by Andrew T. Goldstein [bio], Jill Krapf, Zoe Belkin [bios]
The debate about the role of oral contraceptive pills (OCPs) in vulvodynia has been underway for almost two decades. More than a dozen different research articles have been written on the topic, both supporting and refuting the association. In this article we will examine this very important issue. We will begin our discussion with describing very basic anatomy of the vulva, how OCPs work, and the potential mechanisms by which hormonal contraceptive might cause vulvodynia. This foundation will allow us to review the studies previously published on this topic. Finally, we will look at the results of our new genetic study, which provides overwhelming evidence for the impact of OCPs on vulvodynia.
The vulva and vagina can be thought of as three separate and distinct organs due to their embryological (prenatal) development. Very early after conception the cells divide into three tissue types- ectoderm, endoderm, and mesoderm. The ectoderm forms the tissue of the outer vulva, which includes the labia majora, the interlabial sulcus, the outer labia minora, the hood of the clitoris, the clitoris, and the perineum. The vulvar vestibule, which starts at Hart’s line on the inner aspect of the labia minora and extends to just inside the hymen, is derived from the endoderm. The vagina is mostly comprised from tissue coming from cells of medodermal origin. Because these tissues are derived from three different origins, it is logical they would respond differently to different hormonal states (such as too much, too little, or an imbalance in hormones) and to specific insults such as infections, allergic reactions, chemical irritation, and trauma. A recent study presented by our group at the International Society for the Study of Women’s Sexual Health (ISSWSH) Annual Meeting showed that more than 90% of women with vulvodynia have pain confined to the tissue of the vulvar vestibule, and not the outside vestibule or inside the vagina. The historical name for this pain, vulvar vestibulitis, has been more recently discarded, as we now understand that there are several causes of this localized pain, and most of them are not due to inflammation- an “itis.” The new name “vestibulodynia” is a more inclusive term, literally meaning and abnormal pain sensation confined to the vestibule but it still does not address the issue of the cause or causes of the pain.
With the understanding that the vestibule is comprised of tissue distinct from that of the outer vulva or the vagina, we can now ask how this difference affects its function. The tissue of the vestibule contains openings of several glands- the Skene’s glands, the Bartholin's glands, and the minor vestibular glands. These glands, when stimulated by hormones, make mucin, an extremely slippery substance that acts as the primary lubricant during intercourse, giving women the sensation of feeling “wet” during arousal . However, when most people think of the hormone that is most necessary for vulvar or vaginal health, they think only of estrogen. Interestingly, these glands don’t rely on estrogen, or progesterone, but instead depend on testosterone and other very similar hormones that we collectively call “androgens.” These androgens act on a hormone receptor called the “androgen receptor” in the cells of these glands to cause the production of mucin. To visualize this, you may think of the androgens as a key that fits into a lock (androgen receptors) which open factory doors to allow the machines (the glands) to make mucin. Unfortunately, this system may malfunction in several ways. First, you can imagine that if there are not enough keys- low levels of androgens- then the locks cannot open and the factory will not work. Secondly, if the locks are rusty or sticky – a poorly functioning androgen receptor- then the doors of the factories will not open and the machines will not work. Use of OCPs can cause both problems of low androgens and “sticky” androgen receptors. And lastly, some women genetically have “stickier” or “inefficient” androgen receptors which make them even more susceptible to the negative effects of OCPs.
So now that we know that that the glands (and the rest of the mucosa of the vestibule) are dependent on androgens and working androgen receptors to function properly, we must now discuss how OCPs work and how they can “throw a wrench” into our mucin factory.
Almost all OCPS that are currently being used contain a combination of two synthetic hormones, a synthetic estrogen, and a synthetic progesterone (a progestin). All pills contain the same synthetic estrogen- Ethinyl Estradiol (EE). The primary ways in which the dozens of brands of OCPs differ is that they contain varying types of progestins, and have variable amounts of EE. The OCPs that have come to market in the last 15 years typically contain “3rd generation” progestin such as desogestrol, norgestimate, and drosperinone. In fact, OCPs containing drosperinone became so popular after the turn of the century that they comprised more than 40% of all OCPs prescribed in the United States. In addition, there has been a trend toward lower doses of EE. While any pill that contains 35 micrograms of EE is considered a low dose OCP, recent pills contain as little as 10 micrograms of EE. While this may seem like a good idea, we will soon discuss how OCPs with lower doses of EE and the progestin drosperinone significantly increase the risk of developing vestibulodynia. However, first we will finish our discussion on how OCPs work.
