Hormonally Mediated Vestibulodynia

Synonyms

Hormonally Associated Vestibulodynia
Vestibulodynia
Vestibulitis
Vulvar vestibulitis syndrome
Vaginal atrophy
Genitourinary Syndrome of Menopause (GSM)

Subdivisions

General Discussion

Vestibulodynia is a general term used to describe pain in the vestibule. The vestibule is the tissue within the vulva that sits at the opening of the vagina. The vestibule is the transition between external and internal, just like a vestibule of a building is the entrance.

Vestibulodynia can be considered a subcategory of vulvodynia. Vulvodynia is an even broader term used to describe chronic pain in the vulva. The terms vulvodynia and vestibulodynia are really only a description of symptoms, though they are often given as a diagnosis. Vulvodynia is typically used to describe generalized pain in the vulva, where the patient has chronic vulvar pain in external regions of the vulva rather than just in the vestibule. Ongoing research has improved our understanding of the underlying biological causes of pain, so terminology has changed and gotten more specific. ISSWSH, alongside two other international societies, published updated terminology in 2015.(1) We now recognize a few subtypes of vestibulodynia based on the root cause of the pain:

Neuroproliferative vestibulodynia
Hormonally-mediated vestibulodynia
Inflammatory vestibulodynia

The vestibule tissue is fundamentally different from the skin around it, and even develops from a different part of the embryo. This inherent biological difference is crucial to understanding what causes pain specifically in the vestibule. In people with hormonally-mediated vestibulodynia, the vestibule tissue is painful because it is not getting the hormone signals that it needs. Hormones are molecules that our cells use to communicate, and these messages are important for any cell to be healthy. The vestibule tissue is very sensitive to a lack of hormone signals. Anything that causes the estrogen or testosterone levels in the body to drop (or change) can cause the vestibule tissue to become irritated and painful. Often the cause is medications that lower hormone levels in the body or the levels decreasing due to menopause or breastfeeding. The reasons that some people develop vestibulodynia and others do not is still being investigated (see below).

Signs & Symptoms

People with vestibulodynia feel pain at the entrance of the vagina, called the vestibule. There are many ways to describe the pain in the vestibule. People with hormonally-mediated vestibulodynia may describe their pain as burning, stinging, or tearing. Tearing usually occurs at the posterior fourchette. Pain can also be classified by when it occurs. Provoked vestibulodynia is vestibule pain that occurs with touch or pressure, while unprovoked pain occurs spontaneously. Sometimes it can be difficult to distinguish provoked from unprovoked pain before all the triggers are recognized, especially when they are seemingly simple things like sitting or wearing tight clothing.

People often feel pain any time that there is contact or pressure on the vestibule. Patients with vestibulodynia almost always feel pain with vaginal penetration (called dyspareunia), including pain with penetration, using a tampon, and speculum exams. Day-to-day activities that put pressure on the vestibule can also cause pain, including wearing tight clothing, sitting for long periods or on hard surfaces, and wiping with toilet paper.

Many people with vestibulodynia will also have tight muscles in the pelvic floor, referred to as hypertonic pelvic floor dysfunction. In people with hypertonic pelvic floor dysfunction, the muscles in the pelvic floor are tight, which can cause pain and spasming. In some scenarios, spasms of the pelvic floor muscles is called vaginismus. We think pelvic floor dysfunction may develop in people with vestibulodynia due to a subconscious guarding response against pain. When you are in pain or anticipating pain, your muscles tense up to protect you. In many cases the response in helpful, for example, what would happen if you put your hand on a hot stove? Your muscles would contract without you telling them to. However, chronic tightening of the pelvic floor muscles only creates more pain. The muscles can accumulate knots (trigger points) and become shortened and weak. Additional symptoms of pelvic floor dysfunction can include feeling tension, pain, and burning in the hips, legs, lower back, and vulva, especially the vestibule. You can also experience urinary symptoms like frequency, urgency, and leakage, as well as bowel symptoms like constipation or pain with bowel movements. Hypertonic pelvic floor dysfunction alone can be a cause of vestibulodynia, and it is important to determine the root cause of the vestibulodynia.

