In September 2006, the CDC recommended that the interpretation of "general consent" for medical care include HIV screening, which eliminated the need for a separate, written consent.
In September 2006, the CDC recommended that the interpretation of "general consent" for medical care include HIV screening, which eliminated the need for a separate, written consent. Routine baseline prenatal screening should include an HIV test, with re-screening in the third trimester for women at high risk for HIV infection, including women with symptoms of acute HIV infection or women residing in a community with a high incidence of HIV infection among women of childbearing age (17 or more cases of HIV infection per 100,000 person-years).1 The goal of this recommendation is to increase identification of unrecognized HIV infection so as to expand the delivery and benefit of antiretroviral therapy and to decrease mother-to-child transmission.1
Because of these recommendations, providers can anticipate seeing an increased number of known HIV-positive persons in their practices. Furthermore, because women constitute the majority of persons younger than 25 years who are infected with HIV and because the number of HIV infections in women is increasing,2 it is likely that many of these patients will be young women. Control of fertility and the option of effective, reversible birth control will become more significant issues as these women choose to have families and to space rather than avoid pregnancies.
Health care providers thus need to be well versed in the contraceptive options available to women and the clinical issues related to their use. Hormonal contraceptive methods are of particular interest to women of reproductive age because of their effectiveness.3
OVERVIEW OF HORMONAL CONTRACEPTION
Hormonal contraception includes some of the most effective contraceptive methods available to women and some of the most commonly used contraceptive options in the United States.3 The hormonal contraceptive methods that are available are summarized in the Table. Among HIV-positive women, the numb
er who use hormonal contraception is smaller than the number who use other forms of birth control.4 However, this minority is not insignificant in number and is increasing.5 Wilson and colleagues6 found that 7.3% of their HIV-positive female patients used oral contraceptive pills, 7.2% used depot medroxyprogesterone acetate (DMPA), and 0.9% used subcutaneous levonorgestrel implants. Massad and colleagues7 reported that among 20-year-old HIV-positive women in their study, almost 40% used hormonal contraception. Globally, more than 100 million women use some form of hormonal contraceptive, most commonly oral contraceptive pills or DMPA.8 As the percentage of women known to be infected with the virus increases, and as these women live longer with HIV infection as they gain access to lifesaving antiretroviral therapy, the number of those using hormonal contraception is likely to increase.5,9
There are a wide variety of issues related to the use of hormonal contraceptives by HIV-positive women. At the very least, issues that need to be considered include the following10:
•Whether or not hormonal contraception facilitates HIV transmission to sex partners.
•Whether or not hormonal contraception facilitates disease progression.
•Which hormonal contraceptive methods interact with antiretroviral therapy, and what this means for hormonal contraceptive management.
•Does hormonal contraceptive use aggravate the metabolic adverse effects commonly encountered in the management of HIV disease with antiretroviral therapy?
The first 3 issues will only be briefly reviewed because they have already received much attention in the literature. The fourth has received little, if any, attention and is the focus of this column.
DOES HORMONAL CONTRACEPTION FACILITATE HIV TRANSMISSION?
Whether or not hormonal contraception facilitates HIV transmission has been elegantly summarized by Morrison and Cates.10 Briefly, there is no solid evidence regarding the influence of hormonal contraception on the infectiousness of HIV in women. This lack of information is largely due to the difficulty in directly evaluating HIV transmission risk. A proxy measure used for determining infectiousness is genital shedding of HIV, but even here, conclusions are conflicting: some researchers point to an increase in genital shedding with hormonal contraceptive use,11 while others indicate that this is not the case.12
It is important for providers to keep in mind that HIV-positive women who wish to avoid conception need to protect not only their partners from becoming infected but also themselves against HIV superinfection. Unfortunately, there is no one contraceptive method that provides both protection against transmission and reliable contraception. Barrier methods in general and condoms in particular are central to the prevention of HIV transmission, but barrier methods are far less effective as contraceptives, having higher failure rates than many other methods.3 Conversely, while hormonal contraception provides excellent contraceptive reliability, it does not prevent transmission. Thus, women must be counseled to use both methods.
