MODERN TRENDS. Triphasic oral contraceptives: review and comparison of various regimens. Edward E. Wallach, M.D. Associate Editor

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1 FERTILITY AND STERILITY VOL. 77, NO. 1, JANUARY 2002 Copyright 2002 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. MODERN TRENDS Edward E. Wallach, M.D. Associate Editor Triphasic oral contraceptives: review and comparison of various regimens Marcelle I. Cedars, M.D. Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of California, San Francisco, San Francisco, California Objective: To review and compare the risk benefit profile of triphasic oral contraceptives with that of low-dose monophasic oral contraceptives. Design: Literature on currently marketed triphasics and monophasics. Patient(s): Healthy women of reproductive age. Main Outcome Measure(s): Comparison of the rationale for development, composition, mechanism, efficacy, menstrual cycle control, side effects, health benefits, and risk benefit profile. Result(s): All triphasics contain ethinyl estradiol ( mg/d) and one of several progestins in doses ( mg/d) related to their relative potencies, which are substantially lower overall (total dose) than those in monophasics. The triphasics are highly efficacious. In general, menstrual cycle control and side effects are similar in both types, but triphasics containing the newer progestins (desogestrel, gestodene, and norgestimate) have better cycle control and a reduced incidence of androgenic side effects compared with those with norethindrone or levonorgestrel. Both triphasics and monophasics have minimal effects on carbohydrate and lipid metabolism and hemostasis parameters, and therefore comparable low risks of coronary heart disease. The health benefits of triphasics and monophasics are similar and include decreased incidence of unwanted and ectopic pregnancies, ovarian cysts, endometrial and ovarian cancers, benign breast disease, and acute pelvic inflammatory disease; less menstrual blood loss and iron deficiency anemia; and lower frequency of irregular bleeding and menorrhagia. Conclusion(s): The risk benefit profiles of both triphasics and monophasics are favorable and similar. (Fertil Steril 2002;77: by American Society for Reproductive Medicine.) Key Words: Oral contraceptives, triphasic contraceptives, 3rd generation contraceptives, birth control pills Received April 23, 2001; revised and accepted July 19, Reprint requests: Marcelle I. Cedars, M.D., Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of California, San Francisco, 350 Parnassus Avenue, Suite 300, San Francisco, California (FAX: ; cedarsm@ obgyn.ucsf.edu) /02/$22.00 PII S (01) The combined estrogen progestin oral contraceptive has provided women with a reliable, convenient, and affordable means of contraception for 40 years. Today, oral contraceptives are among the most widely prescribed agents throughout the world. Since their introduction, our understanding of the pharmacology of these agents has advanced significantly. Their effects on the hypothalamic pituitary ovarian axis and on other metabolic pathways and the relationship of the hormonal components to adverse reactions have been extensively studied. This information has facilitated the development of new oral contraceptive formulations designed to maintain benefit while reducing risk. The optimization of the risk benefit profile is an appropriate developmental goal in this therapeutic class because the target population consists of healthy women of reproductive age. The triphasic oral contraceptives, which are reviewed in this article, represent one approach to risk benefit optimization. The strategies employed in the development of oral contraceptive formulations have evolved with the expansion of our knowledge base. The recognition that the metabolic and cardiovascular side effects associated with oral contraceptive use were dose dependent led to the development of oral contraceptive formulations containing the minimum steroid doses necessary to inhibit ovulation (1). The estrogen dose found in today s oral contraceptives has been reduced to 20% of that employed in the earliest preparations (2). In the most recent formulations, daily doses of ethinyl estradiol (EE), the most widely used estrogen, are in the mg to mg range (2 4). Dose reduction has also been applied to the progestin component, with modern formulations now containing 10% of the original 1

2 doses (2). Other considerations have also played a role in changing the progestin component. Because the undesirable effects related to progestin, which include cosmetic side effects and alterations of lipid and carbohydrate metabolism, depend on the androgenicity of progestin as well as its dose (5), drug development strategies have included the creation of new progestins with specific affinity for progesterone receptors and reduced androgenic activity (2). The newer low-dose oral contraceptives are efficacious and have minimal metabolic impact. However, as ever-lower estrogen and progestin doses are employed, bleeding complications, including breakthrough bleeding (BTB), spotting, and amenorrhea, may occur if the estrogen progestin ratio is too low to produce a stable endometrium (6, 7). The triphasic oral contraceptives were developed in an attempt to reduce the total steroid dose still further while maintaining adequate cycle control in the absence of endometrial proliferation. These contraceptive regimens consist of three phases, each with a different progestin dose (8 10); in some formulations, the estrogen dose is increased in the second phase as well. In this article, published data on triphasic contraceptives are reviewed, and the regimens are compared with regard to efficacy, cycle control, tolerability, side-effect profile, metabolic effects, and the known or predicted risks and benefits of long-term use. COMPOSITION OF TRIPHASIC ORAL CONTRACEPTIVE REGIMENS Four triphasic regimens are currently marketed in the United States. The progestins in these regimens are norethindrone (Ortho-Novum 7/7/7, Ortho-McNeil Pharmaceutical, Raritan, NJ; Tri-Norinyl, G.D. Searle & Co., Chicago, IL), norgestimate (OrthoTri-Cyclen, Ortho-McNeil Pharmaceutical, Raritan, NJ), levonorgestrel (Tri-Levlen, Berlex Laboratories, Wayne, NJ; Triphasil, Wyeth-Ayerst Laboratories, Philadelphia, PA; Trivora, Watson Laboratories, Inc., Corona, CA), and desogestrel (Cyclessa, Organon, Inc., West Orange, NJ) (1 6, 8, 11). In Europe, a triphasic