Menstrual cyclicity has a profound effect on glucose homeostasis*t

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1 FERTILITY AND STERILITY Copyright" 1989 The American Fertility Society Printed in U.S.A. Menstrual cyclicity has a profound effect on glucose homeostasis*t Michael P. Diamond, M.D.:j: Donald C. Simonson, M.D II~ Ralph A. DeFronzo, M.D.II# Yale University School of Medicine, New Haven, Connecticut Results from oral glucose tolerance tests have frequently demonstrated a deterioration in glucose metabolism during the luteal phase of the menstrual cycle. To examine this issue further, eight women underwent both midfollicular (days 3 to 10) and midluteal (days 20 to 25) phase hyperglycemic clamp studies (+125 mg glucose/dl) after an overnight fast. Glucose levels rose from 83 ± 1 to 207 ± 2 and 87 ± 1 to 207 ± 2 mg/dl, respectively, during the follicular and luteal phases. The basal (6 ± 1 versus 7 ± 1ILU/ ml) and glucose-stimulated (42 ± 5 versus 43 ± 6 ILU/ml) insulin responses were similar in the follicular and luteal studies. However, glucose uptake was significantly higher during the follicular versus the luteal phase (10.99 ± 0.97 versus 6.93 ± 0.37 mg/kg-min; P < 0.01), as was the ratio of glucose uptake to insulin concentration (30.0 ± 5.5 versus 19.7 ± 3.7, P < 0.01). The authors conclude that: (1) Glucose metabolism is impaired in the luteal phase of the menstrual cycle; (2) This defect cannot be explained by differences in the plasma insulin response; and (3) This impairment in the ability to promote glucose uptake under hyperglycemic conditions suggests a defect in the mass action effect of glucose per se. Fertil Steril52:204, 1989 The literature contains conflicting reports on the effect ofthe phase ofthe menstrual cycle on glucose homeostasis. Consistent with the concept of deterioration in glucose homeostasis during the luteal Received January 13, 1989; revised and accepted April 18, * Presented in part at the Forty-Fourth Annual Meeting of The American Fertility Society, October 10 to 13, 1988, Atlanta, Georgia. t Supported by grant no from the Juvenile Diabetes Foundation to M.P.D. and by grant no. RR00125 from the General Clinical Research Center. :j: Mellon Fellow in the Reproductive Sciences. Reprint requests: Michael P. Diamond, M.D., Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, P.O. Box 3333, New Haven, Connecticut II Department of Medicine. 1f Present address: Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts. # Present address: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas. 204 Diamond et al. Menstrual cycle glucose homeostasis phase are reports that demonstrate elevated fasting glucose levels and impaired glucose tolerance during oral glucose tolerance tests (OGTT).1,2 Additionally, progesterone (P) administration to men and women results in fasting hyperinsulinemia and an increased plasma insulin response to an OG TT or to a tolbutamide tolerance test. 3 Finally, several reports have demonstrated a deterioration in metabolic control and an increased incidence of diabetic ketoacidosis during the luteal phase and menstruation in women with diabetes mellitus. 4-6 In contrast, other investigators have failed to identify any variation in glucose or insulin response to an OGTT 7,8 or an intravenous glucose tolerance test (IVGTT)9 as a function of the phase of the menstrual cycle. Furthermore, evaluation of insulin sensitivity using the euglycemic hyperinsulinemic clamp technique has failed to identify an impairment during the luteal phase of the menstrual cycle.lo,n To further assess this issue, hyperglycemic

