The Efficacy of Dienogest in Reducing Disease and Pain Recurrence After Endometriosis Surgery: a Systematic Review and Meta-Analysis.

The objective of this study is to determine whether dienogest therapy after endometriosis surgery reduces the risk of recurrence compared with placebo or alternative treatments (GnRH agonist, other progestins, and estro-progestins). The design used in this study is systematic review with meta-analysis. The data source includes PubMed and EMBASE searched up to March 2022. A systematic review and meta-analysis were performed in accordance with guidelines from the Cochrane Collaboration. Keywords such as "dienogest," "endometriosis surgery," "endometriosis treatment," and "endometriosis medical therapy" were used to identify relevant studies. The primary outcome was recurrence of endometriosis after surgery. The secondary outcome was pain recurrence. An additional analysis focused on comparing side effects between groups. Nine studies were eligible, including a total of 1668 patients. At primary analysis, dienogest significantly reduced the rate of cyst recurrence compared with placebo (p < 0.0001). In 191 patients, the rate of cyst recurrence comparing dienogest vs GnRHa was evaluated, but no statistically significant difference was reported. In the secondary analysis, a trend toward reduction of pain at 6 months was reported in patients treated with dienogest over placebo, with each study reporting a significantly higher reduction of pain after dienogest treatment. In terms of side effects, dienogest treatment compared with GnRHa significantly increased the rate of spotting (p = 0.0007) and weight gain (p = 0.03), but it was associated with a lower rate of hot flashes (p = 0.0006) and a trend to lower incidence of vaginal dryness. Dienogest is superior to placebo and similar to GnRHa in decreasing rate of recurrence after endometriosis surgery. A significantly higher reduction of pain after dienogest compared with placebo was reported in two separate studies, whereas a trend toward reduction of pain at 6 months was evident at meta-analysis. Dienogest treatment compared with GnRHa was associated with a lower rate of hot flashes and a trend to lower incidence of vaginal dryness.

Immune-Onco-Microbiome: A New Revolution for Gynecological Cancers.

Despite significant advances in understanding the pathogenetic mechanisms underlying gynaecological cancers, these cancers still remain widespread. Recent research points to a possible link between microbiota and cancer, and the most recent attention is focusing on the relationship between the microbiome, the immune system, and cancer. The microbiome diversity can affect carcinogenesis and the patient's immune response, modulating the inflammatory cascade and the severity of adverse events. In this review, we presented the recent evidence regarding microbiome alterations in patients with gynaecological tumours to understand if the link that exists between microbiome, immunity, and cancer can guide the prophylactic, diagnostic, and therapeutic management of gynaecological cancers.

Expectant, Medical, and Surgical Management of Ovarian Endometriomas.

Management options for ovarian endometriomas include expectant management, medical treatment, surgical treatment, in vitro fertilization (IVF), or a combination of the above. The choice of management depends on many clinical parameters that should be taken into consideration, the first of which is the main presenting symptom. Most patients are today referred to medical therapy as a first option in the case of associated pain, and to IVF in the case of associated infertility. When both symptoms are present, usually surgery is the preferred approach. Recently, however, surgical excision of an ovarian endometrioma has been associated with a postoperative reduction in the ovarian reserve, and recent guidelines suggest that the clinician should caution the patient as to the possible damage to the ovarian reserve in the case of surgery. However, evidence has been published as to a possible detrimental effect of the ovarian endometrioma on the ovarian reserve even if expectant management is followed. In this review, the current evidence on the conservative management of ovarian endometriomas, with particular focus on the issue of the ovarian reserve, is evaluated, and the different surgical techniques for the treatment of ovarian endometriomas are discussed.

Chronic Pelvic Pain, Vulvar Pain Disorders, and Proteomics Profiles: New Discoveries, New Hopes.