formulation containing gestodene is marketed under various trade names (10). The composition of each regimen is presented in Table 1 (4, 10 17). During the normal menstrual cycle, progesterone levels begin to rise 1 2 days before ovulation, reach a peak level on days 19 to 20 of the cycle, and subsequently decline to baseline at day 28 (8). Although not actually simulating the cyclic rhythm of progesterone, the daily progestin dose of triphasic contraceptives is progressively increased in three steps or phases during the 21-day cycle (Table 1). Although none of the available formulations attempts to simulate the cyclic estrogen rhythm, Tri-Levlen, Triphasil, and the EE gestodene formulation include a higher EE dose on cycle days 7 to 11, a period corresponding to the preovulatory rise in endogenous estrogen levels (8). All triphasic and most modern monophasic contraceptives include EE as the estrogenic constituent. Among the triphasic regimens (see Table 1), the EE daily ( mg) and per-cycle ( mg) dose ranges are quite narrow, which is consistent with the EE daily and per-cycle dose ranges included in most of the currently available monophasic products (i.e., to mg/d for 21 days). The triphasic contraceptives differ in the type and dosages of the progestin component (Table 1). The dosage differences are related to the relative potencies of the various progestins. Compared with monophasic contraceptives containing the same progestin, the triphasic contraceptives deliver substantially lower total (per-cycle) progestin doses. Typical daily doses of the various progestins, when used in monophasic contraceptive preparations, generally correspond to the daily dosages delivered in triphasic formulations during the third phase of the cycle; thus, the monophasic formulations deliver per-cycle progestin doses that are approximately times higher than those used in the triphasic regimens. The total amounts of estrogen and progestin in oral contraceptives are varied by different manufacturers to optimize the balance between good cycle control and unwanted side effects. The higher doses of estrogen result in better support of the endometrium and fewer episodes of BTB. However, these doses may cause unwanted side effects that result in improper use of the oral contraceptive. In a recent study, Rosenberg et al. (18) showed that cycle control was not always dependent on the EE dose. During the first two menstrual cycles, women taking a 20- g EE (Mircette, Organon) had similar BTB to those taking a higher EE dose (35 g) of triphasic oral contraceptive than those taking the lower EE dose (20 g) monophasic agent (Alesse, Wyeth- Ayerst Laboratories). However, side effects of bloating, breast tenderness, and nausea were 50% more common in the women taking the 35- g EE oral contraceptive. In cases in which patient compliance is a concern, less cycle control and fewer unwanted side effects could be a benefit. All five progestins used in triphasic contraceptives are 19-nortestosterone derivatives. The three newer progestins (norgestimate, desogestrel, and gestodene) can be considered derivatives of levonorgestrel (3) (Figure 1), with structural changes that result in reduced androgenic effects without the loss of menstrual cycle control. Desogestrel has a C-11 methylene group and is a prodrug that is rapidly converted to its active 3-keto derivative in vivo. Gestodene has a double bond between C-15 and C-16 and is active in its parent form without biotransformation. Norgestimate has a C-17 acetate group and a C-3 oxime group. This progestin is active in its parent form and has active metabolites, in particular, 17- deacetylnorgestimate (2). The spectrum of activities of these gonane-type progestins is dependent on the specific substituent groups, and the 2 Cedars Triphasic oral contraceptives Vol. 77, No. 1, January 2002

3 TABLE 1 Triphasic oral contraceptive regimens ranked by lowest total estrogen dose. Ethinyl estradiol Triphasic preparation (manufacturer [reference]) Dose (mg/d) No. of days Total dose per cycle (mg) Name Progestin dose (mg/d) No. of days Total dose per cycle (mg) Cyclessa (Organon [4]) Desogestrel Ethinyl estradiol and gestodene [10] Gestodene Tri-Levlen (Berlex [15]) Levonorgestrel Triphasil (Wyeth-Ayerst [16]) Levonorgestrel Trivora (Watson [17]) Levonorgestrel Ortho-Novum 7/7/7 (Ortho-McNeil) Norethindrone Ortho Tri-Cyclen (Ortho-McNeil [14]) Norgestimate Tri-Norinyl (Searle [13]) Norethindrone Cedars. Triphasic oral contraceptives. Fertil Steril various compounds demonstrate pharmacological differences in terms of their affinities for progesterone and androgen receptors (see Table 2) (5). The gonane-type progestins have a stronger binding affinity to these receptors than the older progestins. Table 2 also indicates that the newer progestins are more potent (usual strength) and better able to suppress bleeding (endometrial activity) than the older progestins. A comparison of progestins (or their active metabolites, as appropriate) using a selectivity index, which reflects the ratio of relative binding affinities for the progesterone receptor vs. the androgen receptor, reveals that the newer gonane-type progestins are highly selective to the progesterone receptor and have selectivity ratios seven to eight times higher than those of the older progestins (5). For example, the selectivity index for norethindrone has been reported as 5.0, compared with values of 26 for gestodene and 40 for 3-keto-desogestrel (19). The varying androgenic side effects associated with oral contraceptive use are also due to the relative antiestrogenic activities of the various progestins. For example, the older progestins with lower selectivity ratios inhibit the estrogeninduced rise in sex hormone binding globulin (SHBG). This effect results in an increase in the free testosterone levels in serum and hence in increased androgenic activity. In contrast, the newer gonane-type progestins (desogestrel, gestodene, and norgestimate) have a higher ability to bind SHBG, which results in less circulating testosterone and a decrease in androgenicity (5). Differences in the relative androgenic (antiestrogenic) activities of the progestins may be manifested by differences in the frequency of cosmetic androgenic side effects (acne, weight gain), effects on SHBG capacity, and systemic androgenic effects on carbohydrate and lipid metabolism, FERTILITY & STERILITY 3