OCPs prevent the pituitary gland from producing normal levels of two important signally hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). As a result, ovulation is inhibited and pregnancy is prevented. The inhibition of LH and FSH also causes a very significant reduction in the ovarian production of estrogen, progesterone, and androgens. In addition, the synthetic hormones in OCPs, which are metabolized in the liver, induce the liver to increase production of a protein called Sex Hormone Binding Globulin (SHBG). SHBG binds to sex hormones, preferentially to androgens, rendering them inactive. The progestins, drosperinone, (which is in YasminTM, YazTM, BeyazTM, and generic equivalents of these pills) and etonogestrel (which is in the vaginal contraceptive ring NuvaRingTM) are especially effective at raising SHBG levels. The combined effect of decreased ovarian production of androgen from the ovary and increased production of SHBG result in a reduction of greater than 75% of “bioavailable” or “free” androgens. In our, key, lock, and factory analogy, this means that OCPs reduce the number of keys by at least 75%. If this was not bad enough, the drosperinine also binds to the androgen receptor rendering it inactive or “sticky.”
While we discussed earlier that low androgens or a “sticky” androgen receptor could theoretically cause problems in the vulvar vestibule, we have found that medical research has already demonstrated these results. A recent study by Battaglia and his colleagues showed that women who took the OCP YasminTM had shrinkage of their labia minora, a reduction in the diameter of the vulvar vestibule, and a reduction in clitoral blood flow as measured by ultrasound after just 3 months of taking this OCP.1 Another study by Johannesson et al. showed that women on OCPs develop microscopic structural changes in the mucosa of the vulvar vestibule that makes them more susceptible to tears and fissures when exposed to trauma.2 In addition, a study by Nina Bohm-Starke and her associates showed that “healthy” women without vulvodynia on OCPs sense pain in their vestibules at a much lower pressure (have a lower pain threshold) than women who do not take OCPs.3
So what about published studies looking at OCPs and vulvodynia? The results are contradictory. Let’s look at the individual studies to examine why.
In a prospective study, Bazin et al. showed that women who started taking OCPs before that age of seventeen were 11 times (1100%) more likely to develop vestibulodynia in comparison to women who had never taken OCPs.4 In addition, a study by Bouchard and colleagues in Quebec showed that women who were examined in a vulvar specialty clinic and who were found to have vestibulodynia were 9.6 times (960%) more likely to develop vestibulodynia if they started OCPs prior to the age of 16, and showed an increasing risk of developing vestibulodynia with longer durations of OCP use.5
In addition, we recently published in Sexual Medicine a case series of 50 consecutive women who developed vestibulodynia while taking OCPs.6 Women with other potential identifiable causes of vulvodynia, such as tight pelvic floor muscles or pudendal nerve injury were excluded from this study. The women were treated by having them stop OCPs and by applying a compound that contained topical estrogen and testosterone to the vestibule. On average their vestibular pain dropped from 7.5 to 2 on a ten-point pain scale after three months of treatment. Although this was not a placebo controlled study, the results are so compelling that it is our opinion that women who developed vestibulodynia while taking OCPs should consider this treatment approach as first line treatment.
In contrast, a study recently published by Barbara Reed and colleagues in the British Journal of Obstetrics and Gynecology concluded that “for women aged < 50, OCP use did not increase the risk of developing vulvodynia.”7 Unlike the three studies discussed above whose participants were all examined in vulvar specialty clinics and were found to have pain localized to the vestibule, the women in the Reed study were identified as having vulvodynia only through a questionnaire and were never physically examined. Furthermore, Reed acknowledges in the conclusion of her paper that “further work is needed to assess these findings in a prospective study including subgroups that may differ in risk,” and clearly, our study is a subgroup study of women with increased risk.
In addition, is it common practice, even among physicians, to consider all forms of OCPs as simply the “The Pill.” However, as discussed previously OCPs are a vastly heterogeneous group of medications with different synthetic hormonal components in different dosages. Therefore, in investigating the relationship between vulvodynia and OCP use, it is crucial to distinguish between pill types in order to not miss important associations. While Reed and colleagues did not differentiate between pill types in their study, Greenstein and colleagues showed that women taking OCPs containing only 20 micrograms of EE were more likely to develop vestibulodynia than women taking OCPs with higher doses of EE.8
Given that the majority of studies discussed above have shown that OCPs increase the risk of developing vestibulodynia, our group wanted to try to figure out why some women develop pain from OCPs while others do not. We hypothesized that women who genetically have inefficient androgen receptors would be more susceptible to develop vestibulodynia from the hormonal changes that occur by taking OCPs. As we mentioned earlier, an ineffiecnt androgen receptor (“sticky lock”) won’t work well if there are low levels of free androgens (“less keys’). The efficiency of an androgen receptor is determined by the length of the androgen receptor gene, which is located on the X chromosome. Women, who have two X chromosomes, have two androgen receptor genes, one from each parent, but men only have one from their mother. The longer the androgen receptor gene, the more inefficient the androgen receptor. In order to confirm this hypothesis, we looked at two groups: a study group and a control group. The study group consisted of 30 women who developed vestibulodynia while taking OCPs and had complete resolution of symptoms with treatment (cessation of OCPs and application of topical estradiol and testosterone to the vestibule). All women in this group were taking OCPs at their initial presentation. Of these 30 women, 21 were taking OCPs that contained the progestin drospirenone. The second group was the control group, which consisted of 17 women who were currently taking OCPs containing the progestin drospirenone who did not complain of vulvar pain or pain with sex, nor did they have any evidence of vestibulodynia on physical exam. We took blood from both groups of women which was then used for genetic analysis.