Chronic pelvic pain (CPP) is generally defined as non-cyclic pain perceived in the pelvic area that has persisted from three to six months or longer and is unrelated to pregnancy. The etiology of CPP is complex, multifactorial, with heterogeneous presentation, and includes several diseases such as endometriosis, adenomyosis, and interstitial cystitis/bladder pain syndrome. It may also be associated with sexual dysfunction, musculoskeletal disorders, and comorbid psychiatric symptoms. Vulvar pain disorders (VPDs) are typically categorized separately from chronic pelvic pain; among all VPDs, vulvodynia is a chronic vulvar pain of unknown etiology, lasting at least 3 months and that might be associated with other potentially linked factors. Proteomics represents a useful approach to study the proteome profiles of clinical samples. In this review, we have considered a selection of articles that have analyzed the protein abundance and novel protein species from various biological samples, including eutopic/ectopic endometrium, urine, serum, follicular, peritoneal fluid, and cervical mucus, potentially involved in the pathogenesis and progression of CPP and VPDs. These findings could represent valuable targets for paving the way for the differential diagnosis and therapeutic management of CPP and VDPs, thereby optimizing both the prevention and treatment of these conditions.

Fertility after Cancer: Risks and Successes.

The incidence of cancer in reproductive-aged women is 7%, but, despite the increased number of cancer cases, advances in early diagnosis and treatment have raised the survival rate. Furthermore, in the last four decades, there has been a rising trend of delaying childbearing. There has been an increasing number of couples referred to Reproductive Medicine Centers for infertility problems after one partner has been treated for cancer. In these cases, the main cause of reduced fertility derives from treatments. In this review, we describe the effects and the risks of chemotherapy, radiotherapy, and surgery in women with cancer, and we will focus on available fertility preservation techniques and their efficacy in terms of success in pregnancy and live birth rates.

The role of microbiota in female fertility and infertility.

In recent years, the introduction of advanced technologies has led to a new scientific revolution: the discovery of the human microbiota. Next-generation sequencing allowed the identification of microbial communities in all districts of the human body and, among these, 9% are distributed in the genitourinary system. The microbiota plays a key role in controlling the homeostasis, therefore dysbiosis can lead to an alteration of the physiological state of health. An alteration of female reproductive microbial communities may affect fertility due to an alteration of the vaginal and endometrial ecosystem. A perturbation of the vaginal, cervical or endometrial flora may also have an impact on the outcome of assisted reproductive technology procedures, particularly in vitro fertilization and embryo transfer. This review examines the role of microbiota in human reproduction and its contribution to infertility. In addition we investigate the role of endometrial bacteria in recurrent implantation failure.

Endometriosis-associated infertility: surgery or IVF?

Endometriosis is a chronic disease frequently associated with female infertility. The choice of treatment in case of endometriosis is one of the most discussed topics in Reproductive Medicine. The approach to the patient with endometriosis and infertility should be tailored based on different parameters. The localization of the disease, the severity of symptoms and the age of the patient are just some of them. Management options include surgery, in-vitro fertilization (IVF), or a combination of both. Data, mostly uncontrolled, would favor surgery at any stage of endometriosis, increasing the chances of natural conception compared to expectant management. Laparoscopic excision of the ovarian endometrioma should be the treatment of choice when there is associated pain. Surgery should be performed following appropriate techniques to reduce the possible damage to the ovarian reserve. Pregnancy rates around 50% have been consistently reported after surgery, which compare favorably with those obtained with IVF. IVF, on the other hand, may be preferred in case of associated male or tubal factor, in case of a reduced ovarian reserve, or if previous surgery has failed, particularly if there is no associated pain, and when the ultrasonographic features of the ovarian cyst are reassuring. Sometimes IVF may be preceded by surgery, when a difficult access to follicles at pick-up, due to the size and location of the ovarian cyst, or to severe adhesions, is anticipated. Due to the lack of solid evidence in the scenario of endometriosis-associated infertility, robust data from randomized clinical trials (RCTs) are strongly needed.

The role of alpha lipoic acid in female and male infertility: a systematic review.