2 clamp studies were performed in the same women in their follicular and luteal phases. This technique allows one to quantitate insulin secretion and whole body glucose metabolism in response to a uniform hyperglycemic stimulus. Since each subject serves as her own control, one has a highly reproducible method to examine the effect of the follicular and luteal phases on: (1) insulin secretion in response to a glucose challenge, and (2) tissue glucose uptake in response to a hyperglycemic hyperinsulinemic stimulus. Study Subjects MATERIALS AND METHODS Eight regularly menstruating, nonobese healthy women were studied in both the follicular and luteal phases of their menstrual cycles. Follicular phase studies were performed on cycle days 3 to 10; luteal phase studies on cycle days 20 to 25. The subjects' ages ranged from 24 to 34 (mean, 28.9 ± 1.2) years and their percent ideal body weight (based on 1983 Metropolitan Life Insurance Co. Tables) ranged from 80% to 109.5% (mean, 95.2% ± 3.4%). All women had a normal OGTT, were not taking oral contraceptives or other drugs that may influence carbohydrate metabolism, and had no recent change in body weight. They were instructed to maintain normal food intake (containing at least 200 gm of carbohydrate/day) and activities for 3 days prior to study. All subjects were informed of the nature, purposes, and the risks of the study, and gave their informed, voluntary written consent before their participation. The experimental protocol was approved by the Human Investigation Committee of Yale University School of Medicine. Experimental Protocol Two studies were performed in each subject; the sequence of follicular and luteal studies was varied. The studies were performed with the subjects supine, beginning at 8:00 A.M. after an overnight fast of 10 hours. A Teflon catheter was inserted into an antecubital vein for infusion of glucose. Another Teflon cannula was inserted into a wrist vein in a retrograde fashion for blood sampling, and kept patent by an isotonic saline drip. The hand then was placed in a box that was heated to 70 C. In this manner, it was possible to collect "arterialized" venous blood samples through the wrist cannula.i2 Hyperglycemic Clamp During the hyperglycemic clamp study, the plasma glucose concentration was acutely raised by 125 mg/dl above baseline, and maintained at this level for a total of 2 hours. This was accomplished using the protocol of DeFronzo et al.,13 and consisted of a priming dose of glucose administered over the first 15 minutes. Subsequently, the plasma glucose concentration was measured every 5 minutes, and a 20% glucose solution was adjusted based on a negative feedback principle to maintain the plasma glucose constant at the desired hyperglycemic plateau.i3 Plasma samples for glucose and insulin were drawn at 10-minute intervals during the basal period, at 2-minute intervals during the initial 10 minutes of glucose infusion, and every 5 to 10 minutes thereafter. Samples for determination of estradiol (E2), and P were obtained three times during the basal period; prolactin (PRL), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were sampled twice during the basal period. Analytical Procedures Plasma glucose concentration was determined in duplicate by the glucose oxidase method on a Beckman Glucose Analyzer II (Beckman Instruments Inc, Fullerton, CA). Insulin, E 2, P, PRL, LH, and FSH were measured by radioimmunoassay.i4-i7 Calculations Insulin secretion was characterized as follows: first phase, mean plasma insulin concentration from time 0 to 10 minutes; second phase, mean plasma insulin concentration from 10 to 120 minutes; and total insulin secretion, mean plasma insulin concentration from 0 to 120 minutes. The basal insulin concentration represents the mean of at least three values. Under steady-state plasma glucose concentrations, as occurs during the last hour of the hyperglycemic clamp, hepatic glucose production is completely suppressedi8 and the amount of glucose infused must equal the amount of glucose taken up (M) by all of the cells of the body after a small correction for urinary glucose losses (0.1 to 0.2 mg/kgminute).13 Additionally, during the last hour of the hyperglycemic clamp, the M/I ratio provides an estimate of the quantity of glucose metabolized per unit of plasma insulin (I) concentration under hyperglycemic conditions.i3 Diamond et al. Menstrual cycle glucose homeostasis 205