DOES HORMONAL CONTRACEPTION FACILITATE HIV DISEASE PROGRESSION?
There are solid, theoretical reasons for being concerned that exposure to hormonal contraceptives may facilitate HIV disease progression, including not only the interference of reproductive hormones with cell-mediated immunity, natural killer cells, and IgG and IgM activity, but also the role that hormonal contraceptives may play in the regulation of HIV gene transcription.13 In particular, some animal studies have pointed toward the potential role of progesterone in the rapid progression of HIV disease.4 But studies of the menstrual cycle in women indicate decreased viral load during the luteal phase of the cycle, when progesterone levels are at their highest.13 Furthermore, studies indicate that women who are pregnant do not experience more rapid HIV disease progression.14 Of course, extrapolating from studies that look at physiological conditions to those that involve exogenous hormones at pharmacological doses is precarious at best, and more studies are needed. However, there does not yet appear to be any definitive conclusion that hormonal contraceptive use leads to more rapid viral progression.
DOES HORMONAL CONTRACEPTION INTERACT ADVERSELY WITH ANTIRETROVIRAL THERAPY?
All contraceptive steroids are substrates of the cytochrome P-450 (CYP) 3A4 microsomal enzyme system and therefore have the potential to interact with other medications, such as many of the antiretroviral agents, that are metabolized through this same enzyme system.15-17 Other avenues of interaction are possible, eg, through protein binding or P-glycoprotein specificity, but many researchers feel that the primary pathway by which antiretroviral agents and contraceptive steroids interact is through their common metabolic pathway of CYP3A4.18
The newly updated Department of Health and Human Services guidelines provide a convenient summary of the interactions between oral contraceptive pills and various antiretroviral drugs (see also Table 22 in these guidelines for more specific information).19 Unfortunately, these guidelines focus on the impact of different antiretroviral drugs on oral norethindrone and ethinyl estradiol. Other progestins and nonoral formulations are not addressed. For example, the efficacy and reliability of oral levonorgestrel as emergency contraception has not been explored in the context of HIV infection nor has it been studied in the context of antiretroviral use.20
Nonoral formulations are not subject to first-pass metabolism15; nevertheless, they are metabolized by the same microsomal enzyme system, and thus the potential for interactions exists. DMPA levels have been studied in women receiving nelfinavir, efavirenz, and nevirapine, and no significant changes in any of the hormonal parameters were noted in comparison with control groups at 2, 4, 6, 8, 10, and 12 weeks after DMPA dosing.15,21 Some suggest that DMPA be given every 10 weeks rather than every 12 weeks because of concerns regarding efficacy in the presence of antiretroviral therapy, but there is as yet no evidence that supports this option.22
Efficacy of newer levonorgestrel implants, the combined contraceptive patch, the combined hormonal contraceptive vaginal ring (NuvaRing), and the levonorgestrel intrauterine device (IUD) system (Mirena) have yet to be investigated. It is assumed that for those methods with predominantly local action and minimal systemic absorption, such as the levonorgestrel intrauterine system, interactions with antiretroviral drugs may be less of a concern. However, HIV health care providers are well aware of the interactions between antiretroviral agents and inhaled corticosteroids23––agents like contraceptives that have a predominantly local effect. Therefore, assumptions that drug interactions are not significant with these primarily locally acting contraceptives need to be verified.
Conversely, hormonal contraceptives appear to have minimal impact on serum levels of antiretroviral drugs and on the efficacy of antiretroviral therapy.15,21,24 These concerns should not lead one to avoid prescribing this form of contraception, but use of such contraceptives should prompt close follow-up and thorough counseling.
DOES HORMONAL CONTRACEPTIVE USE AGGRAVATE DRUG-RELATED METABOLIC ADVERSE EFFECTS?
