Giovanni Grandi

Prevalence of menstrual pain in young women: what is dysmenorrhea?

Objectives This study aimed to determine the frequency of dysmenorrhea, as identified by different definitions, in a population of young women, and to investigate factors associated with this complaint. Materials and methods A final group of 408 young women completed a self-assessment questionnaire. This was a cross-sectional analytical study. Results Menstrual pain was reported by 84.1% of women, with 43.1% reporting that pain occurred during every period, and 41% reporting that pain occurred during some periods. Women with menstrual pain had an earlier menarche (P = 0.0002) and a longer menstrual flow (P = 0.006), and this group was characterized as having a higher prevalence of smokers (P = 0.031) and a lower prevalence of hormonal contraception users (P = 0.015). Pain intensity was correlated (r = 0.302, P < 0.0001) positively with menstrual flow length (CR = 0.336), history of abortions (CR = 3.640), and gynecological pathologies (CR = 0.948), and negatively with age at menarche (CR = −0.225), use of hormonal contraception (CR = −0.787), and history of gynecological surgery (CR = −2.115). Considering the parameters of menstrual pain, a need for medication, and inability to function normally (absenteeism from study or social activities) alone or together, the prevalence of dysmenorrhea is 84.1% when considering only menstrual pain, 55.2% when considering the association between menstrual pain and need for medication, 31.9% when considering the association between menstrual pain and absenteeism, and 25.3% when considering the association between menstrual pain, need for medication, and absenteeism (P < 0.0001). The probability of having more severe dysmenorrhea is directly related to pain intensity as measured by a visual analog scale, but does not coincide with it. Conclusion Menstrual pain is a very common problem, but the need for medication and the inability to function normally occurs less frequently. Nevertheless, at least one in four women experiences distressing menstrual pain characterized by a need for medication and absenteeism from study or social activities.

Hereditary Ovarian Cancer: Not Only BRCA 1 and 2 Genes

More than one-fifth of ovarian tumors have hereditary susceptibility and, in about 65–85% of these cases, the genetic abnormality is a germline mutation in BRCA genes. Nevertheless, several other suppressor genes and oncogenes have been associated with hereditary ovarian cancers, including the mismatch repair (MMR) genes in Lynch syndrome, the tumor suppressor gene, TP53, in the Li-Fraumeni syndrome, and several other genes involved in the double-strand breaks repair system, such as CHEK2, RAD51, BRIP1, and PALB2. The study of genetic discriminators and deregulated pathways involved in hereditary ovarian syndromes is relevant for the future development of molecular diagnostic strategies and targeted therapeutic approaches. The recent development and implementation of next-generation sequencing technologies have provided the opportunity to simultaneously analyze multiple cancer susceptibility genes, reduce the delay and costs, and optimize the molecular diagnosis of hereditary tumors. Particularly, the identification of mutations in ovarian cancer susceptibility genes in healthy women may result in a more personalized cancer risk management with tailored clinical and radiological surveillance, chemopreventive approaches, and/or prophylactic surgeries. On the other hand, for ovarian cancer patients, the identification of mutations may provide potential targets for biologic agents and guide treatment decision-making.

Does dienogest influence the inflammatory response of endometriotic cells? A systematic review.

Objective and designA systematic review of all literature was done to assess the ability of the progestin dienogest (DNG) to influence the inflammatory response of endometriotic cells.Main outcome measuresIn vitro and in vivo studies report an influence of DNG on the inflammatory response in eutopic or ectopic endometrial tissue (animal or human).ResultsAfter strict inclusion criteria were satisfied, 15 studies were identified that reported a DNG influence on the inflammatory response in endometrial tissue. These studies identified a modulation of prostaglandin (PG) production and metabolism (PGE2, PGE2 synthase, cyclo-oxygenase-2 and microsomal PGE synthase-1), pro-inflammatory cytokine and chemokine production [interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, monocyte chemoattractant protein-1 and stromal cell-derived factor-1], growth factor biosynthesis (vascular endothelial growth factor and nerve growth factor) and signaling kinases, responsible for the control of inflammation. Evidence supports a progesterone receptor-mediated inhibition of the inflammatory response in PR-expressing epithelial cells. It also indicated that DNG inhibited the inflammatory response in stromal cells, however, whether this was via a PR-mediated mechanism is not clear.ConclusionsDNG has a significant effect on the inflammatory microenvironment of endometriotic lesions that may contribute to its clinical efficacy. A better understanding of the specific anti-inflammatory activity of DNG and whether this contributes to its clinical efficacy can help develop treatments that focus on the inhibition of inflammation while minimizing hormonal modulation.

