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Six-month carbohydrate metabolism studies in women using oral contraceptives containing gestodene and ethinyl estradiol
Contraception
45:533-539,
1992
Six-month Carbohydrate Metabolism Studies in Women Using Oral Contraceptives Containing Gestodene and Ethinyl Estradiol*
William N. Spellacy, M.D. John C.M. Tsibris, Ph.D. Debra L. Hunter-Bonner, B.S. Shelley Smalling, R.N., B.S. Ronald A. Chez, M.D. Jeffrey L. Angel, M.D. William F. O'Brien, M.D. The Department of Obstetrics and Gynecology, of the University of South Florida College of Medicine, Suite 514, 4 Columbia Drive, Tampa, Florida 33606
Abstract Twenty-five women had their carbohydrate metabolism prospectively evaluated during the six months that they used a gestodene and ethinyl estradiol monophasic oral contraceptive. Serum glucose and insulin levels were measured during a 75-gram three-hour oral glucose tolerance test. At the six-month test, the three-hour glucose and the fasting and three-hour insulin values were significantly elevated. The literature on carbohydrate metabolism during gestodene oral contraceptive use is also reviewed.
*Sunoort: These studies were supported by a grant from the WyethAyerst Laboratories, Philadelphia, PA. Submitted Accepted
for publication for publication
Copyright
0
1992
January April 14,
1992 1992
6,
Butterworth-Heinemann
534
Contraception
Introduction During the last forty years, oral contraceptives (OC) have become a leading method of family planning. Over that time many modifications have occurred in the OC formulations, including a significant reduction in the steroid content and three alterations in the steroid dose during the month or the triphasic types. Recently, the OC has again been altered by introducing several new progestins into the formulation. This study prospectively evaluated the effects of a combination type oral contraceptive containing the progestin gestodene on carbohydrate metabolism during the six months of use. Methods Twenty-five women seeking oral contraceptives (OC) were asked to participate in this study. They were evaluated to determine that there were no contraindications to OC use (1). They had not been pregnant or used steroid contraceptives for at least three months. All of the women signed informed consents approved by the Institutional Review Board. Each subject had a control oral glucose tolerance test performed in the morning after a ten-hour fast. A venous blood sample was drawn from the arm and they then drank a solution containing 75 grams of glucose. Repeat blood samples were drawn at 0.5, 1,2 and 3 hours. The blood samples were allowed to clot and the serum was separated and stored at -22°C until later analysis. Each subject was then informed about the OC and the importance of daily use and they were given a supply of the drug.a At the end of the sixth cycle of use, each women had another identical oral glucose tolerance test performed. All samples from the two tests on a subject were run in duplicate in the same assay. The glucose content was determined using a Beckman glucose analyzer (Fullerton, California). The interassay and intraassay precision had a standard deviation less than 3.0 and 2.5 mg/dl, respectively. The insulin content was determined using an "51-insulin radioimmunoassay technique (kits purchased from Diagnostic Products Corporation, Los Angeles, California). The serum insulin data from the Beckman Gamma 5500 B counter were transported to a Beckman Data Capture program and were analyzed using a logit/log curve fit. The interassay and intraassay coefficients of variation did not exceed 10% in the 5200 uIU/ml range (2).
aEach monthly supply of the monophasic oral contraceptive consisted of 21 active tablets: each tablet containing 75 mcg gestodene and 30 mcg ethinyl estradiol.
535
Contraception
Changes between the baseline and cycle tests were analyzed paired Student's t tests, with probability values taken from tailed tables.
