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Drugs

, Volume 50, Issue 2, pp 364–395 | Cite as

Gestodene

A Review of its Pharmacology, Efficacy and Tolerability in Combined Contraceptive Preparations
  • Michelle I. Wilde
  • Julia A. Balfour
Drug Evaluation

Abstract

Synopsis

The newer progestogens gestodene, desogestrel and norgestimate were developed in an attempt to produce agents with more selective progestational activity that would improve cycle control and minimise metabolic changes and adverse events while effectively preventing pregnancy. In clinical practice, gestodene is combined with ethinylestradiol in monophasic or triphasic combined oral contraceptive preparations. The drug has pharmacokinetic advantages over the other new progestogens in that it is active per se (the others are prodrugs) and has high bioavailability (approximately 100%). The ability of gestodene-containing oral contraceptives to inhibit ovulation is similar to that of preparations containing other progestogens although the required dosage is lower.

In common with oral contraceptives containing desogestrel or norgestimate, and in contrast with those containing levonorgestrel, gestodene-containing preparations are associated with neutral or positive changes in lipid and carbohydrate metabolism. The effects of gestodene preparations on coagulation parameters, like those of desogestrel and levonorgestrel, are balanced by changes in the fibrinolytic system. Although the impact of these changes on clinical cardiovascular end-points has not been determined, the altered lipid profile is not likely to have significant clinical relevance because of the predominantly thrombogenic nature of cardiovascular disease in oral contraceptive users.

Pregnancy rates and Pearl Indices with gestodene-containing preparations are low and similar to those with preparations containing other progestogens. Most pregnancies are attributable to user failure. Cycle control appears to be better with gestodene preparations than with levonorgestrel preparations, and available data suggest that cycle control may also be better with monophasic gestodene/ethinylestradiol than with monophasic desogestrel- or norgestimate-containing preparations, and better with triphasic gestodene- than with triphasic levonorgestrel- or norgestimate-containing preparations. However, differences between the new progestogen-containing preparations need to be confirmed in further large-scale trials.

The most common adverse events with gestodene/ethinylestradiol are headaches and breast tension; the incidence of short term adverse events, including acne, is similar to that with preparations containing other progestogens. Changes in blood pressure and bodyweight are negligible. There are no comparative data on the incidence of cardiovascular events with gestodene-containing and other combined preparations. While the risk of breast cancer appears to be increased with long term combined oral contraceptive use in certain patient subgroups, this risk needs to be balanced against the noncontraceptive benefits of these preparations.

Thus, there is evidence to suggest that gestodene-containing oral contraceptives may have advantages over those containing desogestrel or norgestimate in terms of cycle control, and also over more established progestogen-containing preparations in terms of cycle control, lipid metabolism and possibly carbohydrate metabolism. However, the impact of the observed metabolic changes on cardiovascular end-points are unknown and further large clinical trials are required to confirm the possible advantages of gestodene in terms of cycle control over the other new progestogens.

Pharmacodynamic Properties

The ability of gestodene-containing oral contraceptive preparations to inhibit ovulation is similar to that of preparations containing the other new progestogens desogestrel and norgestimate as well as more established progestogens. The dosage of gestodene required to inhibit ovulation is lower than that for other progestogens, and preparations containing gestodene may have a greater suppressive effect on the hypothalamic-pituitary axis. Furthermore, the dosage of progestogen required to transform the endometrium appears to be lower for gestodene and desogestrel than for norgestimate and levonorgestrel.

Gestodene binds to the human progesterone receptor with a lesser affinity than that of 3-keto desogestrel and levonorgestrel. Gestodene also binds to the rat androgen receptor, with a similar affinity to that of 3-keto desogestrel and levonorgestrel. The antiestrogenic activity of gestodene [in terms of changes in sex hormone-binding globulin (SHBG) levels] is less than that of levonorgestrel and similar to that of desogestrel; the relative binding affinity of gestodene for SHBG is slightly greater than that of levonorgestrel and 3-keto desogestrel. However, no significant differences in effects on testosterone levels have been reported in women receiving contraceptive preparations containing one of these progestogens.

The binding affinity of gestodene for animal mineralocorticoid and, to a lesser extent, glucocorticoid receptors appears to be greater than that of levonorgestrel or desogestrel.

Although several differences between the pharmacodynamic effects of gestodene and norgestimate have been reported, they are likely to be of little clinical relevance because norgestimate is rapidly metabolised in vivo and levonorgestrel accounts for at least part of its activity.

In common with desogestrel- and norgestimate-containing oral contraceptive preparations and in contrast with longer established high-dose combined oral contraceptive preparations, gestodene-containing formulations appear to have a neutral or favourable effect on the lipid profile although increased triglyceride levels have been reported. Oral contraceptives containing desogestrel tend to have a more favourable effect on high density lipoprotein-cholesterol levels than those containing gestodene. Although the effects of these lipid changes in terms of cardiovascular end-points have not been determined, their clinical relevance is likely to be low considering the thrombogenic nature of cardiovascular disease in oral contraceptive users. The overall effects of gestodene-containing preparations on haemostatic parameters appear to be similar to those of both desogestrel-and levonorgestrel-containing preparations, with small increases in some parameters associated with coagulation being balanced by an increase in fibrinolytic activity.

