Hannele Ronkainen, M.D. t

Transcription

1 FERTILITY AND STERILITY Copyright P 1985 The American Fertility Society Vol. 44, No. 6, December 1985 Printed in U.S.A. Depressed follicle-stimulating hormone, luteinizing hormone, and prolactin responses to the luteinizing hormone-releasing hormone, thyrotropin-releasing hormone, and metoclopramide test in endurance runners in the hard-training season* Hannele Ronkainen, M.D. t Department of Obstetrics and Gynecology, University o{oulu, Oulu, Finland The responses of serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to luteinizing hormone-releasing hormone (LH -RH) and the responses of prolactin (PRL) to thyrotropin-releasing hormone (TRH) and metoclopramide (MC) were measured in the late luteal phase of the cycle in 12 endurance runners and 11 control women and in 12 joggers and control women. LH -RH (1 00 j.lg) and TRH (200 w;) were injected intravenously at the beginning of the test, and MC (1 0 mg) was injected 60 minutes later. Blood samples were obtained before and 20, 60, 80, and 120 minutes after the beginning of the test. Runners had significantly lower serum concentrations of estradiol and progesterone than control subjects, whereas the concentrations of FSH, LH, and PRL were similar at the beginning of the study. Compared with their controls, the runners had significantly lower FSH (P < 0.05) and LH responses at 20 minutes (P < 0.05) and lower LH responses at 80 minutes (P < 0.01) to LH-RH and lower PRL responses to MC 20 minutes after MC injection (P < 0.05). Joggers and their control subjects had similar LH, FSH, and PRL responses to these pharmacologic stimuli. It is concluded that decreased ovarian activity explains, at least partly, the lowf!red responses of FSH and LH to LH-RH and the lowered response of PRL to MC in endurance runners. Fertil Steril44:55, 1985 Competitive running and recreational jogging are popular among women. Extensive physical training, however, has endocrinologic consequences such as delayed menarche, 1 oligomenorrhea and amenorrhea, 2 and luteal phase insufficiency.3 Some investigators, 4 but not all, 5 have found jogging to affect menstruation by lengthening the menstrual cycle. Received March 26, 1985; revised and accepted August 13, *Supported by grants from the Ministry of Education of Finland. treprint requests: Hannele Ronkainen, M.D., Department of Obstetrics and Gynecology, University of Oulu, SF Oulu, Finland. Exercise-associated impaired gonadotropin release6 has been proposed to explain dysfunction of the hypothalamus and the anterior pituitary gland. Decreased circulating estrogen 4 5 and progesterone (P) 3-5 concentrations also indicate disordered ovarian function. Information concerning the functional capacity of the anterior pituitary of runners is, however, scanty. The reproductive endocrinologic features of female athletes has been examined in longitudinal studies in which each woman has been her own control. We performed a prospective, controlled study to obtain additional information concerning the function of the anterior pituitary of endurance runners and joggers in which their responses to luteinizing hormone-releasing hormone (LH-RH), thyrotropin-releasing Vol. 44, No. 6, December 1985 Ronkainen Anterior pituitary and female athletics 55

2 Table 1. Demographic Data of the Subjects at the Beginning of the Study (Mean ± SD) Variable Runners Controls Joggers Controls No. Age (yrs) Height (em) Weight (kg) Body fat(%) Age at menarche (yrs) ap < bp < ± ± ± ± 3.3a 13.6 ± 1.1b ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 1.6 hormone (TRH), and metoclopramide (MC), a known dopamine inhibitor, were tested successively in a 2-hour test 8 and compared with the respective responses of control subjects. MATERIALS AND METHODS Twelve endurance runners at the end of a hardtraining period (March through May) and 11 nonrunning control women, and 12joggers and nonrunning control women of the same age, participated in this study (Table 1). All participants were healthy and did not use hormonal medication or contraception during the 6-month period before the study or during it, and the mean length of the study menstrual cycles did not differ significantly between the runners (29.6 ± 3. days) ( ± standard deviation [SD]) and their controls (29.3 ± 3. days) or between the joggers (29.4 ± 4.1 days) and their controls (2.4 ± 1.9 days) during the study months in the spring. The runners were older at menarche and were leaner at the beginning of the study than their control subjects (Table 1). The Harpender skinfold caliper method was used for measuring skinfold thicknesses at three places (biceps, triceps, and subscapularis) to estimate the relative body fat of the subjects. Body density was estimated by the logarithm of the skinfold thickness, and the percentage of body fat was determined with Siri's formula. 