Is the multinational, surveillance PRO-E2 study informative for all countries? The Italian data on VTE and contraceptive effectiveness.

PURPOSE: To evaluate whether the thromboembolic risk and contraceptive effectiveness of NOMAC-E2 observed in the PRO-E2 study can be extended to each participating country, as lifestyle, cardiovascular risk factors and prescribing habits may differ geographically. This analysis was performed on the PRO-E2 Italian subpopulation, where smoking habit and women over 35 years were more prevalent compared with the overall study population. MATERIALS AND METHODS: Data from NOMAC-E2 or levonorgestrel-containing COCs (COCLNG) new users were descriptively analysed. Incidence rates of thrombosis (events/10,000 women-years [WY]) and the Pearl Index (pregnancies/100 WY) were calculated. RESULTS: Overall, 11,179 NOMAC-E2 and 8,504 COCLNG users were followed up to 2 years (34,869 WY). The NOMAC-E2 cohort included more women over 35 vs. COCLNG (37.7% vs. 31.8%; p = 0.001). A comparable low risk of combined deep venous thrombosis of lower extremities (DVT) and pulmonary embolism (PE) was observed in NOMAC-E2 (1.7/10,000 WY; 95% CI: 0.21-6.2) and COCLNG users (6.6/10,000 WY; 95% CI: 2.4-14.4). Similar results were obtained by considering all thromboembolic events (VTE). Unintended pregnancies did not differ between NOMAC-E2 (0.12/100 WY; 95% CI: 0.06-0.21) and COCLNG (0.15/100 WY; 95% CI: 0.08-0.26) cohorts. CONCLUSION: Despite the higher age and tobacco use, findings from the Italian subpopulation were broadly consistent with overall PRO-E2 results, confirming a similar low thromboembolic risk and high contraceptive effectiveness of NOMAC-E2 and COCLNG. SHORT CONDENSATION: This subgroup analysis of the PRO-E2 study provides comprehensive epidemiological data on the use of combined oral contraceptives in a large Italian cohort, with a higher prevalence of women over 35 years and smokers. The study confirms the low thromboembolic risk and high contraceptive effectiveness of NOMAC-E2 pill.

Adenomyosis diagnosis among adolescents and young women with dysmenorrhoea and heavy menstrual bleeding.

RESEARCH QUESTION: What is the prevalence of adenomyosis at ultrasonography among adolescents and young women reporting dysmenorrhoea and/or heavy menstrual bleeding (HMB)? DESIGN: This observational cohort study involved adolescents and young women referred for dysmenorrhoea and/or HMB to the Adolescent Medicine Unit at Careggi University Hospital, Italy. Patients with endometriosis and bleeding disorders were excluded. Transvaginal ultrasonography or transrectal sonography using a transvaginal probe was performed. The myometrium was described according to the Morphological Uterus Sonographic Assessment criteria. Details of baseline characteristics, clinical data and symptoms were collected. The presence of sonographic features of adenomyosis and the association between imaging findings and clinical symptoms were evaluated. RESULTS: The cohort included 95 patients aged between 13 and 25 years, referred for dysmenorrhoea (88.4%), HMB (23.2%) or both (13.7%). According to the MUSA criteria the sonographic diagnosis of adenomyosis was made in 27.4% of patients, with the diffuse type the most prevalent. Uterine wall asymmetry, hyperechoic intramyometrial islands, translesional vascularity and an interrupted junctional zone were the most common features. Patients with imaging findings of adenomyosis had significantly higher rates of HMB than those with a normal myometrial appearance (38.5% versus 17.4%, P = 0.030). In addition, the coexistence of dysmenorrhoea and HMB was significantly associated with adenomyosis (odds ratio 5.68, 95% confidence interval 1.65-19.5). CONCLUSIONS: Adenomyosis may be diagnosed among teenagers and young women referred with dysmenorrhoea and/or HMB. The clinical presentation is relevant for the diagnosis, with HMB alone and HMB plus dysmenorrhoea significantly associated with the sonographic identification of adenomyosis.

The Role of Genetics, Epigenetics and Lifestyle in Polycystic Ovary Syndrome Development: the State of the Art.

Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disease affecting about 20-25% of women in reproductive age. Different mechanisms could contribute to the development of its typical clinical features (i.e. hirsutism, acne, oligo-amenorrhea, alopecia). Some genetic and epigenetic aspects and lifestyle changes seem to be involved in PCOS development. In this review, we shall summarize data from principal studies evaluating the impact of major genetic, epigenetic and environmental factors on the appearance of this female disorder. Literature review and analysis of the most relevant data until May 2020. Current data suggest the importance of genetics and epigenetics in the appearance of PCOS. Several genes, including those related to adrenal and ovarian steroidogenesis as well as those associated with hormonal response to gonadotrophins, androgens and insulin, have been demonstrated to be associated with PCOS. Besides, the phenomenon of methylation of genes and the presence of specific microRNA (miRNA) could take part in PCOS aetiology. Intrauterine exposure to androgens, glucocorticoids and/or some stressful conditions for foetus could contribute to the development of PCOS and other disorders observed in adolescence and later (e.g. premature adrenarche, atypical puberty, metabolic syndrome). Emerging studies report a theoretical role of endocrine disruptors, intestinal dysbiosis and Advanced Glycation End products (AGEs) in PCOS. PCOS is a polygenic and multifactorial hormonal and metabolic dysfunction. An appropriate knowledge of personal and/or family history, lifestyle and nutritional habits of PCOS patients has a great importance to early identify and manage this syndrome.

Effects of progestin-only contraceptives on the endometrium.

INTRODUCTION: The contraceptive activity of synthetic progestins is mediated through three basic mechanisms: (a) An anti-gonadotrophic action leading to the inhibition of ovulation; (b) Changes in cervical mucus characteristics that inhibit sperm penetration and (c) desynchronization of the endometrial picture necessary for implantation. AREAS COVERED: Mechanisms involved in the progestin-induced endometrium desynchronization are individually reviewed for each of the routes of administration and, whenever possible, by individual members of the various families of synthetic progestin derivatives. EXPERT OPINION: For contraceptive purposes, progestins are today administered through several routes: orally, as injections, subdermally and via the vagina or the uterine cavity. Given this variety of modalities, their effects may differ, depending on the route of administration, concentration reached at the level of the endometrium and the duration of use. These are characterized by inactivation of the endometrium. Progestin-only contraception provides a safe and effective control of fertility regulation, although, they are associated with the problem of endometrial break through bleeding that may lead to discontinuation. Unfortunately, in spite of a major research effort over two decades, there is not, as yet, an established long-term intervention available to manage bleeding irregularities, making mandatory a deeper understanding of the mechanisms involved is required.

Premature ovarian insufficiency in young girls: repercussions on uterine volume and bone mineral density.

STUDY OBJECTIVE: To evaluate biological differences among young subjects with premature ovarian insufficiency (POI) commencing at different stages of life. DESIGN: Retrospective observational study. SETTING: Careggi University Hospital Participants: One hundred sixty-two females aged between 15 and 29 years with premature ovarian insufficiency. METHODS: Data were collected as a retrospective chart review of baseline evaluation at diagnosis of premature ovarian insufficiency (POI). About 162 participants were divided into four groups based on gynecological age. Two primary outcome variables (uterine development and bone mineral density (BMD)) were analyzed in terms of differences among groups and in a multivariate logistic regression analysis. RESULTS: Uterine development was clearly jeopardized when estrogen insufficiency started at a very young age. Total body BMD showed significant differences among the four groups studied, clearly corresponding to the duration of ovarian function. Data were discussed in relation to the choice of hormone replacement therapy regimens.

Hepatotoxicity with low- and ultralow-dose flutamide: a surveillance study on 203 hyperandrogenic young females.

OBJECTIVE: To investigate the impact of low- and ultralow-dose regimens of flutamide on liver function of young hyperandrogenic females. DESIGN: A 10-year surveillance study. SETTING: University teaching hospital. PATIENT(S): Two hundred three hyperandrogenic young females (mean age: 20.9 ± 4.9 years). INTERVENTION(S): Inclusion criterion was receiving low- or ultralow-dose of flutamide as antiandrogenic treatment. Patients were categorized into Groups A and B, according to the administered dose (Group A = 62.5 mg/daily, Group B = 125 mg/daily). The two groups were further subdivided into subgroups (A1, A2, B1, B2) depending on the coadministration of estroprogestagen oral contraceptives (OCs) (A2, B2). MAIN OUTCOME MEASURE(S): Serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were periodically evaluated and used as markers of hepatotoxicity. RESULT(S): Mild-to-severe increase of circulating AST/ALT was detected in 19 (9.4%; 95% CI = 5.9%-14.4%) patients during the first year of treatment (mild = 16 [7.9%, 95% CI = 4.7%-12.7%], moderate = 2 [0.9%, 95% CI = 0.1%-3.9%], severe = 1 [0.5%, 95% CI = 0.0%-3.1%]). No statistical differences were observed in relation to flutamide dose regimens and coadministration of OC. The median time to hypertransaminasemia was 12 weeks (range: 2-48) with no difference between Group A and Group B. A significant correlation was observed between hepatotoxicity and pretreatment BMI, ALT basal level, and AST basal level. CONCLUSION(S): Hepatotoxicity is a rare but possible event using low- and ultralow-dose regimens of flutamide. We need larger study populations in order to identify risk patterns for hepatotoxicity development.