3 VARIABLE GLUCOSE INFUSION 60 VARIMLE 0WC06E INFUSION F--. o l.1*li Glucose (mg/dl) 150 Follicular o Luteal Insulin {jillim1) Minutes 20 Figure 1 Mean plasma glucose levels during a hyperglycemic clamp (+125 mg/dl) in eight women during follicular (e) and luteal (0) phases ofthe menstrual cycle. Statistics All data are expressed as mean ± standard error of the mean. Statistical significance was defined as P < Statistical analysis was performed by the paired t and Spearman rank correlation coefficient tests. RESULTS There were no significant differences in the basal follicular and luteal phase levels of E2 (54.0 ± 9.8 versus 79.4 ± 4.9 pg/ml, respectively), PRL (12.5 ± 1.5 versus 14.4 ± 2.2 ng/ml, respectively), LH (5.8 ± 0.7 versus 4.8 ± 0.8 miu/ml, respectively), or FSH (4.5 ± 0.5 versus 3.1 ± 0.6 miu/ml, respectively). The fasting P concentration was significantly higher in the luteal phase (0.2 ± 0.1 versus 20.3 ± 4.9 ng/ml, respectively, P < 0.01). During the hyperglycemic clamp, the plasma glucose concentration was raised from 83 ± 1 to 207 ± 2 and from 87 ± 1 to 207 ± 2 mg/dl during the follicular and luteal phases, respectively (Fig. 1). The mean fasting plasma glucose level was significantly lower in the follicular phase (P < 0.05). There was no difference in either the basal plasma insulin concentration (6 ± 1 versus 7 ± 1 JLU/ml) or the mean 60- to 120-minute plasma insulin response (42 ± 5 versus 43 ± 6 JLU/ml) to hyperglycemia during the follicular and luteal phases, respectively (Fig. 2). The first phase (26 ± 4 versus 28 ± 7 JLU/ml), second phase (35 ± 5 versus 36 ± 6 JLU/ ml), and total (34 ± 5 versus 35 ± 6 JLU/ml) insulin secretion were nearly identical during the follicular and luteal portions of the menstrual cycle, respectively. As shown in Figure 3, comparing the follicular 206 Diamond et al. Menstrual cycle glucose homeostasis Minutes Figure 2 Mean serum insulin levels during a hyperglycemic clamp (+125 mg/dl) in eight women during follicular (e) and luteal (0) phases ofthe menstrual cycle. and the luteal phases, the rate of glucose utilization from 60 to 120 minutes (10.99 ± 0.97 versus 6.93 ± 0.37 mg/kg-minute, respectively) was significantly higher during the follicular phase (P < 0.01), as was the M/I ratio (30.0 ± 5.5 versus 19.7 ± 3.7 mg/kg-minute per JLU/ml X 100, respectively, P < 0.01). Furthermore, comparing each woman individually, a decreased M/I ratio was observed in every subject during the luteal phase (Fig. 2). Similar decreases in both M and M/I were observed if examined during the 20- to 120-minute period of the follicular and luteal phase studies (9.79 ± 1.04 versus 6.78 ± 0.43; P < 0.05 and 32.9 ± 6.2 versus 23.8 ± 4.5, respectively; P < 0.05). The reduction in glucose uptake correlated positively with the increase in P levels (r = 0.66, P < 0.01). There was no correlation between glucose uptake and either E 2, PRL, LH, or FSH I~. ~ Glucose Glucose Uptakal Insulin Responss ~ke 40 < 'IIlin) 8 <='IIlin par x 100) I~~ FoIIialIar l.uiiai FoIIiaAar I..uIIIaI Figure 3 Hyperglycemic clamp (+ 125 mg/dl) glucose uptake (M) (left) and ratio of glucose uptake to insulin response (Mil ratio) (right) in the follicular and luteal phases of the menstrual cycle in eight women. Data displayed represent individual levels of each woman, and mean levels in each phase of the cycle.