Gestodene-containing combined oral contraceptive preparations administered for up to 1 year appear to have no or minimal effects on carbohydrate metabolism in healthy women and in women with diabetes mellitus. In common with desogestrel- and norgestimate-containing preparations, oral contraceptives containing gestodene appear to have fewer effects on carbohydrate metabolism than those containing longer established agents. Long term studies, especially in women aged >35 years, are needed to confirm the results of these short term studies.

Pharmacokinetic Properties

Gestodene is an active progestogen whereas the other 2 new progestogens desogestrel and norgestimate are prodrugs. As with other progestogens, the pharmacokinetics of gestodene show considerable intra- and interindividual variation.

Gestodene has high oral bioavailability (almost 100%) and exhibits dose-linear pharmacokinetics. Maximum serum gestodene concentrations following multiple dose gestodene/ethinylestradiol administration are 4-fold higher than after single doses, and progressively increased during each and subsequent treatment cycles for up to 12 cycles. Area under the concentration-time curve (AUCo-24h) values for gestodene are approximately 5- to 8-fold higher after multiple gestodene/ ethinylestradiol administration than after single doses.

AUC values for ethinylestradiol were greater after multiple monophasic or triphasic gestodene/ethinylestradiol administration than after single dose administration. Although gestodene strongly inactivates the cytochrome P450 CYP3A4, the major enzyme involved in the metabolism of ethinylestradiol, the drug does not appear to inhibit the metabolism of ethinylestradiol in vivo. Most available studies report no significant differences in ethinylestradiol concentrations between gestodene- or desogestrel-containing preparations.

Gestodene is extensively metabolised by the liver; several metabolites have been identified including dihydro-gestodene, 3,5 tetrahydro-gestodene and hydroxy-gestodene. The clearance of gestodene is decreased and the terminal elimination half-life is increased with multiple dose compared with single dose gestodene/ ethinylestradiol administration; clearance is dependent on the free-fraction of drug and is therefore sensitive to changes in SHBG levels.

Contraceptive Efficacy and Cycle Control

In noncomparative trials of monophasic gestodene/ethinylestradiol 75μg/30μg (gestodene 75/30) or triphasic gestodene 50/30, 70/40, 100/30, pregnancy rates and Pearl Indices of 0 to 0.11% and 0 to 0.22, respectively, were reported during 6 to 36 cycles of administration to > 100 000 women, despite up to 14% of women missing at least 1 tablet in total. User failure accounted for most pregnancies.

The efficacy of monophasic or triphasic gestodene-containing oral contraceptive preparations in preventing pregnancy appears to be similar to that of monophasic and triphasic desogestrel- and norgestimate-containing preparations and preparations containing the more established progestogens levonorgestrel or norethisterone. Pregnancy rates of 0 to 0.001% and Pearl Indices of 0 to 1 were reported despite a number of pill-taking errors; most pregnancies were attributable to patient failure.

Evidence suggests that the effects of monophasic gestodene/ethinylestradiol on cycle control may be more favourable than those of monophasic desogestrel-, norgestimate- and levonorgestrel-containing oral contraceptive preparations although further large-scale comparative trials are required to confirm these findings. Cycle control with triphasic gestodene/ethinylestradiol also appears to be at least equal to that with triphasic norethisterone/ethinylestradiol or levonorgestrel/ethinylestradiol. Bleeding irregularities decreased after the first few cycles of use and were more common in women with a history of irregular bleeding and in first-time oral contraceptive users.

Tolerability

The most common adverse events with monophasic and triphasic gestodene/ ethinylestradiol preparations are headache (0.6 to 13.1%) and breast tension (0.5 to 12.4%); less common are nervousness (0 to 8.4%), nausea (0 to 6%), depression (0 to 3.9%) and dizziness (0 to 2.9%). Weight gain and increased blood pressure are generally negligible and acne occurs in 0.3 to 5.8% of women. The incidence of these effects after 3 or 4 cycles was similar to that at baseline.

The overall short term adverse event profile of monophasic gestodene/ ethinylestradiol was similar to that of desogestrel/ethinylestradiol, norgestimate/ ethinylestradiol and levonorgestrel/ethinylestradiol. Of note, the incidence of acne was similar to that with levonorgestrel, and tended to decrease from baseline more with gestodene- than with desogestrel- or norgestimate-containing preparations. Adverse events including headache, breast tension, nausea, depression and breakthrough bleeding led to treatment withdrawal in 2 to 8% of patients. No significant between-preparation differences in effects on blood pressure or body weight have been reported.

Based on the apparently balanced effects of gestodene-containing oral contraceptive preparations on haemostasis, a relatively low risk of thromboembolic events is expected with these preparations. However, in common with other combined oral contraceptive agents, it is recommended that these preparations should be avoided in patients with a history of thromboembolic disease.

There appears to be an increased risk of breast cancer with long term (≥4 years) oral contraceptive use in certain subgroups, especially in women aged <20 years. However, it is important to balance the effects of combined oral contraceptive use on breast cancer risk and other potential risks with the positive noncontraceptive benefits of these preparations, principally a reduced risk of endometrial and epithelial ovarian cancer.

Dosage and Administration

Gestodene 75μg is combined with ethinylestradiol 20 or 30μg in monophasic preparations and gestodene 50, 70 and 100μg is combined with ethinylestradiol 30, 40 and 30μg in triphasic preparations. Worldwide standardised guidelines for the administration of individual combined oral contraceptive preparations are not available; the UK prescribing guidelines for the 21-day pack of monophasic gestodene 75/30 are described.

