Guy I. Benrubi, MD

Of American women aged 15 to 44 years who are at risk of unintended pregnancy, 40% are 	currently using hormonal contraception, and more than 75% previously used hormonal birth control.

 	In 1997, gynecologic cancers (e.g., breast, endometrial, ovarian, cervical) will be diagnosed in an estimated 256,000 	US women and result in the deaths of 69,000.2 If use of hormonal contraception can reduce the risk of reproductive 	cancer, the public health impact and clinical implications would be significant. This review details these associations 	and provides reas-surance that the use of hormonal contraceptives including combination oral contraceptives (OCs), 	progestin-only OCs, levonorgestrel subdermal implants, and depot medroxyprogesterone acetate (DMPA) injections 	prevents ra- ther than promotes gynecologic cancer.

Breast cancer remains the most prevalent cancer in American women; an estimated 180,000 new cases will be diagnosed 	in 1997, and approximately 44,000 deaths will occur. As a cause of cancer death in women, breast cancer ranks second 	only to lung cancer a mortality figure that is considerably greater than the combined number of deaths from endometrial, 	ovarian, and cervical cancers in the United States.

 Because breast cancer is 	both common and lethal, understanding the research on potential associations between hormonal contraception and 	breast cancer is a high clinical priority.

Factors unrelated to risk of breast cancer

A meta-analysis that reassessed 54 studies of breast cancer risk and OC use encompassed 90% of all available epidemiologic 	data. It included more than 53,000 breast cancer cases and 100,000 controls.

Current OC users and those who had discontinued use within the past 10 years were found to be at slightly increased 	risk compared with nonusers. However, breast cancers diagnosed in women with a history of OC use were more localized 	than those in nonusers. The most important finding of this massive reanalysis was that at 10 to 20 years after 	OC discontinuation, the estimated cumulative number of breast cancer cases in OC ever-users was the same as in 	never-users (Table).

Although follow-up data on mortality were not available from the studies assessed by this meta-analysis, the 	results raise the possibility that a decade or more after OC discontinuation, cumulative deaths from breast cancer 	may have been lower in OC ever-users than in never-users. Factors that did not im- pact the overall findings regarding 	OC use and breast cancer risk included reproductive history, family history of breast cancer, duration of OC use, 	age at first OC use, and steroid dosage or type. This report represents the most comprehensive study of OC use 	and breast cancer risk ever published and should broadly reassure both clinicians and patients.


 	Endometrial cancer is the most common genital cancer in the United States, with an incidence second only to that 	of breast cancer. In 1997, approximately 35,000 cases of endometrial cancer will be diagnosed, and an estimated 	6,000 women will die from this disease.

Estrogenic proliferation of the endometrium combined with absent or inadequate progestional suppression characterizes 	the majority of women who develop endometrial adenocarcinoma. In women who use hormonal contraception, the endometrium 	is almost continuously under the influence of synthetic progestins and thus might be less susceptible to malignant 	transformation.

Strong evidence indicates that the risk of endometrial cancer in women younger than age 60 is substantially 	reduced by current or prior use of OCs. Furthermore, this protection increases markedly with longer duration of 	OC use.

A study from the Centers for Disease Control and Prevention (CDC) assessed 433 cases of endometrial cancer in 	women 20 to 54 years of age and 3,191 controls. Compared with never-users, women who had used combination OCs were 	50% less likely to develop endometrial cancer.6 Twelve other case-control studies and three cohort studies have 	also examined the association between endometrial cancer risk and OC use. All but two of these investigations found 	a protective effect

One case-control study looked at endometrial cancer risk up to 20 years after OC discontinuation

 	and found that the protection against endometrial cancer persisted for at least two decades. Therefore, women who 	use OCs in their late 30s and 40s may be able to reduce their likelihood of developing endometrial cancer for the 	decades when they will be at highest risk.


 	Ovarian cancer remains the most lethal female reproductive-tract malignancy, with regional or distant metastasis 	present in 75% of patients at the time of diagnosis. The incidence of ovarian cancer rises slowly during the reproductive 	years. It becomes more common after menopause and peaks among women in their 70s. In the United States, some 27,000 	cases of ovarian cancer will be diagnosed in 1997, and an estimated 14,200 women will die from this disease. Overall, 	the 5-year survival rate among ovarian cancer patients is only 40%.

Epithelial tumors account for 80% to 90% of ovarian cancers. A high lifetime total of ovulatory cycles may increase 	ovarian cancer risk; for example, pregnancy and lactation both of which suppress ovulation reduce ovarian cancer 	risk.

 By the same token, prolonged use of ovulation-induction therapy may increase 	ovarian cancer risk.

 Since OC use suppresses ovulation, it is biologically plausible 	that ovarian cancer risk might be lower among women using this method of contraception.