Causes

The vestibule tissue is fundamentally different from the skin around it, and even develops from a different part of the embryo. This inherent biological difference is crucial to understanding what causes pain specifically in the vestibule. The vestibule is embryonically derived from the primitive urogenital sinus and is endodermal tissue. In contrast, the external labia minora, like all skin, is ectodermal tissue. The delineation between the two is called Hart’s line.

The vestibule tissue is exceptionally sensitive to hormone signals and can become irritated when hormone levels are low.(2) There are many causes of low hormone levels that have been linked to hormonally-mediated vestibulodynia. The most common cause of vestibulodynia is anti-androgenic medications, including hormonal birth control pills and spironolactone, used to treat acne or high blood pressure.(3, 4) Combined hormonal contraceptives (“the birth control pill”) contain synthetic estrogen and progestin. These hormones cause the pituitary gland to stop making other hormones that trigger ovulation (FSH and LH). Because ovulation is not happening, the ovaries don’t produce estrogen and testosterone. At the same time, birth control pills cause a protein called sex hormone binding globulin (SHBG), a molecule that binds to testosterone in the blood, to increase. High amounts of SHBG bind to more testosterone and make it inactive. On top of that, some progestins block testosterone from binding its receptor in the tissue. Overall, birth control pills cause the level of free, active testosterone to be very low.

There are several different medications used to treat breast cancer, e.g., tamoxifen, that affect hormones and may also lead to hormonally mediated vestibulodynia. Any medication that can alter hormones can potentially affect the tissue of the vestibule.

While medications can cause hormone levels to drop, they aren’t the only causes. Some new parents experience hormonally-mediated vestibulodynia because while breastfeeding, prolactin levels are high and estrogen levels are low. Estrogen levels also drop in peri-menopause and menopause. More than half of women experience symptoms collectively called the genitourinary syndrome of menopause (GSM). Symptoms of GSM include vaginal dryness, itching, burning, irritation, discharged, and pain, vulvar skin changes (namely shrinking of the labia minora), and urinary tract infections.

Researchers are investigating the reason why some people develop hormonally-mediated vestibulodynia when others do not. There may be a genetic difference in the androgen hormone receptor that makes some people more susceptible than others. A 2014 study investigated the gene encoding the androgen receptor in women taking hormonal birth control.(5) The researchers compared the gene sequences from women who developed vestibulodynia to women that did not. They found that women who developed vestibulodynia had more repeats in a specific portion of the androgen receptor gene. These results suggest that there may be a genetic risk factor for developing vestibulodynia when taking anti-androgenic medication. The researchers speculate that the length of this repetitive sequence might affect the function of the receptor by making it “weaker”; if the receptor is less able to respond to the hormone signals, then the vestibule tissue is more likely to become unhealthy when hormone signals are low. More research is needed to fully understand the function of different versions of the androgen receptor.

Affected Populations

Anyone with a vestibule can have vestibulodynia. It is difficult to estimate the prevalence of vestibulodynia, but studies using questionnaires of the general population in the US found that 8-10% of women have chronic vulvar or vestibule pain causing pain with intercourse. (6, 7) Hormonally-associated vestibulodynia happens in premenopausal women taking anti-androgenic medications, e.g., hormonal birth control and spironolactone, because the medication decreases hormone signals to the vestibule. People with low hormone levels due to natural or surgical menopause experience many symptoms, collectively called the genitourinary syndrome of menopause (GSM), and they can have vestibulodynia as part of GSM. Some breastfeeding mothers also experience hormonally-mediated vestibulodynia due to similar impacts on hormone levels. Patients receiving gender-affirming treatment that completely blocks estrogen signaling can also have symptoms. There are also infrequent cases where there are no identifiable causes for the hormone levels to be too low to be effective, but these patients also improve with treatment. Unfortunately, it often takes a long time and multiple providers for patients to be accurately diagnosed with vestibulodynia, so patients are usually adults when diagnosed.(6)

Diagnosis

First, a knowledgeable provider should do a thorough history of your story. A patient’s story holds important clues to their diagnosis. People with hormonally-mediated vestibulodynia may have pain that developed later in life after any of the associated factors discussed above, including starting a medication, surgery, breastfeeding, or menopause.