by two-
Results The women in the study had a mean age (+ SRM) of 26.1 + 1.1 Their mean control years and their mean parity was 0.7 + 0.1. weight was 143.5 + 6.1 pounds and at the sixth month their mean weight was 144.2 f 6.2 pounds (t = 0.43, p not significant). There were no complications experienced by the women with the OC and no pregnancies occurred. Glucose The statistical studies of the serum glucose results are elevated listed in Table I. The three-hour value was significantly at the sixth-month test. Insulin The serum insulin results are shown in Table II. There was a significant elevation of the fasting and three-hour values at the sixth-month test. Discussion In recent years, there has been a large increase in the development and testing of new orally active progestin steroids. These products have shown a wide range of receptor binding and androgenic, The estrogenic and progestogenic biologic activity. steroid gestodene shows little estrogen receptor binding and strong These affinity for progestin and androgen receptors (3). characteristics suggested that it would be an excellent progestin Several formulations were produced for oral contraceptive use. utilizing both the monophasic and triphasic design in combination with the estrogen ethinyl estradiol. These drugs have been tested In addition, and show good cycle control and pregnancy prevention. the metabolic effects, especially for lipid and carbohydrate metabolism, have received special attention. The present study extends the experience with a gestodene monophasic oral contraceptive where carbohydrate metabolism was prospectively evaluated over a six-month period using an oral glucose tolerance dynamic testing procedure. Table III summarizes the data from the present study along with published data from studies on carbohydrate metabolism during gestodene OC use (4-12). The results of this study suggest that gestodene has the ability to alter carbohydrate its androgen metabolism possibly through receptor activity. This trend was suggested in other studies but These the data were not always statistically significant (4-8). new data also suggest that the triphasic preparations have a similar effect on carbohydrate metabolism to that seen with the
536
Contraception
N.S.
N.S.
co.03
P
N.S.*
2.3
t
8.5 0.8
7.0
5.7
0.7
S.E.M.
59.1
1.4
63.4
57.8
7.2
Mean
2
0.9
1
0.5
Control
Fasting
Time in hours
Test
3.6
2.6
16.7
3
0.9
8.6
Fasting
7.0
62.7
0.5
7.5
73.7
1
tOleranCe
estradiol
9.5
67.5
2
4.5
31.6
3
Six-Month
Table II. Mean + SEM serum insulin values (u IUnits/ml) during an Oral glUCOSe in women before and after using a monophsic gestodene/ethinyl contraceptive for six months (N=25)
test oral
d.
C.
b.
a.
12 6 6
19
50
25
1991
1991
Fasting Blood
-
Monophasic OGTT
Monophasic OGTT
Monophasic OGTT
Triphasic
22
1990
6
Monophasic
1989
Monophasic OGTT (d)
6
10
1989
OGTT
Triphasic
6
18
OGTT
1989
Triphasic
6
10
1988
Review of the literature on the effects of contraceptives on carbohydrate metabolism Year Duration Type Type of Number Published of Women of OC Use OC testing Tested in Months 1987 10 6 Triphasic OGTT (b) (a)
Elevated 3-hour value
N.S.
N.S.
N.S.
N.S.
N.S.
N.S.
Increased but N.S. Increased area under curve Increased but N.S. Increased but N.S. N.S.
Increased but N.S. (c) N.S. Increased but N.S. Increased but N.S. N.S.
Insulin Results
Glucose Results
gestodene-containing
oral
Elevated fasting: 3-hour value The triphasic pills contained gestodene at 50, 70 and 100 mcg and ethinyl e&radio1 at 30, 40 and 30 mcg. OGTT indicates oral glucose tolerance test. N.S. indicates no significant change. The monophasic pills contained gestodene at 75 mcg and ethinyl estradiol at 30 mcg.
Van der Vange et a1.(4) Petersen et al. (5) Miccolii et al. (6,7) Fioretti et al. (8) Runnebaum and Rabe (9) Ball et al. (10) Petersen et al. (11) Creatsas et al (12) Present Study
Author/ Reference
Table III.
? ? : % z 2
zl co
Contraception
This probably can be attributed to a similar monophasic pills. total steroid dose per cycle in the triphasic preparations (gestodene 1650 vs. 1575 mcg and ethinyl estradiol 680 vs. 630 mcg per cycle in triphasic relative to monophasic preparations). These preliminary results suggest that, when the oral contracep:i;;s containing low amounts of the progestin gestodene are The long-term carbohydrate metabolism may be slightly altered. effects of these formulations will need further study. Little data oral progestin new these that show currently exists to contraceptives are superior to the ones currently in use.
