Use of Oral Contraceptive Pills and Vulvar Vestibulitis: A Case-Control Study

Céline Bouchard1, Jacques Brisson2, Michel Fortier1, Carol Morin3 and Caty Blanchette2

1 Department of Obstetrics-Gynecology, Hôpital du Saint-Sacrement du Centre hospitalier affilié universitaire de Québec, Québec, QC, Canada.
2 Population Health Research Unit, Hôpital du Saint-Sacrement du Centre hospitalier affilié universitaire de Québec, Québec, QC, Canada.
3 Department of Pathology and Cytology, Hôpital du Saint-Sacrement du Centre hospitalier affilié universitaire de Québec, Québec, QC, Canada.

Received for publication April 26, 2001; accepted for publication April 17, 2002.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Vulvar vestibulitis is characterized by superficial pain during intercourse. Exploratory studies have suggested that oral contraceptives (OCs) could be associated with occurrence of vulvar vestibulitis. This 1995–1998 case-control study in Québec, Canada, sought to reassess this association. Included were 138 women with vulvar vestibulitis whose symptoms had appeared in the previous 2 years and 309 age-matched controls who were consulting their physicians for reasons other than gynecologic problems or contraception. Cases and controls were interviewed to obtain a detailed history of OC use and information on potential confounding factors. Relative risks were estimated by using logistic regression. The authors found that 4 percent of cases had never used OCs compared with 17 percent of controls. The relative risk of vulvar vestibulitis was 6.6 (95 percent confidence interval: 2.5, 17.4) for ever users compared with never users. When OCs were first used before age 16 years, the relative risk of vulvar vestibulitis reached 9.3 (95 percent confidence interval: 3.2, 27.2) and increased with duration of OC use up to 2–4 years. The relative risk was higher when the pill used was of high progestogenic, high androgenic, and low estrogenic potency. The possibility that OC use may contribute to the occurrence of vulvar vestibulitis needs to be evaluated carefully. Am J Epidemiol 2002;156:254–61.

case-control studies; contraceptives, oral; dyspareunia; pain; vulvar diseases; vulvitis

Abbreviations: Abbreviations: CI, confidence interval; OC, oral contraceptive.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Vulvar vestibulitis is a subset of vulvar pain syndrome causing superficial pain during intercourse (dyspareunia) (1). In 1987, Friedrich (2) defined vulvar vestibulitis as severe pain on vestibular touch or attempted vaginal entry, tenderness to pressure localized within the vulvar vestibule, and physical findings confined to various degrees of vestibular erythema. The openings of Bartholin’s glands are the most painful and inflamed sites in vulvar vestibulitis. This type of pain is reported in a young, sexually active female population and has a major impact on sexual life. Medical treatment of vulvar vestibulitis (3) is often unsuccessful, and surgical removal of inflamed mucosa of the vulvar vestibule (4) is often necessary to resume sexual relations without dyspareunia.

Little is known about the etiology of vulvar vestibulitis. Initially, it was thought that coital pain was an unusual psychosomatic gynecologic problem (5). The cause of vulvar vestibulitis is now thought to be multifactorial. Proposed risk factors include bacterial infections (6); chronic candidiasis (2, 7); destructive treatments such as laser vaporization, an altered vaginal acid-base balance, or excess oxalate in the urine (8); and exposure to irritant agents (e.g., soaps, sprays), antiseptics, creams (e.g., fluorouracil cream) (6), or topical medications. However, studies have been small, and observations have not been replicated. Virus infections, especially with human papillomavirus, have received more attention (912), but findings to date suggest that this virus is not involved in the etiology of most cases of vulvar vestibulitis (9).