In 1987, the CDC analyzed data on 492 cases of malignant epithelial and borderline ovarian cancer and 4228 controls. 	It found that ovarian cancer risk in OC users was 40% lower than in nonuser controls. Furthermore, the risk of 	ovarian cancer declined with in-creasing duration of OC use, with an 80% risk reduction in women who had used OCs 	for 10 years or longer

. Extensive worldwide literature assessing OC use and 	ovarian cancer risk including 20 case-control and 3 cohort studies strongly supports the CDC findings that use 	of combination OCs helps prevent this lethal disease.

One well-controlled study found that OC use protected against ovarian cancer for up to 20 years following discontinuation.

 This suggests that women in their 40s who use OCs may be able to reduce the likelihood 	of developing ovarian cancer during the years when the incidence of this disease peaks.

A reanalysis of the CDC data found that the protective effect of OCs applies to women at higher risk for ovarian 	cancer.

 Nulli- parous women who used OCs for at least 5 years reduced their 	risk of ovarian cancer to a level equal to or less than that experienced by parous women. Likewise, women with 	a positive family history of ovarian cancer who used OCs for 10 years or more reduced their risk to a similar or 	lower level than that of women with a negative family history.

 Because lay-media 	publicity on ovarian cancer has focused on serum CA-125 tumor markers and vaginal ultrasonography screening, few 	US women are aware that OC use may reduce their ovarian cancer risk. Therefore, physicians must inform their patients 	that ovarian cancer risk may be decreased through use of OCs.


 	Cervical squamous cell neoplasia appears to be a sexually transmitted disease. The lifetime number of male sexual 	partners and incidence of human papillomavirus (HPV) infection are positively associated with cervical cancer, 	while use of barrier contraception (e.g., con-dom, diaphragm) and spermicides containing nonoxynol-9 protects against 	this disease. The marked decline of invasive cervical cancer incidence and mortality in the United States is presumably 	the result of widespread Papanicolaou cytologic screening, allowing identification and treatment of preinvasive 	cervical intraepithelial neoplasia.

The unique epidemiology of cervical neoplasia makes assessment of any association with OC use difficult. Women 	who use OCs often have more sexual partners and are less likely to use barrier contraception than other women.

 In addition, because of examinations associated with prescription renewals, women using 	OCs undergo cytologic screening more frequently than do other women. Each of these factors can confound the potential 	associations between OC use and cervical cancer risk. Three large, well-controlled studies failed to find a significant 	association between the risk of invasive cervical cancer and ever use of OCs


 	Adenocarcinoma, which accounts for approximately 10% of cervical cancers, may have an epidemiology distinct from 	that of the more common squamous cell tumors. The incidence of adenocarcinoma appears to be increasing among US 	women. Although the literature is conflicting, two large, thorough case-control studies found that OC use was associated 	with a significantly increased risk of adenocarcinoma of the cervix


 	The same inconsistent findings and methodologic challenges exist for cervical intraepithelial neoplasia (CIN) as 	for invasive cervical cancer. Most well-controlled studies including 3 case-controlled re- ports have found no 	association between OC use and CIN

The declining incidence of invasive cervical cancer among US women presumably reflects widespread screening 	for CIN. All women at risk for cervical neoplasia, including those who use hormonal contraception, should re- ceive 	regular cytologic screening. Women with a history of CIN (including those who have undergone conization, cryotherapy, 	laser, or loop excision) as well as those being evaluated for CIN remain appropriate candidates for hormonal birth 	control.


 	Although DMPA was first marketed in the United States in the 1960s, concern over possible links with breast and 	other reproductive cancers delayed Food and Drug administration (FDA) approval of this injectable contraceptive 	until the early 1990s.

 Publication of reassuring World Health Organization (WHO) 	studies assessing cancer risk and DMPA played a major role in its ultimate regulatory and clinical acceptance in 	this country.

Overall, DMPA appears to have no impact on the risk of breast cancer

. However, 	a pattern of increased risk in recent users but not in long-ago past users is similar to that observed with OCs 	and term pregnancy.

 Use of DMPA de- creases the risk of endometrial cancer, 	with the WHO study observing an 80% risk reduction i.e., even greater protection than that seen with OCs.

Because DMPA suppresses ovulation, it also might be expected to reduce the risk of epithelial ovarian adenocarcinoma. 	However, the WHO investigators found ovarian cancer risk to be similar in DMPA users and nonusers. In the countries 	studied, DMPA was used only by parous women. Thus, the investigators concluded that DMPA may not confer additional 	protection against ovarian cancer beyond that provided by full-term pregnancy.

 	As with OCs, use of DMPA does not appear to alter the risk of squamous intraepithelial or invasive cervical neoplasia.


