Contraception
46:335-347,
1992
CLINICAL AND METABOLIC EFFECTS OF A TRIPHASIC PILL CONTAINING GESTODENE
F. Fruzzetti, C. Ricci, I. Nicoletti, P. Fioretti Department of Obstetrics and Gynecology University of Pisa Pisa, Italy
ABSTRACT
The clinical and metabolic effects of a low-dose triphasic oral contraceptive containing gestodene were investigated in 42 healthy women during 6 months of treatment. No pregnancies and no severe side effects occurred during the study. The pill exerted good cycle control and the incidence of irregular bleeding was very low. As for the coagulator-y system, there was an increase in prothrombin activity and in fibrinopeptide A plasma levels, and a decrease in activated partial thromboplastin time. Antithrombin III activity, fibrinogen concentration and platelets count did not change during pill intake. No significant modifications in plasma total-cholesterol, low density lipoprotein-cholesterol or in the subfraction high density lipoprotein2-cholesterol (HDL2CH) were observed. Serum triglycerides, HDL-CH and HDLj-CH levels were significantly higher at the end of treatment. The pill did not alter fasting insulin and glucose levels or their response to an oral glucose tolerance test. These minimal effects on metabolism, combined with its high efficacy and acceptability, may suggest that this triphasic formulation with gestodene seems to be a safe and reliable contraceptive agent.
Submittedfor publication Accepted
for publication
January
July
CopyrightQ1992Butterworth-Heinemann
14,
6, 1992
1992
336
Contraception
INTRODUCTION The goal of research on oral contraception has been to a pill with an improved safety profile while obtain maintaining high contraceptive efficacy and cycle control. means of achieving these goals has been the One of the reduction of steroid dosages. Reducing the ethinylestradiol (EE) dose to below 50 mcg per day has led to a decreased risk of venous thromboembolic disease and a lower frequency of thromboembolic arterial disease (1,2). Besides estrogens, the progestogen component of oral contraceptives (OCs) may arterial disease in OC users (2-4). In fact, also increase are known to alter lipoprotein composition and progestogens glucose hoemostasis (3-6). However, as well documented, all these metabolic effects are strictly related to the dose and type of the progestin. 19-Nortestosterone derivatives, like levonorgestrel, at high dosages, decrease the levels of high density lipoprotein-cholesterol (HDL-CH) and enhance the concentrations of low density lipoprotein-cholesterol when (LDL-CH) these progestins are (4,5). Moreover, the associated with estrogens, like in OC preparations, metabolic effects may be counterbalanced by the estrogen component. Thus, in order to overcome any metabolic effects due to OC ingestion, research has been directed towards modifying the progestogen component of ocs, either by reducing the dosage, or by creating new progestins, or by improving the estro/progestin ratio, such as in triphasic pills. Gestodene, a 4 15-levonorgestrel, is a 19-nortestosterone derivative which exerts a greater inhibitory effect on ovulation than its parent compound levonorgestrel (7). Therefore, gestodene has been used at lower doses than levonorgestrel in OC preparations. Clinical data obtained on women taking a low dose monophasic OC with gestodene showed that it has a high efficacy, a good cycle control and that it doesn't have any negative metabolic effects (8-10). The aim of the present study was to evaluate the clinical and metabolic effects of a short-term treatment with a triphasic combination containing gestodene. MATERIALS AND METHODS Forty-two healthy women, aged 19-43 years (M + SE : 25.7 +. 0.8), participated in the study. The criteria used to enter the study included the absence of any absolute or relative contraindications to hormonal contraception, a body mass index (BMI; calculated as weight (kg)/height (m2)) of no more than 26.9, and no use of OCs or other endocrine active drugs for at least 12 months before the study. The study had received the approval of the Local Ethical Committee.