References Spellacy MN. Family Planning Risk Scoring System updated. Fert Steril 1991;55:828-29. for 2. Dudley RA, Edwards P, Ekins RP et al. Guidelines immunoassay data processing. Clin Chem 1985;31:1264-71. 3. Pollow K, Juchem M, Grill HJ et al. Gestodene, a novel synthetic progestin - characterization of binding to receptor and serum proteins. Contraception 1989;40:325-41. 4. Van der Vange N, Kloosterboor HJ, Haspels AA. Effect of seven low-dose combined contraceptive preparations on oral carbohydrate metabolism. Am J Obstet Gynecol 1987;156:918-22. 5. Petersen KR, Skouby SO, Dreisler A, Kuhl C, Svenstrup B. Comparative trial of the effects on glucose tolerance and lipoprotein metabolism of two new oral contraceptives containing gestoden and desogestrel. Acta Obstet Gynecol Stand 1988;67:37-41. 6. Miccoli R, Orlandi MC, Fruzzetti F et al. Metabolic effects of three new low-dose pills. A six-month experience. Contraception 1989;39:643-53. Effetti dei 7. Miccoli R, Orlandi MD, Fruzzetti F et al. contracettivi orali a basse dosi sul metabolismo glucidico. Minerva Ginecol 1989;41:441-44. 8. Fioretti P, Fruzzetti F, Navalesi R et al. Clinical and metabolic effects of a pill containing 30 mcg ethinyl estradiol plus 75 mcg gestodene. Contraception 1989;40:64963. 9. Runnebaum B, Rabe TH. Neue Gestagene in oralen hormonalen. Kontrazeptiva.Arch Gynecol Obstet 1989;245:1000-05. 10. Ball MJ, Ashwell E, Jackson M, Gillmer MDG. Comparison of two triphasic contraceptives with differentprogestogens. Effects on metabolism Contraception and coagulation proteins. 1990;41:363-76. Desogestrel and 11. Petersen KR, Skouby SO, Pedersen RG. gestodene in oral contraceptives. 12 months' assessment of Cbstet Gynecol carbohydrate and lipoprotein metabolism. 1991;78:666-72. 12. Creatsas G, Adamopoulos F, Eleftherious N et al. Clinical and gestodene/ethinyl metabolic effects of the monophasic estradiol pill for contraception during adolescence. Adolesc Fediatr Gynecol 1991:4:76-81. 1.
45:533-539,
1992
Six-month Carbohydrate Metabolism Studies in Women Using Oral Contraceptives Containing Gestodene and Ethinyl Estradiol*
William N. Spellacy, M.D. John C.M. Tsibris, Ph.D. Debra L. Hunter-Bonner, B.S. Shelley Smalling, R.N., B.S. Ronald A. Chez, M.D. Jeffrey L. Angel, M.D. William F. O'Brien, M.D. The Department of Obstetrics and Gynecology, of the University of South Florida College of Medicine, Suite 514, 4 Columbia Drive, Tampa, Florida 33606
Abstract Twenty-five women had their carbohydrate metabolism prospectively evaluated during the six months that they used a gestodene and ethinyl estradiol monophasic oral contraceptive. Serum glucose and insulin levels were measured during a 75-gram three-hour oral glucose tolerance test. At the six-month test, the three-hour glucose and the fasting and three-hour insulin values were significantly elevated. The literature on carbohydrate metabolism during gestodene oral contraceptive use is also reviewed.