 	An exhaustive review found that the overall association between progestin-only OCs ( minipills ) and reproductive-tract 	cancers parallel those of combination OCs.23 No published data have assessed cancer risks in women using contraceptive 	implants.


 	An overwhelming body of epidemiologic data reassures clinicians that overall, hormonal contraceptive use does not 	increase cancer risk. Indeed, in the case of ovarian and endometrial cancers, OC use provides substantial protection. 	Therefore, an important public health question remains: Why are misperceptions of hormonal contraception so common, 	and why are so many women unaware of their associated health benefits?

A 1985 Gallup poll sponsored by the American College of Obstetricians and Gynecologists found that half the 	women surveyed believed the possibility of cancer and other supposed risks of OC use exceeded those of childbear-ing. 	Approximately 30% of these women thought that OCs actually caused cancer.

 In 	a survey of 247 women aged 16 to 68 years receiving care at Yale University s health clinic, 38% believed that 	cancer was associated with OC use.25 Between 80% and 95% of the women surveyed were unaware of the noncontraceptive 	health bene-fits of OC use. A 1993 Gallup poll found a national sample of US women to be similarly misinformed 	regarding OCs.

The responsibility to provide balanced information about hormonal contraception rests with clinicians. Time 	spent directly educating patients regarding the benefits and risks of these modalities is time well spent. Likewise, 	physicians who make themselves available to the media can help facilitate more accurate and objective reporting 	on this topic. While some epidemiologic issues involving gynecologic cancer remain to be resolved, clinicians can 	be confident that for appropriately counseled and selected candidates, the risks are far outweighed by the substantial 	benefits offered by hormonal 
 	contraception.

    1. Forrest JD, Fordyce RR. Women s contraceptive attitudes and use in 1992. Fam Plann Perspect. 1993;25:175 179.

    2. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1997. CA Cancer J Clin. 1997;47:5 27.

    3. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraception: Collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemilogic studies. Lancet. 1996;247: 1713 1727.

    4. Grimes DA, Economy KE. Primary prevention of gynecologic cancers. Am J Obstet Gynecol. 1995;172:227 235.

    5. Schlesselman JJ. Net effect of oral contraceptive use on the risk of cancer in women in the United States. Obstet Gynecol. 1995;85:793 801.

    6. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. Combination oral contraceptive use and the risk of endometrial cancer. JAMA.1987;257: 796 800.

    7. Jick SS, Walker AM, Jick H. Oral contraceptives and endometrial cancer. Obstet Gynecol. 1993;82:931 935.

    8. Whittemore AS, Harris R, Itnyre J. Collaborative Ovarian Cancer Group. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies, II: invasive epithelial ovarian cancers in white women. Am J Epidemiol. 1992;136:1212 1220.

    9. Rossing MA, Daling JR, Weiss NS, et al. Ovarian tumors in a cohort of infertile women. N Engl J Med. 1994;331:771 776.

    10.Centers for Disease Control and National Institute of Child Health and Development. The Cancer and Steroid Hormone Study: the reduction of risk of ovarian cancer associated with oral contraceptive use. N Engl J Med.1987;316: 650 655.

    11. Rosenberg L, Palmer JR, Zauber AG, et al. A case-control study of oral contraceptive use and invasive epithelial ovarian cancer. Am J Epidemiol.1994;139:654 651.

    12. Gross TP, Schlesselman JJ. The estimated effect of oral contraceptive use on the cumulative risk of epithelial ovarian cancer. Obstet Gynecol.1994;83:419 424.

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

    14. Brinton LA, Reeves WC, Brenes MM, et al. Oral contraceptive use and risk of invasive cervical cancer. Int J Epidemiol. 1990;19:4 11.

    15. Kjaer SK, Engholm G, Dahl C, et al. Case-control study of risk factors for cervical squamous-cell neoplasia in Denmark, III: role of oral contraceptive use. Cancer Causes Control.1993;4:513 519.

    16. Ursin G, Peters RK, Henderson BE, et al. Oral contraceptive use and adenocarcinoma of cervix. Lancet.1994;334: 1390 1394.

    17. Coker AL, McCann MF, Hulka BS, Walton LA. Oral contraceptive use and cervical intraepithelial neoplasia. J Clin Epidemiol. 1992;45(10):1111 1118.

    18. Schiffman M, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human papilloma infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst. 1993;85:958 964.

    19. Kaunitz AM. Long-acting injectable contraception with depot medroxyprogesterone acetate. Am J Obstet Gynecol. 1994;170:1543 1549.

Articles

Of American women aged 15 to 44 years who are at risk of unintended pregnancy, 40% are currently using hormonal contraception, and more than 75% previously used hormonal birth control.

Guy I. Benrubi, MD

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The Good News About Hormonal Contraception and Gynecologic Cancer