Claudia Tosti

Pathogenetic Mechanisms of Deep Infiltrating Endometriosis.

Endometriosis is a benign gynecologic disease, affecting women of reproductive age associated with chronic pelvic pain, dysmenorrhea, dyspareunia and infertility. Ovarian endometrioma (OMA), superficial peritoneal endometriosis (SPE), and deep infiltrating endometriosis (DIE) are, till now, recognized as major phenotypes. The discussion is to know whether they share the same pathogenetic mechanisms. Till today, DIE is recognized as the most severe clinical form of endometriosis and has a complex clinical management. The DIE lesions have been considered in the present article, without distinguishing between the anterior (bladder) or the posterior (vagina, uterosacral ligaments, rectum, and ureter) compartment. The present knowledge indicates that hormonal function (estrogen and progesterone receptors) and immunological factors, such as peritoneal macrophages, natural killer cells, and lymphocytes, are critically altered in DIE. The aggressive behavior of DIE may be explained by the highly decreased apoptosis (nuclear factor kappa-light-chain-enhancer of activated B cells [NF-kB], B-cell lymphoma 2 [Blc-2], and anti-Mullerian hormone) and by the increased proliferation activity related to oxidative stress (NF-kB, reactive oxygen species, extracellular regulated kinase (ERK), advanced oxidation protein product). Invasive mechanisms are more expressed (matrix metalloproteinases and activins) in DIE in comparison to the OMA and SPE. Correlated with the increased invasiveness are the data on very high expression of neuroangiogenesis (nerve growth factor, vascular endothelial growth factor, and intercellular adhesion molecule) genes in DIE. Therefore, at the present time, several of the DIE pathogenetic features result specific in comparison to other endometriosis phenotypes, pleading for the existence of a specific entity. These evidence of specific pathogenetic features of DIE may explain the more severe symptomatology related to this form of endometriosis and suggest possible future target medical treatments.

Ultrasound mapping system for the surgical management of deep infiltrating endometriosis

OBJECTIVE To assess the accuracy of transvaginal sonography (TVS) in defining size and location of deep infiltrating endometriosis (DIE) with laparoscopic/histologic confirmation. DESIGN Prospective observational study. SETTING University hospital. PATIENT(S) One hundred four women with suspected DIE on the basis of TVS. INTERVENTION(S) Patients with DIE underwent TVS evaluation before laparoscopic surgery. An accurate mapping of the extent of the disease was recorded during TVS and at laparoscopy. This new mapping system was developed to assess the extent of endometriosis by measuring the size and depth of the lesions at the various pelvic locations. MAIN OUTCOME MEASURE(S) Surgical and histologic confirmation of the ultrasonographic data to evaluate the presence and location of DIE and creation of a new mapping methodology for detecting DIE by TVS. RESULT(S) Depending on the different location of the lesions, the accuracy of TVS ranged from 76%-97%. The lowest sensitivity (59%) and accuracy (76%) were obtained for TVS in the diagnosis of vaginal endometriosis, whereas the greatest accuracy (97%) was shown in detecting bladder lesions and Douglas obliteration. CONCLUSION(S) This new ultrasound mapping system is accurate for detecting the extent of DIE and may be useful for preoperative planning and intraoperative management of symptomatic patients with DIE.

Preoperative and postoperative clinical and transvaginal ultrasound findings of adenomyosis in patients with deep infiltrating endometriosis

Objectives: Deep infiltrating endometriosis (DIE) represents the most complex form of endometriosis and its treatment is still challenging. The coexistence of DIE with other appearances of endometriosis stimulates new studies to improve the preoperative diagnosis. Adenomyosis is a clinical form that shares several symptoms with DIE. The present study investigated the possible presence of adenomyosis in a group of women with DIE and its impact on pre- and postoperative symptoms. Materials and Methods: A group of women (n = 121) undergoing laparoscopic treatment for DIE were enrolled. Clinical and ultrasound evaluations were performed as preoperative assessment. The ultrasonographical appearances of DIE and of adenomyosis were recorded by 2-dimensional ultrasound. The following symptoms were considered: dysmenorrhea, dyspareunia, abnormal uterine bleeding, bowel, and urinary symptoms. Pain was evaluated by the visual analog scale system and menstrual bleeding was assessed by the use of the pictorial blood assessment chart. In a subgroup of women (n = 55), a follow-up evaluation (3-6 months after surgery) was done. Results: A relevant number of patients with DIE showed adenomyosis (n = 59; 48.7%); in this group, dysmenorrhea (P = .0019), dyspareunia (P = .0004), and abnormal uterine bleeding (P < .001) were statistically higher than that in the group with only DIE. After surgery, painful symptoms improved in the whole group but remained significantly higher (P < .001) in the group with adenomyosis. Conclusions: Deep infiltrating endometriosis is frequently associated with adenomyosis, significantly affecting pre- and postoperative symptoms and thus influencing the follow-up management.