4 DISCUSSION Using the hyperglycemic clamp technique, we have demonstrated that differences in glucose homeostasis exist between the follicular and luteal phases ofthe menstrual cycle in healthy, regularly menstruating women. Using each woman as her own control, the Mjl ratio was demonstrated to be higher in every individual during the follicular phase compared with the luteal phase. A highly significant inverse correlation was observed between the rate of glucose disposal and the serum P concentration, suggesting that this hormone might be responsible for the impairment in glucose metabolism. No correlation was noted between the serum E2, prolactin, LH, or FSH concentration and the rate of glucose metabolism during the hyperglycemic clamp. These findings and their temporal occurrence are consistent with the report of Kalkhoff et al.3 that administration of P for only 5 to 6 days leads to an impairment in glucose homeostasis. The finding of impaired glucose disposal during the luteal phase is consistent with several previous reports based on glucose tolerance tests,1,2 but in disagreement with others. 7-9 However, it is well known that the OGTT is poorly reproducible,19,20 in part because of variable glucose absorption. Because of small expected differences between the follicular and luteal phases, the variability inherent in the OGTT may exceed intraindividual cyclical differences. The use of the IVGTT eliminates the variability in glucose absorption and may be more reproducible than the OGTT in this respect. However, the report of Spellacy et al.,9 using the IV GTT, failed to detect any difference in the glucose decay rate between the follicular and luteal phases. In that report, the mean fasting plasma insulin concentration was 18 and 16 ~Ujml on cycle days 5 and 25, respectively. These values are quite high for normal subjects10,1l,18 and (if not due to methodologic differences) raise potential questions about the patient population selected for the study. Finally, the report of Toth et al.ll characterized the luteal phase as cycle days 20 to 28 in women with 28- to 30-day cycles. Thus, the luteal phase studies may have been performed in a weakly progestational milieu, and this was confirmed by the mean luteal phase P level of 4.4 ± 0.5 ngjml. Of concern nevertheless is the failure of previous investigators, using the euglycemic insulin clamp,lo,ll to demonstrate a difference in insulinmediated glucose disposal between the follicular and luteal phases, whereas in the present study a consistent impairment in glucose uptake was observed during the hyperglycemic clamp. This difference cannot be explained by a reduction in insulin secretion during the hyperglycemic clamp, since the plasma insulin levels during the follicular and luteal studies were virtually identical. One major difference between these previous studieslo,n and our own centers on the plasma glucose concentration. During the euglycemic insulin clamp, the plasma glucose concentration is maintained constant at the basal level, while during the hyperglycemic clamp, it is raised by 125 mgjdl above baseline. Hyperglycemia per se is known to enhance glucose uptake by a mass action effect It is interesting to speculate, therefore, that the luteal phase impairs the ability of glucose to promote its own uptake whereas it has no effect on insulin-mediated glucose disposal. Consistent with this speculation, glucose-mediated glucose uptake has been shown to be impaired in other states of abnormal carbohydrate metabolism such as noninsulin-dependent diabetes mellitus23 and obesity.24 Our results, taken alone, also are consistent with an alternative hypothesis, namely that the estrogen or progesterone dominant phases of the cycle are associated with alteration in insulin-mediated glucose uptake at target tissues. Such an hypothesis would predict that a difference in glucose utilization also would occur if glucose levels are maintained constant while elevating circulating insulin levels. However, such an effect is unlikely because no difference in glucose utilization in the follicular and luteal phases of the menstrual cycle has been reported under euglycemic, hyperinsulinemic conditions.1o,n Thus, the difference in glucose uptake in the follicular and luteal phases