As you can see in graph taken from our paper, our hypothesis was correct. Lets explain what this graph shows. As you move from left to right on the graph the length of the androgen receptor gene is increasing (the androgen receptor is becoming more inefficient). As you move from bottom to top, the percentage of women with a given androgen receptor gene length increases. So the women developed vestibulodynia from OCPs (the red line) have significantly longer androgen receptor genes (and therefore more inefficient androgen receptors) than women who don’t develop vestibulidynia from OCPs.
Another analogy might help to crystallize these results in your mind. Take two groups of women. The women in the first group all drive Hummers (a gas guzzling huge SUV) and the women in the second group all drive a Prius (a very fuel efficient compact car). Now if there is plenty of gas to go around, both groups of women have no problems driving as much as they want. But, if there is a gas shortage, then the women who drive a Hummer will run out of gas well before the women who drive a Prius. Women with long androgen receptor gene are “driving a Hummer” and there is a gas shortage caused by taking OCPs.
There are a several questions that we have been asked many times when we have presented these results and we think that it would be useful to answer them now before we end this paper with a few conclusions.
Is a longer androgen receptor gene the only genetic defect that can cause women to develop vulvodynia from OCPs? No, it is likely that there are other genetic defects in the androgen receptor gene and possibly defects in the SHBG gene and the estrogen receptor gene that also may play a role. We will be looking for these genetic changes in the future. It is our hope that in the future there will be a quick test and inexpensive test that looks at all the possible negative genetic changes so that women will be able determine if they are at risk before staring OCPs. As the cost of genetic testing continues to drop, this is could happen within in the not too distant future.
If OCPs are he cause of my vulvodynia, won’t just stopping the OCPs allow the vulvodynia to go away?
Unfortunately, for many women, just stopping OCPs does not cause the vulvodynia to resolve. This is because even after stopping OCPs the levels of SHBG frequently do not go back down to the levels they were before stopping OCPs. This leads to persistently low free androgens and the persistence of the vestibulodynia. In our experience, the only way to overcome the persistently low hormones is to apply a compound of topical testosterone and estrogen to the vestibule.
Can I remain on OCPs and just use the topical hormones as treatment?
Unfortunately, the progestin in OCPs can inhibit the androgen receptor so using topical hormones without stopping OCPs typically does not work.
If my vulvodynia goes away after the combination of stopping OCPs and by using the topical hormones, will I ever be able to go back on OCPs?
In our expereience, the pain returns after restarting OCPs. We typically recommend Intrauterine devices (IUDs) for our patients who need contraception after their vestibulodynia has resolved.
Can my health care provider order the genetic test that you used in your study?
To our knowledge, the test is not currently offered by any commercial clinical laboratory (Quest, Labcorp, etc.).
If this is this is the cause of my vulvodynia, is my daughter at risk for developing vulvodynia? Should she not take OCPs?
If the combination of a genetic change (such as a longer androgen receptor gene) and OCPs caused your vulvodynia, your daughter may also be at increased risk. It is possible that her risk would be lower than your risk, however, because one of her two androgen receptor genes comes from her father and it may be shorter (more efficient) than either of your two genes.
In conclusion, the most exciting thing about the results of our research and the others studies discussed above is that it we can finally end the controversy regarding the role of OCPs in vulvodynia.
We clearly know that all women who take OCPs don’t develop vulvodynia, BUT SOME WOMEN DO DEVELOP VULVODYNIA FROM OCPs.
Women may be genetically susceptible to develop vestibulodynia from OCPs. Women with longer androgen receptor genes are more likely to develop vestibulodynia from OCPs then women with shorter genes.
OCPs that contain either of the progestins drosperinone or etonogestrel appear to cause a greater risk than OCPs that contain progestins with less “anti-androgenic” properties.
OCPs with lower levels of EE might cause a greater risk of developing vestibulodynia than OCPs with higher doses of EE.
Jill Kraft is the Director of the Gynecologic Division of the Center for Sexual Health at The George Washington Medical Faculty Associates. She is an Assistant Professor of Obstetrics and Gynecology at The George Washington University and Assistant Clerkship Director for Obstetrics and Gynecology
Zoe Belkin is a medical student at George Washington University School of Medicine and Health Sciences. Prior to beginning school she worked as a birth doula in New York City and then as research assistant at The Centers for Vulvovaginal Disorders in Washington, DC.
We would like to acknowledge our colleagues for their essential contributions in this research: Mohit Khera, Weitao Song, Noel Kim, Lara Burrows, Sarah Jutrzonka, and Irwin Goldstein