Substrate and hormonal responses to exercise in women using oral contraceptives A. BONEN,

F. W. HAYNES,

AND

Division of Kinesiology and Department Scotia B3H 3J5; and School of Human

T. E. GRAHAM of Physiology and Biophysics, Dalhousie University, Halifax, Nova Biology, University of Guelph, Guelph, Ontario NlG 2W1, Canada

BONEN, A., F. W. HAYNES, AND T. E. GRAHAM. Substrate and hormonal responses to exercise in women using oral contraceptiues. J. Appl. Physiol. 70(5): 1917-1927, 1991.-Hormone and substrate responsesto mild and heavy treadmill exercise were compared in women who used oral contraceptives (OC group; n =7) and in normally menstruating women (control group; n = 8). Venous blood sampleswere obtained before exercise (-5 min), during exercise (15, 30, 45, and 60 min), and 30 min after exercise. All sampleswere analyzed for glucose,lactate, free fatty acids (FFA), glycerol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), human growth hormone (hGH), cortisol, insulin, estradiol (E,), and progesterone (P). Substrate patterns during exercise were not altered by the phaseof the menstrual cycle or OC usage.However, in the OC group the FFA concentrations were consistently higher during mild exerciseand the glucoseconcentrations were lower at rest and during exercise than in the control group (P < 0.05). No differences in lactate or glycerol responseswere observed between the groups (P > 0.05). The responsesof insulin and hGH to exercise were not related to the OC useper sebut rather to the steroid status, either endogenousor exogenous. Specifically, during the steroid phases (OC use phase and luteal phase) 1) insulin concentrations were not quite as markedly reduced (i.e., 12% higher when luteal phase and OC usage phasedata were combined; P < 0.05), and 2) hGH concentrations at rest and during light exercise were higher in the OC group during the OC use phase (P < 0.05). LH patterns were not affected by exercise (P > 0.05), but a slight decreasewas found in FSH (P < 0.05). Increments in P and Ez were observed in the control group in both the follicular and luteal phase(P < 0.05), but much greater increments in P occurred in the luteal phasethan in the follicular phase(P < 0.05). In contrast to the control group, no increments in P, E,, or cortisol occurred in the OC users during exercise (P > 0.05). Therefore the new observations in this study are that 1) insulin and growth hormone respondin a complex manner during exercise with either the phase of the menstrual cycle or the phasesof OC use and disuseand 2) the steroid concentrations (P, E,, cortisol) are increasedin the controls but not in the OC users during exercise. The latter point suggeststhat normal steroid increments are due to an increasedrate of secretion rather than a decrease in the hepatic clearance of these steroids. It also appearsthat transiently different alterations in insulin, cortisol, and hGH between the two groups are not significant at the level of muscle substrate metabolism. insulin; follicle-stimulating hormone; luteinizing hormone; progesterone; estradiol; cortisol; growth hormone; progesterone; glucose;free fatty acids; lactate; glycerol