Active tablets should be started on day 1 of bleeding and continued for 21 consecutive days followed by 7 tablet-free days. Subsequent packs are started on the corresponding day after the tablet-free interval. When changing from another oral combined contraceptive preparation, patients should begin gestodene 75/30 on the first day immediately after the last active pill of the previous contraceptive course. Gestodene 75/30 may be started 21 days after a vaginal delivery if the patient is fully ambulant and there are no puerperal complications, and may be started immediately after a first-trimester abortion.

A missed active tablet should be taken as soon as possible; if >1 tablet has been missed, only the most recently missed tablet should be taken. If >12 hours have elapsed after missing 1 tablet, if >1 tablet has been missed or if vomiting or diarrhoea occurs, additional methods of contraception (i.e. barrier methods and spermicides) must be used for the following 7 days while the next 7 active tablets are taken. Additional contraception is also advised in patients receiving concomitant barbiturate, phenylbutazone, phenytoin, rifampicin (rifampin), griseofulvin, or antibacterial therapy.

As with other combined oral contraceptives, there are a number of contraindications to gestodene 75/30 including pregnancy, thrombotic disorders, sickle cell anaemia, disorders of lipid metabolism, liver disease, breast or endometrial cancer and abnormal vaginal bleeding of unknown cause. Onset of migraine or exacerbation of pre-existing migraine, unusually frequent or severe headaches, acute visual or hearing disturbance, significant increase in blood pressure, jaundice, exacerbation of conditions known to be capable of deteriorating during oral contraceptive use or pregnancy, or suspicion of thrombosis or infarction are grounds for immediate withdrawal.

