Correspondence

Combined Estrogen–Progestin Oral Contraceptives

N Engl J Med 2004; 350:307-308January 15, 2004

Article

To the Editor:

Petitti (Oct. 9 issue)1 offers recommendations regarding the use of estrogen–progestin oral contraceptives. Since third-generation compounds containing desogestrel or gestodene as progestin are associated with a higher risk of venous thromboembolism than those containing other types of progestin,2 it is preferable for women with an increased base-line risk of venous thromboembolism to use second-generation compounds. Among them are carriers of the factor V Leiden mutation, which is the most common cause of thrombophilia and is present at a frequency of 2 to 15 percent in populations of Caucasian descent.3 Petitti's statement that oral contraceptives are contraindicated in carriers of factor V Leiden is valid only for homozygotes or for women who have previously had thrombosis. However, the majority of carriers are heterozygotes and remain asymptomatic, despite their exposure to transient risk factors for thrombosis.4 We believe that, in general, asymptomatic heterozygous carriers of factor V Leiden should be given information on the relative and absolute increased risk of thrombosis, without discouraging the use of second-generation oral contraceptives.

Ida Martinelli, M.D., Ph.D.
Tullia Battaglioli, M.D.
Pier Mannuccio Mannucci, M.D.
University of Milan, 20122 Milan, Italy
martin@policlinico.mi.it

4 References

1. 1

   Petitti DB. Combination estrogen-progestin oral contraceptives. N Engl J Med 2003;349:1443-1450
   Full Text | Web of Science | Medline

2. 2

   Bloemenkamp KWM, Rosendaal FR, Buller HR, Helmerhorst FM, Colly LP, Vandenbroucke JP. Risk of venous thrombosis with use of current low-dose oral contraceptives is not explained by diagnostic suspicion and referral bias. Arch Intern Med 1999;159:65-70
   CrossRef | Web of Science | Medline

3. 3

   Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995;346:1133-1134
   CrossRef | Web of Science | Medline

4. 4

   Martinelli I, Mannucci PM, De Stefano V, et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood 1998;92:2353-2358
   Web of Science | Medline

To the Editor:

Oral contraceptive therapy has become the preferred method of birth control because of its high rate of effectiveness. Meant to provide a measure of sexual freedom through reproductive control, oral contraceptives do so at the cost of biochemical insults to a woman's androgenic milieu. Omitted from Petitti's discussion of the potential cons of these agents are their detrimental effects on women's sexual function. She notes the association between oral contraceptives and decreased free testosterone concentrations, but only as it relates to the improvement of acne.

Oral contraceptives decrease bioavailable testosterone by inhibiting ovarian testosterone synthesis, while promoting the hepatic production of steroid hormone–binding globulin. The influence of bioavailable androgens on sexual function is known,1 and significant improvements after testosterone therapy have been reported.2,3 Emotional and sexual side effects have been identified as the main reason for discontinuation of oral contraceptives,4 which have also been implicated as a cause of dyspareunia due to vulvar vestibulitis.5

Women should be informed about the potential side effects of oral contraceptives on sexual function, and they should be encouraged to discuss these side effects with their health care provider.

Suzette E. Sutherland, M.D.
Metropolitan Urologic Specialists, St. Paul, MN 55305
sesuthrlnd@aol.com

Ricardo M. Munarriz, M.D.
Irwin Goldstein, M.D.
Boston University School of Medicine, Boston, MA 02118

5 References

1. 1

   Bachmann G, Bancroft J, Braunstein G, et al. Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment. Fertil Steril 2002;77:660-665
   CrossRef | Web of Science | Medline

2. 2

   Goldstat R, Briganti E, Tran J, Wolfe R, Davis SR. Transdermal testosterone therapy improves well-being, mood, and sexual function in premenopausal women. Menopause 2003;10:390-398
   CrossRef | Web of Science | Medline

3. 3

   Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:682-688
   Full Text | Web of Science | Medline

4. 4

   Sanders SA, Graham CA, Bass JL, Bancroft J. A prospective study of the effects of oral contraceptives on sexuality and well-being and their relationship to discontinuation. Contraception 2001;64:51-58
   CrossRef | Web of Science | Medline

5. 5

   Bouchard C, Brisson J, Fortier M, Morin C, Blanchette C. Use of oral contraceptive pills and vulvar vestibulitis: a case-control study. Am J Epidemiol 2002;156:254-261
   CrossRef | Web of Science | Medline

Author/Editor Response

The absolute risk of venous thromboembolism must be considered when making recommendations about the use of combined estrogen–progestin oral contraceptives in women with the factor V Leiden mutation. In an analysis of data from three case–control studies of venous thromboembolism, the pooled odds ratio for venous thromboembolism was 10.3 among users of oral contraceptives who were carriers of factor V Leiden, a group that included both homozygotes and heterozygotes.1 The odds ratio for venous thromboembolism among users of oral contraceptives who were not carriers was 2.3. The average incidence of venous thromboembolism among women of reproductive age who do not use oral contraceptives (50 per million per year)2 and these odds ratios can be used to estimate the “number needed to harm” — that is, the number of women per year who would have a thromboembolic event if they were using oral contraceptives. This number is 2222 for carriers of factor V Leiden and 20,000 for noncarriers.

Oral contraceptives are thought to increase the risk of venous thromboembolism by enhancing resistance to activated protein C. This effect has recently been shown to be estrogen-dependent.3 For this reason, progestin-only pills are recommended for carriers of factor V Leiden who wish to use oral contraceptives. Progestin-only oral contraceptives currently marketed in the United States include Ovrette, which contains norgestrel, and Micronor and Nor-QD, both of which contain norethindrone.

The effect of oral contraceptives on sexual function is not predicted by their effect on bioavailable testosterone.4 The sexual response of women to oral contraceptives is affected by culture and the context of use.5 Women should definitely discuss with their health care provider any perceived adverse effect of oral contraceptives on sexual function. When negative effects of oral contraceptives are reported, a change in formulation may foster continuation.

Diana B. Petitti, M.D., M.P.H.
Kaiser Permanente Southern California, Pasadena, CA 91188
diana.b.petitti@kp.org

5 References

1. 1

   Emmerich J, Rosendaal FR, Cattaneo M, et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism -- pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Thromb Haemost 2001;86:809-816[Erratum, Thromb Haemost 2001;86:1598.]
   Web of Science | Medline

2. 2

   Farley TM, Collins J, Schlesselman JJ. Hormonal contraception and risk of cardiovascular disease: an international perspective. Contraception 1998;57:211-230
   CrossRef | Web of Science | Medline

3. 3

   Kemmeren JM, Algra A, Meijers JC, et al. Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor VLeiden mutation: a randomized trial. Blood (in press).
   

4. 4

   Bancroft J, Sherwin BB, Alexander GM, Davidson DW, Walker A. Oral contraceptives, androgens, and the sexuality of young women. II. The role of androgens. Arch Sex Behav 1991;20:121-135
   CrossRef | Web of Science | Medline

5. 5

   Graham CA, Ramos R, Bancroft J, Maglaya C, Farley TM. The effects of steroidal contraceptives on the well-being and sexuality of women: a double-blind, placebo-controlled, two-centre study of combined and progestogen-only methods. Contraception 1995;52:363-369
   CrossRef | Web of Science | Medline