of the menstrual cycle appears to be an effect mediated by glucose per se, under hyperglycemic conditions. In summary, this present study has demonstrated that an impairment in glucose disposal does exist during the luteal phase of the menstrual cycle. This defect is clearly demonstrated using the hyperglycemic clamp and cannot be explained by a defect in insulin secretion. In view of previous studies describing no difference in glucose uptake during euglycemic, hyperinsulinemic clamp studies, the reduction in glucose uptake under hyperglycemic conditions may result from a defect in the mass action effect of glucose to promote its own uptake. REFERENCES 1. Peppler U, Thefeld W, Wineenty U: Oraler Glukosetoleranztest bei Frauen in Abhangigkeit vorn Menstruationszyklus. Klin Woehensehr 56:659,1978 Diamond et al. Menstrual cycle glucose homeostasis 207

5 2. Jarrett RJ, Graver HJ: Changes in oral glucose tolerance during the menstruation cycle. Br Med J 2:528, Kalkhoff RK, Jacobson M, Lemper D: Progesterone, pregnancy and the augmented plasma insulin response. J Clin Endocrino131:24, Cramer HI: The influence of menstruation on carbohydrate tolerance in diabetes mellitus. Can Med Assoc J 47:51, Walsh CH, Malins JM: Menstruation and control of diabetes. Br Med J 11:177, Sacerdote A, Bleicker SJ: Oral contraceptives abolish luteal phase exacerbation of hyperglycemia in Type I diabetes. Diabetes Care 5:651, Cudworth AG, Veevers A: Carbohydrate metabolism in the menstrual cycle. Br J Obstet Gynaeco182:162, Bonora E, Zavaroni I, Alpi 0, Pezzarossa A, Dall'Aglio E, Coscelli C, Butturini U: Influence ofthe menstrual cycle on glucose tolerance and insulin secretion. Am J Obstet Gynecol 157:140, Spellacy WN, Carlson KL, Schade SL: Menstrual cycle carbohydrate metabolism. Am J Obstet Gynecol 99:382, Yki-Jarvinen H: Insulin sensitivity during the menstrual cycle. J Clin Endocrinol Metab 59:350, Toth EL, Suthijumroon A, Crockford PM, Ryan EA: Insulin action does not change during the menstrual cycle in normal women. J Clin Endocrinol Metab 64:74, Abumrad NN, Rabin D, Diamond MP, Lacy WW: Use of a heated superficial hand vein as an alternative site for the measurement of amino acid concentrations and for the study of glucose and alanine kinetics in man. Metabolism 30:936, DeFronzo RA, Tobin JD, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physio1237:E214, Wahren J, Felig P, Hagenfeldt L: Effect of protein ingestion on splanchnic and leg glucose metabolism in normal man and in patients with diabetes mellitus. J Clin Invest 57:987, Lavy G, Pellicer A, Diamond MP, DeCherney AH: Ovarian stimulation for in vitro fertilization and embryo transfer, human menopausal gonadotropin versus pure human follicle stimulating hormone: a randomized controlled study. Fertil Steril50:74, Laufer N, Botero-Ruiz W, DeCherney AH, Haseltine F, Polan ML, Behrman HR: Gonadotropin and prolactin levels in follicular fluid of human ova successfully fertilized in vitro. J Clin Endocrinol Metab 58:430, Botero-Ruiz W, Laufer N, DeCherney AH, Polan ML, Haseltine FP, Behrman HR: The relationship between follicular fluid steroid concentration and successful fertilization of human oocytes in vitro. Fertil Steril41:820, DeFronzo RA, Ferrannini E, Hedler R, Felig P, Wahren J: Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes 32:35, McDonald GW, Fisher GF, Burnham C: Reproducibility of the oral glucose tolerance test. Diabetes 14:473, Harding PE, Oakley NW, Wynn V: Reproducibility of oral glucose tolerance data in normal and mildly diabetic subjects. Clin Endocrino12:387, Cherrington AD, Williams P, Harris M: Relationship between the plasma glucose level and glucose uptake in the conscious dog. Metabolism 27:787, Aden M, Pacini G, Ysug YJ, Bergman RN: Importance of glucose per se to intravenous glucose tolerance: comparison of the minimal-model prediction with direct measurements. Diabetes 34:1,092, DeFronzo RA, Simonson DC, Del Prato S: Glucose resistence in diabetes: evidence for impaired insulin-independent glucose uptake. Diabetes 34(Suppll):87A, Bergman RN, Phillips LS, Cobelli C: Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and B-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest 68:1,456, Diamond et a1. Menstrual cycle glucose homeostasis