337 Before starting pill treatment, information from each woman pattern, parity, abortion on menstrual and previous contraceptive methods was obtained. Pelvic and physical examinations were also done, including measurement of body weight and blood pressure. The triphasic pill containing 30, 40 and 30 mcg of EE, combined with 50, 70 and 100 mcg of gestodene, the first pills taken for the first 6 days, then the second for 5 days 6 months and finally the third for 10 days, was given for with the following instructions: tablet-taking started on the first day of the menstrual period; a 7-day treatmentfree interval had to be observed before starting the next Details concerning cycle length, duration package. and intensity of withdrawal bleedings and missed tablets were carefully recorded by the women on charts given to them. Intermenstrual bleedings were classified as "breakthrough bleeding" when the amount of the blood loss required the use of a sanitary protection, and as "spotting" in all other cases. All these clinical events were evaluated and recorded in special charts during the check-ups made after 3 and 6 On these occasions, detailed months of pill intake. gynecological and physical examinations were also performed including blood pressure and body weight measurements. Siderecorded only if they were reported by the effects were women. for measurement of biochemical Fasting blood specimens parameters of liver and renal functions and the coagulator-y system (fibrinopeptide A (FPA), antithrombin III (AT III) activity, fibrinogen, activated partial thromboplastin time count and prothrombin activity) were (aPTT), platelets collected in all subjects before treatment and at the 6th cycle, during the last 3 days of pill intake. The effects of the pill on carbohydrate and lipid metabolism were also evaluated. Lipid metabolism was evaluated in 28 women. All of them were instructed to observe a fasting period of 13 hours before the metabolic tests. Blood specimens were collected at 8:00 in the morning, before and after 6 months of treatment for total-cholesterol (T-CH), triglycerides (TG), HDL-CH and its fractions HDL2-CH and HDL3-CH, and LDL-CH. In 14 of the 42 women taking the pill on the effects of triphasic preparation, the carbohydrate metabolism were also evaluated. These subjects drank no more than 2 ounces of alcohol per day and had a standard Mediterranean diet (about 45% carbohydrate, 35% fat, 20% protein per day). No differences in eating, smoking and drinking habits were found among these women before and strenuous during the study. None of them were engaged in physical exercise. All of them were instructed to take more than 250 gm per day of carbohydrates for 3 days before the metabolic test. At 8:00 in the morning, a fasting blood specimen was collected for blood glucose and insulin. An oral glucose tolerance test (OGTT) (75 gm of glucose to drink) was then performed to evaluate changes in glucose and
338
Contraception
insulin response. Blood samples were drawn after 30, 60, 90 and 120 minutes. Blood specimens for FPA measurement were collected as previously described (11). All samples from each subject using a radioimmunoassay assayed in duplicate, were technique (Mallinckrodt; St. Louis, Missouri, U.S.A.). AT III activity was measured using a commercial kit employing a chromogenic substrate (Boehringer Biochemia Robin; Milan, Italy). Measurements of fibrinogen, prothrombin activity and aPTT were performed by using commercial kits (Baldacci; Pisa, Italy). Blood specimens for lipid and glucose determinations were analyzed immediately. TG and T-CH were measured by enzymatic methods (Boehringer Biochemia; Milan, HDL-CH was measured in the supernatant after Italy); precipitation of very low density lipoprotein and LDL with heparin and manganese chloride. HDL2-CH and HDL3-CH fractions were separated according to Gidez et al. (12). Immediately after HDL2-CH precipitation, the levels of HDL3CH were estimated. HDL2-CH was calculated by subtracting the HDL3-CH value from the total HDL-CH value. LDL-CH was determined by the equation of Friedewald and associates determination were specimens for insulin (13). Blood centrifuged and plasma was stored at -20' C until analyzed. All samples from each subject were assayed in duplicate in the same assay by using a radioimmunoassay technique. Plasma glucose was measured with a glucose oxidase method using a Beckman Glucose Analyzer. results was Statistical analysis of the biochemical performed by using the Student's "t" test for paired data or the two-way analysis of variance, as appropriate.
RESULTS All results are reported as the percentage absolute values + standard error (M + SE).