4 FIGURE 1 Chemical structures of progesterone and 19-nortestoterone. Also shown are the chemical structures of the 19-nortestoterone derivative progestins employed in triphasic contraceptives, including the older (norethindrone and levonorgestrel) and newer (norgestimate, desogestrel, and gestodene) progestins (3). Cedars. Triphasic oral contraceptives. Fertil Steril whereas differences in endometrial activity may be related to differences in cycle control. However, the estrogenic and progestogenic components, the relative doses of each component, and the duration of the three phases employed in each triphasic formulation can contribute to the overall efficacy, safety, and metabolic profile of each product. Thus, a comparative evaluation of the various triphasic contraceptives must consider the clinical trial data obtained for each individual regimen, as well as expected differences related to the progestins contained in each formulation. 4 Cedars Triphasic oral contraceptives Vol. 77, No. 1, January 2002

5 TABLE 2 Potency and relative receptor binding activity of newer compared with older progestins. a Progestin Potency ( g) b Considering the lower progestin doses employed in the triphasic versus monophasic contraceptives, one of the requirements for an acceptable triphasic regimen is the maintenance of satisfactory cycle control in the absence of endometrial proliferation. There are a limited number of studies in the literature in which monophasic and triphasic contraceptives containing similar EE doses and the same progestin have been directly compared with regard to bleeding parameters. In one study, no difference was found in the bleeding patterns associated with Ortho-Novum 7/7/7 and a monophasic regimen (Ortho-Novum 1/35) (7). In contrast, Tri- Norinyl was reported to have reduced BTB during midcycle compared with a monophasic low-dose contraceptive and a biphasic contraceptive that also employed norethindrone as a progestin (9). In a recent study by Kaunitz (4), cycle control for Cyclessa was statistically significantly better than that for Ortho-Novum 7/7/7. Data regarding intermenstrual bleeding reported in largescale studies of individual triphasic contraceptives and smaller comparative trials are summarized in Table 3 (4, 6, 10, 20 31). Additional data regarding bleeding patterns associated with monophasic and triphasic contraceptives and included in articles published before 1992 have been reviewed by Rosenberg and Long (32). In Table 3, information related to BTB and/or spotting, the bleeding parameters most frequently defined and reported in a consistent manner, is presented for the various studies. Direct comparisons among these studies must be made with caution because of variability in the sample sizes, the duration of treatment, the period (cycles) during which the bleeding parameters were evaluated, and the way in which the intermenstrual bleeding data are reported (percentage of subjects with bleeding or spotting compared with average number of days of bleeding or spotting) (32). As with monophasic oral contraceptives, the incidence of intermenstrual bleeding during triphasic contraceptive therapy tends to be highest during the initial cycles, with decreasing incidence after continued treatment (4, 9, 32). Finally, it has been suggested that there is a direct relationship between missed pills and the incidence of intermenstrual bleeding (2). Because most publications do not adjust for compliance, the data presented in Table 3 generally correspond to intent-to-treat results (e.g., Kaunitz (4) did adjust for compliance). In general, the rates of BTB, spotting, and any intermen- Progestinbinding activity c Androgenbinding activity d MECHANISM OF ACTION AND CONTRACEPTIVE EFFICACY Endometrial activity e Gestodene 75 Desogestrel 150 Levonorgestrel 150 Norgestimate 250 Norethindrone a Adapted from Kaplan (5). b Usual strength of dose for comparable contraceptive efficacy. c On the basis of the amount required to induce vacuoles in human endometrium; desogestrel, gestodene, levonorgestrel, and norgestimate based on oral stimulation of endometrium in immature estrogen-primed rabbits relative to levonorgestrel 5.3. d Comparative potency (oral) based on rat ventral prostate assay (norethindrone 1.0 when methyltestosterone 50; norgestimate relative to levonorgestrel 8.3; gestodene relative to levonorgestrel 8.3). e On the basis of the amount required to suppress bleeding for 20 days in 50% of women. Cedars. Triphasic oral contraceptives. Fertil Steril The widespread use of oral contraceptives, including both monophasic and triphasic formulations, is chiefly due to their high degree of efficacy. It is likely that the remarkable effectiveness of these agents is a result of multiple effects of estrogens and progestins on the hypothalamic pituitary ovarian axis (10). Together, these actions lead to suppression of LH and FSH levels, a reduction in endogenous steroid levels, and the absence of the midcycle LH surge, with the net result being the inhibition of follicular development and ovulation. Other actions associated with estrogen and progestin administration (e.g., alteration of cervical mucus, prevention of endometrial proliferation, and so on) can interfere with conception or implantation, even in the absence of complete suppression of ovarian activity (11). The multiplicity of pharmacological effects of oral contraceptives is reflected in the extremely low pregnancy rates reported during clinical trials of these agents, including the newer, low-dose monophasic and triphasic formulations (3, 4, 9). In most oral contraceptive trials, the majority of treatment failures are related to incorrect product usage or poor compliance. Pregnancy rates are generally calculated and reported in the literature using either the Pearl Index (PI; number of pregnancies per 100 women-years of use) or a life-table method to assess failure rates as a function of time (5). The low pregnancy rates reported (e.g., PI 0.5 for Cyclessa (4) 1.0 for Ortho-Novum 7/7/7 (4), 0.33 for Triphasil (20), and 4.4 for Tri-Cyclen (18)) during large clinical studies of triphasic formulations (4, 10, 18, 20 25) provide further documentation of the excellent efficacy of contraceptive agents that are currently available and being developed. Moreover, these findings do not suggest any differences among the various triphasic regimens with regard to contraceptive efficacy. CYCLE CONTROL FERTILITY & STERILITY 5

