Nondaily hormonal contraceptives: Establishing a fit between product characteristics and patient preferences

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Applied Evidence

Nondaily hormonal contraceptives: Establishing a fit between product characteristics and patient preferences

J Fam Pract. 2004 November;53(11):904-913

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References

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21. Bjarnadottir RI, Tuppurainen M, Killick SR. Comparison of cycle control with a combined contraceptive vaginal ring and oral levonorgestrel/ethinyl estradiol. Am J Obstet Gynecol 2002;186:389-395.

22. Audet MC, Moreau M, Koltun WD, et al. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: a randomized controlled trial. JAMA 2001;285:2347-2354.

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24. Backman T, Huhtala S, Luoto R, Tuominen J, Rauramo I, Koskenvuo M. Advance information improves user satisfaction with the levonorgestrel intrauterine system. Obstet Gynecol 2002;99:608-613.

25. den Tonkelaar I, Oddens BJ. Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral contraceptive use, and hormone replacement therapy use. Contraception 1999;59:357-362.

26. Danli S, Qingxiang S, Guowei S. A multicentered clinical trial of the long-acting injectable contraceptive Depo Provera in Chinese women. Contraception 2000;62:15-18.

27. Moore LL, Valuck R, McDougall C, Fink W. A comparative study of one-year weight gain among users of medroxyprogesterone acetate, levonorgestrel implants, and oral contraceptives. Contraception 1995;52:215-219.

28. Espey E, Steinhart J, Ogburn T, Qualls C. Depo-provera associated with weight gain in Navajo women. Contraception 2000;62:55-58.

29. Risser WL, Gefter LR, Barratt MS, Risser JM. Weight change in adolescents who used hormonal contraception. J Adolesc Health 1999;24:433-436.

30. Taneepanichskul S, Reinprayoon D, Khaosadad P. Comparative study of weight change between long-term DMPA and IUD acceptors. Contraception 1998;58:149-151.

31. Pelkman CL, Chow M, Heinbach RA, Rolls BJ. Short-term effects of a progestational contraceptive drug on food intake, resting energy expenditure, and body weight in young women. Am J Clin Nutr 2001;73:19-26.

32. Dieben TO, Roumen FJ, Apter D. Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring. Obstet Gynecol 2002;100:585-593.

33. Dubuisson JB, Mugnier E. Acceptability of the levonorgestrel-releasing intrauterine system after discontinuation of previous contraception: results of a French clinical study in women aged 35 to 45 years. Contraception 2002;66:121-128.

34. Ronnerdag M, Odlind V. Health effects of long-term use of the intrauterine levonorgestrel-releasing system. A follow-up study over 12 years of continuous use. Acta Obstet Gynecol Scand 1999;78:716-721.

35. Gupta N, O’Brien R, Jacobsen LJ, et al. Mood changes in adolescents using depot-medroxyprogesterone acetate for contraception: a prospective study. J Pediatr Adolesc Gynecol 2001;14:71-6.

36. Westhoff C, Truman C, Kalmuss D, et al. Depressive symptoms and Depo-Provera. Contraception 1998;57:237-240.

37. Civic D, Scholes D, Ichikawa L, et al. Depressive symptoms in users and non-users of depot medroxyproges-terone acetate. Contraception 2000;61:385-390.

38. Smallwood GH, Meador ML, Lenihan JP, Shangold GA, Fisher AC, Creasy GW. Efficacy and safety of a transder-mal contraceptive system. Obstet Gynecol 2001;98:799-805.

39. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1996;347:1713-1727.

40. Skegg DC, Noonan EA, Paul C, Spears GF, Meirik O, Thomas DB. Depot medroxyprogesterone acetate and breast cancer. A pooled analysis of the World Health Organization and New Zealand studies. JAMA 1995;273:799-804.

41. The Who Collaborative Study of Neoplasia and Steroid Contraceptives. Endometrial cancer and combined oral contraceptives. Int J Epidemiol 1988;17:263-269.

42. Ness RB, Grisso JA, Klapper J, et al. Risk of ovarian cancer in relation to estrogen and progestin dose and use characteristics of oral contraceptives. SHARE Study Group. Steroid Hormones and Reproductions. Am J Epidemiol 2000;152:233-241.

43. Stanford JL, Thomas DB. Depot-medroxyprogesterone acetate (DMPA) and risk of epithelial ovarian cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Cancer 1991;49:191-195.

44. Parazzini F, La Vecchia C, Negri E, Maggi R. Oral contraceptive use and invasive cervical cancer. Int J Epidemiol 1990;19:259-263.