or the mean
of
Clinical data There were no pregnancies during treatment. All the subjects completed the 6 cycles of treatment except for one subject who dropped out at the 4th cycle for gallstone disease. Before pill intake, the majority of women (78.5%; 33 subjects) reported regular cycles (from 28 to 32 days). Four subjects (9.5%) had a cycle length longer than 33 days. In 4.7% of the women (2 patients), the cycle length was 23 to 25 days and in 3 subjects (7.1%) it was 26 to 27 days (Tab. I). During the first cycle of treatment, 40 women (95.2%) had a cycle length between 21 and 25 days, according to the modality of first pill-package assumption (Tab. I). At the 3rd cycle of treatment, the cycle length was 28-29 days in 41 subjects (97.6%). At the 6th cycle, all subjects
339
Contraception
had a cycle length of 28-29 days (Tab I). None of the women showed amenorrhoea during the entire observation period. During the last cycle prior to the start of the study, most patients (47.6%) were having periods of approximately 6-7 days (Tab. II). During the course of treatment, there was a slight transition from longer menstruations to shorter ones with an increase of patients with withdrawal bleeding lasting 2 or 3 days (from 9.5% before treatment to 14.2% at the 3rd cycle and to 19.5% at the end of observation). at the 3rd and 6th cycle of pill intake, the However, majority of subjects (83.3% and 80.5%, respectively) had menstrual bleeding for 4-5 days (Tab. II). The amount of menstrual flow did not change greatly. It was scanty in 2 women (4.7%) before the study, and in 5 (11.9%) and in 8 patients (19.5%) at the 3rd and at the 6th month of treatment, respectively. The amount was normal in 85.3% of the subjects at the 3rd cycle and in 78% of the subjects at the end of observation (Tab. II). As for the incidence of irregular bleedings, both spotting breakthrough bleeding rarely occurred (Tab. III). and The spotting rate was 5.9%, as computed in terms of the total number of pill cycles. In 4.7% of all cycles, spotting the first 3 months of pill intake. occurred within Breakthrough bleeding, reported by one subject before treatment, was present in the same woman only in the first cycle of pill intake (Tab. III).
Table I. Effects of the triphasic pill containing gestodene on cycle length ____________________----------__________-------------------_ CYCLE LENGTH CYCLE OF TREATMENT (DAYS) -_--------------------------------LAST UNTREATED 1 3 6 CYCLE 23-25
4.7
26-27
7.1
28-32
78.5
2 33
No.of patients
95.2
4.7
2.1
-
97.6
100 _
9.5
42
42
42
41
____------------------------------------The results are reported as percentage of total patients.
Contraception
340
Table II. Effects of the triphasic pill containing gestodene on duration and amount of menstrual bleeding DURATION (DAYS)
CYCLE OF TREATMENT __-______--_____--__-__--LAST UNTREATED CYCLE
3
9.5
13 4-5
42.8
26
41.6
6
14.2
19.5
83.3
80.5
2.3
AMOUNT SCANTY
4.7
11.9
19.5
NORMAL
76.1
85.7
78
PROFUSE
19
No. of patients
42
2.3
2.4
42
41
The results are reported as percentage of total patients.
Table III. Incidence of irregular bleeding during treatment with the triphasic pill containing gestodene CYCLE OF TREATMENT LAST UNTREATED CYCLE SPOTTING
4.7
BREAKTHROUGH BLEEDING
2.3
1
2
3
4
19
7.1
2.3
4.7
5
6
2.3
-
No.of patients 42 42 42 42 42 41 41 ---____----__-----------------------------~------~------~--The results are reported as percentage of total patients.
Contraception
341
There were few side effects and none of the patients stopped taking the pill because of them. The pill did not modify BMI values (from 21.1 2 0.4 Kg/m2 before study to 21.3 + 0.4 Kg/m2 at the 3rd cycle and to 21.3 + 0.3 Kg/m2 at the end of treatment), or blood pressure values (Systolic values: 112.3 + 8 mm Hg before study; 111.2 + 9.4 mm Hg at the 3rd month; 110.9 + 8.2 mm Hg at the 6th month. Diastolic values: 73 + 7.8 mm Hg before study; 72.6 + 5.6 mm Hg at the 3rd month; 74.3 + 6.5 mm Hg at the 6th month). Before pill intake, 45.2% and 30.9% of women suffered from breast tension and headaches, respectively. At the end of pill intake, breast tension was reported by 26.8% and headaches by 24.3% of the women. Reduced libido occurred in one subject. Besides a very low incidence of side effects, an improvement in premenstrual symptoms was reported during pill use. In particular, at the end of observation, dysmenorrhoea, nausea, depression and nervousness had disappeared in all the subjects affected by these symptoms prior to pill intake.