6 TABLE 3 Clinical trials of triphasic oral contraceptives: cycle control. Trial reference no. Progestin Brand name Cycles (no. subjects) Breakthrough bleeding (% cycles) Spotting (% cycles) Breakthrough bleeding or spotting (4) DSG Cyclessa 6 (2,547) Ortho-Novum 7/7/7 6 (2,596) 4.1 (P.006) 11.8 (P.001) 15.5 (P.01) (23) DSG 13 (1,095) (6) LNG Triphasil 4 (107) NE Ortho-Novum 7/7/7 4 (97) 23.9 (P.05) 34.9 (P.05) 39.5 (P.05) NE Tri-Norinyl 4 (109) 28.8 (P.05) 40.8 (P.05) 49.0 (P.05) (20) LNG Triphasil 24 (3,546) (30) LNG a 27 (52) b 27 (31) (31) LNG a e (601) NE c e (599) LNG d e (600) 0.4 f 0.2 f (10) GTD 36 (1,933) (25) GTD (639) GTD 6 (161) NE 6 (136) (24) NGS Ortho Tri-Cyclen 12 (661) 5.4 (cycle 3) 2.6 (cycles 7 12) (29) h NGS Ortho Tri-Cyclen 24 (1,783) (22) NE 6 (405) DSG 6 (407) 3.2 (P.05) 7.2 (P.05) 10.3 (P.05) (26) NE Ortho-Novum 7/7/7 6 (48) LNG Tri-Levlen 6 (48) 21 (P.03) (P.015) NE Tri-Norinyl 6 (50) (27) NE Ortho-Novum 7/7/7 3 (1,259) 15.3 (cycle 3) 16.8 (cycle before study) (28) NE Ortho-Novum 7/7/7 12 (34) LNG Triphasil 12 (38) (P.05) DSG desogestrel; LNG levonorgestrel; NE norethindrone; GTD gestodene; NGS norgestimate. a Regimen contains the same dose of EE and LNG as Triphasil and Tri-Levlen. b Monophasic regimen of mg of EE and mg of LNG for 21 days per cycle. c Monophasic regimen of mg of EE and 0.40 mg of NE. d Monophasic regimen of 0.03 mg of EE and mg of LNG. e 18,282 women-years of use for the three regimens combined. f Data for cycle 12. g All GTD combined. h Data for cycles Cedars. Triphasic oral contraceptives. Fertil Steril strual bleeding (BTB or spotting) reported for the various triphasic contraceptives are in the range of the rates reported for monophasic contraceptives, including those containing the five progestins included in the triphasic formulations (2, 32). These findings indicate that triphasic contraceptives, in which the estrogenic component is dominant during the first part of the cycle, have met the objective of maintaining good cycle control with reduced progestin doses. Overall, cycle control appears to be somewhat better for the triphasics containing the newer progestins, desogestrel, gestodene, and norgestimate, compared with the formulations containing norethindrone or levonorgestrel. In the trials presented in Table 3 that involved a direct comparison of triphasic contraceptives, statistically significant differences in intermenstrual bleeding favored a triphasic containing desogestrel over the norethindrone-containing triphasic, which had significantly higher BTB and breakthrough spotting during cycles 1, 2, and 3 and overall (22). Even the triphasic containing the lowest dose of EE and desogestrel (Cyclessa) (4) had rates of BTB and spotting that were low, indicating good cycle control. In another series, the percentages of women who experienced BTB alone or BTB and spotting were lower among those treated with a triphasic containing gestodene than in those who received a norethindrone-containing triphasic (25). Comparisons of products containing levonorgestrel or 6 Cedars Triphasic oral contraceptives Vol. 77, No. 1, January 2002

7 norethindrone showed mixed results, with data favoring levonorgestrel-containing formulations in two studies (6, 26) and Ortho-Novum 7/7/7 (norethindrone and EE) over Triphasil (levonorgestrel and EE) in the third study (28). It should be noted that the results reported by Schilling et al. (6) may have been confounded by different start dates for the first cycle of treatment with the various triphasic regimens evaluated (see Table 3). OVERALL SIDE EFFECT PROFILE The side effects most frequently associated with the use of triphasic oral contraceptives are generally similar to those reported for commonly used, low-dose monophasic contraceptives (2, 30). In the publications of triphasic trials that reported safety information, the incidence of drug-related adverse experiences was low (less than about 10% for each symptom) and comparable for each type of progestin formulation (4, 6, 21, 22, 25, 30). Frequently occurring side effects typically include headache, gastrointestinal complaints (abdominal pain or discomfort, nausea, vomiting), dysmenorrhea, and breast pain or discomfort (4, 6, 10, 20 25, 27, 30, 31). As observed for commonly prescribed low-dose monophasic contraceptive formulations, mean weight and blood pressure generally did not change appreciably during triphasic contraceptive therapy, and individual cases of clinically significant weight gain or blood pressure elevation were rare (4, 6, 10, 20, 22 25). COSMETIC EFFECTS RELATED TO ANDROGENICITY At the doses used in triphasic contraceptives, the various progestins have varying degrees of androgenic or antiestrogenic activity, which can be manifest systemically, by effects on glucose and lipoprotein metabolism and SHBGbinding capacity, or symptomatically, by cosmetic side effects, including acne, oily skin, hirsuitism, and weight gain (33). The importance of cosmetic side effects related to androgenicity is underscored by the finding that approximately one fourth of subjects who discontinue oral contraceptive therapy do so because of acne or weight gain (34). Thus, contraceptive formulations that contain the newer progestins (desogestrel, gestodene, or norgestimate), with higher selectivity for progesterone compared with androgen receptors and a reduced effect on estrogen-induced increases in SHBG, may be associated with a reduced incidence of androgenic side effects and better subject compliance (34). In addition, contraceptives containing the less androgenic progestins have been proposed as treatment for women with androgen-related syndromes, including acne and hirsutism (35). A placebo-controlled trial of a triphasic contraceptive containing norgestimate (Ortho Tri-Cyclen) found that this contraceptive regimen provided effective treatment of moderately severe acne vulgaris (36). Although no similar trials of triphasics containing desogestrel or gestodene have been reported, trials of monophasic contraceptives have demonstrated improvement in acne vulgaris in women treated with formulations containing these progestins (37, 38), with better results clinically (but not statistically significant) found for women who received desogestrel and EE compared with those treated with gestodene and EE in one series (37). A low-dose monophasic agent containing desogestrel was also shown to be effective in correcting the hormonal imbalances, decreasing body weight, increasing depilation intervals, reducing hair coarseness, and eliminating acne in women with polycystic ovary syndrome (39). Taken together, the available data suggest that triphasics containing desogestrel, gestodene, or norgestimate may be preferred for women with acne or other conditions associated with hyperandrogenicity, as well as for women who experience androgenic side effects when treated with triphasic contraceptives containing norethindrone or levonorgestrel. However, data from placebocontrolled clinical trials with these triphasic regimens are required before definitive conclusions can be made. METABOLIC EFFECTS The effects of oral contraceptives on carbohydrate and lipid and lipoprotein profiles have been the subject of numerous clinical investigations primarily because of the associations found between these parameters and cardiovascular risk (1, 40). Changes in carbohydrate and lipid metabolism similar to those associated with increased risk of coronary heart disease (elevations in serum insulin and trigylcerides; deterioration in glucose tolerance; and reductions in serum levels of high-density lipoprotein [HDL] cholesterol, in particular the HDL 2 fraction) have been observed during treatment with some oral contraceptives (40). However, the importance of these metabolic alterations is questionable in light of epidemiological evidence suggesting that the use of oral contraceptives, including those with significant metabolic effects, is not associated with increased mortality from cardiovascular disease (1). Nonetheless, minimizing the metabolic impact of oral contraceptives has been one of the goals of new drug development, and the relative effect of the various triphasic contraceptives on carbohydrate and lipid profiles is a component of any risk benefit assessment of the available formulations. Moreover, one study of the effects of various monophasic and triphasic oral contraceptive regimens, all of which contained daily estrogen doses similar to those employed in current triphasic formulations (i.e., mg EE), found considerable differences among the regimens evaluated in terms of carbohydrate and lipid metabolism (40); these differences were related to the dose and type of progestin used in the various regimens. Published information related to the effects of triphasic FERTILITY & STERILITY 7

8 TABLE 4 Published data on the effects of various triphasic contraceptives on carbohydrate metabolism. Reference no. Cycles of treatment a Triphasic formulation (N) Summary of results (4) 6 Cyclessa (2,768) Abnormal elevations in glucose developed in 0.4% of subjects treated with Cyclessa and 0.1% of those treated with Ortho-Novum 7/7/7. 6 Ortho-Novum 7/7/7 (2,784) (40) 3 Triphasil/Tri-Levlen (152) Small decrease in OGT observed with both triphasic formulations, with a somewhat greater effect for the formulations containing LNG vs. NE. (Monophasic DSG-containing OC had minimal effects on OGT.) 3 Ortho-Novum 7/7/7 (66) (41) 12 Triphasil (28) Both formulations had minimal effects on carbohydrate metabolism. EE effect on carbohydrate metabolism predominant (i.e., less impact on carbohydrate metabolism) with NE-containing triphasic. 12 Ortho-Novum 7/7/7 (33) (43) 12 LNG/EE (23) There was a small, clinically unimportant deterioration in OGT observed (monophasic greatest deterioration; LNG EE least deterioration). Study population included Chinese women. (44) 12 Triphasil (27) Increases in carbohydrate metabolism were statistically significant relative to baseline (pretreatment) for both triphasics, but all changes for both treatment groups were within the normal limits for glucose, insulin, and OGT. 12 Ortho-Novum 7/7/7 (30) (45) 6 Tri-Levlen (45) All three formulations were associated with statistically significant, but clinically unimportant, changes in OGT after six cycles of treatment. No differences were observed among formulations. 6 Ortho-Novum 7/7/7 (42) 6 Tri-Norinyl (43) (46) 12 LNG/EE b (24) Both of these triphasics have only minimal effects on carbohydrate metabolism after 12 months of treatment. 12 GTD/EE (20) (47) 24 Ortho Tri-Cyclen (1,783) Statistically significant elevation in glucose response at 12 months, but not 24 months. After 24 months, there appears to be minimal effect on overall carbohydrate metabolism. (48) 18 Triphasil (17) Triphasil produced only minimal carbohydrate metabolic changes (no change in glucose levels, small increase in fasting insulin levels) after 18 months of treatment. (42) 12 Ortho-Novum 7/7/7 (22) No change in carbohydrate metabolism after 12 months of treatment. DSG desogestrel; EE ethinyl estradiol; GTD gestodene; LNG levonorgestrel; NE norethindrone; OC oral contraceptive; OGT oral glucose tolerance. a Months on OC treatment. b Regimen includes the same EE and LNG doses as Triphasil and Tri-Levlen. Cedars. Triphasic oral contraceptives. Fertil Steril oral contraceptives on carbohydrate metabolism and lipid profiles is summarized below and in Table 4 and 5, respectively. Because the design, subject populations, methods, and data analyses employed in the various metabolic investigations differ substantially, the information contained in these tables should be viewed as qualitative data. The differences in methodology generally do not permit a rigorous quantitative comparison between studies. Effects of Triphasic Contraceptives on Carbohydrate Metabolism Table 4 summarizes the results of studies that evaluated the effects on carbohydrate metabolism associated with more than 3 months of treatment with various triphasic contraceptives (40 48). An additional report by Spellacy et al. (49), which is not included in Table 4, includes a summary of other published studies related to a levonorgestrel-containing triphasic contraceptive. In general, the published reports presented in Table 4 and that by Spellacy et al. (49) indicate that longer term treatment with the various triphasic formulations is associated with only minimal, clinically insignificant effects on fasting glucose and insulin levels and oral glucose tolerance (4, 42, 50). The studies that included serial evaluations (45 47) found that small deteriorations in glucose tolerance occurred at earlier months of treatment, with glucose and insulin values tending to return toward baseline with continued therapy (Table 4). These results are not surprising given that the disturbances in carbohydrate metabolism associated with older, high-dose oral contraceptives were likely related to the dose and androgenicity of the progestin component (2). Thus, the 8 Cedars Triphasic oral contraceptives Vol. 77, No. 1, January 2002

