1983;116:46\54. the induction of systemic hyperprolactinemia in female SHN mice. The severity of the disease is determined by the degree of endometrial invasion into the myometrium. In this model, endometriosis was inhibited by clinical gold standards such as progestins and anti\estrogenic approaches. PRLR blockade completely inhibited endometriosis in this mouse model to the same extent as the anti\estrogen faslodex or the GnRH antagonist cetrorelix. In contrast to cetrorelix and faslodex, the PRLR antibodies did not decrease Difloxacin HCl relative uterine weights and were thus devoid of anti\estrogenic effects. We therefore hypothesize that PRLR antibodies may present a novel and highly efficient treatment option for endometriosis with a good safety and tolerability profile. Clinical studies are on the way to test this hypothesis. strong class=”kwd-title” Keywords: endometriosis, murine endometriosis interna model, prolactin, prolactin receptor antibody Abstract AbbreviationsADAsanti\drug antibodiesCDRscomplementarity\determining regionsD2R dopamine 2 receptor DSCDifferential Scanning CalorimetryFcconstant fragmentJAK/STATJanus Kinase/Signal transducer and activator of transcriptionPRLRprolactin receptor 1.?INTRODUCTION Endometriosis is an estrogen\dependent, gynecological disease that affects up to 15% of premenopausal women and is characterized by the presence of endometrial tissue outside the uterine cavity. 1 Endometriosis is usually associated with pain symptoms such as dysmenorrhea as well as with infertility [2, for review]. There is growing evidence that endometriosis interna (presence of ectopic endometrium in the myometrium) and endometriosis externa (presence of ectopic endometrium in the pelvic cavity) represent two phenotypes of the same disease. 3 Treatment of endometriosis relies on Difloxacin HCl laparoscopy as well as hormonal interventions using combined oral contraceptives, progesterone, GnRH agonists, and antagonists. In addition, nonsteroidal anti\inflammatory drugs are used for the treatment of inflammatory pain [4, for review]. As the hormonal and antihormonal approaches often cause symptoms such as warm flashes, Difloxacin HCl vaginal dryness, and loss of bone mass density, there are continuous efforts to identify novel treatment options devoid of these side effects. 4 There are several hints in the literature that this hormone and proinflammatory cytokine prolactin might be involved in the pathogenesis of endometriosis. Elevated systemic prolactin levels or occult hyperprolactinemia as well as changed nocturnal peaks of prolactin secretion have been described in infertile women suffering from endometriosis [5, for review]. A case report describing the galactorrhea\endometriosis syndrome 6 pointed toward a link between systemic hyperprolactinemia and endometriosis. Recently, it was exhibited that prolactin\lowering drugs such as dopamine 2 receptor (D2R) agonists effectively reduced lesion burden in preclinical experiments in mice 7 as well as in clinical studies in hyperprolactinemic women suffering from endometriosis. 8 Prolactin mediates its effects by the prolactin receptor (PRLR) that belongs to the class 1 cytokine receptor superfamily. The PRLR has three Difloxacin HCl different isoforms, the short, the long, and the intermediate form that differ by the length of their cytoplasmic tails. 9 Prolactin binding leads to dimerization of two PRLR molecules and predominant activation of the Janus Kinase/Signal transducer and activator of transcription (JAK/STAT) pathway stimulating the transcription of prolactin target genes. 9 Prompted by our findings that prolactin as well as its receptor are upregulated in human endometriotic lesions when compared to eutopic endometrium, we generated the hypothesis that not only systemic hyperprolactinemia but also enhanced local PRLRCmediated signaling in endometriotic lesions might contribute to the pathophysiology of Difloxacin HCl endometriosis. 10 In humans, prolactin secretion from pituitary and extra\pituitary sites is usually controlled by different promotors 11 and D2R agonists are only able to interfere with pituitary prolactin secretion. 12 To achieve complete blockade of PRLR\mediated signaling activated by prolactin from pituitary as well as extra\pituitary origin PRLR antagonists are required. We previously identified and characterized the PRLR antibodies 005\C04 13 and Mat3 which is usually closely related to its precursor antibody 005\C04. 14 , 15 Both antibodies act as PRLR antagonists in vitro and in vivo. 10 , 13 , 14 , 15 Here, we analyze the effects of these two PRLR antibodies in a murine endometriosis interna model in comparison to the D2R agonist bromocriptine and several (anti)hormonal approaches to support further clinical development of the antibody Mat3 for the treatment of women suffering from endometriosis. 2.?MATERIALS AND METHODS 2.1. Murine endometriosis interna experiments To compare the in vivo effects of the PRLR antibodies 005\C04 and Mat3 we used an endometriosis interna (= adenomyosis) model in SHN mice. 16 We applied this model previously to study the effects of danazol (androgenic progestin), cetrorelix (GnRH antagonist), and faslodex (estrogen receptor antagonist). 17 It turned out that these treatment approaches that are efficacious in the treatment of human endometriosis were also able to reduce endometriosis interna Gdf6 in mice. 17 SHN mice develop endometriosis interna spontaneously with increasing age whereby they pass between 4 and 9?weeks of age a critical phase in which the foundation for.