Effects of Breastfeeding on Endometriosis-Related Pain: A Prospective Observational Study.

Endometriosis is a gynecological estrogen-dependent disease whose commonest pain symptoms are dysmenorrhea, dyspareunia, and acyclic chronic pelvic pain (CPP). Hormonal changes occurring during breastfeeding seem to reduce pain and disease recurrence. The aim of this observational prospective study was to assess the effect of breastfeeding on pain and endometriotic lesions in patients with endometriosis and to evaluate a possible correlation between the duration of breastfeeding, postpartum amenorrhea, and pain. Out of 156 pregnant women with endometriosis enrolled, 123 who breastfed were included in the study and were monitored for 2 years after delivery; 96/123 exclusively breastfed for at least 1 month. Mode of delivery, type and duration of breastfeeding, intensity of pain symptoms, and lesion size before pregnancy and during the 24-month follow-up were analyzed. All patients experienced a significant reduction in dysmenorrhea proportional to the duration of breastfeeding. CPP was significantly reduced only in women who exclusively breastfed. No significant improvement in dyspareunia was observed. Ovarian endometriomas were significantly reduced. Therefore, breastfeeding, particularly if exclusive, may cause improvement in dysmenorrhea and CPP proportional to the duration of breastfeeding, as well as a reduction in the size of ovarian endometriomas.

A deep insight into pelvic pain and endometriosis: a review of the literature from pathophysiology to clinical expressions.

INTRODUCTION: Endometriosis is a chronic inflammatory disease that affects approximately 10% of women of reproductive age. Its clinical manifestations are highly heterogeneous, but pelvic pain is the most frequent, causing functional disability. Cyclic or acyclic chronic pelvic pain (CPP), dysmenorrhea and dyspareunia are frequent symptoms which often compromise all aspects of the women's quality of life (QoL). The pathophysiology of endometriosis-related pain is extremely complex and not always clear. The aim of this systematic review was to focus on recent updates on the clinical presentation, the pathophysiology and the most important mechanisms involved in the pathogenesis of pelvic pain in endometriosis. EVIDENCE ACQUISITION: A literature search in the Cochrane library, PubMed, Scopus and web of Science databases has been performed, identifying articles from January 1995 to November 2020. EVIDENCE SYNTHESIS: Several processes seem to be involved in the pathogenesis of pain, but many aspects are still unclear. Scientific evidence has shown that a correlation between pain severity and stage of endometriosis rarely occurs, whereas there is a significant correlation between pain and the presence of deep endometriosis. Onset and intensity of pain may be due to a complex process involving central sensitization and peripheral activation of nociceptive pathways as well as dysfunction of the immune system and of the hypothalamic-pituitary-adrenal (HPA) axis. CONCLUSIONS: A deeper understanding of these different pathogenetic mechanisms may improve future treatments in women with painful endometriosis.

Dienogest versus continuous oral levonorgestrel/EE in patients with endometriosis: what's the best choice?

OBJECTIVE: Combined oral contraceptives (COC) and progestogens are widely used for the treatment of endometriosis. The objective of the study is to compare the efficacy of dienogest 2 mg vs continuous oral levonorgestrel/EE (levonorgestrel 0.1 mg/ethinyl estradiol 0.02 mg) on ovarian endometriomas, deep infiltrating endometriosis (DIE), chronic pelvic pain (CPP), dyspareunia, analgesic use, quality of life (QoL), compliance and side effects. METHODS: Prospective cohort study. Two cohorts of patients with endometriosis, 50 taking dienogest (group A) and 50 taking continuous levonorgestrel/EE (group B), were evaluated at the beginning of therapy (t0), after 3 (t3) and 6 months (t6). Size of endometriomas, DIE, QoL, pain symptoms, and side effects were assessed. RESULTS: Dienogest was significantly effective on CPP (p = .002), dyspareunia (p = .021) ovarian endometriomas (p = .015) and DIE lesions reduction (p = .014). Levonorgestrel/EE was significantly effective on dyspareunia (p = .023). Analgesics consumption significantly decreased in both groups (p < .001). Both treatments significantly improved the QoL. Over 6 months a significant improvement was found, more frequently in patients taking dienogest. The only side effect that both groups complained about was vaginal bleeding, present in the first 3 months of treatment (p < .001). CONCLUSIONS: Both treatments are effective and safe for patients with endometriosis. Patients compliance and side effects are similar in both groups, however, there was a significantly higher reduction in endometriotic lesions, pain symptoms, and improvement of the QoL in women taking dienogest than in women taking continuous COC.