Keywords

Oral Contraceptive Levonorgestrel Combine Oral Contraceptive Oral Contraceptive User Desogestrel 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    London RS. The new era in oral contraception: pills containing gestodene, norgestimate, and desogestrel. Obstet Gynecol Surv 1992; 47: 777–82PubMedGoogle Scholar
  2. 2.
    Jordan VC, Jeng MH, Catherino WH, et al. The estrogenic activity of synthetic progestins used in oral contraceptives. Cancer 1993 Feb 15; 71 Suppl.: 1501–5PubMedGoogle Scholar
  3. 3.
    Fotherby K, Caldwell ADS. New progestogens in oral contraception. Contraception 1994; 49: 1–32PubMedGoogle Scholar
  4. 4.
    Rebar RW, Zeserson K. Characteristics of the new progestogens in combination oral contraceptives. Contraception 1991; 44: 1–10PubMedGoogle Scholar
  5. 5.
    Speroff L, DeCherney A. Evaluation of a new generation of oral contraceptives. Obstet Gynecol 1993; 81: 1034–47PubMedGoogle Scholar
  6. 6.
    Shoupe D. New progestins — clinical experiences: gestodene. Am J Obstet Gynecol 1994; 170 (Part 2): 1562–8PubMedGoogle Scholar
  7. 7.
    Shenfield GM, Griffin JM. Clinical pharmacokinetics of contraceptive steroids. An update. Clin Pharmacokinet 1991; 20: 15–37Google Scholar
  8. 8.
    Pollow K, Juchem M, Grill H-J, et al. Gestodene: a novel synthetic progestin — characterization of binding to receptor and serum proteins. Contraception 1989; 40: 325–41PubMedGoogle Scholar
  9. 9.
    Runnebaum B, Rabe T. New progestogens in oral contraceptives. Am J Obstet Gynecol 1987; 157 (4 Pt 2): 1059–63PubMedGoogle Scholar
  10. 10.
    Fitzgerald C, Feichtinger W, Spona J, et al. A comparison of the effects of two monophasic low dose oral contraceptives on the inhibition of ovulation. Contraception 1994; 10: 5–18Google Scholar
  11. 11.
    Refn H, Kjaer A, Lebech A-M, et al. Clinical and hormonal effects of two contraceptives: correlation to serum concentrations of levonorgestrel and gestodene. Contraception 1990; 41: 259–69PubMedGoogle Scholar
  12. 12.
    Hemrika DJ, Slaats EH, Kennedy JC, et al. The effects of levonorgestrel, desogestrel and gestodene on the pulsatile release of luteinizing hormone in oral contraceptive users. Gynecol Endocrinol 1993; 7: 191–200PubMedGoogle Scholar
  13. 13.
    Phillips A. The selectivity of a new progestin. Acta Obstet Gynecol Scand Suppl. 1990; 152 Suppl.: 21–4PubMedGoogle Scholar
  14. 14.
    Fuhrmann U, Slater EP, Fritzemeier K-H. Characterization of the novel progestin gestodene by receptor binding studies and transactivation assays. Contraception 1995; 51: 45–52PubMedGoogle Scholar
  15. 15.
    Elger W, Steinbeck H, Schillinger E, et al. Endocrine-pharmacological profile of gestodene. Adv Contra Delv Syst 1995; II: 182–97Google Scholar
  16. 16.
    Phillips A, Hahn DW, McGuire JL. Relative binding affinity of norgestimate and other progestins for human sex hormone-binding globulin. Steroids 1990; 55: 373–5PubMedGoogle Scholar
  17. 17.
    van der Vange N, van der Berg H, Kloosterboer HJ, et al. Effects of seven low-dose combined contraceptives on vitamin B6 status. Contraception 1989; 40: 377–84PubMedGoogle Scholar
  18. 18.
    Jung-Hoffmann C, Heidt F, Kuhl H. Effect of two oral contraceptives containing 30 μg ethinylestradiol and 75 μg gestodene or 150 μg desogestrel upon various hormonal parameters. Contraception 1988; 38: 593–603PubMedGoogle Scholar
  19. 19.
    Dibbelt L, Knuppen R, Jutting G, et al. Group comparison of serum ethinyl estradiol, SHBG and CBG levels in 83 women using two low-dose combination oral contraceptives for three months. Contraception 1991; 43: 1–21PubMedGoogle Scholar
  20. 20.
    Humpel M, Tauber U, Kuhnz W, et al. Protein binding of active ingredients and comparison of serum ethinyl estradiol, sex hormone-binding globulin, corticosteroid-binding globulin, and cortisol levels in women using a combination of gestodene/ ethinyl estradiol (Femovan) or a combination of desogestrel/ ethinyl estradiol (Marvelon) and single-dose ethinyl estradiol bioequivalence from both oral contraceptives. Am J Obstet Gynecol 1990; 163 (1 Pt 2): 329–33PubMedGoogle Scholar
  21. 21.
    Fotherby K. Desogestrel and gestodene in oral contraception: a review of European experience. J Drug Dev 1991; 4: 101–11Google Scholar
  22. 22.
    Phillips A, Hahn DW, McGuire JL. Preclinical evaluation of norgestimate, a progestin with minimal androgenic activity. Am J Obstet Gynecol 1992; 167 (4 Pt 2): 1191–6PubMedGoogle Scholar
  23. 23.
    Kuhnz W, Blode H, Mahler M. Systemic availability of levonorgestrel after single oral administration of a norgestimate-containing combination oral contraceptive to 12 young women. Contraception 1994; 49: 255–63PubMedGoogle Scholar
  24. 24.
    Fotherby K. The new low dose oral contraceptives. J Obstet Gynaecol 1994; 14: 327–32Google Scholar
  25. 25.
    Hemrika DJ, Slaats EH, Kennedy JC, et al. Pulsatile luteinizing hormone secretion during the first and the fourth cycle on two different oral contraceptives containing gestodene. Acta Endocrinol 1993; 129: 229–36PubMedGoogle Scholar
  26. 26.
    Levaillant JM, Levaillant C, Colin MC, et al. Study of gonadotrophic function during and after use of a triphasic combination with gestodene [in French]. Rev Fr Gynecol Obstet 1988; 83: 655–61PubMedGoogle Scholar
