determined only every third 20 min-period per hour.

Statistical analysis

Normally distributed values are given as the arithmetic mean and SD, whereas other values are given as the median and range. Results were analyzed using a one-way ANOVA. The Bonferroni procedure was performed to make pairwise and nonpairwise comparisons among means. If the assumption of equality of population variances was not tenable, an ANOVA model with separate variance estimates was used, Proc Mixed in SAS (SAS Inc., Cary, NC). The distribution for some of the variables were skewed and have therefore been log transformed. Correlations were assessed using Pearson’s coefficient or Spearman’s rank-order correlation according to distribution.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Baseline characteristics

The three athlete groups, AM, OM, and RM, and the sedentary controls were comparable as to age, body weight, height, and BMI (Table 1). Age at menarche was significantly higher in OM than in all other groups. Estradiol levels were not significantly different between groups (AM 30.0 ± 11.2, OM 36.8 ± 15.8, RM 36.2 ± 12.8, and CTR 47.9 ± 16.1 pg/ml). Conversion factor to SI unit pmol/liter: 3.7. Body composition showed significantly lower fat mass percent in AM than in RM and CTR and significantly higher LBM in OM than RM and CTR. AM had significantly higher LBM than CTR. BMD was significantly lower in AM than OM and RM. There were no differences in the age at onset of training and amount of specific-endurance training among the athlete groups. The athlete groups had significantly higher VO₂ max (liters per minute) than the controls.

Diurnal hormone levels in AM, OM, RM, and CTR are shown in Table 2. Testosterone secretion was characterized by higher concentrations in the morning in most subjects. Diurnal testosterone secretion (AUC) was significantly higher in the OM group than AM and RM + CTR, respectively. LH pulsatility (peaks per 24 h) was significantly lower in AM, compared with RM and CTR, whereas LH pulsatility in OM only was lower than CTR and comparable with the combined group of RM + CTR. Representative 24-h profiles of testosterone and LH in an AM, OM, RM, and CTR are shown in Fig. 1. Diurnal peak amplitude of PRL was significantly lower in AM but not in OM, compared with regularly menstruating subjects.

View larger version (23K): [in this window] [in a new window]   FIG. 1. Diurnal profiles of testosterone and LH in three individual athletes, one athlete with AM, OM, and RM, respectively, and one sedentary CTR. Conversion factor for testosterone to SI unit, 0.035. *, Significant LH pulses detected by the PULSAR analyses.

Correlations

There was a significant positive correlation between 24-h testosterone secretion (AUC) and age at menarche in the whole material (r = 0.47, P < 0.01). In the athletes with menstrual disturbances (AM + OM), the 24-h testosterone secretion (AUC) was positively correlated with diurnal LH pulsatility (peaks per 24 h) (r_s = 0.57, P < 0.05) and PRL (mean peak amplitude) (r = 0.67, P < 0.01). Furthermore, testosterone (AUC), LH (peaks per 24 h) and PRL (mean peak amplitude) were positively correlated (r = 0.50, P < 0.05; r_s = 0.54, P < 0.05; and r = 0.60, P < 0.05) and cortisol (baseline mean) negatively correlated (r_s = -0.57, P < 0.05) with the number of menstruations during the last year in athletes with menstrual disturbances (Fig. 2). Number of menstruations were also positively correlated with total BMD in AM + OM (r = 0.64, P < 0.01).

View larger version (22K): [in this window] [in a new window]   FIG. 2. Number of menstruations last year vs. diurnal secretions of testosterone (AUC per 24 h), LH pulsatility (peaks per 24 h), PRL (mean peak amplitude per 24 h), and cortisol (baseline mean per 24 h) among athletes with menstrual disturbance. Conversion factors to SI unit, testosterone, 0.035; cortisol, 27.59.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
To our knowledge this is the first report on diurnal hormone profiles in athletes with different types of menstrual disorder. We found that 24-h profiles of testosterone, LH, and PRL were positively correlated and cortisol negatively correlated with the number of menstruations during the last year in these athletes. However, the endocrine profiles in amenorrheic and oligomenorrheic athletes were apparently different. Amenorrehic athletes displayed a hormonal pattern in agreement with hypothalamic inhibition. In contrast, oligomenorrheic athletes had higher 24-h secretion of testosterone than all other groups. Furthermore, the diurnal secretions of LH, PRL, GH, and cortisol in this oligomenorrheic group did not differ from the regularly menstruating subjects.

In agreement with previous studies, we found significantly decreased LH pulsatility, higher diurnal cortisol secretion, and mean baseline secretion of GH in amenorrheic athletes, compared with regularly menstruating athletes and controls (3, 4, 5, 10, 11). These endocrine changes have been associated with energy deficiency (10, 17). The amount of 2700 kcal in the present study was recommended by nutritional experts within the Swedish Olympic Committee to meet the energy needs in average weighing endurance training women athletes (13, 18). However, as previously reported, the habitual daily energy intake among these athletes may be considerable lower (18). Therefore, it cannot be excluded that this amount was higher than their usual energy intake, which may have blunted the endocrine symptoms of undernutrition in amenorrheic athletes.