The triphasic formulation did not modify renal or liver functions. Alkaline phosphatase decreased significantly before treatment to 109.4 + (p
46:335-347,
1992
CLINICAL AND METABOLIC EFFECTS OF A TRIPHASIC PILL CONTAINING GESTODENE
F. Fruzzetti, C. Ricci, I. Nicoletti, P. Fioretti Department of Obstetrics and Gynecology University of Pisa Pisa, Italy
ABSTRACT
The clinical and metabolic effects of a low-dose triphasic oral contraceptive containing gestodene were investigated in 42 healthy women during 6 months of treatment. No pregnancies and no severe side effects occurred during the study. The pill exerted good cycle control and the incidence of irregular bleeding was very low. As for the coagulator-y system, there was an increase in prothrombin activity and in fibrinopeptide A plasma levels, and a decrease in activated partial thromboplastin time. Antithrombin III activity, fibrinogen concentration and platelets count did not change during pill intake. No significant modifications in plasma total-cholesterol, low density lipoprotein-cholesterol or in the subfraction high density lipoprotein2-cholesterol (HDL2CH) were observed. Serum triglycerides, HDL-CH and HDLj-CH levels were significantly higher at the end of treatment. The pill did not alter fasting insulin and glucose levels or their response to an oral glucose tolerance test. These minimal effects on metabolism, combined with its high efficacy and acceptability, may suggest that this triphasic formulation with gestodene seems to be a safe and reliable contraceptive agent.
Submittedfor publication Accepted
for publication
January
July
CopyrightQ1992Butterworth-Heinemann
14,
6, 1992
1992
336
Contraception
INTRODUCTION The goal of research on oral contraception has been to a pill with an improved safety profile while obtain maintaining high contraceptive efficacy and cycle control. means of achieving these goals has been the One of the reduction of steroid dosages. Reducing the ethinylestradiol (EE) dose to below 50 mcg per day has led to a decreased risk of venous thromboembolic disease and a lower frequency of thromboembolic arterial disease (1,2). Besides estrogens, the progestogen component of oral contraceptives (OCs) may arterial disease in OC users (2-4). In fact, also increase are known to alter lipoprotein composition and progestogens glucose hoemostasis (3-6). However, as well documented, all these metabolic effects are strictly related to the dose and type of the progestin. 19-Nortestosterone derivatives, like levonorgestrel, at high dosages, decrease the levels of high density lipoprotein-cholesterol (HDL-CH) and enhance the concentrations of low density lipoprotein-cholesterol when (LDL-CH) these progestins are (4,5). Moreover, the associated with estrogens, like in OC preparations, metabolic effects may be counterbalanced by the estrogen component. Thus, in order to overcome any metabolic effects due to OC ingestion, research has been directed towards modifying the progestogen component of ocs, either by reducing the dosage, or by creating new progestins, or by improving the estro/progestin ratio, such as in triphasic pills. Gestodene, a 4 15-levonorgestrel, is a 19-nortestosterone derivative which exerts a greater inhibitory effect on ovulation than its parent compound levonorgestrel (7). Therefore, gestodene has been used at lower doses than levonorgestrel in OC preparations. Clinical data obtained on women taking a low dose monophasic OC with gestodene showed that it has a high efficacy, a good cycle control and that it doesn't have any negative metabolic effects (8-10). The aim of the present study was to evaluate the clinical and metabolic effects of a short-term treatment with a triphasic combination containing gestodene. MATERIALS AND METHODS Forty-two healthy women, aged 19-43 years (M + SE : 25.7 +. 0.8), participated in the study. The criteria used to enter the study included the absence of any absolute or relative contraindications to hormonal contraception, a body mass index (BMI; calculated as weight (kg)/height (m2)) of no more than 26.9, and no use of OCs or other endocrine active drugs for at least 12 months before the study. The study had received the approval of the Local Ethical Committee.
