Sex hormones matter: Reduced concentrations of vaginal metabolites involved in steroid hormone biosynthesis are associated with increased vulvar vestibular pain and vaginal muscle tenderness in provoked vestibulodynia

Provoked vestibulodynia or PVD is characterized by vestibular hypersensitivity and severe pain upon vaginal penetration. PVD is one of the most common pathologies underlying painful intercourse. The onset of PVD is mostly idiopathic and pathophysiology is not well understood but is likely a complex interplay of environmental, genetic, psychosocial, neurobiological and immune factors. Some of the etiological factors that have been implicated in the development of PVD include infection, inflammation, hormonal abnormalities, dysfunction of pelvic floor muscles, maladaptive neuroplasticity, and genetic factors. Many but not all studies suggest women consuming oral contraceptives are at an increased risk of developing PVD. Oral contraceptives increase the levels of sex hormone-binding globulin which leads to a decrease in the levels of androgens in circulation. Androgens play a significant role in the pathogenesis of PVD given the fact that these hormones affect the epithelial integrity and function of the genital mucosa. Metabolomics refers to an analytic profiling technique that works by measuring the metabolites or biochemical products of metabolic reactions in the body. This technique can be employed to identify pathologic biological pathways as indicated by altered concentrations of the metabolites in women with PVD compared to those without PVD.

Taking advantage of advances in mass spectrometry (mass accuracy, sensitivity, resolution, and range), it is possible to go beyond standard in-vitro and in-vivo characterization methods and create a comprehensive picture of the biochemistry for a given biological process. Further coupling mass spectrometry to front-end chromatographic separation enhances the resolution of complex mixtures, allowing for the detection of hundreds to thousands of metabolites in a single sample. Metabolomics studies can be further divided into two branches, “targeted” and “untargeted” studies. Targeted metabolomics studies involve the identification and/or quantification of a set of known metabolites while untargeted metabolomics studies involve the identification and/or quantification of as many metabolites without imposing a bias, providing a detailed look of the global metabolic profile in a given sample. Using the basic principles of untargeted liquid chromatography–mass spectrometry (LC–MS) metabolomics assessment, Drs. Jennifer Labus, Andrea Rapkin and Emeran Mayer from the David Geffen School of Medicine at the University of California investigated the differences between steroid hormone biosynthesis metabolites of healthy women vs. women who were suffering from PVD. The steroid hormones are capable of modifying both peripheral and central pain processing pathways. These metabolites were assessed locally in the vaginal fluid, and in the plasma peripherally. The steroids included corticosteroids, androgen, progestin, and pregnenolone. Clinical symptom phenotyping and resting-state brain imaging was utilized to elucidate the potential functional mechanisms underlying alterations levels of steroid biosynthesis metabolites. Dr Kjersti Aagaard from the Baylor College of Medicine and Dr. Katarzyna Broniowska from Metabolon, Inc were also co-authors in the study. The key findings are published in the peer-reviewed journal – Molecular Pain.

The research team showed that women suffering from PVD have significantly reduced levels of progestin and pregnenolone in the plasma while the vaginal fluids contain a lower concentration of progestin, pregnenolone, and androgens. Decreases in vaginal levels of androgens were associated with increased vulvar vestibular pain and vaginal muscle tenderness. Given the lack of differences observed in plasma compared to vagina levels of steroid hormones, the influence of steroid hormone alterations appear to be localized to the vagina and vestibule rather than systemic. Reduced levels of androgens make the vaginal mucosa susceptible to damage as well as reduce the local formation of estrogen from androgenic substrates. These hormone changes can contribute to the onset of mechanical allodynia.

The new study highlights the important role of steroid hormones in the development of PVD and identifies use of systemic contraceptives as potential risk factor. The study also demonstrated associations between vaginal levels of androgens and reduced global resting state connectivity of primary sensorimotor cortices. The authors focused on only associations between steroid hormone biosynthesis and pain processing pathways and did not investigate in-depth other brain circuitry associated with PVD such as the default mode and cognitive control networks, providing an opportunity for future researchers to assess these associations. Moreover, further research employing prospective longitudinal designs is required to investigate the effects of timing of initiation, different dosages and types of hormonal contraceptives on the pathogenesis of PVD.

The debate about the role of contraceptives in PVD has been underway for two decades. The new study examined this very important issue and supported the association. According to the authors, PVD patients tend to have reduced steroid hormone metabolites in the vaginal fluid that contribute to muscle tenderness and vulvar vestibule pain. These steroid hormone metabolites serve as important biologic markers to understand the pathophysiology of PVD.