TLR4 T399I Polymorphism and Endometriosis in a Cohort of Italian Women.

BACKGROUND: Endometriosis is a widespread multifactorial disease in which environmental, genetic, and epigenetic factors contribute to the phenotype. Single Nucleotide Polymorphisms (SNPs) in genes implicated in pivotal molecular mechanisms have been investigated as susceptible risk factors in distinct populations. Among these, Toll-like receptor 4 (TLR4) represents a good candidate due to its role in the immune/inflammatory response and endometriosis pathogenesis. METHODS: The TRL4 gene T399I SNP (C/T transition, rs4986791) was investigated in 236 Italian endometriosis patients and 150 controls by using the PCR-RFLP method. One-tailed Fisher's exact test was used to compare differences between categorical variables. T399I genotype distribution was evaluated for Hardy-Weinberg equilibrium in both groups using the Chi-squared test for given probabilities. RESULTS: Fisher's exact test comparing C and T allele frequencies showed a difference in the frequency of T alleles between patients and controls (OR = 1.96, 95% confidence interval 0.91-4.23; p-value = 0.0552). Genotype frequencies did not show any significant difference between patients and controls. The homozygous TT genotype was observed in 2% of endometriosis women and not in controls. CONCLUSIONS: Our results show that the TLR4 rs4986791 T variant may be considered a genetic risk factor for endometriosis in Italian women. More extensive studies in other populations are needed to confirm this result.

Endometriosis and Pregnancy: A Single Institution Experience.

Endometriosis may compromise the physiological course of pregnancy. The aim of this prospective observational study was to evaluate whether endometriosis causes a higher prevalence of obstetric and neonatal complications as well as a higher risk of caesarean section and to detect a possible correlation between the presence, type, and location of endometriosis and obstetric complications, previous surgery, and pregnancy outcome, as well as the influence of pregnancy on the course of the disease. We compared two cohorts of women with spontaneous pregnancy, with and without endometriosis. Obstetric and neonatal outcomes, mode of delivery, presence, type, and location of endometriotic lesions and the effect of pregnancy on the disease were analyzed. A total of 425 pregnancies were evaluated: 145 cases and 280 controls. Patients with endometriosis showed a higher incidence of miscarriage, threatened miscarriage, threatened preterm labor, preterm delivery, placental abruption, and a higher incidence of caesarean section. A significant correlation with pregnancy-induced hypertension and preeclampsia was found in the presence of adenomyosis. No difference in fetal outcome was found. One case of hemoperitoneum during pregnancy was observed. Pregnancy in women with endometriosis carries a higher risk of obstetric complications, such as miscarriage, threatened miscarriage, preterm labor, preterm birth, and a higher caesarean section rate. Endometriosis does not seem to influence fetal well-being.

Environmental Contaminants Exposure and Preterm Birth: A Systematic Review.

Preterm birth is an obstetric condition associated with a high risk of infant mortality and morbidities in both the neonatal period and later in life, which has also a significant public health impact because it carries an important societal economic burden. As in many cases the etiology is unknown, it is important to identify environmental factors that may be involved in the occurrence of this condition. In this review, we report all the studies published in PubMed and Scopus databases from January 1992 to January 2019, accessible as full-text articles, written in English, including clinical studies, original studies, and reviews. We excluded articles not written in English, duplicates, considering inappropriate populations and/or exposures or irrelevant outcomes and patients with known risk factors for preterm birth (PTB). The aim of this article is to identify and summarize the studies that examine environmental toxicants exposure associated with preterm birth. This knowledge will strengthen the possibility to develop strategies to reduce the exposure to these toxicants and apply clinical measures for preterm birth prevention.