IT IS NOW WELL-KNOWN that sex steroids are markedly

increased during exercise, particularly during the luteal phase of the menstrual cycle (6, 8, 25). Comparisons of substrates and hormones in the follicular phase and luteal phase of normal, fasted, and glucose-fed women indicate that the metabolic responses to exercise depend on the nutritional status and the phase of the menstrual cycle when ovarian steroid hormone concentrations are increased (6). This suggests that the ovarian steroids might influence substrate metabolism, because estrogens can increase glycogen storage in mouse skeletal muscle and liver (1). Oral contraceptives (OC) contain potent synthetic steroids.Indeed, their chronic use over several years can increase insulin resistance in women (44). OC use also increases cholesterol and triglycerides but seems not to affect free fatty acid (FFA) turnover at rest (23). Animal studies have also shown that administration of estrogens and progesterone increases hepatic gluconeogenesis (30). In skeletal muscle of ovariectomized rats estrogen treatment stimulated FFA oxidation and inhibited glucose oxidation at rest and during exercise (24). The effects of OC use on hormonal and substrate responses to exercise have not been determined. However, given the fact that there can be differences in metabolic responses between the follicular and luteal phases during exercise in normally menstruating women when steroid levels are low and high, respectively (7), the presence of synthetic steroids in OC preparations may have an effect on carbohydrate and/or lipid metabolism during exercise. Based on animal data (24), we hypothesized that during mild exercise, when fat metabolism predominates, FFA mobilization would be more pronounced in OC users but that during heavy exercise glycolysis will predominate, independent of OC use, because of the inhibitory effects of lactate on FFA mobilization (35). In addition, we hypothesized that the inhibitory effects of OCs on ovarian (26, 36) and adrenal steroidgenesis (18, 26, 36) would impede the normal ovarian and adrenal steroid increments that occur during exercise (6, 8, 25), suggesting that it is not the reduced hepatic clearance that provokes the increments in these steroids during exercise as has been suggested in other studies (27). Therefore, to examine these suggestions we compared the hormonal and substrate responses to mild [(40% maximal 0, uptake (VO 2max)] and heavy exercise (85% . vo 2max) in women who used OCs and in normally menstruating women.

0161-7567/91 $1.50 Copyright 0 1991 the American Physiological

Society

1917

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1918

EXERCISE,

HORMONES,

AND

SUBSTRATES

METHODS

Fifteen nulliparous women (aged 19-24 yr) agreed to participate in this study. Ethical approval was obtained for these studies, and written informed consent was obtained from all subjects who were free to withdraw from the study at any time. Each subject had experienced menarche at least 5 yr before the study. Seven subjects (age 23 t 1.2 yr, wt 55.6 t 1.2 kg, Vozmax 39.7 t 1.0 ml. kg-l 6min-I) were using OCs and had done so for at least 1 yr. Eight subjects (age 24.3 t 1.2 yr, wt 57.5 t 1.7 min-l) were not using kg9 v”2 max 43.2 t 2.9 ml. kg-l these agents and had not done so for at least 1 yr before the study. These latter subjects experienced normal regular menstrual cycles 24-34 days in length, which was confirmed by the elevated progesterone (P) concentrations in the luteal phase at rest. Several weeks before the experiments subjects were familiarized with the experimental procedures. Submaximal treadmill work loads (40 and 85% VO, max) while the subjects were walking were established as we have reported previously (6). The group of control women performed exercise in the follicular and luteal phases of the menstrual cycle, and the group taking OCs participated in the exercise experiments when they were taking OCs (days 6-l 1) and when they were briefly abstaining from OC use (days 3-5) in the normal course of OC consumption (i.e., 21 days of OC use followed by 7 days of no OC use). The following OCs were being used: Ortho-Novum l/50 (50 kg mestranol + 1 mg norethindrone, n = 5), Ovral(50 pg ethinyl estradiol + 0.5 mg dl-norgestrel, n = l), Minovral (30 pg ethinyl estradiol + 0.3 mg dl-norgestrel, n = 1). The experimental procedures employed are the same as those reported in a previous study (6). Briefly, on the day of testing a light meal was consumed 3 h before exercise. Before exercise subjects rested for 60 min; this was followed by a 30-min treadmill walk (5.6 km/h) up a slight incline at ~40% Vo2 maxand then immediately by a 30-min walk (5.6 km/h) up a steeper incline designed to elicit ~85% vo2 max. Venous blood samples (venipuncture) were obtained as described in previous work (6) before exercise (-5 min), during exercise (15,30,45, and 60 min), and 30 min after exercise. The experimental protocol for the second test was identical and occurred at the same time of day. Both sessions were *scheduled late afternoon when cortisol concentrations are known to be stable. All blood samples were treated and stored in an appropriate manner (5,6) and were subsequently analyzed for glucose, lactate, FFA, and glycerol (6). Follicle-stimulating hormone (FSH), luteinizing hormone (LH), human growth hormone (hGH), cortisol, insulin, estradiol (E,), and P were measured with commercially available radioimmunoassays as described previously (6). For each of these assays all samples from the two experiments of a given subject were analyzed together, and at least one subject from each of the two groups was included in each assay. All exercise samples were corrected for hemoconcentration (5, 6). The intra-assay variabilities ranged from t5.2 to t9.4% for all hormones. l