9 The running women, with a mean of 6 years training experience, belonged to the top national level in their age groups in Finland (Table 2). The joggers had run regularly for 3 to 10 years. They jogged approximately 2 to 5 times weekly and ran for a total of 15 to 0 km. The control women did not practice any physical activity regularly; they were chosen from hospital personnel, the School of Nu.rsing, and senior high school. The test took place in the late luteal phase of the menstrual cycle on days 24 to 26. The subjects were instructed not to run before the test, which started at 8:00 A.M. A baseline blood sample was obtained through an indwelling forearm catheter, followed immediately by an intravenous injection of 100 j..lg of LH-RH (Hoechst AG, Frankfurt am Main, West Germany) and 200 f..lg of TRH (Hoffmann-La Roche, Basel, Switzerland). A bolus of 10 mg ofmc (Emperal, Neofarma, Helsinki, Finland) was injected 60 minutes later. Additional blood samples were obtained 20, 60, 80, and 120 minutes after the first injection. After centrifugation, the serum samples were stored at - 20 C until assayed for follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL). From the baseline samples, the concentrations of estradiol (E 2 ) and P were also determined. ASSAYS Serum concentrations of FSH, LH, E 2, and P were measured by radioimmunoassays (RIAs) with the use of reagent kits obtained from Farmos Diagnostica, Turku and Oulunsalo, Finland. The sensitivity of the FSH assay was 0.8 ; the coefficient of interassay variation was.6% and that of intraassay variation, 4.5%. The respective values for the LH assay were 1.0, 6.3%, and 3.2%; for the E 2 assay, 0.03 nmol/1, 9.%, and 8.0%; and for the P assay, 0.9 nmol/1, 8.4%, and.4%. The values of FSH and LH were standardized against Table 2. Training Schedule of the Runners (Mean ± SD)a No. of training sessions/wk Training hrs/wk Strength-training hrs/wk Running km/wk Seasons Competition light train- Hard training (autumn) ing (spring) 5. ± ± ± ± ± ± ± ± ± ± ± ± 28.4 afrom Ronkainen et al. 5 (Reproduced with the permission of the publisher, The Journal of Clinical Endocrinology and Metabolism.) 56 Ronkainen Anterior pituitary and female athletics Fertility and Sterility

3 FSH LH PRL 1' /; MIN 0 20 LRH-TRH -~ ~ MC 120 Figure 1 Mean ( ± SEM) concentrations of serum FSH, LH, and PRL in 12 endurance runners at the end of a hard-training period (.._.) and in their 11 control subjects (x-x) during the late luteal phase of the menstrual cycle in the LH-RH, TRH, and MC stimulation test. LH-RH (100 ~Jog) and TRH (200 jj.g) were injected at time zero, and MC (10 mg) was injected 60 minutes later. Asterisks indicate the significance of the difference between the groups. *P < 0.05; **P < the World Health Organization (WHO) 194 1st International Reference Preparation (no. 69/104 for FSH and no. 68/40 for LH). Serum PRL was assayed with the use of RIA kits from Diagnostic Products Corporation, Los Angeles, CA. The sensitivity was 1.4 J.Lg/1; the interassay variability,.5%; and the intraassay variability, 3.2%. The assay was standardized in terms of the WHO 1st International Reference Preparation of Prolactin for Immunoassay, no. 5/504. STATISTICS Student'~ two-tailed t-test was used for comparison of the hormone concentrations of the runners and their controls and joggers and their controls. In cases in which the distribution of the values was not exactly normal, the nonparametric Mann-Whitney U test was employed. RESULTS BASELINE LEVELS OF PITUITARY AND OVARIAN HORMONES Baseline levels oflh, FSH, and PRL were similar in runners and in their controls (Fig. 1). The levels of E2 (0.3 ± 0.1 nmolll, versus 0.5 ± 0.1 nmol/1, mean ± standard error of the mean [SEMJ) and P (16.9 ± 5.6 nmolll, versus 38.5 ± 9. nmolll) were lower in runners than in control subjects. There were no differences between the joggers and their controls in these hormonal parameters. RESPONSES OF LUTEINIZING HORMONE AND FOLLICLE STIMULATING HORMONE TO LUTEINIZING HORMONE RELEASING HORMONE In the runners, the mean responses of LH and FSH to LH-RH were significantly lower, compared with their controls; for FSH (P < 0.05) and LH (P < 0.05) at 20 minutes and for LH (P < 0.01) at 80 minutes after the LH-RH injection (Fig. 