Body composition variables and leptin levels in functional hypothalamic amenorrhea and amenorrhea related to eating disorders.

The purpose of the study was to identify diagnostic criteria that can distinguish between subjects with functional hypothalamic amenorrhea largely related to minimal energy deficiency and those in whom failure of adaptive response to stress prevails. We studied 59 young women with secondary amenorrhea related to modest eating disorders and 58 who complained of stressful events in their history. We assessed anthropometric measurements, body composition using dual energy X-ray absorptiometry (DEXA) and bioelectrical impedance analysis (BIA), and basal endocrine profile. Subjects with disordered eating had lower body mass index (BMI), fat mass (FM) measured with both techniques, lumbar mineral density and direct and indirect measures of lean mass. Leptin and free tri-iodothyronine(FT(3)) concentrations also proved lower in the group of subjects with eating disorders, although there was no significant difference in cortisol between the two groups. Leptin levels were positively associated not only with fat mass, but also with body cell mass indexed to height and phase angle, parameters studied with BIA as expression of active lean compartment. A multivariate model confirmed the utility of integrating endocrine data with the study of body composition. The use of bioelectrical impedance analysis proved to be, in clinical use, a valid diagnostic alternative to DEXA, especially considering body cell mass and phase angle.

Polycystic ovary syndrome in adolescence.

The definition of polycystic ovary syndrome in very young girls is complicated by the fact that many features typical of the syndrome can also be seen as physiological stages in the maturation of the hypothalamus-pituitary-ovarian axis. The role of reduced insulin sensitivity in the pathogenesis and evolution of the disorder has gained more importance over recent years: both elevated androgen levels and being overweight may influence the impairment of glucose metabolism. Our study focused on 250 girls in the first 8 years of gynecological age. We analyzed the prevalence of different phenotypes according to the Rotterdam criteria and the impact of higher BMI on androgen levels and on fasting screening markers of glucose metabolism. In a smaller sample, we performed a more detailed evaluation of the glucose metabolism parameters; our findings indicated that in this age group, being overweight plays a major role in the deterioration of the clinical picture.

Large-muscle endometriosis involving the adductor tight compartment: case report.

Extrapelvic endometriosis is an uncommon condition but can involve nearly every organ, resulting in a wide range of clinical manifestations. Herein, we describe the case of a 45-year-old woman not a candidate for hormonal therapy who had cyclic pain in the left thigh associated with progressive impairment of walking ability. Clinical, instrumental, and laboratory data supported the diagnosis of endometriosis involving the adductor muscles compartment associated with ovarian endometriomas. Laparoscopic bilateral salpingo-oophorectomy and local wide excision in collaboration with an experienced orthopedic oncologist were performed, and definitive histologic analysis confirmed the diagnosis of endometriosis. The patient was pain-free at 6-month follow-up and demonstrated substantial improvement in ambulation and quality of life. Large-muscle endometriosis is a rare entity that can compromise musculoskeletal integrity and decrease quality of life. In this case, surgical excision in collaboration with an orthopedic oncologist was the cornerstone of treatment.

Vulvovaginitis in childhood.

Symptoms related to vulvitis and vulvovaginitis are a frequent complaint in the paediatric age. Knowledge of the risk factors and the pathogenetic mechanisms, combined with thorough clinical examination, helps to distinguish between dermatological diseases, non-specific vulvitis and vulvovaginitis proper. On the basis of microbiological data, the most common pathogens prove to be Streptococcus pyogenes, Haemophilus influenzae and Enterobius vermicularis; fungal and viral infections are less frequent. The possibility of isolating opportunistic pathogens should also be considered. In rare situations, the isolation of a micro-organism normally transmitted by sexual contact should prompt a careful evaluation of possible sexual abuse. Current treatments for specific and non-specific forms are outlined, together with pointers for the evaluation of recurrence.