45. Kjaer SK, Engholm G, Dahl C, Bock JE, Lynge E, Jensen OM. Case-control study of risk factors for cervical squamous cell neoplasia in Denmark. Role of oral contraceptive use. Cancer Causes Control 1993;4:513-519.

46. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-medroxyprogesterone acetate and risk of invasive squamous cell cervical cancer.The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Contraception 1992;45:299-312.

47. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1995;346:1575-1582.

48. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1997;349:1202-1209.

49. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Haemorrhagic stroke, overall stroke risk, and combined oral contraceptives: results of an international, multicentre, case-control study. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1996;348:505-510.

50. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives. Results of an international, multicenter, case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Contraception 1998;57:315-324.

51. Prior JC, Kirkland SA, Joseph L, et al. Oral contraceptive use and bone mineral density in premenopausal women: cross-sectional, population-based data from the Canadian Multicentre Osteoporosis Study. CMAJ 2001;165:1023-1029.

52. Banks E, Berrington A, Casabonne D. Overview of the relationship between use of progestogen-only contraceptives and bone mineral density. BJOG 2001;108:1214-21.

53. Tang OS, Tang G, Yip PS, Li B. Further evaluation on long-term depot-medroxyprogesterone acetate use and bone mineral density: a longitudinal cohort study. Contraception 2000;62:161-164.

54. Orr-Walker BJ, Evans MC, Ames RW, Clearwater JM, Cundy T, Reid IR. The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post-menopausal women. Clin Endocrinol (Oxf) 1998;49:615-618.

55. Petitti DB, Piaggio G, Mehta S, Cravioto MC, Meirik O. Steroid hormone contraception and bone mineral density: a cross-sectional study in an international population. Obstet Gynecol 2000;95:736-744.

56. Scholes D, Lacroix AZ, Ichikawa LE, Barlow WE, Ott SM. Injectable hormone contraception and bone density: results from a prospective study. Epidemiology 2002;13:581-587.

57. Sivin I, el Mahgoub S, McCarthy T, et al. Long-term contraception with the levonorgestrel 20 mcg/day (LNg 20) and the copper T 380Ag intrauterine devices: a five-year randomized study. Contraception 1990;42:361-378.

58. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med 2002;346:2025-2032.

TABLE 2
Nondaily hormonal contraceptive side effects and long-term safety

Side effect	Combined oral contraceptives	Depo-Provera	Mirena	NuvaRing	Ortho Evra
Bleeding patterns
Regular cycles	Yes	No	Variable	Yes	Yes
Intermenstrual bleeding/spotting		7.6%–27% at 1 year^17,18	16% at 1 year²⁰	3.8% at 1 year³²	<10% at 1 year^22,38
Menorrhagia		6.7% at 9 mo¹⁶	Rare²⁰	None reported³²	None reported²²
Amenorrhea		70%–73% at 1 year^17,18	20%–50% at 1 year^5,20	None reported³²	0.1%²²
Discontinuation due to bleeding changes		20% at 1 year¹⁶	10.6% at 1 year⁵⁷	<1% at 1 year³²	<1% at 1 year²²
Weight gain	Mean 1.3 kg at 1 year²⁹	Mean 2.5–3.0 kg at 1 year^13,29	<1.0 kg at 1 year³³	<1.0 kg at 1 year³²	<1.0 kg at 1 year²²
Mood	Depression, 4.8%⁴⁰	Depression, <2%¹⁹	Depression 5%⁵	Emotional lability 2.8%³²	Emotional lability 1.5%³⁸
Hormone delivery system–related side effects	Allergies to dyes in pills; efficacy may be compromised by gastrointestinal or hepatic metabolism	Minor injection sitepain (<1%)¹³	Expulsion (6.6%)²⁰ Sepsis, PID, embedment/perforation⁵	Vaginitis (5.6%) leukorrhea (4.8%) device-related events (4.4%)³²	Patch application site reactions (20%)²²
Breast and gynecologic cancers*
Breast	1.24 (1.15–1.33)^39†§	1.5 (1–2.2)^40†§	No studies	No studies	No studies
	1.01 (0.96–1.05)^58‡	1.1 (0.97–1.4)^40‡
Endometrial	0.55 (0.26–1.17)⁴¹	0.21 (0.06–0.79)⁸
Ovarian	0.5 (0.3–0.6)⁴²	1.07 (0.6–1.8)⁴³
Cervical	1.30 (0.5–3.3)⁴⁵	1.11 (0.96–1.29)⁴⁶
	1.53 (0.99–2.36)⁴⁴
Relative risk of cardiovascular disease
All stroke	1.41 (0.90–2.20)⁴⁹	0.89 (0.53–1.49)⁵⁰	No studies	No studies	No studies
Acute MI	4.69 (2.02–10.9)^48§	0.66 (0.07–6.0)⁵⁰
Smokers <35 y	34.9⁴⁷
Smokers 35 y	396.24^7§
VTE	4.32 (2.88–6.49)^47§	2.19 (0.66–7.26)⁵⁰
Effects on bone mineral density	Variable, but usually positive	Reversible reduction	No studies	No studies	No studies
*Relative risk (95% CI). †Current use; ‡Any use; §Likelihood was significantly different relative to control; §Confidence intervals not reported.
PID, pelvic inflammatory disease; CI, confidence interval; MI, myocardial infarction; VTE, venous thromboembolism.

