Androgens, Endometriosis and Pain

Abstract

The intriguing relationship between androgens, endometriosis and chronic pain continues to unfold. Determining this relationship is of crucial importance to gynecologists managing people with these conditions, as common treatments dramatically alter her hormonal profiles, with both intended and unintended consequences. Although they may be present in the same individual, there is a recognized disconnect between pain or pain-related symptoms, and the presence or extent of endometriosis lesions. Reduced androgen levels provide a potential mechanism to link the development of endometriosis lesions and the presence of chronic pain. This research paper expands the presentation of our research at the World Endometriosis Congress in 2021, subsequently published in the Journal of Pain Research which demonstrated a strong inverse relationship between androgen levels and days per month of pelvic and period pain. Here we extend and further explore the evidence for a role for androgens in the etiology and management of dysmenorrhea and pelvic pain in women, both with and without endometriosis. We explore the potential for inflammation to induce low androgen levels and consider ways in which clinicians can optimize levels of androgens when treating women with these conditions. This article prompts the question: Is it estrogens that predispose people to a life of pain, or androgens that are protective?

The challenge of endometriosis for female sexual health

“…This could be obtained by prescribing a hormonal therapy that maintains ovarian androgen production despite suppressing menstrual cycles (eg, levonorgestrel intrauterine devices) or a progestogen-only contraceptive that avoids an estrogen-induced increase in hepatic synthesis of SHBG (sex hormone-binding globulin), which normally results in low free testosterone levels. 70 An alternative strategy is represented by exogenous administration of transdermal testosterone, which is expected to exert a beneficial effect on desire and other sexual domains; however, this is off-label in most countries, and efficacy data on women in reproductive age, unlike those in postmenopausal women, have to be confirmed. 71 A surgical approach of endometriosis may offer significant improvement in dyspareunia and quality of sex life among patients with DIE, at least in the short term (by 6-10 months from the operation), 72 especially if combined with postsurgical hormonal treatment.…”

Prenatal Origins of Endometriosis Pathology and Pain: Reviewing the Evidence of a Role for Low Testosterone

“… 54 Women with dysmenorrhea-related pelvic pain demonstrate strong inverse correlations between measures of chronic pain and androgen levels, especially for the correlation between days per month of pelvic pain and the free androgen index which measures the unbound fraction of testosterone within blood. 55 , 56 …”

“…The recent resurgence of interest in roles for testosterone as treatment for chronic pain and infertility, with its relatively advantageous hormonal profile when compared with danazol, suggests that a new, more nuanced role for androgen therapy in a proportion of women with endometriosis or associated pain-related symptoms may be possible. 55 , 56 Navigating a path forward with menstrual suppression, reduced estrogen effects, enhanced androgen effects, and minimization of intralesional conversion of testosterone to estradiol via the enzyme aromatase will require innovative developments in hormonal therapeutics.…”

“…54 Women with dysmenorrhea-related pelvic pain demonstrate strong inverse correlations between measures of chronic pain and androgen levels, especially for the correlation between days per month of pelvic pain and the free androgen index which measures the unbound fraction of testosterone within blood. 55,56 Experimental and observational studies in humans and animal models have consistently shown that treatment with testosterone can ameliorate chronic pain in a proportion of individuals. Female-to-male transsexuals report lower levels of chronic pain following hormonal transition using testosterone therapy, while male-to-female transsexuals report increased pain.…”

Molecular Mechanisms of Endometriosis Revealed Using Omics Data

“…Genetic variants of the AR are associated with the development of endometriosis [ 141 , 142 , 143 ]. Moreover, androgens are associated with endometrial apoptosis [ 144 ], pain caused by endometriosis [ 145 ], and endometrioma [ 146 ]. In addition to “regulation of cell death”, several terms, such as “cell motility”, “cell adhesion”, “defense response”, and “immune response”, which are relevant to endometriosis pathophysiology, were highly significant GOBP terms ( Table 7 ).…”