OBJECTIVE: Infertility is an increasingly frequent health condition, which may depend on female or male factors. Oxidative stress (OS), resulting from a disrupted balance between reactive oxygen species (ROS) and protective antioxidants, affects the reproductive lifespan of men and women. In this review, we examine if alpha lipoic acid (ALA), among the oral supplements currently in use, has an evidence-based beneficial role in the context of female and male infertility. METHODS: We performed a search from English literature using PubMed database with the following keywords: 'female infertility', 'male infertility', 'semen', 'sperm', 'sub-fertile man', 'alpha-lipoic acid', ' alpha lipoic acid', 'lipoid acid', 'endometriosis', 'chronic pelvic pain', 'follicular fluid' and 'oocytes'. We included clinical trials, multicentric studies and reviews. The total number of references found after automatically and manually excluding duplicates was 180. After primary and secondary screening, 28 articles were selected. RESULTS: The available literature demonstrates the positive effects of ALA in multiple processes from oocyte maturation (0.87 ± 0.9% of oocyte in MII vs 0.81 ± 3.9%; p < .05) to fertilization, embryo development (57.7% vs 75.7% grade 1 embryo; p < .05) and reproductive outcomes. Its regular administration both in sub-fertile women and men shows to reduce pelvic pain in endometriosis (p < .05), regularize menstrual flow and metabolic disorders (p < .01) and improve sperm quality (p < .001). CONCLUSIONS: ALA represents a promising new molecule in the field of couple infertility. More clinical studies are needed in order to enhance its use in clinical practice.

Medical treatment of ovarian endometriomas: a prospective evaluation of the effect of dienogest on ovarian reserve, cyst diameter, and associated pain.

The aim of the present study was to evaluate the effect of medical treatment of ovarian endometriomas on cyst diameter, associated pain, and ovarian reserve as measured with antral follicle count (AFC) and anti-Mullerian hormone (AMH). In this prospective study, 32 patients with unilateral endometrioma associated with pelvic pain, underwent 6-month medical treatment with dienogest. Before treatment, and at the end of 6 months of treatment, patients underwent evaluation of endometrioma diameter and AFC at transvaginal ultrasonography, measurement of AMH, and evaluation of associated pain. Mean cyst diameter was 4.0 ± 1.3 cm at baseline, and 2.4 ± 1.2 cm after 6 months of treatment (p < .0001), for a reduction in diameter of 40% and a reduction in volume of 79%. Mean visual analog scale score at enrollment was 6.3 ± 2.0, with a significant improvement at 6 months (0.9 ± 1.0, p < .0001). AFC for the affected ovary improved from 4.2 ± 2.8 at baseline, to 8.6 ± 4.2 cm after 6 months (+105%; p < .0001). AMH did not change significantly from baseline (3.40 ± 2.32 ng/mL) to end of treatment (2.80 ± 1.90 ng/mL, -18%, p = .27). Medical treatment with dienogest significantly reduces endometrioma diameter and associated pain, whereas the ovarian reserve appears to be preserved, with a significant improvement of AFC and no significant change in AMH.

Immunotherapy in endometrial cancer: new scenarios on the horizon.

This extensive review summarizes clinical evidence on immunotherapy and targeted therapy currently available for endometrial cancer (EC) and reports the results of the clinical trials and ongoing studies. The research was carried out collecting preclinical and clinical findings using keywords such as immune environment, tumor infiltrating lymphocytes, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) expression, immune checkpoint inhibitors, anti-PD-1/PD-L1 antibodies and others' on PubMed. Finally, we looked for the ongoing immunotherapy trials on ClinicalTrials.gov. EC is the fourth most common malignancy in women in developed countries. Despite medical and surgical treatments, survival has not improved in the last decade and death rates have increased for uterine cancer in women. Therefore, identification of clinically significant prognostic risk factors and formulation of new rational therapeutic regimens have great significance for enhancing the survival rate and improving the outcome in patients with advanced or metastatic disease. The identification of genetic alterations, including somatic mutations and microsatellite instability, and the definition of intracellular signaling pathways alterations that have a major role in in tumorigenesis is leading to the development of new therapeutic options for immunotherapy and targeted therapy.

Ovarian Reserve Reduction With Surgery Is Not Correlated With the Amount of Ovarian Tissue Inadvertently Excised at Laparoscopic Surgery for Endometriomas.