9 TABLE 5 Published data on the effects of various triphasic contraceptives on lipid profiles. Reference no. Cycles of treatment a Triphasic (N) Summary of results (4) 6 Cyclessa (2,768) The incidence of subjects with clinically significant high cholesterol and triglyceride levels was low and similar for Cyclessa (0%) and Ortho- Novum 7/7/7 (0.3%) treatment groups. 6 Ortho-Novum 7/7/7 (2,784) (40) 3 Triphasil/Tri-Levlen (243) Compared with nonusers, subjects treated with LNG EE or NE EE triphasic contraceptives showed the following changes in serum lipids: NC in total cholesterol, LDL, or HDL; 1TG and apolipoproteins A-1, A-2; and B; and HDL 3. The LNG EE formulation was associated with 2HDL 2. (The most antiatherogenic effects on lipid metabolism (1HDL and HDL 3 ) were observed for monophasic DSG EE.) 3 Ortho-Novum 7/7/7 (82) (43) 12 LNG EE b (23) Triphasic administration to Chinese women was associated with NC in total cholesterol or VLDL, 1TG (6 mo), HDL (6 and 12 mo), and LDL (6 and 12 mo). (Monophasic DSG EE produced the greatest increase in HDL in this study.) (46) 12 LNG EE b (24) Treatment with either agent associated with NC in mean total cholesterol, HDL, LDL, VLDL, or apolipoprotein A-1; 1from pretreatment in TG (6 mo of LNG; 6 and 12 mo. of GTD) and apoprotein B (6 and 12 mo). GTD EE, but not LNG EE, associated with 2from pretreatment in LDL HDL ratio. There was a statistically significant difference in 1HDL with GTD over LNG. Although the changes noted were statistically significant, all lipid concentrations recorded during treatment with either agent were within the normal ranges. 12 GTD EE (20) (51) 3 LNG EE b (NR) LNG EE triphasic associated with 2HDL, HDL LDL ratio, and apoprotein A-1 apoprotein B-1 ratio; 1apolipoprotein A-1 and LDL. A biphasic formulation of DSG EE produced the most antiatherogenic lipid changes (i.e., 1HDL, HDL LDL ratio, and apoprotein A-1 apoprotein B-1 ratio) in this series. (52) 6 (each treatment) LNG EE b (14) In this crossover study of middle-aged premenopausal women, the lipid effects of the triphasic were compared with those of monophasic DSG EE. Both formulations 1TG, but only monophasic DSG EE significantly 1HDL. (56) 6 LNG EE b (20) Both regimens associated with NC in total cholesterol, HDL, or apolipoprotein B; statistically significant 1TG, HDL 3, and apolipoprotein A-1. Statistically significant changes observed only for GTD EE vs. LNG/EE included 2LDL, and LDL HDL ratio. (Lipid effects observed in a third group of 20 subjects who received monophasic DSG EE were the most antiatherogenic.) 6 GTD EE (20) (57) 6 Tri-Levlen (45) All three formulations associated with statistically significant changes from baseline, including 1TG (3 and 6 mo), apolipoprotein B (3 and 6 mo), and VLDL (3 and 6 mo), and HDL 3 (6 mo); 2HDL 2 (3 and 6 mo), and few or no changes in HDL. Tri-Norinyl alone was associated with statistically significant 1total cholesterol, LDL, and LDL HDL ratio (3 and 6 mo). No consistent differences were observed between treatments. 6 Ortho-Novum 7/7/7 (44) 6 Tri-Norinyl (47) (58) 12 LNG/EE b (24) After 12 months of triphasic treatment, lipid effects in Oriental women included 1total cholesterol and HDL; NC in LDL, TG, and HDL LDL ratio. (Lipid effects with the triphasic formulation were somewhat more favorable than a monophasic LNG EE formulation, but none of the effects observed with either product was considered clinically significant.) FERTILITY & STERILITY 9

10 TABLE Reference no. 5 Continued. Cycles of treatment a Triphasic (N) Summary of results (59) 12 Triphasil (34) After 12 months of treatment, new users of the OCs exhibited the following lipid effects: NC in HDL after either treatment. Triphasil alone was associated with statistically significant 1TG and LDL. 12 Ortho-Novum 7/7/7 or 12 monophasic NE/EE (19) (60) 12 GTD/EE (25) After 12 months of treatment, Triphasic was associated with 1total cholesterol, TG, HDL, HDL 3, apolipoproteins A-1 and B; NC in HDL 2, LDL, total cholesterol HDL ratio, and HDL LDL ratio. The changes noted were statistically significant but not considered clinically important. (61) 6 GTD/EE (42) Treatment associated with the following statistically significant changes: 1TG, HDL, and HDL 3. NC in total cholesterol, HDL 2, or LDL. (47) 24 Ortho Tri-Cyclen (1,783) (53) 24 Ortho Tri-Cyclen (1,783) Treatment associated with statistically significant 1total cholesterol, TG, LDL, and HDL, and 2LDL HDL ratio at 12 and 24 mo (all changes from pretreatment). Triphasic treatment associated with statistically significant 1total cholesterol, TG, HDL, LDL, and HDL LDL ratio after 12 and 24 cycles. (55) 6 Ortho Tri-Cyclen (34) NGM EE formulation associated with 1HDL and 2LDL HDL ratio. Significant differences between treatments favoring NGM EE over LNG EE in terms of 1HDL (vs. 2 with LNG EE) and 1HDL 2 (vs. 2 with LNG EE). TG1 with both treatments, although there was not a statistically significant difference between them. 6 Triphasil (32) (42) 12 Ortho-Novum 7/7/7 (22) Triphasic treatment associated with statistically significant 1total cholesterol (cycle 9), TG (cycles 3 and 9), apoprotein B (cycles 3, 6, 9, 12). NC in HDL, LDL, or the HDL LDL ratio. (54) 12 Ortho-Novum 7/7/7 (20) Treatment associated with NC in total cholesterol, LDL, and HDL; statistically significant 1HDL 3, TG, VLDL; statistically significant 2HDL 2. DSG desogestrel, EE ethinyl estradiol, GTD gestodene, HDL high-density lipoprotein cholesterol, LDL low-density lipoprotein cholesterol, LNG levonorgestrel, NE norethindrone, NGM norgestimate; NC no change; OC oral contraceptive, TG triglycerides, VLDL very-low-density lipoprotein cholesterol. a Refers to months on OC treatment. b Regimen includes the same EE and LNG doses as Triphasil and Tri-Levlen. Cedars. Triphasic oral contraceptives. Fertil Steril absence of significant effects on glucose tolerance and insulin sensitivity observed for the triphasic contraceptives is probably related to the substantially lower progestin doses used in these formulations compared with the older regimens or modern, low-dose monophasic contraceptives and/or with the newer, less androgenic progestins employed in some of the regimens. The studies that compared various triphasic formulations did not reveal any important differences between the products evaluated in terms of their effects on carbohydrate metabolism (40, 41, 44 46). Further, the results presented in Table 4 for the triphasic oral contraceptives are similar to those