Clinical outcome and bone healing of implants placed with high insertion torque: 12-month results from a multicenter controlled cohort study

This study evaluated the clinical outcome and the crestal bone resorption of implants placed with high insertion torque (up to 80 N cm). 102 patients were treated with 156 tapered implants. 42 implants (control group) presented insertion torque between 30 and 45 N cm (mean=37.4 SD 8.2). 114 implants (experimental group) were placed with insertion torque between 50 and 80 N cm (mean=74.8 SD 7.9). All implants were early loaded after 2 months. Peri-implant marginal bone levels were assessed immediately after surgery, and at 6- and 12-month follow up examinations. At the 12-month follow up all implants were clinically stable. After 12 months, patients in the experimental group lost an average of 0.41 mm (CI 95% 0.522; 0.263) of crestal bone compared with 0.45 mm (CI 95% 0.561; 0.286) for those in the control group. There were no significant differences between the two groups. No direct or inverse relationship was observed between the insertion torque values and crestal bone resorption. The results show that the use of high insertion torque (up to 80 N cm) did not prevent osseointegration and did not increase bone resorption around tapered implants early loaded up to 1 year after implant placement.

Inflammation influences steroid hormone receptors targeted by progestins in endometrial stromal cells from women with endometriosis

Endometriosis is an estrogen-dependent disease characterised by the growth of endometrial epithelial and stromal cells outside the uterus creating a chronic inflammatory environment that further contributes to disease progression. The first choice treatment for endometriosis is currently progestin mediated hormone modulation. In addition to their progestogenic activity however, progestins also have the potential to bind to other nuclear receptors influencing their local activity on endometriotic cells. This local activity will be dependent on the steroid hormone receptor expression that occurs in endometrial cells in a chronic inflammatory environment. We therefore aimed to quantify receptors targeted by progestins in endometrial stromal cells after exposure to inflammation. Using primary endometrial stromal cells isolated from women with endometriosis we examined the mRNA and protein expression of the progesterone receptors A and B, membrane progesterone receptors 1 and 2, androgen receptors, mineralocorticoid receptors and glucocorticoid receptors after exposure to the inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β). The results indicate that both cytokines reduced the expression of progesterone receptors and increased the expression of the glucocorticoid receptors in the endometrial stromal cells. The change in expression of progestin targets in endometrial stromal cells in an inflammatory environment could contribute to the progesterone resistance observed in endometriotic cells and ultimately influence the design of hormonal therapies aimed at treating this disease.

Pelvic Pain and Quality of Life of Women With Endometriosis During Quadriphasic Estradiol Valerate/Dienogest Oral Contraceptive. A Patient-Preference Prospective 24-Week Pilot Study

Objective: The progestin dienogest (DNG) given alone effectively reduces pelvic pain of women with endometriosis. It is not clear whether the same occurs when DNG is associated with estradiol (E2). Design: Patient preference prospective observational study. Setting: Outpatient centre of university hospital. Patients: 40 patients with endometriosis and menstrual pain. Interventions: 24-week treatment with a quadriphasic association of E2 valerate (E2V) and DNG or a nonsteroidal anti-inflammatory drug (NSAID) to be used only in case of pain (ketoprofene 200-mg tablets). Main Outcome Measures: Menstrual pain and, when present, intermenstrual pain, and dyspareunia were investigated by means of a 10-cm visual analogue scale (VAS). Quality of life was investigated by the short form 36 (SF-36) of the health-related quality of life questionnaire. Results: Final study group consists of 34 patients, 19 in the E2V/DNG group and 15 in the NSAID group. After 24 weeks, no significant modification of menstrual pain, intermenstrual pain, dyspareunia, or SF-36 score was observed in the NSAID group. Treatment with E2V/DNG reduced the VAS score of menstrual pain by 61% (P < .0001). In the subgroups of women with intermenstrual pain or dyspareunia, E2V/DNG reduced these complaints by 65% (P = .013) and 52% (P = .016), respectively. The reduction in menstrual (P = .0001) and intermenstrual pain (p = 0.03) was significantly greater during E2V/DNG than NSAID. Quality of life improved during E2V/DNG (P = .0002), both in physical (P = .0003) and mental domains (P = .0065). Only a few minor adverse effects were described during E2V/DNG, and none caused withdrawal from treatment. Conclusion: In patients with endometriosis and pelvic pain, the 24-week administration of the quadriphasic association of E2V/DNG decreases pelvic pain and improves quality of life.