The aim of the present study was to evaluate the effect of laparoscopic cystectomy on ovarian reserve by means of anti-Müllerian hormone (AMH) serial measurements and to compare AMH values with the number of inadvertently removed follicles in histological specimens. Fifty-two women were enrolled: 34 patients with endometriomas (group 1) and 18 patients with other benign ovarian cysts (group 2). All patients underwent laparoscopic cystectomy performed by a single experienced surgeon. The AMH was measured before, and 1, 3, and 6 months after cystectomy in group 1, and before and 6 months after surgery in group 2. Preoperative AMH levels (mean [standard deviation, SD]) in group 1 (3.39 [2.43] ng/mL) were not significantly different from group 2 (3.74 [2.57] ng/mL; P = .68). In group 1, a significant decrease in AMH levels of 43.4% was observed at 1 month (1.93 [1.36]; P = .003), and of 63.1% at 3 months (1.25 [1.00]; P = .007) postoperatively. The AMH increased not significantly between the third and sixth months in group 1 (+9.4%). Six months after surgery, AMH was reduced by 59.3% compared to baseline values in group 1 (P = .012), and by 29.5% in group 2 (P = .200). A significant difference in the AMH decrease was present between bilateral and monolateral endometriomas (P = .006). There was no correlation between the reduction rate of AMH and the number of follicles inadvertently removed in patients with endometriomas (P = .669). In conclusion, AMH decreases significantly after surgical excision of ovarian endometriomas. The postoperative decrease does not appear to correlate with the amount of ovarian tissue inadvertently excised with the endometrioma wall.

Orally Administered Combination of Hyaluronic Acid, Chondroitin Sulfate, Curcumin, and Quercetin in the Prevention of Postcoital Recurrent Urinary Tract Infections: Analysis of 98 Women in Reproductive Age After 6 Months of Treatment.

OBJECTIVE: The aim of this study is to assess the efficacy of orally administered combination of hyaluronic acid (HA), chondroitin sulfate (CS), curcumin, and quercetin for the prevention of postcoital recurrent urinary tract infection (UTI) in reproductive age women. METHODS: Ninety-eight consecutive patients in reproductive age affected by UTI were considered for the study. All 98 patients received a combination of HA, CS, curcumin, and quercetin two tablets per diem for the first month and one tablet every day for the next 5 months. We investigate recurrence of UTI with the Urinary Tract Infection Symptoms Assessment and the Pelvic Pain and Urinary Urgency Frequency. The quality of life and sexual function were valued using 36-Item Short Form Survey, Female Sexual Function Index, and the Female Sexual Distress Scale questionnaires. The same investigations were performed at the first visit and after 6 months of treatment. RESULTS: The symptoms associated with UTI significantly decreased after 6 months of treatment, in particular dysuria episodes diminished and number of voiding decreased (P < 0.0001). During the treatment period, only seven patients (7.1%) experienced a UTI recurrence, confirmed by positive urine culture with bacteriuria of greater than 10 colony forming units/mL. The Pelvic Pain and Urinary Urgency Frequency, Female Sexual Function Index, Female Sexual Distress Scale, and 36-Item Short Form Survey showed a statistically significant improvement after 6 months. CONCLUSIONS: Oral administration of a combination of HA, CS, curcumin, and quercetin is a valid and well-tolerated nonantibiotic treatment for prevention of postcoital UTI in reproductive age women.

Management of endometriosis from diagnosis to treatment: roadmap for the future.

Endometriosis, in spite of decades of research on the topic, remains a mysterious and elusive disease. Both in the fields of diagnosis and treatment, many issues remain unresolved, and the scientific community strives in trying to find universal criteria for diagnosis, and algorithms of treatment that may be universally applied. Recently, there has been a shift away from the view of the need of invasive diagnosis and therapy with the universal use of laparoscopy. Today the diagnosis of endometriosis may be reliably performed with noninvasive methods, and therapy can be nonsurgical in most cases. Recent guidelines state that diagnostic laparoscopy may be better seen as a second line of investigation, whereas medical therapy with either oral estroprogestins or progestogens is the first therapeutic option in case of associated pain. A thorough discussion with the patient should address all the available treatments, so as to make a shared decision on which treatment best fits the needs of that single patient.

