ORIGINAL ARTICLE
A comparison study of lipid and androgen metabolism with triphasic oral contraceptive formulations containing norgestimate or levonorgestrel ALAINJANAUD, M.D.," JACQUES ROUFFY, M.D.," DAVIDUPMALIS,M.D.,b AND MARIE-PAULE DAIN,M.D.c From t h e HBpital Saint-Louis, Paris,a The R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey.b and CILAG, Francec
Acici
Obsiei Gytiecol Scanrl 1992; Vol 71, Suppl 156: 33-38
The effects of norgestimate triphasic (Ortho Tri-Cyclen@,Tri-Cilest@)and levonorgestrel triphasic (TriphasiP) formulations on lipid and androgen metabolism were assessed in a study o f 66 healthy women treated through six menstrual cycles. Levels of the following were measured: cholesterol and its subfractions, triglycerides. carrier lipoproteins, estradiol, testosterone, and sex hormone binding globulin (SHBG). Comparison of baseline values with values after 3 and 6 months of treatment indicated that both regimens influenced lipid and androgen metabolism. There was a statistically significant betweenregimen difference in levels of high-density lipoprotein, which were favorably increased with norgestimate triphasic hut reduced with levonorgestrel triphasic. Related data on SHBG showed that plasma levels of this marker of estrogen/androgen balance were increased significantly more in the norgestimate triphasic group, providing additional evidence of low androgenicity. Both regimens inhibited follicular growth to the same extent, a s evidenced by low mean levels of estradiol in all on-therapy cycles; and both decreased free testosterone. Side effects in both groups were minor and characteristic of those observed with low-dose oral contraceptive agents. The results of the study support the reported safety and positive effects of norgestimate on lipid and androgen metabolism. in comparison with a levonorgestrel-containingcombined oral contraceptive. Key wortfs: Norgestimate, lipid metabolism, androgenicity
Introduction Estrogen dosage in modern low-dose combined oral contraceptive (OC) agents is sufficient to provide contraceptive action with good cycle control while avoiding many of the estrogen-related risks associated with earlier formulations. However, use of the low-estrogen preparations has revealed the androgenic potential of the progestins used, raising concern about the consequences of their effects on lipid metabolism as well as the possibility of other unwanted androgenic activity. Serum levels of highdensity lipoprotein (HDL) cholesterol are reduced
by androgens and androgenic progestins in OCs (1-2). Low HDL cholesterol levels are associated with an increased risk of coronary heart disease (3). Reducing the androgenicity of an OC progestin might be expected to avert untoward reduction of HDL cholesterol levels, possibly altering the OC's atherogenic potential (4). The new progestin norgestimate (NGM) was developed as part of research efforts directed at finding effective, nonandrogenic (i .e., selectively progestational) progestins. NGM is reported to be a highly effective yet minimally androgenic agent with pharmacologic similarities to natural progesterone. Acta Obstei Gynecol Scand Sirppl 1.56 (1992)
34
A . Janaud et al.
8
0 150
Days
r
15
21
125
I c19
0
12
7
reported good cycle control, a low incidence o f side effects, and no pregnancies during 12 months' use of N G M 250 pg/EE 35 pg (6). In another study of 19 women, there were no changes in fibrinopeptide A. a sensitive marker of coagulation-system activation, or in the balance between coagulant and anticoagulant factors after six treatment cycles (6). The triphasic preparation of N G M / E E was forniulated to reduce the total progestin content while maintaining the estrogen dosage constant over the course of the menstrual cycle. This phased-dose preparation of NGM/EE has been under study in the United States and abroad for several years. Thc study reported here was undertaken in France to compare metabolic effects of the NGM triphasic (Tri-Cilest@ in Europe, Ortho Tri-Cyclen@ in the United States) with those of a triphasic preparation of levonorgestrel (LNG; Trinordiol@in Europe, Triphasil@or Triquilar@in the United States) in a population of women representative of potential users.
21
Days Fig. I . Regimens of norgestimate (NGM)/ethinyl estradiol (EE) and levonorgestrel (LNG)/EE.