reported for low-dose monophasic formulations, including those containing the newer, less androgenic progestins (3). It should be noted that Table 4 includes only one study (46) in which a triphasic gestodene and EE formulation is evaluated and only one (4) for a desogestrel and EE triphasic regimen. However, the study by Godsland et al. (40) also evaluated a monophasic desogestrel-containing contraceptive formulation, which proved to have a lesser effect on insulin resistance and glucose tolerance than either the levonorgestrel and EE or the norethindrone and EE triphasic formulations. Although none of these studies provided a direct comparison of monophasic and triphasic contraceptives that included the less androgenic progestins, the study by Kaunitz (4) indicates that Cyclessa had a low incidence of effects on carbohydrate metabolism that did not differ significantly from that of Ortho-Novum 7/7/7. Monophasic regimens with these progestins are also not associated with clinically significant effects on carbohydrate metabolism. More studies are needed to clarify whether other triphasic regimens containing lower doses of less androgenic progestins would show notably different metabolic effects compared with Cyclessa or with monophasic regimens containing the same progestin. 10 Cedars Triphasic oral contraceptives Vol. 77, No. 1, January 2002

11 Effects of Triphasic Contraceptives on Lipid Profiles The impact of oral contraceptives on lipid and lipoprotein metabolism is due to the net effect of the often opposing actions of the estrogen and progestin components. Whereas estrogens cause an increase in HDL and may lead to cellular uptake of LDL, these effects are opposed by the androgenic effects of progestins (1). Thus, the effects of different oral contraceptive regimens on lipid profiles vary depending on the doses of estrogen and progestin components as well as on the relative androgenic activity of the progestin. Historically, the estrogen-related changes in lipids and lipoproteins have been associated with a lower risk of cardiovascular events related to atherosclerosis, and the observed reduction in the incidence of cardiovascular disease in postmenopausal women receiving estrogen replacement therapy has been attributed to these changes. It is now clear that most of the cardioprotection associated with estrogens occurs through direct effects on the vessel wall (51). These recent data highlight our limited understanding of the mechanisms underlying cardiovascular disease and call into question the use of various metabolic parameters as indicators of cardiovascular risk. With regard to the effects of oral contraceptives on lipids and lipoproteins, current thinking favors formulations that have minimal metabolic impact or that produce changes in lipoprotein profiles that are considered to be antiatherogenic. It might be expected that the triphasic contraceptives, which generally include similar estrogen doses combined with lower progestin doses compared with modern monophasic regimens, might exhibit an estrogen dominance, resulting in overall effects on lipid metabolism that are either neutral or somewhat antiatherogenic, with an additional advantage observed for triphasic regimens that include less androgenic progestins (2). Table 5 summarizes the results of studies that investigated the effects of triphasic contraceptives on lipid profiles. In these studies, various lipid and lipoprotein levels were evaluated before the start of treatment and after 3 24 cycles of triphasic administration (4, 40, 42, 43, 46, 47, 51 61). Whereas individual triphasic regimens were found to have varying effects on total cholesterol, HDL, LDL, and the ratio of HDL to LDL in these studies, the most consistent conclusions across studies were that the regimens evaluated were associated with elevations in serum triglycerides and that most of the lipid changes observed during treatment with triphasics were considered clinically insignificant. On the basis of the studies that compared various contraceptive regimens, some differences can be discerned with regard to the lipid changes associated with the various oral contraceptive formulations. In a comparison of triphasic and monophasic regimens of levonorgestrel and EE, Loke et al. (58) found somewhat greater reductions in total cholesterol with the triphasic formulation compared with the monophasic formulation; these findings tend to support a potential benefit of the lower progestin doses used in triphasic versus monophasic contraceptives. However, this same study showed no clinically significant difference between the monophasic and triphasic regimens in terms of the HDL LDL ratio (Table 5). Three studies compared the lipid changes associated with triphasic contraceptives containing levonorgestrel or norethindrone (40, 57, 59). In one of these studies (40), the lipid effects were comparable for the triphasics containing levonorgestrel (Triphasil or Tri-Levlen) or norethindrone (Ortho-Novum 7/7/7), whereas two studies (56, 58) found statistically significant differences between the treatments in various lipids measured. Data obtained by Janaud et al. (55) found increases in HDL associated with the norgestimatecontaining triphasic, Ortho Tri-Cyclen, compared with an observed decrease in HDL with Triphasil. Two studies compared triphasic contraceptive regimens of levonorgestrel and EE and gestodene and EE (46, 56). In both studies, only the gestodene and EE triphasic was associated with a decrease in the ratio of LDL to HDL after treatment; however, lipid changes associated with both regimens in the second study were considered clinically unimportant after 12 months of treatment (46). Five of the studies presented in Table 5 evaluated monophasic (40, 43, 56), biphasic (51), or triphasic (4) regimens of desogestrel and EE. In the monophasic and biphasic studies, the desogestrel-containing contraceptive had a greater antiatherogenic effect on lipid profiles than the triphasic comparators, which included levonorgestrel and EE regimens (Triphasil or Tri-Levlen) (40, 43, 51, 56), norethindrone and EE (Ortho-Novum 7/7/7) (40), and/or gestodene and EE (Table 5) (56). In these monophasic and biphasic studies, the desogestrel-containing formulations were consistently associated with increases in HDL and, in some cases, with increases in the HDL LDL ratio, whereas the comparative triphasic regimens without desogestrel produced smaller increases, no change, or decreases in these lipid markers. In contrast, the triphasic study of the desogestrel-containing contraceptive Cyclessa (4) showed no change in the cholesterol and triglyceride levels. Taken together, the published literature indicates that the currently available triphasic formulations have only minimal or no impact on lipid and lipoprotein metabolism. Some of the studies suggest that less-atherogenic lipid profiles may be associated with contraceptive regimens that contain the more selective, less-androgenic progestins (desogestrel, norgestimate, or gestodene). For regimens that include desogestrel, norgestimate, or gestodene, it is unclear whether triphasic formulations containing lower progestin doses would confer any additional advantages over monophasic formulations in terms of lipid effects. FERTILITY & STERILITY 11