Usefulness of Ospemifene in the treatment of urgency in menopausal patients affected by mixed urinary incontinence underwent mid-urethral slings surgery.

The aim of this study was to assess the effectiveness and safety of Ospemifene in the improvement of urgency component in women affected by mixed urinary incontinence (MUI) who underwent surgery with mid-urethral sling (MUS). Eighty-one patients with MUI underwent surgical intervention with MUS were enrolled. After surgical intervention 38 patients received Ospemifene 60 mg one tablet daily per os for 12 weeks. Physical examination, 3-day voiding diary, urodynamic testing were performed at the start and the follow-up after 12 weeks in the Trans-Obturator-Tape (TOT)-Alone group and TOT-Ospemifene. Patients completed the Overactive Bladder Symptom and Health-Related Quality of Life Short-Form (OAB-Q SF), International Consultation on Incontinence Questionnaire (ICIQ-UI-SF), and King' s Health Questionnaire (KHQ). A significant difference between the two groups was observed in peak flow (ml/s), in first voiding desire (ml), in maximum cystometric capacity (ml), and in detrusor pressure at peak flow (cmH2O) at urodynamic evaluation. A significative difference between the two groups at voiding diary was observed in the mean number of voids, urgent micturition episodes/24 h, urge urinary incontinence, and in nocturia events. The OAB-Q symptoms and OAB-Q (HRQL) scores after 12 weeks showed a significative difference between the two groups. Ospemifene is an effective potential therapy after MUSs in women with MUI improving urgency symptoms and quality of life.

Antimüllerian hormone is reduced in the presence of ovarian endometriomas: a systematic review and meta-analysis.

OBJECTIVE: To evaluate if the presence of endometriomas impacts on the ovarian reserve as evaluated with antimüllerian hormone (AMH). DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Patients with unoperated endometriomas versus controls without endometriomas. INTERVENTION(S): Electronic databases searched up to June 2017 to identify articles evaluating AMH levels in patients with unoperated endometriomas versus controls without endometriomas. MAIN OUTCOME MEASURE(S): The primary analysis was aimed at evaluation of AMH levels (mean and SD) in patients with and without endometriomas. Secondary analyses were aimed at evaluating AMH levels in patients with ovarian endometriomas compared to patients with either non-endometriosis benign ovarian cysts or healthy ovaries. RESULT(S): Of the 39 studies evaluated in detail, 17 were included, for a total of 968 patients with endometriomas and 1874 without endometriomas. AMH was significantly lower in patients with unoperated endometriomas compared to patients with no endometriomas (mean difference -0.84, with 95% confidence interval [CI] -1.16 to -0.52). At secondary analyses, AMH in patients with endometriomas was significantly lower both versus non-endometriosis benign ovarian cysts (mean difference -0.85, 95% CI -1.37 to -0.32, and versus women with healthy ovaries (mean difference -0.61, 95% CI -0.99 to -0.24). CONCLUSION(S): Ovarian reserve evaluated with AMH is reduced in patients with ovarian endometriomas compared both to patients with other benign ovarian cysts, and to patients with healthy ovaries.

Pelvic Inflammatory Disease: Possible Catches and Correct Management in Young Women.

The incidence of adnexal masses increases exponentially with age and the most frequent causes in young women are physiologic cysts and pelvic abscesses with pelvic inflammatory disease (PID). Clinical examination can direct physicians to an appropriate management of adnexal mass, but the role of transvaginal ultrasound is crucial for diagnosis and treatment decision, even if it sometimes can be misleading, especially in young women. Ca 125, blood count, and CRP are useful to clarify suspected etiology of a pelvic mass, but specificity and positive predictive value are low because elevation of laboratory tests may occur in several benign conditions. In our work we present four cases of suspected pelvic masses. Despite guidelines for management of PID, the right timing to switch to surgical therapy is not clear. Therefore, the treatment decision should be based on a careful evaluation of various parameters such as signs symptoms and above all age. Moreover, we believe that, for a correct diagnosis and for the best fertility sparing treatment, it is also extremely important to refer to a gynecological oncology unit with an expert surgeon.

Therapeutic vaccines and immune checkpoints inhibition options for gynecological cancers.