In 1994, our group published results of a small, exploratory case-control study (13) suggesting that use of oral contraceptives (OCs) could be related to the occurrence of vulvar vestibulitis. In 1997, Sjöberg et al. (14) also observed that vulvar vestibulitis cases used OCs for a significantly longer period of time than controls did, supporting the possible role of OCs in the development of vulvar vestibulitis. The aim of the present study was to reevaluate the possible association of OC use with vulvar vestibulitis.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
From November 1995 to April 1998, all women newly diagnosed with vulvar vestibulitis who were referred to the vulvar clinic of Saint-Sacrement Hospital in Québec, Canada, were recruited for this study. The 138 cases met Friedrich’s criteria defining vulvar vestibulitis (2). Symptoms of superficial dyspareunia were required to be present for at least 3 months but no more than 24 months. We included only those cases aged 16–35 years whose dyspareu-nia appeared after they had had intercourse without pain. The age-matched control group was composed of 309 sexually active women without vestibular pain during sexual intercourse. These controls were recruited from nongynecologic hospital outpatient clinics, including orthopedic, ear-nose-throat, and family practice clinics. None of these controls had consulted their physicians for gynecologic problems or contraception information. Pregnant women were ineligible as cases or controls. Controls were frequency matched to cases according to 5-year age groups. The hospital’s Ethics Committee approved this study, and informed consent was obtained from all participants.

Weight and height were measured for both cases and controls. All women were interviewed in person by a research nurse about demographic, reproductive, and gynecologic factors. A detailed history of OC use starting from the first use to the day of the interview was obtained. Women were asked to enumerate chronologically each brand of OC used and, for each OC used, to provide the year of start and the duration of continuous use (in months). A visual aid representing all OC brands available on the Canadian market was used to help women remember the types of OCs used. For cases, the duration and intensity of vestibular pain were recorded, and a gynecologic examination, including colposcopy and Papanicolaou test, was performed to verify the presence of vestibular pain at pressure and to exclude other possible pathologies responsible for dyspareunia.

In the analysis, assessment of OC use among cases considered exposure only before symptoms occurred; among controls, assessment of OC use was based on exposure up to 12 months before the interview. Among controls, OCs used within 12 months of the interview were discounted since the mean interval between onset of pain and interview for cases was 11.6 months.

Statistical analysis was conducted by using two separate classifications of the hormonal composition of OCs. The first classification was based on the relative estrogenic, progestogenic, and androgenic hormonal potency of each OC (1519). For the purpose of our analysis, we arbitrarily divided OCs into high and low hormonal potency categories to obtain an adequate number of subjects per category (table 1). In the second classification, OCs were divided according to the type and dosage of estrogen and progestin in the pill, forming three groups of OC generation (20, 21) (table 2).


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TABLE 1. Classification of oral contraceptives,* according to hormonal effect{dagger} and potency,{ddagger} studied to assess their association with vulvar vestibulitis, Québec, Canada, 1995–1998§
 

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TABLE 2. Classification of oral contraceptives,* according to generation,{dagger} studied to assess their association with vulvar vestibulitis, Québec, Canada, 1995–1998
 
Many women had used several OC brands. However, for some of these women, the OCs all belonged to the same hormonal potency category or were all of the same generation. Thus, in the analysis, these women could be grouped according to the potency or generation of OCs they used. Women who had used pills of a different hormonal potency category or of different generations were kept in separate groups labeled "mixed" potency or generation.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Most women, both cases and controls, were young (mean age, 22 years) and single (table 3). Body mass index and lifetime number of sexual partners were lower for cases than for controls. Cases and controls were similar with respect to other variables.


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TABLE 3. Characteristics of cases and controls studied to assess the relation between oral contraceptive use and vulvar vestibulitis,* Québec, Canada, 1995–1998
 
In our study, 4 percent of cases had never used OCs compared with 17 percent of controls (table 4). The relative risk of developing vulvar vestibulitis was 6.6 (95 percent confidence interval (CI): 2.5, 17.4) for ever users compared with never users of OCs. The relative risk of vulvar vestibulitis increased for up to 24–47 months of use; thereafter, it remained relatively stable as the duration of OC use increased. When OCs were first taken at a young age (less than 16 years), a relative risk of 9.3 (95 percent CI: 3.2, 27.2) was observed, and relative risks tended to decrease as age at first use increased. For cases, the median interval between commencement of any type of OC use and occurrence of pain was 5 years.