Increased progesterone receptor expression in uterine leiomyoma: correlation with age, number of leiomyomas, and clinical symptoms

OBJECTIVE To investigate the possible correlation between progesterone receptor (PR) expression in uterine leiomyoma or adjacent myometrium and patients age, size/number of leiomyomas, or clinical symptoms such as dysmenorrhea, acyclic pelvic pain, or menstrual and intermenstrual uterine bleeding. DESIGN Cross-sectional study. SETTING Referral center. PATIENT(S) Sixty-two Chinese women undergoing elective hysterectomy for uterine leiomyomata. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Evaluation of PR-total and PR-B mRNA with real-time polymerase chain reaction; PR-A and PR-B proteins quantified by Western blot in leiomyoma tissue and myometrium; symptoms rated by the patients using visual analog scores. RESULT(S) The PR-B mRNA and PR-A and PR-B proteins were more concentrated in leiomyomas than in matched myometrium. A direct correlation between PR-B mRNA levels in leiomyoma and age (r = 0.347) and number of tumors (r = 0.295) was found. Conversely, there was an inverse correlation between PR-B mRNA levels in leiomyoma and dysmenorrhea (r = -0.260) and intermenstrual bleeding (r = -0.266). Multiple regression analysis indicated that age (β = 0.363) and the number of myomas (β = 0.296) were independently associated with PR-B mRNA levels in leiomyoma tissue. CONCLUSION(S) The levels of PR-B mRNA in leiomyoma tissue are directly associated with the number of tumors and inversely correlated with the intensity of intermenstrual bleeding and dysmenorrhea, suggesting that PR signaling may favor leiomyoma growth while attenuating clinical symptoms. This duality should be taken into account in the clinical management of patients with symptomatic uterine leiomyoma.

Transvaginal sonographic features of diffuse adenomyosis in 18–30‐year‐old nulligravid women without endometriosis: association with symptoms

To investigate whether there are sonographic features of diffuse adenomyosis in 18–30‐year‐old nulligravid women without endometriosis and to examine their association with symptoms of dysmenorrhea and abnormal uterine bleeding.

Ulipristal Acetate Modulates the Expression and Functions of Activin A in Leiomyoma Cells

Uterine leiomyoma is the most common benign gynecological tumor in women of reproductive age and represents the single most common indication for hysterectomy. A development of new treatments is necessary for a medical management, and in this direction, several hormonal drugs are under investigation. Ulipristal acetate (UPA; a selective progesterone receptor modulator) is considered as one of the most promising because progesterone has a critical role in development and growth of uterine leiomyoma. The effect of steroids is partly mediated by growth factors like activin A which increases extracellular matrix expression contributing to the growth of leiomyoma. The present study aimed to test whether UPA acts on leiomyoma cells affecting expression and functions of activin A system. Cultured myometrial and leiomyoma cells were treated with UPA, and messenger RNA (mRNA) expression levels of activin A (inhibin βA [INHBA] subunits), its binding proteins (follistatin [FST] and FST-related gene), and its receptors (activin receptor-like kinase 4 [ALK4], activin receptor type [ActR] II, and ActRIIB) were evaluated. The effect of UPA on activin A modulation of fibronectin and vascular endothelial growth factor A (VEGF-A) mRNA expression in cultured myometrial and leiomyoma cells was also studied. Ulipristal acetate decreased INHBA, FST, ActRIIB, and Alk4 mRNA expressions in leiomyoma cultured cells. In addition, UPA was able to block the activin A-induced increase in fibronectin or VEGF-A mRNA expression in myometrial and in leiomyoma cultured cells. The present data show that UPA inhibits activin A expression and functions in leiomyoma cells, and this may represent a possible mechanism of action of the drug on uterine leiomyoma.