Treatments for gynecological cancer include surgery, chemotherapy, and radiation. However, overall survival is not improved, and novel approaches are needed. Immunotherapy has been proven efficacious in various types of cancers and multiple approaches have been recently developed. Since numerous gynecological cancers are associated to human papilloma virus (HPV) infections, therapeutic vaccines, targeting HPV epitopes, have been developed. The advancing understanding of the immune system, regulatory pathways and tumor microenvironment have produced a major interest in immune checkpoint blockade, Indeed, immune checkpoint molecules are important clinical targets in a wide variety of tumors, including gynecological. In this review, we will describe the immunotherapeutic targets and modalities available and review the most recent immunotherapeutic clinical trials in the context of gynecological cancers. The synergic results obtained from the combination of HPV therapeutic vaccines with radiotherapy, chemotherapy, or immune checkpoint inhibitors, may underlie the potential for a novel therapeutic scenario for these tumors.

Alpha lipoic acid in obstetrics and gynecology.

Alpha-Lipoic acid (ALA) is a natural antioxidant synthetized by plants and animals, identified as a catalytic agent for oxidative decarboxylation of pyruvate and α-ketoglutarate. In this review, we analyzed the action of ALA in gynecology and obstetrics focusing in particular on neuropathic pain and antioxidant and anti-inflammatory action. A comprehensive literature search was performed in PubMed and Cochrane Library for retrieving articles in English language on the antioxidant and anti-inflammatory effects of ALA in gynecological and obstetrical conditions. ALA reduces oxidative stress and insulin resistance in women with polycystic ovary syndrome (PCOS). The association of N-acetyl cysteine (NAC), alpha-lipoic acid (ALA), and bromelain (Br) is used for prevention and treatment of endometriosis. In association with omega-3 polyunsaturated fatty acids (n-3 PUFAs) with amitriptyline is used for treatment of vestibulodynia/painful bladder syndrome (VBD/PBS). A promising area of research is ALA supplementation in patients with threatened miscarriage to improve the subchorionic hematoma resorption. Furthermore, ALA could be used in prevention of diabetic embryopathy and premature rupture of fetal membranes induced by inflamation. In conclusion, ALA can be safely used for treatment of neuropatic pain and as a dietary support during pregnancy.

Long-term experience of vaginal vault prolapse prevention at hysterectomy time by modified McCall culdoplasty or Shull suspension: Clinical, sexual and quality of life assessment after surgical intervention.

OBJECTIVES: The aim of this study was to evaluate the effectiveness of modified McCall culdoplasty or Shull suspension in preventing vaginal vault prolapse after vaginal hysterectomy and the long-term impact on quality of life and sexual function. STUDY DESIGN: Retrospective analysis in 414 patients underwent vaginal hysterectomy for pelvic organ prolapse (POP) and vaginal suspension through modified McCall culdoplasty (group A) or Shull suspension (group B) was evaluated. Clinical features and concomitant surgical procedures were assessed. Surgical data and perioperative and postoperative complications have also been analyzed. Clinical characteristics, urinary symptoms, POP-Q score classification, Quality of Life and Sexual Function were evaluated at baseline and at median follow up with P-QoL, ICIQ-UI-SF, PISQ-12, FSFI, FSDS questionnaires. RESULTS: The median follow up was 8.9 year (5.1-14.2 years). 200 women in group A and 214 in group B were evaluated. Vaginal vault prolapse occurred in 2 patients in group A and in 2 patients in group B. POP-Q score for all compartments showed a significant (p < 0.001) decrease for both groups without significant differences between the 2 groups. The total vaginal length (TVL) was reduced in greater proportion in McCall group (p < 0.001). P-QoL and ICIQ-UI-SF questionnaires documented an improvement for both groups (p < 0.001). The number of patients who regularly practice sexual activity increased in both groups, but patients in group B experienced a better quality of sexual life evaluated with PISQ-12 and FSFI. CONCLUSIONS: Both surgical techniques showed effectiveness and safety in preventing vaginal vault prolapse in women who underwent vaginal hysterectomy, with a significant improvement in quality of life and sexuality. Shull technique demonstrated greater improvement in sexual function.