IN

ORAL

CONTRACEPTIVE

USERS

The data were analyzed using an analysis of variance with repeated measures. With this analyses we were able to compare the responses in the two groups (i.e., control women vs. OC users), the responses during the 90-min time period (i.e., time), and the effects of the phase (nonOC-use phase or follicular phase vs. OC-use phase or luteal phase). The interactions of these effects (group X phase, group X time, phase X time, and group X phase X time) are especially important because they provide information about differential rates of responses among the experimental treatments. All data in this investigation are reported as means t SE. RESULTS

Both groups of women were tested at similar relative intensities of exercise (%VO 2 max) for the mild and heavy exercise bouts (Table 1). For the control subjects the experiments in the follicular phase occurred B-10 days after the onset of menses, when P and E, were low. The increase in P and E, and the decrease in FSH and LH in the luteal phase suggest that the control subjects had ovulated and were experiencing normal menstrual cycles. In the OC group the increase in FSH at rest confirmed that the subjects had ceased their use of OCs. The use of OCs was confirmed by the reduced FSH concentrations. Other than the expected differences between groups in the ovarian steroids and pituitary gonadotropins at rest, no differences between groups were observed in most substrates and hormones at rest (Table 1). The exceptions were in hGH and glucose. hGH concentrations at rest were markedly increased in the OC-use phase compared with the nonuse phase (P = 0.06). Glucose concentrations were lower (P < 0.05) in the OC group than in the control women before both tests. Substrate Responsesto Exercise Glucose. During heavy exercise the glucose concentrations increased significantly in both groups (P < 0.05; Fig. 1). No differences between phases of menstrual cycle were apparent in either group (P > 0.05). However, compared with the control group the glucose concentrations in the OC group were significantly lower in each of the two phases in these experiments (P < 0.05). Lactate. Lactate levels rose significantly during heavy exercise in both groups (P < 0.05). No differences were apparent between phases of the menstrual cycle or phases of OC usage. Differences between groups were not significant (Fig. 1; P > 0.05). FFA. For both groups the concentrations of FFA changed significantly during exercise (P < 0.05). No differences in the general overall patterns of response were observed between groups or between phases during the light exercise (P > 0.05). The observed patterns consisted of an increase in FFA during light exercise (Fig. 2) and a decrease during the 30 min of heavy exercise (P < 0.05). Differences between groups during this heavy exercise period were not significant (P > 0.05) in either

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EXERCISE,

HORMONES,

AND

SUBSTRATES

IN

ORAL

CONTRACEPTIVE

1919

USERS

TABLE 1. Preexercise concentrations of substrates and hormones and exercise intensities during light and heavy exercise in oral contraceptive users and control subjects OC Group

Non-OC-use

Variable

Substrate concentrations at rest Glucose, pmollml Lactate, pmol/ml FFA, peqlml Glycerol, pmollml Hormones concentrations at rest FSH, mIU/ml LH, mIU/ml P, pmol/ml Ez fmol/ml Insulin, fmol/ml hGH, ~IUlml Cortisol, pmol/ml Exercise intensity VO,, mol kg-’ . mm. -1 Light Heavy %Vo 2 max, ml kg-‘. min-’ Light Heavy Respiratory exchange ratio Light Heavy

phase

4.11~0.2" 0.52tl.O 644k119 0.14t0.02 9.2t1.4 7.6tl.O" 1.3t0.3 150.8t36.3 92.4t24.6 8.9t3.1 258.1k91.4

Control OC use

3.8,tO.Z" 0.38rtO.11 559t75 0.16t0.01 3.8-1-0.5bpc 6.0t0.8" l.Ot0.3" 194.8t100.2 58.8t7.2 29.7~13.0d 268.5k30.9