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

Abstract 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. Chinese abstract 目的：观察成分为非雄激素活性孕激素联合雌二醇或炔雌醇（EE）的两种口服避孕药对人体代谢及体成份的影响。 研究设计：受试者口服激素避孕药戊酸雌二醇（E2V）/地诺孕素（DNG）四相药片（n = 16）或30 μg EE/2 mg 醋酸氯地孕酮（CMA）单相药片（n = 16），于第3周期评估脂蛋白、载脂蛋白及胰岛素抵抗稳态模型评估（HOMA-IR），于第6周期评估体成份与骨代谢骨钙素及C-端肽X标志物。 结果：服用E2V/DNG期间脂蛋白、载脂蛋白及HOMA-IR水平稳定。而服用EE/CMA期间，总胆固醇（p = 0.003）、高密度脂蛋白（HDL）-胆固醇（p = 0.001）、甘油三酯（p = 0.003）、载脂蛋白-A1（Apo-A1; p = 0.001）和载脂蛋白B（Apo B; p = 0.04）水平均升高，低密度脂蛋白/高密度脂蛋白（p = 0.039）比率下降，总胆固醇/高密度脂蛋白与Apo-A1/Apo B比率没有变化。HOMA-IR由1.33±0.87小幅上升至1.95±0.88（p = 0.005）。两组骨代谢标志物均有所下降，体成份没有明显变化。 结论：服用E2V/DNG不影响血脂与血糖代谢，而EE/CMA会产生混合性影响。两种方案均可降低骨代谢，在短期内不影响体成份。

Progestin suppressed inflammation and cell viability of tumor necrosis factor-α-stimulated endometriotic stromal cells

Endometriosis is an estrogen‐dependent inflammatory disease. Progestins are a first‐line treatment for endometriosis via activation of pituitary progesterone receptors and suppression of systemic estrogen: a less than optimal treatment. Increasing evidence is beginning to show that progestins may also influence local endometriotic cells, which may contribute to their clinical efficacy.

The Association between Endometriomas and Ovarian Cancer: Preventive Effect of Inhibiting Ovulation and Menstruation during Reproductive Life

Although endometriosis frequently involves multiple sites in the pelvis, malignancies associated with this disease are mostly confined to the ovaries, evolving from an endometrioma. Endometriomas present a 2-3-fold increased risk of transformation in clear-cell, endometrioid, and possibly low-grade serous ovarian cancers, but not in mucinous ovarian cancers. These last cancers are, in some aspects, different from the other epithelial ovarian cancers, as they do not appear to be decreased by the inhibition of ovulation and menstruation. The step by step process of transformation from typical endometrioma, through atypical endometrioma, finally to ovarian cancer seems mainly related to oxidative stress, inflammation, hyperestrogenism, and specific molecular alterations. Particularly, activation of oncogenic KRAS and PI3K pathways and inactivation of tumor suppressor genes PTEN and ARID1A are suggested as major pathogenic mechanisms for endometriosis associated clear-cell and endometrioid ovarian cancer. Both the risk for endometriomas and their associated ovarian cancers seems to be highly and similarly decreased by the inhibition of ovulation and retrograde menstruation, suggesting a common pathogenetic mechanism and common possible preventive strategies during reproductive life.

Hepatic resection during cytoreductive surgery for primary or recurrent epithelial ovarian cancer

PurposeSurgical cytoreduction remains a cornerstone in the management of patients with advanced and recurrent epithelial ovarian cancer. Parenchymal liver metastases determine stage VI disease and are commonly considered a major limit in the achievement of an optimal cytoreduction. The purpose of this manuscript was to discuss the rationale of liver resection and the morbidity related to this procedure in advanced and recurrent ovarian cancer.MethodsA search of the National Library of Medicine’s MEDLINE/PubMed database until March 2015 was performed using the keywords: “ovarian cancer,” “hepatic,” “liver,” and “metastases.”ResultsIn patients with liver metastases, hepatic resection is associated with a similar prognosis as stage IIIC patients. The length of the disease-free interval between primary diagnosis and occurrence of liver metastases, as well as residual disease after resection, is the most important prognostic factors. In addition, the number of liver lesions, resection margins, and the gynecologic oncology group performance status seem to play also an important role in determining outcome.ConclusionsIn properly selected patients, liver resections at the time of cytoreduction increase rates of optimal cytoreduction and improve survival in advanced-stage and recurrent ovarian cancer patients.