Then there should be a very specific exam of the pelvis, vulva, and vagina. In patients with hormonally-mediated vestibulodynia, the vestibule usually appears very red and irritated (erythema), but also pale (mucosal pallor). To see an example photo, go to https://www.smoa.jsexmed.org/article/S2050-1161(15)30010-6/fulltext (3). The vulva may show signs of hormone depletion outside the vestibule as well, including a smaller clitoris, smaller labia minora, and smaller vaginal opening (introitus).(8) The hormone signals causes the tissue to change on a microscopic level, which is likely why it is more brittle and prone to tearing.(9) The provider should manually examine the pelvic floor muscles to determine if there is excess tension in the muscles. The provider should feel the muscles externally and internally through the vagina. Many patients with vestibulodynia have tension in their pelvic floor, called hypertonic pelvic floor dysfunction. Tight muscles in the pelvic floor can be the sole cause of vestibulodynia or in combination with another cause of vestibulodynia.

There are a few tests important for diagnosing vestibulodynia. A process called a Q-tip test is important for mapping pain in the vulva. The provider will gently press a cotton swab to each part of the vulva while the patient reports their degree of pain at each spot. It is important that the provider touch each region of the vestibule, all the way around the vaginal opening. Locations in the vestibule are referred to using the numbers like a clock, with 12 o’clock at the top above the urethra and 6 o’clock at the bottom closest to the perineum. Patients with hormonally-mediated vestibulodynia typically have pain throughout the vestibule (10), while patients with only hypertonic pelvic floor dysfunction will have pain in the lower half of the vestibule that is worst at 6 o’clock.

Tests to measure hormone levels in the body can help indicate that hormone levels are low. Your doctor can test a total testosterone and SHBG, then use a calculation to determine the concentration of free testosterone. The calculator is available online: http://www.issam.ch/freetesto.htm. Especially in people taking birth control pills, serum hormone binding globulin (SHBG) levels might be high.(3) SHBG binds and inactivates testosterone, so the total testosterone concentration might be very different from the concentration of free, active testosterone. One study found free testosterone levels 0.6-0.8 pg/mL in a healthy patient population with no sexual health complaints.(11, 12)

Standard Therapies

Data to help patients and their providers choose the best treatments for vestibulodynia is growing. Because the subtypes of vestibulodynia that are separated by the biological cause of pain were officially recognized relatively recently, most studies include patients with various kinds of vestibulodynia. While we wait for randomized placebo-controlled studies with distinct patient populations, we rely on the data that we do have, as well as the vast experience of specialists in sexual medicine who have successfully treated thousands of patients.

Fortunately, in the case of hormonally-mediated vestibulodynia, the standard treatment has a very high success rate.(3) If vestibulodynia developed after starting a medication that is known to affect hormone levels, then patients should stop taking that medication. Most often it is hormonal birth control pills. Stopping the medication is often not enough to help the vestibule tissue heal quickly because hormone levels might stay low for a long time after taking birth control pills.(13) Providers should prescribe a topical hormone gel to apply directly to the vestibule to restore the hormone signals to the tissue. The standard is 0.01-0.03% estrogen and 0.1% testosterone gel. The hormone gel is usually made by a compounding pharmacy. Custom compounded medications are especially helpful if someone is sensitive to a medication’s base, the inactive ingredients, and needs a different base. Another treatment, dehydroepiandrosterone (DHEA), is a testosterone and estradiol precursor, meaning it can be converted into those compounds by the body. DHEA is FDA-approved and likely more accessible to patients, however its efficacy as a treatment for hormonally-mediated vestibulodynia has not yet been thoroughly studied. Patients typically use the gel 1 to 2 times daily and start to notice improvement in 6 to 12 weeks. Some patients stop using the hormone gel once the offending medication has been stopped for a while, but many women choose to stay on this therapy. An important thing to note about topical hormone use is that very little of the hormone is absorbed into the bloodstream – it is truly a localized treatment. This means that almost anyone can use this topical hormone treatment without fear of systemic side effects. Breast feeding women should be able to use local vaginal estrogen once breastfeeding is established (4-6 weeks); supporting data should be available soon from an ongoing clinical trial. The estrogen/testosterone combination has not been studied in pregnant or breast-feeding women and more data is needed.