It is well known that metabolic dysregulation––or abnormal serum lipid and glucose levels, insulin function, and bone mineral density (BMD)––is frequently associated with HIV disease and antiretroviral therapy.25-27 Numerous clinical, behavioral, and sociodemographic factors also contribute to the risk of metabolic dysfunction. Perhaps less familiar is the association between metabolic dysfunction and the use of hormonal contraception.28 A familiarity with the relationships among HIV infection, antiretroviral regimens, and metabolic dysregulation is assumed, and these issues will be only briefly reviewed by way of introduction. A more in-depth discussion of the relationship between hormonal contraceptive use and metabolic dysregulation is presented below.
HIV and Metabolic Dysregulation
The cause of HIV-related insulin and glucose dysregulation is unclear but is likely multifactorial. The potential causes include lipoatrophy29; factors related to the HIV disease process, including inflammation and direct viral effects30; duration and severity of HIV disease31; choice of antiretroviral therapy (both class and individual drug choice) and duration of use32; and risk factors found in the general population.30
Dyslipidemia, much like insulin resistance and glucose intolerance, likely results from both disease-related and antiretroviral therapy–related processes. Untreated, HIV infection results in a substantial decrease in serum total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol levels, as is seen in other infectious diseases. Triglyceride levels, on the other hand, increase with the onset of AIDS.33
The initial decrease in serum HDL concentrations is thought to be due to a host response, and antiretroviral therapy per se is not believed to significantly impact HDL levels, although use of NNRTIs may help raise serum HDL concentrations.29 After the initiation of antiretroviral therapy, increases in LDL and total cholesterol levels are seen, typically returning to preinfection levels. These increases in LDL and total cholesterol levels were originally thought to be associated with antiretroviral therapy but are now largely understood to reflect a return to health as well as specific age-related changes.33
Persons who are HIV-positive have lower BMD than their seronegative counterparts, although the severity of this decrease varies across studies. Decreased BMD is more common among HIV-positive persons than among persons who are not HIV-positive, and bone loss begins at a younger age in seropositive populations than in seronegative populations.34 Fortunately, while decreased BMD is an issue of concern, few reported cases of fractures exist.35 Although the increased incidence of low BMD in HIV-positive populations is well documented, there is much less agreement regarding whether HIV disease itself or antiretroviral therapy contributes more to the problem.34,36
Hormonal Contraception and Metabolic Dysregulation
The literature investigating the impact of hormonal contraception on metabolic outcomes is extensive but often contradictory or ambiguous, as are the mechanisms by which hormonal contraception influences metabolic processes.
Hormonal contraception and insulin and glucose dysregulation. Both estrogen deficiency and pharmacological levels of estrogen are associated with a deterioration in glucose homeostasis and with insulin resistance.37 Estrogen, in physiological, nonpregnant concentrations, is associated with normal glucose homeostasis and insulin sensitivity.28
Progestins demonstrate a more complex relationship with glucose tolerance and insulin sensitivity, with effects varying according to progestin type, method of administration, and dose. There are 4 classes of progestins––gonane progestins, estrane progestins, spironolactone-derived progestins, and pregnane progestins––and within these classes are different generations of hormones. Thus, not only do class differences exist with regards to the impact on glucose and insulin metabolism, but there may also be generational differences within the classes. For example, first-generation gonane progestins, norgestrel and levonorgestrel, uniformly cause a progressive increase in glucose intolerance and insulin resistance, both fasting and postglucose load, regardless of formulation, dose, and method of administration.38 The newer-generation gonane progestins, gestodene and desogestrel, have demonstrated a significantly improved metabolic profile over that of their predecessors,39 although the tendency of desogestrel to increase the half-life of insulin may mask the presence of insulin resistance.28
Compared with the gonane progestins, norethindrone, an estrane progestin, appears to have minimal effects on glucose tolerance.40 However, its impact on metabolic outcomes in young, healthy women with few metabolic risk factors may differ significantly from that in women with a significant background risk for metabolic dysfunction.41