NGM's action in a combined OC is capable of influencing lipid metabolism favorably without adversely affecting carbohydrate metabolism or coagulation parameters (4-6).In efficacy studies of 1,473 women treated over 19,078 cycles, there were no statistically significant differences between the pregnancy rates among women using the monophasic preparation Ortho-Cyelen@ (NGM 250 pg/ethinyl estradiol [EE] 35 pg) and those using a monophasic preparation of norgestrel ( N G ) and E E (Lo/Ovral@)( 5 ) . Throughout the same study, mean changes in fasting blood glucose levels were small and clinically insignificant with both preparations. A clear distinction between the metabolic effects of NGM and N G in monophasic OCs was demonstrated in a multicenter study reported by Chapdelaine et al involving 1.261 women (4). Positive effects o n lipids were shown in the NGM/EE group, with a significant increase in H D L and a significant decrease in the low-density lipoprotein (LDL)/HDL ratio. In contrast, users of the NG-containing OC demonstrated a significant reduction in H D L , and a significant elevation in the LDL/HDL ratio. In a subpopulation of 40 women, the effect of the two OC's on sex hormone binding globulin (SHBG) was markedly different (4). SHBG levels were increased 161.1% from baseline by NGM/EE, and only 26.2% by NG/EE. These results in both lipid and S H B G parameters indicate the clear difference in metabolic profile between the two progestins, with NGM demonstrating much less androgenicity. In a study of 147 women in Germany, Becker Acta Ohster Gytiecol Scand Suppl 156 (1992)
Study design The objective of this randomized, &month study was assessment of the comparative effects o f NGM/EE and LNGlEE triphasic formulations o n serum lipids and androgens. Study population The subjects were 66 healthy women between 18 and 38 years of age with regular menstrual cycles who were sexually active and not pregnant. Subjects were excluded from the study for the following reasons: standard contraindications to the use of hormonal contraceptive agents, notably a history of thrombophlebitis or disorders related to the use of estrogens; a family history of hyperlipidemia; signs of masculinization; or a Papanicolaou smear grade 111 or higher. Informed consent was obtained. Metabolic parameters during the reference cycle were required to be within the following limits: total cholesterol
A comparison study of lipid and androgen metabolism with triphasic oral contraceptive formulations containing norgestimate or levonorgestrel ALAINJANAUD, M.D.," JACQUES ROUFFY, M.D.," DAVIDUPMALIS,M.D.,b AND MARIE-PAULE DAIN,M.D.c From t h e HBpital Saint-Louis, Paris,a The R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey.b and CILAG, Francec
Acici
Obsiei Gytiecol Scanrl 1992; Vol 71, Suppl 156: 33-38
The effects of norgestimate triphasic (Ortho Tri-Cyclen@,Tri-Cilest@)and levonorgestrel triphasic (TriphasiP) formulations on lipid and androgen metabolism were assessed in a study o f 66 healthy women treated through six menstrual cycles. Levels of the following were measured: cholesterol and its subfractions, triglycerides. carrier lipoproteins, estradiol, testosterone, and sex hormone binding globulin (SHBG). Comparison of baseline values with values after 3 and 6 months of treatment indicated that both regimens influenced lipid and androgen metabolism. There was a statistically significant betweenregimen difference in levels of high-density lipoprotein, which were favorably increased with norgestimate triphasic hut reduced with levonorgestrel triphasic. Related data on SHBG showed that plasma levels of this marker of estrogen/androgen balance were increased significantly more in the norgestimate triphasic group, providing additional evidence of low androgenicity. Both regimens inhibited follicular growth to the same extent, a s evidenced by low mean levels of estradiol in all on-therapy cycles; and both decreased free testosterone. Side effects in both groups were minor and characteristic of those observed with low-dose oral contraceptive agents. The results of the study support the reported safety and positive effects of norgestimate on lipid and androgen metabolism. in comparison with a levonorgestrel-containingcombined oral contraceptive. Key wortfs: Norgestimate, lipid metabolism, androgenicity
Introduction Estrogen dosage in modern low-dose combined oral contraceptive (OC) agents is sufficient to provide contraceptive action with good cycle control while avoiding many of the estrogen-related risks associated with earlier formulations. However, use of the low-estrogen preparations has revealed the androgenic potential of the progestins used, raising concern about the consequences of their effects on lipid metabolism as well as the possibility of other unwanted androgenic activity. Serum levels of highdensity lipoprotein (HDL) cholesterol are reduced
by androgens and androgenic progestins in OCs (1-2). Low HDL cholesterol levels are associated with an increased risk of coronary heart disease (3). Reducing the androgenicity of an OC progestin might be expected to avert untoward reduction of HDL cholesterol levels, possibly altering the OC's atherogenic potential (4). The new progestin norgestimate (NGM) was developed as part of research efforts directed at finding effective, nonandrogenic (i .e., selectively progestational) progestins. NGM is reported to be a highly effective yet minimally androgenic agent with pharmacologic similarities to natural progesterone. Acta Obstei Gynecol Scand Sirppl 1.56 (1992)
34
A . Janaud et al.