Noncontraceptive health benefits

Nondaily hormonal contraceptive options have documented non-contraceptive health benefits.

DMPA-IM. This drug reduces the risk of endometrial cancer by 80% after 1 year, a protective effect that appears to extend for at least 8 years after cessation of use.⁸ DMPA-IM also decreases risk of iron deficiency anemia, pelvic inflammatory disease⁹ and uterine leiomyomas,¹⁰ and reduces pain crises among users with sickle cell disease.¹¹

Clinical experience has shown that DMPA-IM may be an effective treatment option for a number of gynecologic conditions, including (though these are unapproved off-label uses) menorrhagia and dysmenorrhea, pain associated with endometriosis, ovulatory pain, and menopause-related vasomotor symptoms.^9,12 Many of the menstrual-cycle related benefits of DMPA-IM result from the high incidence of amenorrhea, which may be particularly appealing to women who have menstrual-cycle related disorders, such as mittelschmerz, and for women who have problems with menstrual hygiene.

Additional advantages of progestin-only DMPA-IM compared with estrogen-containing contraceptive options include efficacy that is not compromised by concomitant anticonvulsive therapy.⁹ It also has no adverse effect on lactation, allowing use as early as the sixth week postpartum in breast-feeding women.¹³

L-IUS. This agent may also have several non-contraceptive benefits related primarily to the oligoamenorrhea experienced by many users. These include increased hemoglobin concentrations (thus possibly preventing iron deficiency anemia), off-label use as a treatment for menorrhagia or dysmenorrhea, an alternative to hysterectomy for heavy menstrual bleeding, and for progestin opposition in post-menopausal women on estrogen replacement therapy.¹⁴ Small case-series reports also suggest that L-IUS may have a modulatory effect on endometrial hyperplasia associated with tamoxifen exposure in women with breast cancer.¹⁵

EE-ring, NE-patch. Due to the limited experience with these products, it is not known whether users will enjoy noncontraceptive health benefits, although it is reasonable to assume that since they are derived from combinations of well-studied estrogens and progestins, their benefits may be similar to those of combined oral contraceptives.

Side-effect profiles

Hormone-related side effects—including changes in bleeding pattern, weight gain, mood changes, headaches, breast tenderness, and nausea—can be problematic for many women using hormonal contraceptives (both oral contraceptives and nondaily methods) and are common reasons for discontinuation.^2,16 Therefore, it is important to consider differences in side-effect profiles when helping women to select an appropriate method, and to adequately counsel women regarding the expected effects prior to starting therapy.

Bleeding patterns

Nondaily hormonal contraceptives differ considerably in their effects on bleeding patterns ( Table 2 ).

DMPA-IM is characterized by amenorrhea, which develops in 70% to 73% of users after 1 year.^17,18 Intermenstrual bleeding and spotting has been reported in 7.6% to 27% of DMPA-IM users at 12 months.^17,18 However, among those who experience irregular bleeding, it generally consists of spotting or light bleeding rather than heavy intermenstrual flow.¹⁹

Amenorrhea has been reported in 20% to 50% of L-IUS users after 1 year.^5,20 Among L-IUS users who do not experience amenorrhea, cycles are variable,⁵ with spotting observed in 25% of women at 6 months, decreasing to 11% at 2 years.²⁰

Amenorrhea is rarely seen among women using the EE-ring or NE-patch; rather, similar to oral contraceptives, regular menstrual cycles are established within the first few cycles of use.^21,22 Rates of intermenstrual bleeding/spotting at 1 year are less than 10% for each of these methods, with bleeding changes rarely cited as a reason for drug discontinuation.^21,22