1). The relative increases of FSH and LH from baseline to the 20-minute point did not differ significantly between the groups of comparison. No significant differences were noticed between the joggers and their controls (Fig. 2). RESPONSES OF PROLACTIN TO THYROTROPIN RELEASING HORMONE AND METOCLOPRAMIDE The runners had a significantly lower mean PRL response to MC at 20 minutes after the MC injection (P < 0.05) than their controls had (Fig. 1). No significant differences were noticed between the responses of the joggers and their controis. DISCUSSION The present study, during the luteal phase of the menstrual cycle, and a previous study, 6 during the follicular phase of the menstrual cycle, showed lowered LH and FSH release after LH-RH stimulation in endurance runners. These results, together with the data of studies on runners in unstimulated conditions, 4-6 support the concept of hypothalamic-anterior pituitary dysfunction within the reproductive system. Vol. 44, No.6, December 1985 Ronkainen Anterior pituitary and female athletics 5

4 FSH LH PRL J MIN 0 20 LRH-TRH Figure 2 Mean ( ± SEM) concentrations of serum FSH, LH, and PRL in 12joggers (e-e) and in their control subjects (x-x) during the late luteal phase of the menstrual cycle in the LH-RH, TRH, and MC stimulation test. LH-RH (100 tj..g) and TRH (200 tj..g) were injected at time zero, and MC (10 mg) was injected 60 minutes later MC 120 Changes in body weight are important modifiers of gonadotropin secretion Warren et al. 11 reported impaired gonadotropin responses to LH-RH in amenorrheic women with weight loss; Vigersky and co-workers10 also documented delayed responses to LH-RH in amenorrheic women with simple weight loss. The relative amount of body fat of the runners was 21.8% in the lighttraining season, in autumn, and 19.6% in the hard-training season, in the spring. According to Frisch and McArthur/2 at least 22% of body fat is needed for the regular menstrual period. None of our runners became oligomenorrheic or amenorrheic during this time, which indicated that in our study the loss of body fat was not a determinant for the differences in the results. Hypothalamic LH-RH stimulates the anterior pituitary secretion of gonadotropins, and this 58 Ronkainen Anterior pituitary and female athletics function is modified by gonadal steroid hormones. Estrogens stimulate the secretion of gonadotropins in a dose-dependent manner,13 and P seems to exert a similar effect.14 At the time of our test, the runners had significantly lower mean serum levels of E2 and P than the control women, which could explain the impaired release offsh and LH after LH-RH injection. Secretion of PRL from the anterior pituitary gland is controlled predominantly by inhibitory hypothalamic catecholamines, mainly dopamine.15 Hypothalamic TRH, with a direct stimulatory effect on pituitary lactotropes, can partly overcome the inhibitory action of dopamine.15 In the present study, we used TRH stimulation first and dopamine blocking second successively in a 2-hour test,8 because pretreatment with TRH did not alter the PRL response to dopamine blocking with MC.8 16 In runners, the PRL response to MC was decreased, but the response to TRH was the same as in the control subjects. Boyden et al. 1 found an increased PRL response to TRH in female athletes. It is also noteworthy that in a recent study, 18 running did not influence the PRL response to exogenous dopamine. Hence, the reactivity of pituitary lactotropes to direct stimulation or inhibition was intact in endurance runners. Because blocking of dopamine by MC, acting also at the hypothalamic level, 19 resulted in lowered PRL response, the inhibitory effect of intense running on PRL secretion might be mediated by hypothalamic factors. Strenuous exercise has indeed increased the blood concentrations of catecholamines,20 which include dopamine.21 Repetitious increases of hypothalamic catecholamines may potentiate the dopamine-dependent suppression of pituitary PRL secretion. Powerful suppression of pituitary lactotropes may persist for several weeks, as observed after extended bromocriptine therapy.22 The low PRL response to MC may also occur because of decreased ovarian activity. Estrogens stimulate PRL secretion13 by decreasing the effective physiologic concentrations of dopamine15 and/or directly stimulating the anterior pituitary cells.23 Previous investigations have demonstrated that energetic exercise increases the blood concentrations of j3-endorphins24 and melatonin.25 The changed release of these cerebral neurotransmitters may also modify the capacity of the anterior pituitary to secrete gonadotropic hormones and PRL. Fertility and Sterility