The anorectic and obese adolescent.

In view of the menstrual disturbances involved, gynaecologists frequently come into contact with girls suffering from eating disorders that can rapidly evolve into anorexia nervosa. The ability to make a precocious diagnosis of the severity of both physical and psychopathological involvement, to offer clear explanations of the links between reproductive function and energy availability and to motivate psychotherapy can be of paramount importance for the prognosis. Similarly, obese adolescents might require counselling for menstrual disorders or alleged endocrine dysfunction. Knowledge of the markers of metabolic impairment and of the possible therapeutic approaches to essential obesity is a necessary complement to the management of the more usual conditions related to overweight, such as polycystic ovary syndrome. Presented here is an overview of recent evidence on the pathogenesis, endocrine profile, short- and long-term health repercussions, therapeutic strategies and clinical trials regarding these two opposing pathologies, both related to unhealthy eating behaviour and also to psycho-relational problems.

Satisfaction and compliance in hormonal contraception: the result of a multicentre clinical study on women's experience with the ethinylestradiol/norelgestromin contraceptive patch in Italy.

BACKGROUND: For many women finding the right contraceptive method can be challenging and consistent and correct use over a lifetime is difficult. Even remembering to take a birth control pill every day can be a challenge. The primary objective of this study was to evaluate women's experience with a weekly ethinylestradiol/norelgestromin contraceptive patch (EE/NGMN patch), given new technologies recently developed in hormonal contraception to increase women's options in avoiding daily dosing. METHODS: In 24 Italian sites, 207 women received the EE/NGMN patch for up to 6 cycles. At study end, overall satisfaction and preference, as well as compliance, efficacy and safety, were evaluated. RESULTS: 175 women (84.5%) completed the study. The overall satisfaction rate was 88%; convenience and once-a-week frequency of the patch were especially appreciated. At baseline, 82 women (39.4%) were using a contraceptive method, mainly oral contraceptives and barrier methods, but only 45.1% were very satisfied/satisfied; after 6 months with the patch, 86.3% of this subset was very satisfied/satisfied. Considering the method used in the 3 months before the study entry, 78.1% strongly preferred/preferred the patch, for convenience (53.9%), ease of use/simplicity (28.9%), fewer (9.2%) and less severe (2.6%) side effects. Compliance was very high: 1034/1110 cycles (93.2%) were completed with perfect compliance and the mean subject's compliance score was 90%. One on-therapy pregnancy occurred. The patch was safe and well tolerated: adverse events frequency was low, with predominantly single reports of each event. Most of them started and subsided during cycle 1. CONCLUSION: This study demonstrated that the EE/NGMN patch is associated with high satisfaction levels and excellent compliance. At study end, the majority of women indicated that they would continue using the patch.

Hemangioma of the clitoris presenting as clitoromegaly: a case report.

A 20-year-old woman with massive clitoral enlargement is presented to discuss the differential diagnosis and the treatment of this condition.

Effect of the ethinylestradiol/norelgestromin contraceptive patch on body composition. Results of bioelectrical impedance analysis in a population of Italian women.

BACKGROUND: As weight gain is one of the most frequently cited reasons for not using and for discontinuing hormonal contraceptives, in an open-label, single-arm, multicentre clinical study we evaluated the effect of the ethinylestradiol/norelgestromin contraceptive patch (EVRA, Janssen-Cilag International, Belgium) on body composition using bioelectrical impedance analysis (BIA). METHODS: Body weight and impedance vector components (resistance (R) and reactance (Xc), at 50 kHz frequency, Akern-RJL Systems analyzer) were recorded before entry, after 1, 3 and 6 months in 182 Italian healthy women aged 29 yr (18 to 45), and with BMI 21.8 kg/m2 (16 to 31). Total body water (TBW) was estimated with a BIA regression equation. Vector BIA was performed with the RXc mean graph method and the Hotelling's T2 test for paired and unpaired data. RESULTS: After 6 months body weight increased by 0.64 kg (1.1%) and TBW increased by 0.51 L (1.7%). The pattern of impedance vector displacement indicated a small increase in soft tissue hydration (interstitial gel fluid). Body composition changes did not significantly differ among groups of previous contraceptive methods. Arterial blood pressure did not significantly change over time. CONCLUSION: After 6 months of treatment with the ethinylestradiol/norelgestromin contraceptive patch we found a minimal, clinically not relevant, increase in body weight less than 1 kg that could be attributed to an adaptive interstitial gel hydration. This fluctuation is physiological as confirmed by the lack of any effect on blood pressure. This could be useful in increasing women's choice, acceptability and compliance of the ethinylestradiol/norelgestromin contraceptive patch.