Drospirenone, a new synthetic progestin used in combined oral contraceptive formulations (eg, Yasmin), appears to have a minimal effect on glucose and insulin levels in healthy women, even with prolonged use. This improved adverse-effect profile may be due to drospirenone's ability to more selectively target progesterone receptors than other progestins that frequently bind to estrogen as well as androgen receptors.39
In considering the impact of progestins, not only the type but also the mode of administration may be important. However, the different modalities (pills, injection, implants, vaginal rings, IUDs) often involve different progestins, so it is difficult to determine whether it is the type of progestin, the mode of administration, or both that are responsible for the variations in outcomes. Oral, low-dose, progestin-only contraceptives are generally thought to have minimal metabolic effects.42 However, intramuscular administration of DMPA, one of the pregnane progestins, and levonorgestrel implants are consistently associated with worsening glucose tolerance and insulin resistance.38
Duration of exposure to the hormones may also play a role. In clinical trials, increased exposure to DMPA and levonorgestrel implants has been associated with more severe dysregulation than short-term exposure, especially with regard to insulin resistance.38
Hormonal contraception and lipid dysregulation. Levels of serum lipids and lipoproteins are also altered in women who use hormonal contraceptives. Again, the nature of the change depends on the specific contraceptive used. Levels of very-low-density lipoprotein (VLDL) cholesterol, HDL cholesterol, and triglycerides are most significantly affected. Estrogen increases serum levels of HDL and VLDL cholesterol, while progestins decrease HDL cholesterol levels.43 The introduction of triphasic regimens with varying progestin levels over the 3 weeks of use provided an overall decreased exposure to progestin and demonstrated a minimal impact on HDL cholesterol.43
Elevations in triglyceride levels may be related to the estrogen-induced increase in hepatic VLDL synthesis.43 Estrogens may also alter lipoprotein lipase activity, shifting the flux of triglycerides from storage in adipose tissue to usage in skeletal muscle.44 Progestins may also play a role: desogestrel and gestodene are associated with elevations in triglyceride levels, as is DMPA.45 Levonorgestrel implants, however, reduce triglyceride concentrations in a dose-dependent manner.43
Exogenous hormones also influence serum LDL cholesterol concentrations. Estrogen increases LDL receptor activity. This promotes LDL and remnant uptake by cells thus decreasing plasma LDL cholesterol levels.46 While first-generation progestins antagonize this effect, the newer progestins appear less likely to do so.47
Hormonal contraception and dysregulation of bone metabolism. The relationship between oral contraceptive use and BMD is unclear. Clinical studies are inconsistent, demonstrating everything from a wide range of outcomes including a positive association between oral contraceptive use, decreased BMD, and the occurrence of fractures,48 to no association between oral contraceptive use and any measure of bone metabolism,49 to a positive association between oral contraceptive use and increased BMD.50 This inconsistency in outcomes may simply indicate a lack of association between oral contraceptive use and bone metabolism, or it may be attributable to differences in study design or contraceptive formulation that prevent accurate comparisons across studies.
Progestin-only contraceptives are more likely to negatively impact BMD than estrogen-progestin combination oral contraceptives, although levonorgestrel implants appear to have a neutral effect, possibly because of their increased androgenicity compared with other progestins. DMPA, however, is of particular concern. The FDA has published a black box warning highlighting the possibility that prolonged DMPA use results in a significant decrease in BMD. The degree of bone loss is proportional to the duration of DMPA use and may not be completely reversible, although this point remains controversial.51-53 Of particular concern is the possibility that use of DMPA during the early reproductive years may impair attainment of peak bone mass, which generally occurs around age 30, theoretically placing a woman at greater risk for osteopenia or osteoporosis and fractures postmenopause.54
To summarize, hormonal contraception may adversely impact glucose metabolism and insulin resistance, regardless of the dose of estrogen or the type, dose, and mode of delivery of the progestin. Some of the low-dose oral formulations, however, may improve insulin resistance. Insulin resistance may be present in women who use hormonal contraception, but in otherwise healthy, low-risk women, the short-term clinical significance appears to be negligible. In women who are already at risk for metabolic dysregulation, this additional metabolic stress may lead to adverse outcomes, including increased rates of type 2 diabetes mellitus.41,55 Progestin-only methods of contraception appear to be especially problematic.