Trends in Mortality After Primary Cytoreductive Surgery for Ovarian Cancer: A Systematic Review and Metaregression of Randomized Clinical Trials and Observational Studies.

BACKGROUND: Primary cytoreductive surgery (PDS) followed by platinum-based chemotherapy is the cornerstone of treatment and the absence of residual tumor after PDS is universally considered the most important prognostic factor. The aim of the present analysis was to evaluate trend and predictors of 30-day mortality in patients undergoing primary cytoreduction for ovarian cancer. METHODS: Literature was searched for records reporting 30-day mortality after PDS. All cohorts were rated for quality. Simple and multiple Poisson regression models were used to quantify the association between 30-day mortality and the following: overall or severe complications, proportion of patients with stage IV disease, median age, year of publication, and weighted surgical complexity index. Using the multiple regression model, we calculated the risk of perioperative mortality at different levels for statistically significant covariates of interest. RESULTS: Simple regression identified median age and proportion of patients with stage IV disease as statistically significant predictors of 30-day mortality. When included in the multiple Poisson regression model, both remained statistically significant, with an incidence rate ratio of 1.087 for median age and 1.017 for stage IV disease. Disease stage was a strong predictor, with the risk estimated to increase from 2.8% (95% confidence interval 2.02-3.66) for stage III to 16.1% (95% confidence interval 6.18-25.93) for stage IV, for a cohort with a median age of 65 years. CONCLUSIONS: Metaregression demonstrated that increased age and advanced clinical stage were independently associated with an increased risk of mortality, and the combined effects of both factors greatly increased the risk.

Ixabepilone for the treatment of endometrial cancer.

INTRODUCTION: Endometrial cancer (EC) is the most common gynaecological cancer. Despite significant progress in the multimodality treatment approach, the prognosis remains poor for patients with advanced disease. Thus, there is the necessity of more effective strategies. The microtubule-stabilizing agent ixabepilone is the first drug in this new class of agents that has been approved for metastatic breast cancer treatment. Based on empiric data and on the clinical efficacy demonstrated in breast cancer, several clinical trials were proposed to define its role in EC. The aim of this review is to determine whether ixabepilone improved the clinical outcome in patients with locally advanced, recurrent or metastatic EC. AREAS COVERED: Preclinical and clinical studies of ixabepilone in endometrial cancer were analyzed and discussed. Data were obtained by searching for English peer-reviewed articles on PubMed, phase I and II studies registered on clincaltrials.gov, and related abstracts recently presented at major international congresses. EXPERT OPINION: Advanced or recurrent EC still represents a challenge and an unmet need in the panorama of gynaecological malignancies. Ixabepilone's future therapeutic role in EC remains ill defined. Nevertheless, despite its limited efficacy in EC, clinicians treating gynaecological tumours should be aware of its main aspects.

Folate administration decreases oxidative status and blood pressure in postmenopausal women.

PURPOSE: The purpose of this study was to evaluate whether folate exerts antioxidant effects in postmenopausal women and whether this effect is related to folate-induced modification of 24-h ambulatory blood pressure (BP). METHODS: Double-blind placebo-controlled study performed in 30 apparently healthy postmenopausal women recruited at the outpatient service of University Hospital. Women, free from hormones or substances possibly interfering with the investigated parameters, were randomized to receive orally for 3 weeks placebo (n = 15) or 15 mg/day of 5-methyltetrahydrofolate (5-MTHF; n = 15). Whole-blood free oxygen radicals test (FORT), free oxygen radical defence (FORD), lipids, glucose, insulin, insulin resistance [homeostatic model assessment for insulin resistance (HOMA-IR)], homocysteine and 24-h ambulatory BP values were evaluated. RESULTS: In the entire group of women, FORT was independently and inversely related to the day-night difference of diastolic (r = 0.420; p = 0.03) and mean BP (r = 0.497; p = 0.01). Placebo did not affect any biochemical or BP parameter. 5-MTHF reduced FORT (-71.5 ± 98.2; p = 0.02) and increased FORD (0.5 ± 0.9; p = 0.05), decreased insulin (p = 0.01), HOMA-IR (p = 0.0002) and homocysteine (p = 0.008). During 5-MTHF, night-time mean (p = 0.001) and diastolic BP (p = 0.002) decreased of about 5 mmHg and the day-night difference of mean (p = 0.001) and diastolic BP (p = 0.002) contemporaneously increased. FORT reduction was related to the amplification of the nocturnal decline of mean (0.697; p = 0.006) and diastolic BP (r = 0.777; p = 0.002) and to the amplification of the day-night difference of diastolic BP (r = 0.63; p = 0.015). CONCLUSIONS: Present data show a clear reduction of oxidative stress during 5-MTHF administration and a strong correlation between this decrease and the nocturnal decline of BP. The possible link between the two is worthy to be explored.