For nearly all people with vestibulodynia, referrals for pelvic floor physical therapy and cognitive behavioral therapy are important aspects of treatment. Most people with vestibulodynia have some degree of pelvic floor dysfunction and pelvic physical therapy is the best way to assess and improve the pelvic floor. All sexual dysfunctions, and especially sexual pain, can cause significant psychological distress to patients.(14) It is important that treatment has a biopsychosocial approach that considers all aspects of the patient as a complete person. Cognitive behavioral therapy with a therapist with specialized training in sexual health is also important for healing and navigating the impacts of sexual dysfunction on quality of life and relationships. A multimodal approach is most likely to be successful, so patient should engage with a team of providers throughout their journey.

Investigational Therapies

Support Available

There are many societies with interests in female sexual dysfunctions in addition to ISSWSH. The National Vulvodynia Association (NVA) is a US-based association founded by patient advocates that focuses specifically on vulvodynia. They provide some educational materials for the public and fund research of vulvodynia. Female sexual dysfunctions fall under the umbrella of interests of additional societies as well: International Society for the Study of Vulvovaginal Diseases (ISSVD), Sexual Medicine Society of North America (SMSNA), North American Menopause Society (NAMS), International Pelvic Pain Society (IPPS), International Society for Sexual Medicine (ISSM), and American Association of Sexuality Educators, Counselors and Therapists (AASECT), for example.

There are many online support groups and communities of patients who support each other on social media. To find fellow patients locally, ask a provider if they know of another patient seeking community or any local groups to join.

References

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Maseroli E, Vignozzi L. 2020. Testosterone and Vaginal Function. Sex Med Rev 8:379-392.
Burrows LJ, Goldstein AT. 2013. The treatment of vestibulodynia with topical estradiol and testosterone. Sex Med 1:30-3.
Mitchell L, Govind V, Barela K, Goldstein AT. 2019. Spironolactone May be a Cause of Hormonally Associated Vestibulodynia and Female Sexual Arousal Disorder. J Sex Med 16:1481-1483.
Goldstein AT, Belkin ZR, Krapf JM, Song W, Khera M, Jutrzonka SL, Kim NN, Burrows LJ, Goldstein I. 2014. Polymorphisms of the androgen receptor gene and hormonal contraceptive induced provoked vestibulodynia. J Sex Med 11:2764-71.
Harlow BL, Kunitz CG, Nguyen RH, Rydell SA, Turner RM, MacLehose RF. 2014. Prevalence of symptoms consistent with a diagnosis of vulvodynia: population-based estimates from 2 geographic regions. Am J Obstet Gynecol 210:40 e1-8.
Reed BD, Harlow SD, Sen A, Legocki LJ, Edwards RM, Arato N, Haefner HK. 2012. Prevalence and demographic characteristics of vulvodynia in a population-based sample. Am J Obstet Gynecol 206:170 e1-9.
Battaglia C, Battaglia B, Mancini F, Busacchi P, Paganotto MC, Morotti E, Venturoli S. 2012. Sexual behavior and oral contraception: a pilot study. J Sex Med 9:550-7.
Johannesson U, Blomgren B, Hilliges M, Rylander E, Bohm-Starke N. 2007. The vulval vestibular mucosa-morphological effects of oral contraceptives and menstrual cycle. Br J Dermatol 157:487-93.
Bohm-Starke N, Johannesson U, Hilliges M, Rylander E, Torebjork E. 2004. Decreased mechanical pain threshold in the vestibular mucosa of women using oral contraceptives: a contributing factor in vulvar vestibulitis? J Reprod Med 49:888-92.
Braunstein GD, Reitz RE, Buch A, Schnell D, Caulfield MP. 2011. Testosterone reference ranges in normally cycling healthy premenopausal women. J Sex Med 8:2924-34.
Guay A, Munarriz R, Jacobson J, Talakoub L, Traish A, Quirk F, Goldstein I, Spark R. 2004. Serum androgen levels in healthy premenopausal women with and without sexual dysfunction: Part A. Serum androgen levels in women aged 20-49 years with no complaints of sexual dysfunction. Int J Impot Res 16:112-20.
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Chisari C, Monajemi MB, Scott W, Moss-Morris R, McCracken LM. 2021. Psychosocial factors associated with pain and sexual function in women with Vulvodynia: A systematic review. Eur J Pain 25:39-50.