The impact of hormonal contraception on lipid metabolism is more straightforward, although evidence of clinically important outcomes, such as an increase in cardiovascular disease, is lacking. Estrogen increases serum levels of HDL and VLDL cholesterol, the latter of which is at least partly responsible for the increase in triglyceride levels often seen in women using oral contraceptives. Estrogen also decreases plasma levels of LDL cholesterol. Progestins decrease HDL cholesterol levels, but the lower doses of progestins found in triphasic regimens appear to have minimal impact on HDL cholesterol. Some progestins also increase triglyceride levels, especially the newer-generation gonane progestins and DMPA.
While there is much debate over the impact of combined hormonal contraception on BMD, DMPA has a clearly negative effect.
The importance of hormonal contraception in HIV-positive women is growing. While very effective in preventing pregnancy, however, it is not without problems. There is a theoretical risk that hormonal contraception may worsen HIV disease or make viral control more difficult, although research has not yet definitively addressed this issue. Furthermore, we know very little about how antiretroviral therapy affects hormonal contraceptives, although combined oral contraceptives and DMPA have received some attention. However, there is little if any information on how implants, vaginal rings, levonorgestrel-containing IUDs, and progestin-only emergency contraception function in the presence of antiretroviral therapy. Of particular concern is the potential for overlap of metabolic complications between HIV infection, antiretroviral therapy, and the use of hormonal contraception. Both HIV infection and hormonal contraception use share a common risk profile for metabolic abnormalities, and while there is insufficient evidence that hormonal contraception aggravates the metabolic dysregulation associated with HIV infection, the literature suggests a need for caution and careful, conservative management.
Denying a woman her choice of contraceptive because of these or any other hypothetical concerns is inappropriate, but so is ignoring the potential interactions and increased adverse effects. Research needs to investigate these issues and to provide evidence-based practice guidelines for hormonal contraception management in HIV-positive women. Until these guidelines are available, conservative management that focuses on early identification of problems seems appropriate.
References1. Branson BM, Handsfield HH, Lampe MA, et al; Centers for Disease Control and Prevention. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006;55(RR-14):1-17; quiz CE1-CE4.
2. Centers for Disease Control and Prevention. HIV/AIDS Surveillance in Adolescents and Young Adults (through 2005). Slide Set. June 2007.
3. Hatcher RA, Trussell J, Stewart FH, et al, eds. Contraceptive Technology. 18th rev ed. New York: Ardent Media, Inc; 2004.
4. Cejtin HE, Jacobson L, Springer G, et al. Effect of hormonal contraceptive use on plasma HIV-1-RNA levels among HIV-infected women. AIDS. 2003;17:1702-1704.
5. Clark RA, Theall KP. Trends and correlates of hormonal contraception use among HIV-infected women. J Acquir Immune Defic Syndr. 2004;36:986-988.
6. Wilson TE, Massad LS, Riester KA, et al. Sexual, contraceptive, and drug use behaviors of women with HIV and those at high risk for infection: results from the Women’s Interagency HIV Study. AIDS. 1999;13:591-598.
7. Massad LS, Evans CT, Wilson TE, et al. Contraceptive use among U.S. women with HIV. J Womens Health (Larchmt). 2007;16:657-666.
8. World Contraceptive Use. http://www.un.org/esa/population/publications/contraceptive2005/WCU2005.htm. Accessed March 3, 2007.
9. Blair JM, Hanson DL, Jones JL, Dworkin MS. Trends in pregnancy rates among women with human immunodeficiency virus. Obstet Gynecol. 2004;103:663-668.
10. Morrison CS, Cates W Jr. Preventing unintended pregnancy and HIV transmission: dual protection or dual dilemma? Sex Transm Dis. 2007;34:873-875.