Follicular

5.2t0.2 0.39kO.11 463,t43 0.17~0.01

phase

Group Luteal

phase

5.7kO.6 0.53t0.23 575.9t83.3 0.16t0.03

10.2t0.9 15.0t1.3 1.6kO.3 196.7t68.6 95.4t15.6 10.9t4.5 199.5t35.1

5.1+0.3b 11.9+1.4b 113.8+13.3b 356.0+71.Zb 81.6t12.6 6.522.2 226.9t50.0

l

16.4t0.6 33.6k0.6

15.9t0.6 33.4t1.2

17.0t0.9 36.8t2.3

17.4t0.7 37.9,tZ.l

41.2t1.8 84.6t2.0"

40.1t0.5 84.2t2.8"

40.722.0 86.8k3.2"

40.7t0.6 85.6t2.6"

0.9OkO.02 1.02t0.02"

0.89t0.02 1.00t0.03"

0.88t0.02 0.98t0.02"

l

Values are means _t SE. OC, progesterone; E, , estradiol; hGH, follicular phase, OC use vs. luteal follicular phase (b P < 0.05, d P =

oral contraceptives; FFA, free fatty acids; FSH, follicle-stimulating hormone; LH, luteinizing hormone; P, human growth hormone; VO,, O2 uptake; %OO, max, % maximal Vo,. Between-group comparisons: no OC use vs. phase (” P < 0.05, ’ P < 0.10). Within-group comparisons: OC use phase vs. no OC use phase, luteal phase vs. 0.06). Light exercise vs. heavy exercise (g P < 0.05).

phase (Fig. 2). In contrast, the absolute FFA in the OC group, during the 30 min of mild exercise, were significantly higher than in the control group (Fig. 2; P < 0.05). Glycerol. The levels of this substrate increased significantly during exercise (P < 0.05). No differences were apparent between phases or between groups (Fig. 2; P > 0.05). Endocrine Responsesto Exercise Gonadotropins. Compared with the control group the FSH and LH concentrations in the OC group were significantly lower during both exercise tests (Fig. 3; P < 0.05). In the control group FSH and LH concentrations were higher during the follicular phase than in the luteal phase (P < 0.05). Similar differences in these gonadotropins were observed in the non-OC-use period compared with the OC-use phase (Fig. 3; P < 0.05). Exercise had no effect on the circulating levels of LH in either group (Fig. 3; P > 0.05). A slight but persistent decline occurred in the FSH concentrations during exercise (P < 0.05). Ovarian steroids. In the control group P levels were very low in the follicular phase compared with the luteal phase during exercise (Fig. 4; P < 0.05). In the OC group low P levels occurred when OCs were and were not being taken (P > 0.05). In the control group we observed an increase in P with exercise in both phases (P < 0.05). However, there was a much greater increment in the luteal phase (+18 rig/ml) than in the follicular phase (+0.73 rig/ml; P < 0.05) when concentrations at the end of heavy exercise (60 min) were compared with preexer-

cise concentrations. In contrast, in the OC group no changes in P were found during exercise in either the OC-use or non-OC-use phase (Fig. 4; P > 0.05). E, concentrations were higher in the control group during exercise than in the OC group in both phases (P < 0.05). Increments in E, occurred during exercise in the follicular and luteal phases of the control group (Fig. 4; P < 0.05) that were already evident by 15 min (Fig. 4). The overall patterns of response were the same in the two phases of the menstrual cycle (P > 0.05), although the absolute concentrations of E, were higher in the luteal phase (P = 0.06). In contrast, no change in E, concentrations occurred during exercise in either phase in the OC group (P > 0.05). InsuZin. Insulin rconcentrations declined significantly in both groups during exercise (P

Substrate and hormonal responses to exercise in women using oral contraceptives.

Hormone and substrate responses to mild and heavy treadmill exercise were compared in women who used oral contraceptives (OC group; n = 7) and in norm...
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