Prospective measurement of blood pressure and heart rate over 24 h in women using combined oral contraceptives with estradiol.

OBJECTIVE: Combined oral contraceptives (COCs) containing ethinyl-estradiol are known to increase blood pressure (BP). We evaluated whether COCs containing estradiol (E2) influence 24-h ambulatory BP and heart rate (HR) in normotensive and normal-weight women. STUDY DESIGN: Twenty-four-hour BP and HR were measured every 30 min with an ambulatory BP device in 18 normotensive healthy non-smoking women prior to (Days 3-6 of menstrual cycle) and after 6 months of use (Days 20-24 of cycle 6) of a COC containing either a quadriphasic combination of E2 valerate plus dienogest (n=11) or a monophasic association of micronized E2 plus nomegestrol acetate (n=7). RESULTS: Mean age and body mass index of the final sample were 32.50±7.49 years and 22.87±4.08, respectively. E2-based COCs induced no modification of 24-h systolic BP (+1.65±8.34 mmHg; p=.41), diastolic BP (+0.04±7.36 mmHg; p=.98), mean BP (+0.64±6.42 mmHg; p=.68) or HR (-0.72±5.86 beats/min; p=.61). Differences were not observed even when daytime or nighttime values were separately considered. Though this was not a comparative study, we did not find differences between the effects of the two formulations (24-h mean BP; p=.699). CONCLUSIONS: These data suggest a neutral effect of estradiol-based COCs on independent risk factors for cardiovascular diseases such as BP or HR. IMPLICATIONS: BP and HR of normotensive women are not increased by E2-based COCs.

Modification of body composition and metabolism during oral contraceptives containing non-androgenic progestins in association with estradiol or ethinyl estradiol.

AIM: To observe the influence on metabolism and body composition of two oral contraceptives containing non-androgenic progestins in association with estradiol or ethinyl estradiol (EE). STUDY DESIGN: Women on hormonal contraception with estradiol valerate (E2V)/dienogest (DNG) in a quadriphasic regimen (n = 16) or 30 µg EE/2 mg chlormadinone acetate (CMA) (n = 16) in a monophasic regimen were evaluated at the third cycle for modifications in lipoproteins, apoproteins and homeostatic model assessment for insulin resistance (HOMA-IR), and at the sixth cycle for body composition and the markers of bone turnover osteocalcin and C-telopeptide X. RESULTS: During E2V/DNG lipoprotein, apoproteins and HOMA-IR remained stable. During EE/CMA, total-cholesterol (p = 0.003), high-density lipoprotein (HDL)-cholesterol (p = 0.001), triglycerides (p = 0.003) Apoprotein-A1 (Apo-A1; p = 0.001) and Apo B (p = 0.04) increased, low-density lipoprotein/HDL (p = 0.039) decreased and total-cholesterol/HDL and Apoprotein-B/Apo-A1 ratio did not vary. HOMA-IR slightly increased from 1.33 ± 0.87 to 1.95 ± 0.88 (p = 0.005). There was a reduction of markers of bone metabolism in both groups with no modification of body composition. CONCLUSIONS: Administration of E2V/DNG does not influence lipid and glucose metabolism, while mixed effect are exerted by EE/CMA. Both preparations reduce bone metabolism without influencing short-term effect on body composition.