5 The normal responses of gonadotropins and PRL in joggers to stimulatory agents confirm that jogging, if practiced reasonably, does not interfere with the hormonal regulation of menstruation, 5 but that endurance running does interfere, although the length of the menstrual cycle did not change in either group. In conclusion, an extensive training program is associated with decreased ovarian activity, which at least partly explains the impaired release of FSH and LH to LH-RH, and PRL to MC during the luteal phase of the menstrual cycle. Acknowledgment. We gratefully acknowledge the technical assistance of Ms. Anja Pirnes. REFERENCES 1. Malina RM: Menarche in athletes: a synthesis and hypothesis. Ann Hum Biol10:1, Baker ER: Menstrual dysfunction and hormonal status in athletic women: a review. Fertil Steril 36:691, Shangold M, Freeman R, Thysen B, Gatz M: The relationship between long-distance running, plasma progesterone, and luteal phase length. Fertil Steril 31:130, Dale E, Gerlach DH, Wilhite AL: Menstrual dysfunction in distance runners. Obstet Gynecol 54:4, Ronkainen H, Pakarinen A, Kirkinen P, Kauppila A: Physical exercise-induced changes and season-associated differences in the pituitary-ovarian function of runners and joggers. J Clin Endocrinol Metab 60:416, Boyden TW, Pamenter RW, Stanforth PR, Rotkis TC, Wilmore JH: Impaired gonadotropin responses to gonadotropin-releasing hormone stimulation in endurance-trained women. Fertil Steril 41:359, Schulze-Delrieu K: Metoclopramide. Gastroenterology :68, Kauppila A, Heikkinen J, Viinikka L: Dynamic evaluation of prolactin secretion by successive TRH and metoclopramide stimulations. Acta Endocrinol (Copenh). In press 9. Siri WE: Gross composition of body. In Advances in Biological and Medical Physics, Vol 4, Edited by JH Lawrence, CA Tobias. New York, Academic Press, 1956, p Vigersky RA, Loriaux DL, Andersen AE, Mecklenburg RS, Vaitukaitis JL: Delayed pituitary hormone response to LRF and TRF in patients with anorexia nervosa and with secondary amenorrhea associated with simple weight loss. J Clin Endocrinol Metab 43:893, Warren MP, Jewelewicz R, Dyrenfurth I, Ans R, KhalafS, Vande Wiele L: The significance of weight loss in the evaluation of pituitary response to LH-RH in women with secondary amenorrhea. J Clin Endocrinol Metab 40:601, Frisch RE, McArthur JW: Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science 185:949, Labrie F, Lagace L, Ferland L, Beaulieu M, Massicotte J, Raymond V: New aspects of the control of pituitary hormone secretion. Ann Clin Res 10:109, March CM, Marrs RP, Goebelsmann U, Mishell DR Jr: Feedback effects of estradiol and progesterone upon gonadotropin and prolactin release. Obstet Gynecol 58:10, MacLeod RM: Regulation of prolactin secretion. Front Neuroendocrinol 4:169, Kauppila A, Ylikorkala 0: Effects of oral and intravenous TRH and metoclopramide on PRL and TSH secretion in women. Clin Endocrinol (OxO 1:61, Boyden TW, Pamenter RW, Grosso D, Stanforth P, Rotkis T, Wilmore JH: Prolactin responses, menstrual cycles, and body composition of women runners. J Clin Endocrinol Metab 54:11, Chang FE, Richards SR, Kim MH, Malarkey WB: Twenty-four hour prolactin profiles and prolactin responses to dopamine in long distance running women. J Clin Endocrinol Metab 59:631, McCallum RW, Sorwers JR, Hershman JM, Sturdevant RAL: Metoclopramide stimulates prolactin secretion in man. J Clin Endocrinol Metab 42:1148, Galbo H, Gollnick PD: Hormonal changes during and after exercise. Med Sci Sports 1:9, Favier R, Pequignot IM, Desplanches D, Mayet MH, Lacour JR, Peyrin L, Flandrois R: Catecholamines and metabolic responses to submaximal exercise in untrained men and women. Eur J Applied Physiol 50:393, Yen BH, Cannon W, Sy L, BoothJ, Burch P: Regression of pituitary microadenoma during and following bromocriptine therapy: persistent defect in prolactin regulation before and throughout pregnancy. Am J Obstet Gynecol 142:634, Lloyd HM, Meares JD, Jacobi J: Early effects of stilboestrol on growth hormone and prolactin secretion and on pituitary mitotic activity in the male rat. J Endocrinol 58:22, Colt EW, Wardlag SL, Frantz AG: The effect of running on plasma ~-endorphin. Life Sci 28:163, Bullen BA, Skrinar GS, McArthur JW, Carr DB: Exercise effect upon plasma melatonin levels in women: possible physiological significance. Can J Appl Sport Sci :90, 1982 Vol. 44, No.6, December 1985 Ronkainen Anterior pituitary and female athletics 59