*Sunoort: These studies were supported by a grant from the WyethAyerst Laboratories, Philadelphia, PA. Submitted Accepted
for publication for publication
Copyright
0
1992
January April 14,
1992 1992
6,
Butterworth-Heinemann
534
Contraception
Introduction During the last forty years, oral contraceptives (OC) have become a leading method of family planning. Over that time many modifications have occurred in the OC formulations, including a significant reduction in the steroid content and three alterations in the steroid dose during the month or the triphasic types. Recently, the OC has again been altered by introducing several new progestins into the formulation. This study prospectively evaluated the effects of a combination type oral contraceptive containing the progestin gestodene on carbohydrate metabolism during the six months of use. Methods Twenty-five women seeking oral contraceptives (OC) were asked to participate in this study. They were evaluated to determine that there were no contraindications to OC use (1). They had not been pregnant or used steroid contraceptives for at least three months. All of the women signed informed consents approved by the Institutional Review Board. Each subject had a control oral glucose tolerance test performed in the morning after a ten-hour fast. A venous blood sample was drawn from the arm and they then drank a solution containing 75 grams of glucose. Repeat blood samples were drawn at 0.5, 1,2 and 3 hours. The blood samples were allowed to clot and the serum was separated and stored at -22°C until later analysis. Each subject was then informed about the OC and the importance of daily use and they were given a supply of the drug.a At the end of the sixth cycle of use, each women had another identical oral glucose tolerance test performed. All samples from the two tests on a subject were run in duplicate in the same assay. The glucose content was determined using a Beckman glucose analyzer (Fullerton, California). The interassay and intraassay precision had a standard deviation less than 3.0 and 2.5 mg/dl, respectively. The insulin content was determined using an "51-insulin radioimmunoassay technique (kits purchased from Diagnostic Products Corporation, Los Angeles, California). The serum insulin data from the Beckman Gamma 5500 B counter were transported to a Beckman Data Capture program and were analyzed using a logit/log curve fit. The interassay and intraassay coefficients of variation did not exceed 10% in the 5200 uIU/ml range (2).
aEach monthly supply of the monophasic oral contraceptive consisted of 21 active tablets: each tablet containing 75 mcg gestodene and 30 mcg ethinyl estradiol.
535
Contraception
Changes between the baseline and cycle tests were analyzed paired Student's t tests, with probability values taken from tailed tables.
by two-
Results The women in the study had a mean age (+ SRM) of 26.1 + 1.1 Their mean control years and their mean parity was 0.7 + 0.1. weight was 143.5 + 6.1 pounds and at the sixth month their mean weight was 144.2 f 6.2 pounds (t = 0.43, p not significant). There were no complications experienced by the women with the OC and no pregnancies occurred. Glucose The statistical studies of the serum glucose results are elevated listed in Table I. The three-hour value was significantly at the sixth-month test. Insulin The serum insulin results are shown in Table II. There was a significant elevation of the fasting and three-hour values at the sixth-month test. Discussion In recent years, there has been a large increase in the development and testing of new orally active progestin steroids. These products have shown a wide range of receptor binding and androgenic, The estrogenic and progestogenic biologic activity. steroid gestodene shows little estrogen receptor binding and strong These affinity for progestin and androgen receptors (3). characteristics suggested that it would be an excellent progestin Several formulations were produced for oral contraceptive use. utilizing both the monophasic and triphasic design in combination with the estrogen ethinyl estradiol. These drugs have been tested In addition, and show good cycle control and pregnancy prevention. the metabolic effects, especially for lipid and carbohydrate metabolism, have received special attention. The present study extends the experience with a gestodene monophasic oral contraceptive where carbohydrate metabolism was prospectively evaluated over a six-month period using an oral glucose tolerance dynamic testing procedure. Table III summarizes the data from the present study along with published data from studies on carbohydrate metabolism during gestodene OC use (4-12). The results of this study suggest that gestodene has the ability to alter carbohydrate its androgen metabolism possibly through receptor activity. This trend was suggested in other studies but These the data were not always statistically significant (4-8). new data also suggest that the triphasic preparations have a similar effect on carbohydrate metabolism to that seen with the
536
Contraception
N.S.
N.S.
co.03
P
N.S.*
2.3
t
8.5 0.8
7.0
5.7
0.7
S.E.M.
59.1
1.4
63.4
57.8
7.2
Mean
2
0.9
1
0.5
Control
Fasting
Time in hours
Test
3.6
2.6
16.7
3
0.9
8.6
Fasting
7.0
62.7
0.5
7.5
73.7
1
tOleranCe
estradiol
9.5
67.5
2
4.5
31.6
3
Six-Month
Table II. Mean + SEM serum insulin values (u IUnits/ml) during an Oral glUCOSe in women before and after using a monophsic gestodene/ethinyl contraceptive for six months (N=25)
test oral
d.
C.
b.
a.
12 6 6
19
50
25
1991
1991
Fasting Blood
-
Monophasic OGTT
Monophasic OGTT
Monophasic OGTT
Triphasic
22
1990
6
Monophasic
1989
Monophasic OGTT (d)
6
10
1989
OGTT
Triphasic
6
18
OGTT
1989
Triphasic
6
10
1988
Review of the literature on the effects of contraceptives on carbohydrate metabolism Year Duration Type Type of Number Published of Women of OC Use OC testing Tested in Months 1987 10 6 Triphasic OGTT (b) (a)
Elevated 3-hour value
N.S.