11. Wang CC, McClelland RS, Overbaugh J, et al. The effect of hormonal contraception on genital tract shedding of HIV-1. AIDS. 2004;18:205-209.
12. Clark RA, Theall KP, Amedee AM, et al. Lack of association between genital tract HIV-1 RNA shedding and hormonal contraceptive use in a cohort of Louisiana women. Sex Transm Dis. 2007;34:870-872.
13. Cejtin HE. Gynecologic issues in the HIV-infected woman. Obstet Gynecol Clin North Am. 2003;30:711-729.
14. Tai JH, Udoji MA, Barkanic G, et al. Pregnancy and HIV disease progression during the era of highly active antiretroviral therapy. J Infect Dis. 2007;196:1044-1052.
15. Cohn SE, Park JG, Watts DH, et al. Depo-medroxyprogesterone in women on antiretroviral therapy: effective contraception and lack of clinically significant interactions. Clin Pharmacol Ther. 2007;81:222-227.
16. Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs. 2002;16:263-272.
17. McCann MF, Potter LS. Progestin-only oral contraception: a comprehensive review. Contraception. 1994;50(6 suppl 1):S1-S195.
18. de Maat MM, Ekhart GC, Huitema AD, et al. Drug interactions between antiretroviral drugs and comedicated agents. Clin Pharmacokinet. 2003;42:223-282.
19. Panel oAGfAaA. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 29, 2008. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed April 4, 2008.
20. Delvaux T, NÃ¶stlinger C. Reproductive choice for women and men living with HIV: contraception, abortion and fertility. Reprod Health Matters. 2007;15(29 suppl):46-66.
21. Watts DH, Park JG, Cohn SE, et al. Safety and tolerability of depot medroxyprogesterone acetate among HIV-infected women on antiretroviral therapy: ACTG A5093. Contraception. 2008;77:84-90.
22. Mitchell HS, Stephens E. Contraception choice for HIV positive women. Sex Transm Infect. 2004;80:167-173.
23. le Roux CW, Beckles MA, Besser GM, et al. Cushing’s syndrome secondary to inhaled corticosteroids mimicking HIV-associated lipodystrophy. HIV Med. 2001;2:133-135.
24. Chu JH, Gange SJ, Anastos K, et al. Hormonal contraceptive use and the effectiveness of highly active antiretroviral therapy. Am J Epidemiol. 2005;161:881-890.
25. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med. 2005;352:48-62.
26. Nolan D. Metabolic complications associated with HIV protease inhibitor therapy. Drugs. 2003;63:2555-2574.
27. Friis-MÃ¸ller N, Weber R, Reiss P, et al; DAD Study Group. Cardiovascular disease risk factors in HIV patients-association with antiretroviral therapy. Results from the DAD study. AIDS. 2003;17:1179-1193.
28. Godsland IF. The influence of female sex steroids on glucose metabolism and insulin action. J Intern Med Suppl. 1996;738:1-60.
29. Grunfeld C, Tien P. Difficulties in understanding the metabolic complications of acquired immune deficiency syndrome. Clin Infect Dis. 2003;37(suppl 2):S43-S46.
30. Kotler D. Challenges to diagnosis of HIV-associated wasting. J Acquir Immune Defic Syndr. 2004;37(suppl 5):S280-S283.
31. DubÃ© MP. Disorders of glucose metabolism in patients infected with human immunodeficiency virus. Clin Infect Dis. 2000;31:1467-1475.
32. Noor MA, Seneviratne T, Aweeka FT, et al. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS. 2002;16(5):F1-F8.
33. Grunfeld C, Kotler DP, Shigenaga JK, et al. Circulating interferon-alpha levels and hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med. 1991;90:154-162.
34. Mondy K, Tebas P. Emerging bone problems in patients infected with human immunodeficiency virus. Clin Infect Dis. 2003;36(suppl 2):S101-S105.