8
0 150
Days
r
15
21
125
I c19
0
12
7
reported good cycle control, a low incidence o f side effects, and no pregnancies during 12 months' use of N G M 250 pg/EE 35 pg (6). In another study of 19 women, there were no changes in fibrinopeptide A. a sensitive marker of coagulation-system activation, or in the balance between coagulant and anticoagulant factors after six treatment cycles (6). The triphasic preparation of N G M / E E was forniulated to reduce the total progestin content while maintaining the estrogen dosage constant over the course of the menstrual cycle. This phased-dose preparation of NGM/EE has been under study in the United States and abroad for several years. Thc study reported here was undertaken in France to compare metabolic effects of the NGM triphasic (Tri-Cilest@ in Europe, Ortho Tri-Cyclen@ in the United States) with those of a triphasic preparation of levonorgestrel (LNG; Trinordiol@in Europe, Triphasil@or Triquilar@in the United States) in a population of women representative of potential users.
21
Days Fig. I . Regimens of norgestimate (NGM)/ethinyl estradiol (EE) and levonorgestrel (LNG)/EE.
NGM's action in a combined OC is capable of influencing lipid metabolism favorably without adversely affecting carbohydrate metabolism or coagulation parameters (4-6).In efficacy studies of 1,473 women treated over 19,078 cycles, there were no statistically significant differences between the pregnancy rates among women using the monophasic preparation Ortho-Cyelen@ (NGM 250 pg/ethinyl estradiol [EE] 35 pg) and those using a monophasic preparation of norgestrel ( N G ) and E E (Lo/Ovral@)( 5 ) . Throughout the same study, mean changes in fasting blood glucose levels were small and clinically insignificant with both preparations. A clear distinction between the metabolic effects of NGM and N G in monophasic OCs was demonstrated in a multicenter study reported by Chapdelaine et al involving 1.261 women (4). Positive effects o n lipids were shown in the NGM/EE group, with a significant increase in H D L and a significant decrease in the low-density lipoprotein (LDL)/HDL ratio. In contrast, users of the NG-containing OC demonstrated a significant reduction in H D L , and a significant elevation in the LDL/HDL ratio. In a subpopulation of 40 women, the effect of the two OC's on sex hormone binding globulin (SHBG) was markedly different (4). SHBG levels were increased 161.1% from baseline by NGM/EE, and only 26.2% by NG/EE. These results in both lipid and S H B G parameters indicate the clear difference in metabolic profile between the two progestins, with NGM demonstrating much less androgenicity. In a study of 147 women in Germany, Becker Acta Ohster Gytiecol Scand Suppl 156 (1992)
Study design The objective of this randomized, &month study was assessment of the comparative effects o f NGM/EE and LNGlEE triphasic formulations o n serum lipids and androgens. Study population The subjects were 66 healthy women between 18 and 38 years of age with regular menstrual cycles who were sexually active and not pregnant. Subjects were excluded from the study for the following reasons: standard contraindications to the use of hormonal contraceptive agents, notably a history of thrombophlebitis or disorders related to the use of estrogens; a family history of hyperlipidemia; signs of masculinization; or a Papanicolaou smear grade 111 or higher. Informed consent was obtained. Metabolic parameters during the reference cycle were required to be within the following limits: total cholesterol