An open-label, multicentre trial to evaluate the vaginal bleeding pattern of the combined contraceptive vaginal ring NuvaRing.

OBJECTIVE: The objective of this multicentre, non-controlled, open-label study is the evaluation of the bleeding patterns during the use of a vaginal combined contraceptive, its safety in relation to occurrence of adverse effects, its efficacy as a contraceptive method and user compliance. STUDY DESIGN: Healthy female volunteers (N=165), asking for contraception, were enrolled to participate in the study. Each subject was given seven vaginal rings, releasing an average amount of 120microg etonogestrel (ENG) and 15microg ethinylestradiol (EE) per day. Study period was 7 cycles. A total of 878 cycles was valid for statistical analysis. The primary parameter, (breakthrough bleeding and/or spotting), was recorded for each cycle. The subjects were asked to report any adverse effect experienced during the treatment period, general physical and gynaecological examinations were performed and haematological blood tests were taken. RESULTS: Breakthrough bleeding/spotting occurred in 5.01% cycles (44 out of 878 cycles, of whom 37 were breakthrough spotting only). Absence of withdrawal bleeding during the ring-free period was reported in 1.94% cycles (17 out of 878). Forty-one subjects (24.8%) reported 66 events that were potentially drug-related. The most frequently drug-related events were weight increase (10 cases), headache (9 cases), nausea (4 cases). No pregnancy was reported during the study period. Haematology and chemical chemistry tests showed no clinically significant abnormality. CONCLUSIONS: In the present study, NuvaRing has shown to be a valid contraceptive method to ensure optimal cycle control with low incidence of irregular bleeding and altered withdrawal bleeding. The low incidence of gastrointestinal side effects (nausea, vomiting) may be related the low hormonal dose and to the vaginal delivery of hormones which avoids the gastrointestinal tract.

The laparoscopic Vecchietti's modified technique in Rokitansky syndrome: anatomic, functional, and sexual long-term results.

OBJECTIVE: The objective of the study was to assess the anatomical and functional long-term follow-up results of the laparoscopic Vecchietti approach for the creation of a neovagina in the Rokitansky syndrome. STUDY DESIGN: One hundred ten patients underwent clinical follow-up visits at 1, 3, 6, and 12 months after surgery and every 6 months thereafter. The following were performed: evaluation of the quality of sexual intercourse, vaginal and rectal examinations, vaginoscopy, Schiller's test, and vaginal cytology with microbiologic testing. Functional results were assessed by using Rosen's Female Sexual Function Index questionnaire, of which the results were analyzed comparing normal age-matched controls. RESULTS: Four patients were lost to follow-up. Anatomic and functional success was achieved in 104 of 106 (98%) and 103 of 106 (97%) patients, respectively. Female Sexual Function Index scores were comparable with those of controls. CONCLUSION: Vecchietti's technique is simple, safe, and effective and allows normal and satisfying sexual intercourse, comparable with that of normal controls.

Predictors of bone loss in young women with restrictive eating disorders.

OBJECTIVES: To evaluate the influence of Body Mass Index, body composition and hormonal factors on bone mass in young women with amenorrhea related to restrictive eating disorders. DESIGN: Descriptive study of 55 patients with secondary amenorrhea due to restrictive eating disorders and 14 healthy girls used for comparison. Assessment of Bone Mineral Density, Fat Mass and Lean Mass by DEXA and of the serum hormonal profile. RESULTS: Patients had lower BMI, lower Fat Mass and lower Bone Mass compared to controls; their serum levels of LH, FT(3), DHEAS, Insulin and Leptin were significantly reduced. Low Bone Density, especially in the lumbar region, correlated with concentrations of FT(3), Cortisol, Insulin and Leptin, hormones expressive of metabolic adjustment to malnutrition. Lean Mass was a strong predictor of osteopenia and osteoporosis. CONCLUSIONS: Hormonal nutritional markers, together with soft tissue composition measurements, are viable options for ongoing monitoring of subjects with eating disorders.