35. McComsey G, Huang J, Woolley I, et al. Fragility fractures in HIV-infected subjects, an area for improvement. 11th Conference on retroviruses and opportunistic infections; February 8-11, 2004; San Francisco.
36. Amiel C, Ostertag A, Slama L, et al. BMD is reduced in HIV-infected men irrespective of treatment. J Bone Miner Res. 2004;19:402-409.
37. Godsland IF. Oestrogens and insulin secretion. Diabetologia. 2005;48:2213-2220.
38. Kahn HS, Curtis KM, Marchbanks PA. Effects of injectable or implantable progestin-only contraceptives on insulin-glucose metabolism and diabetes risk. Diabetes Care. 2003;26:216-225.
39. Gaspard U, Scheen A, Endrikat J, et al. A randomized study over 13 cycles to assess the influence of oral contraceptives containing ethinylestradiol combined with drospirenone or desogestrel on carbohydrate metabolism. Contraception. 2003;67:423-429.
40. Spellacy WN. Carbohydrate metabolism during treatment with estrogen, progestogen, and low-dose oral contraceptives. Am J Obstet Gynecol. 1982;142(6, pt 2):732-734.
41. Kjos SL, Peters RK, Xiang A, et al. Contraception and the risk of type 2 diabetes mellitus in Latina women with prior gestational diabetes mellitus. JAMA. 1998;280:533-538.
42. Ludicke F, Gaspard UJ, Demeyer F, et al. Randomized controlled study of the influence of two low estrogen dose oral contraceptives containing gestodene or desogestrel on carbohydrate metabolism. Contraception. 2002;66:411-415.
43. Godsland IF, Crook D. Update on the metabolic effects of steroidal contraceptives and their relationship to cardiovascular disease risk. Am J Obstet Gynecol. 1994;170(5, pt 2):1528-1536.
44. Livingstone C, Collison M. Sex steroids and insulin resistance. Clin Sci (Lond). 2002;102:151-166.
45. Garza-Flores J, De la Cruz DL, Valles de Bourges V, et al. Long-term effects of depot-medroxyprogesterone acetate on lipoprotein metabolism. Contraception. 1991;44:61-71.
46. Knopp RH, LaRosa JC, Burkman RT Jr. Contraception and dyslipidemia. Am J Obstet Gynecol. 1993;168(6, pt 2):1994-2005.
47. Bass KM, Newschaffer CJ, Klag MJ, Bush TL. Plasma lipoprotein levels as predictors of cardiovascular death in women. Arch Intern Med. 1993;153:2209-2216.
48. Vessey M, Mant J, Painter R. Oral contraception and other factors in relation to hospital referral for fracture. Findings in a large cohort study. Contraception. 1998;57:231-235.
49. Bahamondes L, Juliato CT, Villarreal M, et al. Bone mineral density in users of two kinds of once-a-month combined injectable contraceptives. Contraception. 2006;74:259-263.
50. Cobb KL, Kelsey JL, Sidney S, et al. Oral contraceptives and bone mineral density in white and black women in CARDIA. Coronary Risk Development in Young Adults. Osteoporos Int. 2002;13:893-900.
51. FDA. Physician Information. http://www.fda.gov/medwatch/SAFETY/2004/DepoProvera_Label.pdf. Accessed April 9, 2007.
52. Kaunitz AM. Depo-Provera’s black box: time to reconsider? Contraception. 2005;72:165-167.
53. Cundy T, Cornish J, Roberts H, Reid IR. Menopausal bone loss in long-term users of depot medroxyprogesterone acetate contraception. Am J Obstet Gynecol. 2002;186:978-983.
54. Lara-Torre E, Edwards CP, Perlman S, Hertweck SP. Bone mineral density in adolescent females using depot medroxyprogesterone acetate. J Pediatr Adolesc Gynecol. 2004;17:17-21.
55. Kim C, Seidel KW, Begier EA, Kwok YS. Diabetes and depot medroxyprogesterone contraception in Navajo women. Arch Intern Med. 2001;161:1766-1771.