  27. 27.
    Stickland J, Tolowinska IY, Anthony F, et al. The suppression of ovarian function by the new oral contraceptive—Femodene. Contraception 1987; 35: 447–56PubMedGoogle Scholar
  28. 28.
    Thomas K, Vankrieken L. Inhibition of ovulation by low-dose monophasic contraceptive containing gestodene. Am J Obstet Gynecol 1990 Oct; 163 Suppl.: 1404–10PubMedGoogle Scholar
  29. 29.
    Eyong E, Elstein M. Clinical update on a new progestogen-gestodene. Br J Farn Plann 1989; 15: 18–22Google Scholar
  30. 30.
    Kuhnz W, Baumann A, Staks T, et al. Pharmacokinetics of gestodene and ethinylestradiol in 14 women during three months of treatment with a new tri-step combination oral contraceptive: serum protein binding of gestodene and influence of treatment on free and total testosterone levels in the serum. Contraception 1993; 48: 303–22PubMedGoogle Scholar
  31. 31.
    Kuhnz W, Gansau C, Fuhrmeister A. Pharmacokinetics of gestodene in 12 women who received a single oral dose of 0.075 mg gestodene and, after a wash-out phase, the same dose during one treatment cycle. Contraception 1992; 46: 29–40PubMedGoogle Scholar
  32. 32.
    van der Vange N, Blankenstein MA, Kloosterboer HJ, et al. Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and free testosterone. Contraception 1990; 41: 345–52PubMedGoogle Scholar
  33. 33.
    Skouby SO, Andersen O, Petersen KR, et al. Mechanism of action of oral contraceptives on carbohydrate metabolism at the cellular level. Am J Obstet Gynecol 1990; 163 (1 Pt 2): 343–8PubMedGoogle Scholar
  34. 34.
    McKeigue PM, Ferrie JE, Pierpoint T, et al. Association of early-onset coronary heart disease in South Asian men with glucose intolerance and hyperinsulinemia. Circulation 1993; 87: 152–61PubMedGoogle Scholar
  35. 35.
    Young MH, Jeng C-Y, Sheu WH-H, et al. Insulin resistance, glucose intolerance, hyperinsulinemia and dyslipidemia in patients with angiographically demonstrated coronary artery disease. Am J Cardiol 1993; 72: 458–60PubMedGoogle Scholar
  36. 36.
    Brezinka V, Padmos I. Coronary heart disease risk factors in women. Eur Heart J 1994; 15: 1571–84PubMedGoogle Scholar
  37. 37.
    Thorogood M. Oral contraceptives and cardiovascular disease: an epidemiologic overview. Pharmacoepidemiol Drug Saf 1993; 2: 3–16Google Scholar
  38. 38.
    Kuhn FE, Rackley CE. Coronary artery disease in women. Risk factors, evaluation, treatment, and prevention. Arch Intern Med 1993; 153: 2626–36Google Scholar
  39. 39.
    Thorogood M, Villard-Mackintosh L. Combined oral contraceptives: risks and benefits. Br Med Bull 1993; 49: 124–39PubMedGoogle Scholar
  40. 40.
    Consensus development meeting: metabolic aspects of oral contraceptives of relevance for cardiovascular diseases. Am J Obstet Gynecol 1990; 162: 1335–7Google Scholar
  41. 41.
    Petersen KR, Sidelmann J, Skouby SO, et al. Effects of monophasic low-dose oral contraceptives on fibrin formation and resolution in young women. Am J Obstet Gynecol 1993; 168 (Pt 1): 32–8PubMedGoogle Scholar
  42. 42.
    Thorneycroft IH. Oral contraceptives and myocardial infarction. Am J Obstet Gynecol 1990; 163: 1393–7PubMedGoogle Scholar
  43. 43.
    Hoppe G. Gestoden, an innovative progestogen. Contraception 1988; 37: 493–501PubMedGoogle Scholar
  44. 44.
    Miller VT. Lipids, lipoproteins, women and cardiovascular disease. Atherosclerosis 1994; 108 Suppl.: S73–82PubMedGoogle Scholar
  45. 45.
    Moreno GT, Manson JE. Cholesterol and coronary heart disease in women: an overview of primary and secondary prevention. Coron Artery Dis 1993; 4: 580–7PubMedGoogle Scholar
  46. 46.
    Gidding SS. The rationale for lowering serum cholesterol levels in American women. Am J Dis Child 1993; 147: 386–92PubMedGoogle Scholar
  47. 47.
    Fioretti P, Fruzzetti F, Navalesi R, et al. Clinical and metabolic effects of a pill containing 30 mcg ethinylestradiol plus 75 mcg gestodene. Contraception 1989; 40: 649–63PubMedGoogle Scholar
  48. 48.
    Garzaflores J, Debourges VV, Martinez M, et al. Safety and efficacy of a combined oral contraceptive — gestodene 75 μg plus ethinyl estradiol 30 μg in Mexican women. Contraception 1994; 10: 19–26Google Scholar
  49. 49.
    Fruzzetti F, Ricci C, Nicoletti I, et al. Clinical and metabolic effects of a triphasic pill containing gestodene. Contraception 1992; 46: 335–47PubMedGoogle Scholar
  50. 50.
    Fotherby K, Trayner I, Longthorne PN, et al. Metabolic investigations with Femodene — an oral contraceptive containing gestodene and ethinyloestradiol. Contraception 1987; 35: 323–37PubMedGoogle Scholar
  51. 51.
    Moutos DM, Zacur HA, Bachorik PS. Lipoprotein alterations from a triphasic oral contraceptive containing ethinyl estradiol and gestodene. A 12-month trial. J Reprod Med 1994; 39: 720–4PubMedGoogle Scholar
  52. 52.
    Solerte SB, Fioravanti M, Spinillo A, et al. Hemorheological, hemostatic and metabolic long-term (24 months) study of young women taking a monophasic pill containing gestodene and ethinylestradiol. It J Gynaecol Obstet 1993; 3: 85–91Google Scholar
  53. 53.
    Crook D, Godsland IF, Worthington M, et al. A comparative metabolic study of two low-estrogen-dose oral contraceptives containing desogestrel or gestodene progestins. Am J Obstet Gynecol 1993; 169: 1183–9PubMedGoogle Scholar