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TABLE 4. Relative risk of vulvar vestibulitis, according to oral contraceptive use, Québec, Canada, 1995–1998
 
The relative risk of developing vulvar vestibulitis was found to vary with the progestogenic, estrogenic, and androgenic potency of the pills (table 5). Compared with never users, women who had used OCs of only low progestogenic potency had a relative risk of 5.6 (95 percent CI: 2.0, 15.1), while the relative risk was somewhat higher for those using pills of only high progestogenic potency (relative risk = 8.2, 95 percent CI: 2.8, 23.9). Relative risks were also higher for women who had used OCs of low estrogenic or high androgenic potency. Compared with never users, women who had used only second-generation pills in their lifetime had a relative risk of vulvar vestibulitis that reached 6.5 (95 percent CI: 2.4, 17.8) (table 5). For women who had used third-generation pills exclusively, the relative risk was 5.2 (95 percent CI: 1.8, 15.6).


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TABLE 5. Relative risk of vulvar vestibulitis, according to hormonal effect and potency classification and generation classification* of oral contraceptives, Québec, Canada, 1995–1998
 
On the basis of the results shown in table 5, the relative risk was estimated for women with a low-risk profile of OC use, defined as use of pills of only low progestogenic, high estrogenic, and low androgenic potency (table 6). A high-risk profile of OC use was defined as use of pills of only high progestogenic, low estrogenic, and high androgenic potency. For women with a low-risk profile of OC use, the relative risk of developing vulvar vestibulitis was only slightly increased at 3.0 (95 percent CI: 1.0, 9.3), but the relative risk for women with a high-risk profile of OC use reached 19.0 (95 percent CI: 3.0, 120.0). However, this high relative risk was based on very few cases and controls, and the confidence interval was quite wide.


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TABLE 6. Relative risk of vulvar vestibulitis, according to low- and high-risk categories of oral contraceptives, Québec, Canada, 1995–1998
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this study, use of OCs was associated with development of vulvar vestibulitis syndrome, which is consistent with our previously reported findings (13) and those of Sjöberg et al. (14). Moreover, the relative risk of vulvar vestibulitis seemed to increase with increased duration of OC use, at least up to 2–4 years of use, and first use of OCs at a young age appeared more strongly related to the development of vulvar vestibulitis. Finally, our data suggest that the strength of the relation of OC use to vulvar vestibulitis may vary according to the hormonal composition of OCs. Taken together, our results further support the idea that OCs may be involved in the etiology of vulvar vestibulitis.

Interpretation of results should take into consideration the precision of our estimates. Although the observed relation of OC use to vulvar vestibulitis was strong and statistically significant, only a small proportion of women in this age group had never used OCs, resulting in wide confidence intervals. Thus, our findings are compatible with strong, but also with weak effects of OCs on the risk of vulvar vestibulitis. In addition, this study had limited power to examine possible variation in effect according to the hormonal composition of OCs. The high correlation found between the progestogenic, estrogenic, and androgenic potency of OCs seriously impaired our efforts to separate the effects of the different types of hormonal potencies on the relative risk of vulvar vestibulitis. For instance, pills of high progestogenic potency almost invariably have low estrogenic potency. Thus, relative risks associated with progestogenic potency could not be estimated while taking into account the estrogenic potency of the pills. Alternatively, OCs can be classified according to their overall hormonal potency profiles, where potency profiles are defined on the basis of the three hormonal potencies simultaneously. Our data suggest that such an approach can be informative. Women who had used OCs of only high progestogenic, low estrogenic, and high androgenic potency (high-risk potency profile) had a relative risk of 19 for vulvar vestibulitis compared with a relative risk of 3 for women who had used OCs of only low progestogenic, high estrogenic, and low androgenic potency (low-risk profile). However, a small number of women had exclusively used low-risk- or high-risk-profile pills, re-sulting in substantial imprecision and very wide confidence intervals. Future studies of the overall hormonal profile of OCs and vulvar vestibulitis will require a much larger sample size than the one available for this analysis.