We also found that peak amplitude of PRL was lowest in the amenorrheic athletes. In the whole material, LH and PRL were positively correlated and GH negatively correlated with percentage of total fat mass, which may support an association between these hormonal changes and energy deficiency. Furthermore, LH was positively correlated with insulin secretion and negatively correlated with IGFBP-1. In general, our results of endocrine changes in amenorrheic athletes may represent glucoregulatory adaptation to a hypometabolic state, as suggested by Laughlin and Yen (10). In contrast, oligomenorrheic athletes did not display endocrine changes supporting nutritional deficiency. Thus, LH pulsatility was comparable with regularly menstruating subjects, and mean baseline secretion of GH and cortisol levels were not significantly increased in oligomenorrheic as in amenorrheic athletes.

The mechanism for menstrual disturbances in athletes is usually ascribed to inhibition of the HPG axis (1, 2). Diurnal endocrine profiles in amenorrheic athletes in this study were in agreement with this hypothesis. Consequently, these women displayed clearly suppressed diurnal LH pulsatility and the lowest testosterone secretion of all groups. Amenorrheic athletes also had significantly lower diurnal secretion of PRL than regularly menstruating subjects. It has previously been demonstrated that the PRL response to exercise is blunted in amenorrheic athletes (19, 20). This has been explained by reduced estradiol levels and ovarian suppression because estradiol is a known PRL-stimulating factor (21). In the athletes with menstrual disturbances, we found a positive correlation between PRL secretion and diurnal secretion of testosterone, which could support that PRL secretion is dependent on ovarian function.

Our findings of a relationship between decreasing diurnal secretions of testosterone, LH, and PRL, and the degree of menstrual disturbance in female athletes may support a gradual hypothalamic inhibition reflected by the symptom oligomenorrhea as an intermediate state that can progress to amenorrhea. However, in contrast to amenorrheic athletes, the oligomenorrheic group did not show a hormonal pattern characteristic for hypothalamic inhibition. Instead, this group displayed increased levels of diurnal testosterone secretion, compared with all groups. Furthermore, LH pulsatility, mean peak amplitude of PRL, mean baseline secretion of GH, and cortisol secretion were comparable with regularly menstruating subjects. The present data rather indicate that oligomenorrhea and amenonorrhea may be symptoms of two distinct and hormonally different conditions.

We have previously described a hyperandrogenic subgroup of endurance athletes with menstrual disturbance and suggested hyperandrogenism like polycystic ovary syndrome as an alternative mechanism behind menstrual disturbance in endurance athletes (12). Similar findings have also been demonstrated in swimmers (22). This mechanism may be essential, in contrast to hypothalamic inhibition of the HPG axis, which is acquired and considered to be a result from insufficient dietary intake. Hypothetically, hyperandrogenism may imply competitive advantages and could play a role in the selection of subjects to sport activities. Delayed menarche and primary amenorrhea may be associated with hyperandrogenism (23). Here we found a positive correlation between 24-h testosterone secretion and age at menarche, supporting such association. Because the subjects began training before menarche, our data do not allow conclusions on the influence of exercise training on menstrual function.

The oligomenorrheic athletes in this study displayed increased levels of testosterone and late menarche in agreement with essential hyperandrogenism. Clinical symptoms of hyperandrogenism were not systematically evaluated. However, the presence of the typical picture of polycystic ovaries (PCOs) on ultrasound (10 follicles arranged around an increased stroma) was investigated retrospectively, and three of six oligomenorrheic athletes had PCOs, as did one of 10 amenorrheic athletes and one of eight controls. The five individuals with the highest testosterone levels in the whole material were all oligomenorrheic, and three of them had PCOs. In comparison, the proportion of oligomenorrheic women with PCOs has been reported to 70–90%, in women with high androgens to 50–90%, and in regularly menstruating women to 20–25% (23). Although oligomenorrhea in this study seem to represent essential hyperandrogenism, it cannot be excluded that this symptom in some athletes reflect an intermediate state of hypothalamic inhibition.

In conclusion, our results indicate that the symptoms of oligomenorrhea and amenorrhea in female athletes may reflect two hormonally distinct conditions rather than a gradual inhibition of the HPG axis. Thus, amenorrheic athletes displayed a hormonal pattern in agreement with hypothalamic inhibition due to energy deficiency. In contrast, the increased diurnal secretion of testosterone in oligomenorrheic athletes suggest a different mechanism, e.g. essential hyperandrogenism.

	Acknowledgments

 
The authors thank Berit Legerstam, Elisabeth Krog Norén, Carina Levelind, Shirley Karlén, and Ingegerd Svensson for skillful technical assistance.

	Footnotes

 
This work was supported by the Swedish Medical Research Council (05982, 13142), Center for Sports Research, and Karolinska Institutet.

Abbreviations: AM, Athlete with amenorrhea; AUC, area under curve; BMD, bone mineral areal density; BMI, body mass index; CTR, sedentary regularly menstruating control; HPG, hypothalamic-pituitary-gonadal; IGFBP, IGF binding protein; LBM, lean body mass; OM, athlete with oligomenorrhea; PCO, polycystic ovary; PRL, prolactin; RM, regularly menstruating athlete; VO₂ max, maximal oxygen uptake.

Received February 21, 2003.

Accepted October 31, 2003.

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