  54. 54.
    Harvengt C. Effect of oral contraceptive use on the incidence of impaired glucose tolerance and diabetes mellitus [in French]. Diabete Metab 1992; 18: 71–7PubMedGoogle Scholar
  55. 55.
    Skouby SO, Petersen KR, Jespersen J. The influence of new low-dose oral contraceptives on metabolic variables. Advances in Contraception 1991; 7 Suppl 2: 77–88Google Scholar
  56. 56.
    van der Vange N, Kloosterboer HJ, Haspels AA. Effect of seven low-dose combined oral contraceptive preparations on carbohydrate metabolism. Am J Obstet Gynecol 1987; 156: 918–22PubMedGoogle Scholar
  57. 57.
    Spellacy WN, Tsibris JCM, Hunter-Bonner DL, et al. Six-month carbohydrate metabolism studies in women using oral contraceptives containing gestodene and ethinyl estradiol. Contraception 1992; 45: 533–9PubMedGoogle Scholar
  58. 58.
    Spellacy WN, Tsibris AMN, Tsibris JCM, et al. Carbohydrate metabolism studies after one year of using an oral contraceptive containing gestodene and ethinyl estradiol. Contraception 1994; 49: 125–30PubMedGoogle Scholar
  59. 59.
    Petersen KR, Skouby SO, Sidelmann J, et al. Effects of contraceptive steroids on cardiovascular risk factors in women with insulin-dependent diabetes mellitus. Am J Obstet Gynecol 1994; 171: 400–5PubMedGoogle Scholar
  60. 60.
    Daly L, Bonnar J. Comparative studies of 30 μg ethinyl estradiol combined with gestodene and desogestrel on blood coagulation, fibrinolysis, and platelets. Am J Obstet Gynecol 1990 Jul; 163 Suppl.: 430–7PubMedGoogle Scholar
  61. 61.
    Daume E. Influence of modern low-dose oral contraceptives on hemostasis. Adv Contracept 1990 Dec; 6 Suppl.: 51–67 (discussion 68)PubMedGoogle Scholar
  62. 62.
    Fruzzetti F, Ricci C, Fioretti P. Haemostasis profile in smoking and nonsmoking women taking low-dose oral contraceptives. Contraception 1994; 49: 579–92PubMedGoogle Scholar
  63. 63.
    Melis GB, Fruzzetti F, Nicoletti I, et al. A comparative study on the effects of a monophasic pill containing desogestrel plus 20 μg ethinylestradiol, a triphasic combination containing gestodene on coagulatory factors. Contraception 1991; 43: 23–31PubMedGoogle Scholar
  64. 64.
    Jespersen J, Petersen KR, Skouby SO. Effects of newer oral contraceptives on the inhibition of coagulation and fibrinolysis in relation to dosage and type of steroid. Am J Obstet Gynecol 1990; 163 (1 Pt 2): 396–403PubMedGoogle Scholar
  65. 65.
    Meade TW. Oral contraceptives, clotting factors, and thrombosis. Am J Obstet Gynecol 1982; 142: 758–61PubMedGoogle Scholar
  66. 66.
    Omsjø IH, Øian P, Maltau JM, et al. Effects of two triphasic oral contraceptives containing ethinylestradiol plus levonorgestrel or gestodene on blood coagulation and fibrinolysis. Acta Obstet Gynecol Scand 1989; 68: 27–30PubMedGoogle Scholar
  67. 67.
    Cohen H, Mackie IJ, Walshe K, et al. A comparison of the effects of two triphasic oral contraceptives on haemostasis. Br J Haematol 1988; 69: 259–63PubMedGoogle Scholar
  68. 68.
    Refn H, Kjaer A, Lebech A-M, et al. Metabolic changes during treatment with two different progestogens. Am J Obstet Gynecol 1990; 163(1 Pt 2): 374–7PubMedGoogle Scholar
  69. 69.
    Nieuweboer B, Tack J, Täuber U, et al. Development and application of a radioimmunoassay of the new progestagen gestodene. Contraception 1989; 40: 313–23PubMedGoogle Scholar
  70. 70.
    Tauber U, Tack JW, Matthes H. Single dose pharmacokinetics of gestodene in women after intravenous and oral administration. Contraception 1989; 40: 461–79PubMedGoogle Scholar
  71. 71.
    Dibbelt L, Knuppen R, Kuhnz W, et al. Pharmacokinetics and protein binding of gestodene under treatment with a low-dose combination oral contraceptive for three months. Arzneimittel Forschung 1992; 42: 1146–52PubMedGoogle Scholar
  72. 72.
    Orme M, Back DJ, Ward S, et al. The pharmacokinetics of ethynylestradiol in the presence and absence of gestodene and desogestrel. Contraception 1991; 43: 305–16PubMedGoogle Scholar
  73. 73.
    Kuhl H, Jung-Hoffmann C, Heidt F. Alterations in the serum levels of gestodene and SHBG during 12 cycles of treatment with 30 μg ethinylestradiol and 75 μg gestodene. Contraception 1988; 38: 477–86PubMedGoogle Scholar
  74. 74.
    Tauber U, Kuhnz W, Humpel M. Pharmacokinetics of gestodene and ethinyl estradiol after oral administration of a monophasic contraceptive. Am J Obstet Gynecol 1990 Oct; 163 Suppl.: 1414–20PubMedGoogle Scholar
  75. 75.
    Kuhnz W. Pharmacokinetics of the contraceptive steroids levonorgestrel and gestodene after single and multiple oral administration to women. Am J Obstet Gynecol 1990 Dec; 163 Suppl.: 2120–7PubMedGoogle Scholar
  76. 76.
    Jung-Hoffmann C, Kuhl H. Pharmacokinetics and pharmacodynamics of oral contraceptive steroids: factors influencing steroid metabolism. Am J Obstet Gynecol 1990; 163: 2183–97Google Scholar
  77. 77.
    Kuhnz W, Sostarek D, Gansau C, et al. Single and multiple administration of a new triphasic oral contraceptive to women: pharmacokinetics of ethinyl estradiol and free and total testosterone levels in serum. Am J Obstet Gynecol 1991; 165: 596–602PubMedGoogle Scholar