Although we attempted to reduce several possible sources of bias, systematic error still could have affected our results, at least in part. First, classifying the hormonal potency of OCs is a major challenge (16, 19, 22). The hormonal potency classification used in this analysis was based on data derived from in vivo and in vitro studies and is likely to have led to some degree of misclassification of the true hormonal potency of the various OCs women use. However, misclassification of the hormonal potency of OCs would tend to be similar for cases and controls, and such nondifferential misclassification generally tends to underestimate the strength of associations (23). Second, recall bias remains a concern in any case-control study. Cases might have remembered their OC use better than controls did. Such a bias, if it existed, would have tended to overestimate the association of OC use with the relative risk of vulvar vestibulitis. This type of recall bias would appear less likely to have affected associations observed with age at first OC use and hormonal composition of OCs.

Third, cases had been symptomatic for an average of 11.6 months when they were interviewed. During this period, OCs might have been prescribed instead of other contraceptive methods, such as the diaphragm, that result in painful manipulation of the vulva. However, in our analysis, assessment of OC exposure was based on OCs used before pain began, that is, a period during which pain could not have affected contraception. Moreover, before pain began, access to physicians and to contraceptives should have been similar for cases and controls because all women in our study resided in the same region and benefited from the same universal health insurance plan in effect in Québec. Fourth, controls were women who consulted their physicians for reasons not related to OC use. Although, in theory, such controls are appropriate (23), the possibility remains that they did not adequately represent OC use in the population from which cases arose. Finally, while little is known about the epidemiology of vulvar vestibulitis, several potential risk factors for the disease were taken into account in the analysis in an attempt to reduce the possibility that confounding could explain the observed relation of OC use to vulvar vestibulitis. However, since controls did not have a gynecologic examination, assessment of and adjustment for gynecologic infection were not possible. Among common infections, only human papillomavirus has been seriously considered as a potential alternative cause of vulvar vestibulitis, but current evidence does not support such a hypothesis (9).

We propose that vulvar vestibulitis could be linked with OC use in at least two ways. First, OCs could have a direct effect on the epithelium of the vestibule. Presence of steroid hormone receptors in the vulvar and genital area has been reported by many authors (2427). Thus, some OCs, through their interaction with hormone receptors in the vestibule, may alter the vulvar mucosa, which may in turn become more vulnerable to external exposures or irritants and eventually increase local inflammatory response, pain at touch, and dyspareunia.

Second, vulvar vestibulitis may be linked to steroid hormones through their influence on proinflammatory cytokines. Vulvar vestibulitis is characterized by localized inflammation within the vestibule. Periglandular inflammation of the minor vestibular glands has been confirmed histologically in 66 percent of women treated by vestibulectomy for vulvar vestibulitis (28). Foster and Hasday (29) reported an inflammatory cytokine elevation in the vestibular epithelium of women with vulvar vestibulitis, and they concluded that this elevation might contribute to the pathophysiology of mucocutaneous hyperalgesia in patients with vestibulitis. In vivo and in vitro studies have shown that steroid hormones can alter cytokine production in different cell types (3032). Thus, the vulvar inflammation associated with vestibular pain at local touch could result from the modified cytokine content of the vulvar mucosa in response to steroid hormones in OCs.

In conclusion, the possibility that vulvar vestibulitis may be related to OC use and may represent a significant side effect of some OCs in young, healthy women needs to be addressed. If the relation of some OCs to vulvar vestibulitis is confirmed, our results also suggest that pills that carry a relatively low risk of developing vulvar vestibulitis could be identified.


    ACKNOWLEDGMENTS
 
This study was funded by the National Health Research and Development Program (NHRDP) of Canada and by the Foundation of the Centre hospitalier affilié universitaire de Québec, Québec, QC, Canada.


    NOTES
 
Correspondence to Dr. Céline Bouchard, 1000 chemin Ste-Foy, Suite 102, Québec, QC, Canada G1S 2L6 (e-mail: Bouc.Fort{at}sympatico.ca). Back


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 DISCUSSION
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