Hormonal therapy for endometriosis: from molecular research to bedside

Endometriotic lesions are associated with hormonal imbalance, including increased estrogen synthesis, metabolism and progesterone resistance. These hormonal changes cause increased proliferation, inflammation, pain and infertility. Hormonal imbalances are targets for treatment. Therapeutic strategies and innovations of hormonal drugs for endometriosis are increasing. Acting on estrogen receptors are hormonal drugs decreasing systemic and local estrogen synthesis (GnRH analogs, GnRH antagonists, Aromatase inhibitors) or estrogen activity (selective estrogen receptor modulators). The progesterone resistance is counteracted by progestins (Medroxyprogesterone acetate, Dienogest, Danazol, Levonorgestrel) or by Selective progesterone receptor modulators, a class of drugs under development. The future trend will be to define new drugs to use for prolonged period of time and with poor side effects considering endometriosis a chronic disease.

How to Manage Bowel Endometriosis: The ETIC Approach

A panel of experts in the field of endometriosis expressed their opinions on management options in a 35-year-old patient desiring pregnancy with a history of previous surgery for endometrioma and bowel obstruction symptoms. Many questions that this paradigmatic patient may pose to the clinician are addressed, and various clinical scenarios are discussed. A decision algorithm derived from this discussion is proposed as well.

MAP kinases and the inflammatory signaling cascade as targets for the treatment of endometriosis

Introduction: The pathogenesis of endometriosis, a common benign disease, remains ill-defined, although it is clear that chronic inflammation plays a crucial role through mitogen-activated protein kinase (MAPK) signaling pathways. All current medical therapies for endometriosis are antigonadotropic, and therefore have a contraceptive effect. A concerted research effort is hence warranted with the aim of delivering novel therapeutics that reduces disease symptoms without blocking ovulation. Areas covered: The authors review the complex pathogenic mechanisms of chronic inflammation in endometriosis and their relationships with MAPK pathways. The authors conducted a literature search of descriptive and functional targeted validation of MAPK in the pathogenesis of endometriosis. The effects of MAPK inhibitors, which constitute potential agents for future treatments, are also described. Expert opinion: Preliminary studies have highlighted a crucial role for MAPK in driving endometriosis-related inflammation. MAPK inhibitors exhibit potent activity in terms of controlling growth of endometriosis lesions both in vitro and in animal models. As MAPK inhibitors are known to have a multitude of undesirable side effects, their use in humans has to be approached with great care. Indeed, use of these drugs would probably be limited to short exposures prior to surgery in cases involving the most severe disease phenotypes.

Present and future of recombinant gonadotropins in reproductive medicine.

Pharmacological ovarian stimulation has a major role in reproductive medicine and has been used in anovulatory patients and in the induction of multifollicular development required for the procedures of assisted reproductive techniques (ART). Currently, gonadotropins are the most important tools to proceed with ovarian stimulation for all purposes, including ART and anovulation disorders, like hypogonadotropic hypogonadism and hypothalamic hypophyseal dysfunction. Gonadotropin preparations derived from human urine have been used clinically since the early 1960s and the first urine-derived preparation containing only FSH (urofollitropin) became available in 1983. More recently, the application of recombinant DNA technology has resulted in the development of recombinant FSH produced in mammalian cells. In the last period, LH became available by recombinant DNA technology and is now a new option for protocols of ovarian stimulation. Treatment with gonadotropins has been shown to be effective in males affected by hypogonadotropic hypogonadism. This success has resulted in attempts to utilize FSH therapy in oligozoospermic men, aimed at obtaining a quantitative increase in sperm count. The purpose of this review was to examine the pharmacological aspects and different clinical applications of recombinant gonadotropins (FSH, LH, hCG) in the treatment of female infertility in all its aspects and their use also in the treatment of male infertility. This review will trace these events, from the past through to the present, and conclude with a glance towards the future.