  78. 78.
    Kuhnz W, Humpel M, Schutt B, et al. Relative bioavailability of ethinyl estradiol from two different oral contraceptive formulations after single oral administration to 18 women in an intraindividual cross-over design. Horm Res 1990; 33: 40–4PubMedGoogle Scholar
  79. 79.
    Kuhnz W, Back D, Power J, et al. Concentration of ethinyl estradiol in the serum of 31 young women following a treatment period of 3 months with two low-dose oral contraceptives in an intraindividual cross-over design. Horm Res 1991; 36: 63–9PubMedGoogle Scholar
  80. 80.
    Hammerstein J, Daume E, Simon A, et al. Influence of gestodene and desogestrel as components of low-dose oral contraceptives on the pharmacokinetics of ethinyl estradiol (EE2), on serum CBG and on urinary cortisol and 6β-hydroxycortisol. Contraception 1993; 47: 263–81PubMedGoogle Scholar
  81. 81.
    Kuhnz W, Schutt B, Power J, et al. Pharmacokinetics and serum protein binding of gestodene and 3-keto-desogestrel in women after single oral administration of two different contraceptive formulations. Arzneimittel Forschung 1992; 42: 1139–41PubMedGoogle Scholar
  82. 82.
    Kuhnz W, Pfeffer M, al-Yacoub G. Protein binding of the contraceptive steroids gestodene, 3-keto-desogestrel and ethinylestradiol in human serum. J Steroid Biochem 1990; 35: 313–8PubMedGoogle Scholar
  83. 83.
    Hammond GL, Bocchinfuso WP, Orava M, et al. Serum distribution of two contraceptive progestins: 3-ketodesogestrel and gestodene. Contraception 1994; 50: 301–18PubMedGoogle Scholar
  84. 84.
    Ward S, Back DJ. Metabolism of gestodene in human liver cytosol and microsomes in vitro. J Steroid Biochem Mol Biol 1994; 46: 235–43Google Scholar
  85. 85.
    Düsterberg B, Tack J-W, Krause W. Pharmacokinetics and bio-transformation of gestodene in man. In: Elstein M, editor. Gestodene — development of a new gestodene-containing low-dose oral contraceptive. Carnforth: Parthenon Publishing Group Ltd, 1987: 35–44Google Scholar
  86. 86.
    Hoogland HJ, Skouby SO. Ultrasound evaluation of ovarian activity under oral contraceptives. Contraception 1993; 47: 583–90PubMedGoogle Scholar
  87. 87.
    Brill K, Norpoth T, Schnitker J, et al. Clinical experience with a modern low-dose oral contraceptive in almost 100,000 users. Contraception 1991; 43: 101–10PubMedGoogle Scholar
  88. 88.
    Brill K, Schnitker J, Albring M. Long-term experience with a low-dose oral contraceptive. Gynecol Endocrinol 1990; 4: 277–86PubMedGoogle Scholar
  89. 89.
    Merchiers E, Thiery M, Van Kets H, et al. Gestodene: clinical experience with an innovative progestogen used in a combination oral contraceptive preparation. Acta Ther 1990; 16 (2): 129–38PubMedGoogle Scholar
  90. 90.
    Renier M, Buytaert P. Open prospective multicenter trial with a new monophasic contraceptive combination containing gestodene. Contraception 1991; 43: 413–21PubMedGoogle Scholar
  91. 91.
    Weber-Diehl F, Unger R, Lachnit U. Triphasic combination of ethinyl estradiol and gestodene. Long term clinical trial. Contraception 1992; 46: 19–27Google Scholar
  92. 92.
    Affinito P, Monterubbianesi M, Primizia M, et al. Efficacy, cycle control and side-effects of two monophasic combination oral contraceptives: gestodene/ethinylestradiol and norgestimate/ethinylestradiol. Gynecol Endocrinol 1993; 7: 259–66PubMedGoogle Scholar
  93. 93.
    Brill K, Müller C, Schnitker J. The influence of different modern low-dose oral contraceptives on intermenstrual blleding. Advances in Contraception 1991; 7 Suppl 2: 51–61Google Scholar
  94. 94.
    Kirkman RJE, Pedersen JH, Fioretti P, et al. Clinical comparison of two low-dose oral contraceptives, Minulet® and Mercilon®, in women over 30 years of age. Contraception 1994; 49: 33–46PubMedGoogle Scholar
  95. 95.
    Latin American Oral Contraceptive Study Group. Clinical comparison of monophasic oral contraceptive preparations of gestodene/ethinyl estradiol and desogestrel/ethinyl estradiol. Contraception 1994; 50: 201–14Google Scholar
  96. 96.
    Loudon NB, Kirkman RJ, Dewsbury JA. A double-blind comparison of the efficacy and acceptability of Femodene and Microgynon-30. Eur J Obstet Gynecol Reprod Biol 1990; 34: 257–66PubMedGoogle Scholar
  97. 97.
    Weber-Diehl F, Lehnert J, Lachnit U. Comparison of two triphasic oral contraceptives containing either gestodene or norethindrone: a randomized, controlled trial. Contraception 1993; 48: 291–301PubMedGoogle Scholar
  98. 98.
    Dusterberg B, Brill K. Clinical acceptability of monophasic gestodene. Am J Obstet Gynecol 1990 Oct; 163 Suppl.: 1398–404PubMedGoogle Scholar
  99. 99.
    Pratt WF, Bachrach CA. What do women use when they stop using the pill? Family Planning Perspectives 1987; 1: 257–66Google Scholar
  100. 100.
    Hillard PJA. Oral contraception noncompliance: the extent of the problem. Advances in Contraception 1992; 8 Suppl 1: 13–20PubMedGoogle Scholar
  101. 101.
    Chez RA. Clinical aspects of three new progestogens: desogestrel, gestodene, and norgestimate. Am J Obstet Gynecol 1989; 160(5 Pt 2): 1296–300PubMedGoogle Scholar
  102. 102.
    International working Group on Enhancing Patient Compliance and Oral Contraceptive Efficacy. A consensus statement: enhancing patient compliance and oral contraceptive efficacy. Br J Fam Plann 1993; 18: 126–9Google Scholar