12 HEMOSTATIC EFFECTS In recent years, there has been considerable controversy concerning the relationship between oral contraceptive use and the risk of vascular complications, in particular, venous thromboembolism (62, 63). Scientific evidence indicates that estrogen administration increases the synthesis of clotting factors in a dose-related fashion, whereas progestins appear to have no significant effect on clotting factors (62, 63). The small increase in the risk of vascular events observed in oral contraceptive users has been attributed to the estrogen component, with regimens that contain lower estrogen doses ( mg/d of EE) associated with a slightly increased risk of venous thromboembolism, no apparent increase in the risk of myocardial infarction, and a negligible effect on the risk of stroke (64). However, it is important to note that no direct cause-and-effect relationship has been established between changes in hemostasis parameters and the risk of venous thromboembolism in healthy young women. Observational studies indicating an increased risk of thromboembolism in subjects who received desogestrel- or gestodene-containing monophasic contraceptives compared with regimens that employed levonorgestrel called into question the evidence concerning the absence of clinically important hemostatic effects of progestins (62). However, additional studies and more detailed analyses of the original data suggest that the apparent difference in risk was likely due to confounding by age and external bias due to preferential prescribing rather than related to the various progestins (62, 63, 65). To date, there have been a limited number of published studies regarding the hemostatic effects of triphasic oral contraceptives, including regimens containing the progestins levonorgestrel, gestodene, or norethindrone (62 68). These studies indicate that the regimens evaluated have only minimal hemostatic effects and caused no notable differences in fibrinolysis in subjects who received regimens containing levonorgestrel, gestodene, or norethindrone (66 68). Taken together, the available data suggest that the possible risk of vascular complications in women receiving triphasic contraceptives is likely to be comparable with that observed for women using monophasic oral contraceptives that contain similar doses of EE. Although there is insufficient evidence to suggest a differential risk associated with the available triphasic formulations based on their progestin constituents, other risk factors for arterial or venous thrombosis including age, hypertension, smoking, family history, or previous episode of idiopathic thromboembolism, or underlying coagulopathy should be taken into consideration before any oral contraceptive, including triphasic regimens, is prescribed (62). HEALTH BENEFITS ASSOCIATED WITH ORAL CONTRACEPTIVE USE Like all drugs, oral contraceptives have adverse effects ranging from mild, symptomatic complaints to treatmentlimiting side effects and metabolic perturbations. Reviews often tend to focus on adverse events because oral contraceptives are so safe and because of the relatively young, healthy patient population. However, this bias ignores the established benefits of oral contraceptives, other than the obvious benefit of preventing unwanted pregnancies. The benefits fall into three categories: effects related to the inhibition of ovulation, effects on menses, and effects associated with long-term use (69). The benefits associated with short-term use of oral contraceptives include a reduced incidence of ectopic pregnancy and functional ovarian cysts, less menstrual blood loss, less iron deficiency anemia, and a lower frequency of irregular bleeding and menorrhagia (69). In addition, the incidence of dysmenorrhea and premenstrual syndrome is decreased in women taking oral contraceptives (70). Women using oral contraceptives also experience improvement in acne and hirsutism (71). Beneficial effects of long-term use include a decreased incidence of endometrial and ovarian cancers, benign breast disease, endometriosis, and acute pelvic inflammatory disease (69, 72, 73). The decrease in risk of ovarian cancer approaches 40% and lasts from 6 months to 10 years after starting oral contraceptive therapy (70). Similarly, the risk of endometrial cancer is reduced by 50% in women who have used oral contraceptives for a year or more (71). There is no evidence to suggest that there is any difference between triphasic and monophasic contraceptives in terms of the contraceptive or noncontraceptive benefits. The noncontraceptive benefits associated with oral contraceptives have been summarized elsewhere (69, 72, 73), and information related to these benefits is now included in the prescribing information for these products, including triphasic formulations. CONCLUSIONS A balanced consideration of the contraceptive and noncontraceptive health benefits, the relatively benign side effect profiles, and the minimal metabolic effects associated with modern, low-dose triphasic regimens indicates that these products have a favorable risk benefit profile for most healthy women. The relative risks and benefits clearly differ and are less favorable for women who smoke and those with other factors that are independently associated with an increased risk of cardiovascular disease. The triphasic oral contraceptives, which were developed to deliver lower progestin doses during each cycle of treatment, have achieved their initial objective of maintaining a level of cycle control that is at least as favorable as that 12 Cedars Triphasic oral contraceptives Vol. 77, No. 1, January 2002

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