337 Before starting pill treatment, information from each woman pattern, parity, abortion on menstrual and previous contraceptive methods was obtained. Pelvic and physical examinations were also done, including measurement of body weight and blood pressure. The triphasic pill containing 30, 40 and 30 mcg of EE, combined with 50, 70 and 100 mcg of gestodene, the first pills taken for the first 6 days, then the second for 5 days 6 months and finally the third for 10 days, was given for with the following instructions: tablet-taking started on the first day of the menstrual period; a 7-day treatmentfree interval had to be observed before starting the next Details concerning cycle length, duration package. and intensity of withdrawal bleedings and missed tablets were carefully recorded by the women on charts given to them. Intermenstrual bleedings were classified as "breakthrough bleeding" when the amount of the blood loss required the use of a sanitary protection, and as "spotting" in all other cases. All these clinical events were evaluated and recorded in special charts during the check-ups made after 3 and 6 On these occasions, detailed months of pill intake. gynecological and physical examinations were also performed including blood pressure and body weight measurements. Siderecorded only if they were reported by the effects were women. for measurement of biochemical Fasting blood specimens parameters of liver and renal functions and the coagulator-y system (fibrinopeptide A (FPA), antithrombin III (AT III) activity, fibrinogen, activated partial thromboplastin time count and prothrombin activity) were (aPTT), platelets collected in all subjects before treatment and at the 6th cycle, during the last 3 days of pill intake. The effects of the pill on carbohydrate and lipid metabolism were also evaluated. Lipid metabolism was evaluated in 28 women. All of them were instructed to observe a fasting period of 13 hours before the metabolic tests. Blood specimens were collected at 8:00 in the morning, before and after 6 months of treatment for total-cholesterol (T-CH), triglycerides (TG), HDL-CH and its fractions HDL2-CH and HDL3-CH, and LDL-CH. In 14 of the 42 women taking the pill on the effects of triphasic preparation, the carbohydrate metabolism were also evaluated. These subjects drank no more than 2 ounces of alcohol per day and had a standard Mediterranean diet (about 45% carbohydrate, 35% fat, 20% protein per day). No differences in eating, smoking and drinking habits were found among these women before and strenuous during the study. None of them were engaged in physical exercise. All of them were instructed to take more than 250 gm per day of carbohydrates for 3 days before the metabolic test. At 8:00 in the morning, a fasting blood specimen was collected for blood glucose and insulin. An oral glucose tolerance test (OGTT) (75 gm of glucose to drink) was then performed to evaluate changes in glucose and
338
Contraception
insulin response. Blood samples were drawn after 30, 60, 90 and 120 minutes. Blood specimens for FPA measurement were collected as previously described (11). All samples from each subject using a radioimmunoassay assayed in duplicate, were technique (Mallinckrodt; St. Louis, Missouri, U.S.A.). AT III activity was measured using a commercial kit employing a chromogenic substrate (Boehringer Biochemia Robin; Milan, Italy). Measurements of fibrinogen, prothrombin activity and aPTT were performed by using commercial kits (Baldacci; Pisa, Italy). Blood specimens for lipid and glucose determinations were analyzed immediately. TG and T-CH were measured by enzymatic methods (Boehringer Biochemia; Milan, HDL-CH was measured in the supernatant after Italy); precipitation of very low density lipoprotein and LDL with heparin and manganese chloride. HDL2-CH and HDL3-CH fractions were separated according to Gidez et al. (12). Immediately after HDL2-CH precipitation, the levels of HDL3CH were estimated. HDL2-CH was calculated by subtracting the HDL3-CH value from the total HDL-CH value. LDL-CH was determined by the equation of Friedewald and associates determination were specimens for insulin (13). Blood centrifuged and plasma was stored at -20' C until analyzed. All samples from each subject were assayed in duplicate in the same assay by using a radioimmunoassay technique. Plasma glucose was measured with a glucose oxidase method using a Beckman Glucose Analyzer. results was Statistical analysis of the biochemical performed by using the Student's "t" test for paired data or the two-way analysis of variance, as appropriate.
RESULTS All results are reported as the percentage absolute values + standard error (M + SE).
