Adenomyosis : imaging features for diagnosing the disease and treatment effects of bromocriptine

Background: Adenomyosis is a benign uterine disease, causing various symptoms including heavy menstrual bleeding (HMB) and pelvic pain. In affected women, endometrial glands and stroma are located in the myometrium surrounded by hypertrophied myometrial tissue. The eutopic endometrium is associated with increased proliferation, high migration and a high invasive capacity. The knowledge of the pathogenesis is largely unknown; however, mice models have shown a link between increased uterine concentration of prolactin (PRL) and the disease. The gold standard in the treatment for hyperprolactinemia is the dopamine agonist bromocriptine. Vaginal administration is effective in reducing serum PRL and has less gastrointestinal side effects than oral administration. Reducing uterine PRL may improve symptoms and could be a possible medical treatment in the future if PRL is associated with the disease. Whether bromocriptine reduce uterine PRL is not known. In the presence of clinical symptoms adenomyosis diagnosis can be confirmed using Magnetic Resonance Imaging (MRI) or Transvaginal ultrasonography (TVS). The reproducibility has been reported high for both modalities, but consensus criteria for diagnosing the disease are still lacking in both MRI and TVS. Aim: The overall aim was to examine the effects of the dopamine agonist bromocriptine in women with adenomyosis and to assess agreement between MRI and TVS for imaging features associated with the disease. The specific objectives were to assess symptoms before and after treatment with vaginal bromocriptine. Another objective was to assess changes in MRI and TVS during treatment and to analyze changes in the endometrium regarding protein biomarkers and differentially expressed genes. A further objective was to compare the inter-rater agreement between MRI and TVS for diagnosing adenomyosis and for various features in the same set of women. Methods and results: In study I, 18 women from Sweden and 1 woman from the USA with regular HMB and suspected adenomyosis were included. Women were treated with a daily dose of 5mg vaginal bromocriptine for 6 months. Self-administered questionnaires were used to assess symptoms at baseline, 3 months, 6 months, and 9 months (3 months after cessation of the study drug). The Pictorial Blood Assessment Chart (PBLAC) and the Aberdeen Menorrhagia Clinical Outcomes Questionnaire (AMCOQ) were used to assess the amount of bleeding. The Visual Analog Scale for pain (VAS) and the McGill Pain Questionnaire (MPQ) were used to assess pain. The Fibroid Symptom Quality of Life (UFS‐QOL), the Endometriosis Health Profile (EHP‐30) and the Female Sexual Function Index (FSFI) were used to assess quality of life. PBLAC, AMCOQ, VAS, and MPQ showed a significant reduction at 6 months, indicating an improvement in bleeding and pain severity. An improvement in quality of life was seen with UFS-QOL. Total EHP and FSFI did not show any significant differences. Study II was a secondary outcome of study I. The 18 women at the Swedish site underwent MRI and TVS at baseline and after treatment with vaginal bromocriptine. The MRIs were assessed by one radiologist and the TVS were assessed by one gynecologist specialized in gynecologic ultrasound. For MRI, no significant differences were found in Junctional Zone (JZ) max, JZ differential, ratio JZ/myometrium or myometrial cysts. TVS showed a significant reduction in JZmax and in asymmetric wall thickness. No significant changes were seen in irregular JZ, fan shaped shadowing, striations, hyperechogenic islands, or cystic lesions. In study III, MRI and TVS images from the same set of 51 women with HMB and suspected adenomyosis were assessed. MRIs were assessed by four radiologists and the TVS images were assessed by five gynecological ultrasonographers. For MRI, the inter-rater reliability for JZ measurements were ‘moderate to good’. Inter-rater agreement for wall asymmetry and irregular JZ were ‘moderate’, while the inter-rater agreement for globular uterus shape was ‘poor’ and ‘fair’ for cysts. The overall subjective impression if adenomyosis was present or not was ‘fair’. For TVS, the inter-rater agreement for globular uterus shape and wall asymmetry were ‘moderate’. Irregular JZ, fan shaped shadowing and buds or striations were ‘fair’ and the inter-rater agreement for cysts were poor. Measurement of the JZ did not show any agreement between the raters. The overall subjective impression of whether adenomyosis was present or not was ‘moderate’. Study IV was a secondary outcome of study I. Endometrial biopsies were taken at baseline and after treatment with vaginal bromocriptine. 12 paired (i.e 12x2) samples were included in the study. Analyses were carried out to evaluate PRL and differentially expressed genes before and after treatment were performed. A significant reduction in serum PRL was observed following bromocriptine treatment, but no changes in the eutopic endometrium. Gene expression analysis showed a significant upregulation of BAX (a marker of apoptosis) and downregulation of Ki67 (a marker of proliferation) and downregulation of genes associated with glucose metabolism. Conclusion: A significant improvement in menstrual bleeding, pain, and quality of life was seen after 6 months of vaginal bromocriptine treatment. A significant decrease in JZmax and asymmetric myometrial wall thickness were demonstrated with TVS. An anti-proliferative effect by downregulating genes associated with glucose metabolism was seen in the eutopic endometrium after treatment. The inter-rater agreement for diagnosis was higher for TVS than for MRI despite MRI manifesting higher agreement in most features associated with the disease. List of scientific papers I. Vaginal bromocriptine improves pain, menstrual bleeding and quality of life in women with adenomyosis. ANDERSSON JOHANNA KARIN, Khan Z, Weaver AL, Vaughan LE, Gemzell-Danielsson K, Stewart EA. Acta Obstet Gynecol Scand. 2019 Oct;98(10):1341-1350. https://doi.org/10.1111/aogs.13632 II. Vaginal bromocriptine for treatment of adenomyosis: Impact on magnetic resonance imaging and transvaginal ultrasound. ANDERSSON JOHANNA KARIN, Pozzi Mucelli R, Epstein E, Stewart EA, Gemzell-Danielsson K. Eur J Obstet Gynecol Reprod Biol. 2020 Nov;254:38-43. https://doi.org/10.1016/j.ejogrb.2020.08.040 III. Inter-rater agreement for diagnosing adenomyosis using Magnetic Resonance Imaging and Transvaginal Ultrasonography. ANDERSSON JOHANNA KARIN, Pozzi Mucelli R, Dueholm M, Fridsten S, Grigoriadis A, Guerrierro S, Leone F, Valentin L, Van den Bosch T, Voulgarakis N, Gemzell-Danielsson K, Epstein E. [Manuscript] IV. Bromocriptine reduces endometrial cell growth in women with adenomyosis by targeting glucose metabolism. Ponandai-Srinivasan S, ANDERSSON JOHANNA KARIN, Frisendahl C, Korsching E, Tengelin J, Pavone D, Stewart E, Parameswaran Grace Luther L, Rao Bogavarappu N, Gemzell-Danielsson K. [Manuscript]

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