N.S.
N.S.
N.S.
N.S.
N.S.
Increased but N.S. Increased area under curve Increased but N.S. Increased but N.S. N.S.
Increased but N.S. (c) N.S. Increased but N.S. Increased but N.S. N.S.
Insulin Results
Glucose Results
gestodene-containing
oral
Elevated fasting: 3-hour value The triphasic pills contained gestodene at 50, 70 and 100 mcg and ethinyl e&radio1 at 30, 40 and 30 mcg. OGTT indicates oral glucose tolerance test. N.S. indicates no significant change. The monophasic pills contained gestodene at 75 mcg and ethinyl estradiol at 30 mcg.
Van der Vange et a1.(4) Petersen et al. (5) Miccolii et al. (6,7) Fioretti et al. (8) Runnebaum and Rabe (9) Ball et al. (10) Petersen et al. (11) Creatsas et al (12) Present Study
Author/ Reference
Table III.
? ? : % z 2
zl co
Contraception
This probably can be attributed to a similar monophasic pills. total steroid dose per cycle in the triphasic preparations (gestodene 1650 vs. 1575 mcg and ethinyl estradiol 680 vs. 630 mcg per cycle in triphasic relative to monophasic preparations). These preliminary results suggest that, when the oral contracep:i;;s containing low amounts of the progestin gestodene are The long-term carbohydrate metabolism may be slightly altered. effects of these formulations will need further study. Little data oral progestin new these that show currently exists to contraceptives are superior to the ones currently in use.
References Spellacy MN. Family Planning Risk Scoring System updated. Fert Steril 1991;55:828-29. for 2. Dudley RA, Edwards P, Ekins RP et al. Guidelines immunoassay data processing. Clin Chem 1985;31:1264-71. 3. Pollow K, Juchem M, Grill HJ et al. Gestodene, a novel synthetic progestin - characterization of binding to receptor and serum proteins. Contraception 1989;40:325-41. 4. Van der Vange N, Kloosterboor HJ, Haspels AA. Effect of seven low-dose combined contraceptive preparations on oral carbohydrate metabolism. Am J Obstet Gynecol 1987;156:918-22. 5. Petersen KR, Skouby SO, Dreisler A, Kuhl C, Svenstrup B. Comparative trial of the effects on glucose tolerance and lipoprotein metabolism of two new oral contraceptives containing gestoden and desogestrel. Acta Obstet Gynecol Stand 1988;67:37-41. 6. Miccoli R, Orlandi MC, Fruzzetti F et al. Metabolic effects of three new low-dose pills. A six-month experience. Contraception 1989;39:643-53. Effetti dei 7. Miccoli R, Orlandi MD, Fruzzetti F et al. contracettivi orali a basse dosi sul metabolismo glucidico. Minerva Ginecol 1989;41:441-44. 8. Fioretti P, Fruzzetti F, Navalesi R et al. Clinical and metabolic effects of a pill containing 30 mcg ethinyl estradiol plus 75 mcg gestodene. Contraception 1989;40:64963. 9. Runnebaum B, Rabe TH. Neue Gestagene in oralen hormonalen. Kontrazeptiva.Arch Gynecol Obstet 1989;245:1000-05. 10. Ball MJ, Ashwell E, Jackson M, Gillmer MDG. Comparison of two triphasic contraceptives with differentprogestogens. Effects on metabolism Contraception and coagulation proteins. 1990;41:363-76. Desogestrel and 11. Petersen KR, Skouby SO, Pedersen RG. gestodene in oral contraceptives. 12 months' assessment of Cbstet Gynecol carbohydrate and lipoprotein metabolism. 1991;78:666-72. 12. Creatsas G, Adamopoulos F, Eleftherious N et al. Clinical and gestodene/ethinyl metabolic effects of the monophasic estradiol pill for contraception during adolescence. Adolesc Fediatr Gynecol 1991:4:76-81. 1.