or the mean
of
Clinical data There were no pregnancies during treatment. All the subjects completed the 6 cycles of treatment except for one subject who dropped out at the 4th cycle for gallstone disease. Before pill intake, the majority of women (78.5%; 33 subjects) reported regular cycles (from 28 to 32 days). Four subjects (9.5%) had a cycle length longer than 33 days. In 4.7% of the women (2 patients), the cycle length was 23 to 25 days and in 3 subjects (7.1%) it was 26 to 27 days (Tab. I). During the first cycle of treatment, 40 women (95.2%) had a cycle length between 21 and 25 days, according to the modality of first pill-package assumption (Tab. I). At the 3rd cycle of treatment, the cycle length was 28-29 days in 41 subjects (97.6%). At the 6th cycle, all subjects
339
Contraception
had a cycle length of 28-29 days (Tab I). None of the women showed amenorrhoea during the entire observation period. During the last cycle prior to the start of the study, most patients (47.6%) were having periods of approximately 6-7 days (Tab. II). During the course of treatment, there was a slight transition from longer menstruations to shorter ones with an increase of patients with withdrawal bleeding lasting 2 or 3 days (from 9.5% before treatment to 14.2% at the 3rd cycle and to 19.5% at the end of observation). at the 3rd and 6th cycle of pill intake, the However, majority of subjects (83.3% and 80.5%, respectively) had menstrual bleeding for 4-5 days (Tab. II). The amount of menstrual flow did not change greatly. It was scanty in 2 women (4.7%) before the study, and in 5 (11.9%) and in 8 patients (19.5%) at the 3rd and at the 6th month of treatment, respectively. The amount was normal in 85.3% of the subjects at the 3rd cycle and in 78% of the subjects at the end of observation (Tab. II). As for the incidence of irregular bleedings, both spotting breakthrough bleeding rarely occurred (Tab. III). and The spotting rate was 5.9%, as computed in terms of the total number of pill cycles. In 4.7% of all cycles, spotting the first 3 months of pill intake. occurred within Breakthrough bleeding, reported by one subject before treatment, was present in the same woman only in the first cycle of pill intake (Tab. III).
Table I. Effects of the triphasic pill containing gestodene on cycle length ____________________----------__________-------------------_ CYCLE LENGTH CYCLE OF TREATMENT (DAYS) -_--------------------------------LAST UNTREATED 1 3 6 CYCLE 23-25
4.7
26-27
7.1
28-32
78.5
2 33
No.of patients
95.2
4.7
2.1
-
97.6
100 _
9.5
42
42
42
41
____------------------------------------The results are reported as percentage of total patients.
Contraception
340
Table II. Effects of the triphasic pill containing gestodene on duration and amount of menstrual bleeding DURATION (DAYS)
CYCLE OF TREATMENT __-______--_____--__-__--LAST UNTREATED CYCLE
3
9.5
13 4-5
42.8
26
41.6
6
14.2
19.5
83.3
80.5
2.3
AMOUNT SCANTY
4.7
11.9
19.5
NORMAL
76.1
85.7
78
PROFUSE
19
No. of patients
42
2.3
2.4
42
41
The results are reported as percentage of total patients.
Table III. Incidence of irregular bleeding during treatment with the triphasic pill containing gestodene CYCLE OF TREATMENT LAST UNTREATED CYCLE SPOTTING
4.7
BREAKTHROUGH BLEEDING
2.3
1
2
3
4
19
7.1
2.3
4.7
5
6
2.3
-
No.of patients 42 42 42 42 42 41 41 ---____----__-----------------------------~------~------~--The results are reported as percentage of total patients.
Contraception
341
There were few side effects and none of the patients stopped taking the pill because of them. The pill did not modify BMI values (from 21.1 2 0.4 Kg/m2 before study to 21.3 + 0.4 Kg/m2 at the 3rd cycle and to 21.3 + 0.3 Kg/m2 at the end of treatment), or blood pressure values (Systolic values: 112.3 + 8 mm Hg before study; 111.2 + 9.4 mm Hg at the 3rd month; 110.9 + 8.2 mm Hg at the 6th month. Diastolic values: 73 + 7.8 mm Hg before study; 72.6 + 5.6 mm Hg at the 3rd month; 74.3 + 6.5 mm Hg at the 6th month). Before pill intake, 45.2% and 30.9% of women suffered from breast tension and headaches, respectively. At the end of pill intake, breast tension was reported by 26.8% and headaches by 24.3% of the women. Reduced libido occurred in one subject. Besides a very low incidence of side effects, an improvement in premenstrual symptoms was reported during pill use. In particular, at the end of observation, dysmenorrhoea, nausea, depression and nervousness had disappeared in all the subjects affected by these symptoms prior to pill intake.
The triphasic formulation did not modify renal or liver functions. Alkaline phosphatase decreased significantly before treatment to 109.4 + (p