Influence of an oral contraceptive containing drospirenone on insulin sensitivity of healthy women.

OBJECTIVES: Oral contraceptives (OCs) containing androgenic second and third generation progestins decrease insulin sensitivity (SI). In this study we investigated whether an oral contraceptive containing the anti-androgenic progestin drospirenone (DRSP) still alters SI. Lipid modifications were investigated as well. STUDY DESIGN: Eleven young healthy women were allocated to receive for 6 months ethinyl-estradiol (EE) 30µg plus DRSP (3mg). SI and glucose utilization independent of insulin (Sg) was investigated by the minimal model method. Lipid modifications were also analyzed. RESULTS: SI did not vary during EE/DRSP (from 3.72±2.62 to 3.29±2.93; p=0.73). Similarly, values of Sg did not vary (from 0.03±0.02 to 0.032±0.014; p=0.87). An increase was observed in HDL cholesterol (9.4±9.8mg/dl; p=0.05) and triglycerides (46.9±75.1mg/dl; p=0.046), with no modification in LDL cholesterol (-4.64±1.704mg/dl; p=0.6). CONCLUSIONS: EE/DRSP does not deteriorate SI. These results are reassuring for the long-term use of this association.

Intensity of menstrual pain and estimated angle of uterine flexion.

OBJECTIVE: To assess the impact of ultrasound-estimated uterus position on the intensity of pelvic pain. DESIGN: Descriptive analytical study. SETTING: Tertiary university gynecology unit. POPULATION: 181 consecutive patients with pelvic pain. METHODS: Each woman underwent physical examination, transvaginal sonography and filled self-administered questionnaires on pain using a 10-cm visual analog scale (VAS). MAIN OUTCOME MEASURES: Visual analog scale score of menstrual pain, intermenstrual pain and dyspareunia was related to uterine version (ante- or retroversion) and the angle of uterine flexion (actual angle between cervix and uterine body) evaluated by transvaginal sonography. RESULTS: Estimated uterine version was not associated with the intensity of any type of pain. The estimated angle of flexion was higher in retroverted than in anteverted uteri (182.3° ± 50.3° vs. 142.3° ± 24.2°, p < 0.0001). Intensity of menstrual pain was lowest with flexion between 150° and 210° (4.9 ± 3.1) (p = 0.002), intermediate with flexion <150° (6.3 ± 2.8) and highest with flexion ≥210° (7.9 ± 2.3). Severe menstrual pain was more prevalent with flexion ≥210° (77.7%) than between 150° and 210° (31.4%; p = 0.0008) or <150° (45.2%; p = 0.005). The intensity of intermenstrual pain and dyspareunia were not associated with the angle of flexion. In multiple regression analysis, the angle of flexion was independently related only to the intensity of menstrual pain (r = 0.272; p = 0.002). CONCLUSIONS: In women with pelvic pain, ultrasound-estimated uterine flexion represents an independent risk for intense menstrual pain.

Combined oral contraceptive containing drospirenone does not modify 24-h ambulatory blood pressure but increases heart rate in healthy young women: prospective study.

BACKGROUND: Hypertension is a primary cardiovascular risk factor. Oral contraceptives (OCs) may increase blood pressure and cardiovascular events. We evaluated whether an OC containing ethynylestradiol (EE) in association with the spironolactone-derived progestin drospirenone (DRSP) influences 24-h ambulatory blood pressure of normotensive women. STUDY DESIGN: Twenty-four-hour blood pressure was measured every 30 min by an ambulatory blood pressure device in 18 normotensive healthy women prior to and after 6 months of use of an OC containing 30 mcg EE and 3 mg DRSP. RESULTS: OC induced no modification in 24-h, nighttime and daytime blood pressure. Heart rate increased about 4 beats/min in the 24-h (p<.05) and daytime (p<.02) measurements. CONCLUSIONS: In normotensive women, an OC containing 30 mcg EE plus 3 mg DRSP does not modify blood pressure, and significantly increases 24-h and daytime heart rate. These data suggest a neutral effect on hypertension-associated cardiovascular risk and point out an unreported effect on heart rate of which cause and effect require further evaluation.