  103. 103.
    Serfaty D. Medical aspects of oral contraceptive discontinuation. Adv Contracept 1992 Oct; 8 Suppl 1: 21–33PubMedGoogle Scholar
  104. 104.
    Kubba A, Guillebaud J. Combined oral contraceptives — acceptability and effective use. Br Med Bull 1993; 49: 140–57PubMedGoogle Scholar
  105. 105.
    Vessey MP. The Jephcott lecture, 1989, an overview of the benefits and risks of combined oral contraceptives. In: Mann RD, editor. Oral contraceptives and breast cancer. Parthenon Publishing, 1989Google Scholar
  106. 106.
    Rosenberg MJ, Meehan T. The effect of desogestrel, gestodene, norgestimate and other factors on cycle control: a meta-analysis. [abstract]. Third Congress of the European Society of Contraception, Dublin, Ireland, June 1994.Google Scholar
  107. 107.
    Fuchs N, Düsterberg B, Weber-Diehl F, et al. The effect on blood pressure of a monophasic oral contraceptive containing ethinyestradiol and gestodene. Contraception 1995. In pressGoogle Scholar
  108. 108.
    Nichols M, Robinson G, Bounds W, et al. Effect of four combined oral contraceptives on blood pressure in the pill-free interval. Contraception 1993; 47: 367–76PubMedGoogle Scholar
  109. 109.
    Reubinoff BE, Berry E, Grubstein A. Effects of low-dose estrogen oral contraceptives on weight, body composition, and fat distribution in young women. Fertil Steril 1905; 63: 516–21Google Scholar
  110. 110.
    Drife JO. The benefits and risks of oral contraceptives. Parthenon Publishing Group, Carnforth, Lancashire, England 1993.Google Scholar
  111. 111.
    Klitsch M. The new pills: awaiting the next generation of oral contraceptives. Farn Plann Perspect 1992; 24: 226–8Google Scholar
  112. 112.
    Konig H-J, Anagnostopoulos-Schleep J, Mewe R. Cerebrovascular disorders during intake of gestodene containing oral contraceptives — causality or coincidence? [in German]. Med Klin 1991; 86: 333–7Google Scholar
  113. 113.
    Farmer RDT, Preston TD. The risk of venous thromboembolism associated with low oestrogen oral contraceptives. J Obstet Gynaecol 1995; 15: 195–200Google Scholar
  114. 114.
    Pasi KJ, Perry DJ, Lee CA. Thromboembolism and the combined oral contraceptive pill [letter]. Lancet 1995; 345: 1437PubMedGoogle Scholar
  115. 115.
    Vandenbroucke JP, Koster T, Briët E. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453–7PubMedGoogle Scholar
  116. 116.
    van der Burg B, Kalkhoven E, Isbrucker L, et al. Effects of progestins on the proliferation of estrogen-dependent human breast cancer cells under growth factor-defined conditions. J Steroid Biochem Mol Biol 1992; 42: 457–65PubMedGoogle Scholar
  117. 117.
    Rookus MA, van Leeuwen FE. Oral contraceptives and risk of breast cancer in women aged 20-54 years. Lancet 1994; 344: 844–51PubMedGoogle Scholar
  118. 118.
    Colletta A, Wakefield LM, Howell FV, et al. The growth inhibition of human breast cancer cells by a novel synthetic progestin involves the induction of transforming growth factor beta. J Clin Invest 1991; 87: 277–83PubMedGoogle Scholar
  119. 119.
    Iqbal MJ, Valyani SH. Evidence for a novel binding site for the synthetic progestogen, gestodene on oestrogen receptor in human malignant tissue. Anticancer Res 1988; 8: 351–4PubMedGoogle Scholar
  120. 120.
    Catherino WH, Jeng MH, Jordan VC. Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism. Br J Cancer 1993; 67: 945–52PubMedGoogle Scholar
  121. 121.
    Back DJ, Tjia JF, Houlgrave R, et al. Effect of progestogens on the metabolism of ethinyloestradiol by human liver microsomes in vitro [abstract]. Br J Clin Pharmacol 1990; 30: 321PGoogle Scholar
  122. 122.
    Guengerich FP. Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene. Chem Res Toxicol 1990; 3: 363–71PubMedGoogle Scholar
  123. 123.
    Kerlan V, Dreano Y, Bercovici JP, et al. Nature of cytochromes P450 involved in the 2-/4-hydroxylations of estradiol in human liver microsomes. Biochem Pharmacol 1992; 44: 1745–56PubMedGoogle Scholar
  124. 124.
    Back DJ, Houlgrave R, Tjia JF, et al. Effect of the progestogens, gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes. J Steroid Biochem Mol Biol 1991; 38: 219–25PubMedGoogle Scholar
  125. 125.
    Pazzucconi F, Malavasi B, Galli G, et al. Inhibition of antipyrine metabolism by low-dose contraceptives with gestodene and desogestrel. Clin Pharmacol Ther 1991; 49: 278–84PubMedGoogle Scholar
  126. 126.
    Guengerich FP. Inhibition of oral contraceptive steroid-metabolizing enzymes by steroids and drugs. Am J Obstet Gynecol 1990; 163 (6 Pt 2): 2159–63PubMedGoogle Scholar
  127. 127.
    Robinson GE, Burren T, Mackie IJ, et al. Changes in haemostasis after stopping the combined contraceptive pill: implications for major surgery. BMJ 1991; 302: 269–71PubMedGoogle Scholar
  128. 128.
    Skouby SO, Mølsted-Pedersen L, Petersen KR. Contraception for women with diabetes: an update. Baillieres Clin Obstet Gynaecol 1991; 5: 493–503PubMedGoogle Scholar

Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • Michelle I. Wilde
    • 1
  • Julia A. Balfour
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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