Consensus on Recording Deep Endometriosis Surgery: the CORDES statement.

STUDY QUESTION: Which essential items should be recorded before, during and after endometriosis surgery and in clinical outcome based surgical trials in patients with deep endometriosis (DE)? SUMMARY ANSWER: A DE surgical sheet (DESS) was developed for standardized reporting of the surgical treatment of DE and an international expert consensus proposal on relevant items that should be recorded in surgical outcome trials in women with DE. WHAT IS KNOWN ALREADY: Surgery is an important treatment for symptomatic DE. So far, data have been reported in such a way that comparison of different surgical techniques is impossible. Therefore, we present an international expert proposal for standardized reporting of surgical treatment and surgical outcome trials in women with DE. STUDY DESIGN, SIZE, DURATION: International expert consensus based on a systematic review of literature. PARTICIPANTS/MATERIALS, SETTING, METHODS: Taking into account recommendations from Consolidated Standards of Reporting Trials (CONSORT), the Innovation Development Exploration Assessment and Long-term Study (IDEAL), the Initiative on Methods, Measurement and Pain Assessment in Clinical trials (IMMPACT) and the World Endometriosis Research Foundation Phenome and Biobanking Harmonisation Project (WERF EPHect), a systematic literature review on surgical treatment of DE was performed and resulted in a proposal for standardized reporting, adapted by contributions from eight members of the multidisciplinary Leuven University Hospitals Endometriosis Care Program, from 18 international experts and from audience feedback during three international meetings. MAIN RESULTS AND THE ROLE OF CHANCE: We have developed the DESS to record in detail the surgical procedures for DE, and an international consensus on pre-, intra- and post-operative data that should be recorded in surgical outcome trials on DE. LIMITATIONS, REASONS FOR CAUTION: The recommendations in this paper represent a consensus among international experts based on a systematic review of the literature. For several items and recommendations, high-quality RCTs were not available. Further research is needed to validate and evaluate the recommendations presented here. WIDER IMPLICATIONS OF THE FINDINGS: This international expert consensus for standardized reporting of surgical treatment in women with DE, based on a systematic literature review and international consensus, can be used as a guideline to record and report surgical management of patients with DE and as a guideline to design, execute, interpret and compare clinical trials in this patient population. STUDY FUNDING/COMPETING INTERESTS: None of the authors received funding for the development of this paper. M.A. reports personal fees and non-financial support from Bayer Pharma outside the submitted work; H.T. reports a grant from Pfizer and personal fees for being on the advisory board of Perrigo, Abbvie, Allergan and SPD. TRIAL REGISTRATION NUMBER: N/A.

DHEA replacement for postmenopausal women: have we been looking in the right direction?

Dehydroepiandrosterone (DHEA) and its sulfate represent the most abundant sex steroid in humans. In addition to age-related reduction, serum DHEA shows large interindividual variability. Although cross-sectional studies suggest that lower levels are associated with cardiovascular, cognitive and sexual impairment in women, clinical trials of oral DHEA replacement have failed to show benefits. However, current evidence is too imprecise to draw definite conclusions.

Impact of semen microbiota on the composition of seminal plasma.

Several studies have found associations between specific bacterial genera and semen parameters. Bacteria are known to influence the composition of their niche and, consequently, could affect the composition of the seminal plasma. This study integrated microbiota profiling and metabolomics to explore the influence of seminal bacteria on semen metabolite composition in infertile couples, revealing associations between specific bacterial genera and metabolite profiles. Amino acids and acylcarnitines were the predominant metabolite groups identified in seminal plasma. Different microbiota profiles did not result in globally diverse metabolite compositions in seminal plasma. Nevertheless, levels of specific metabolites increased in the presence of a dysbiotic microbiota. Urocanate was significantly increased in abnormal semen samples (adjusted P-value < 0.001) and enriched in samples dominated by Prevotella spp. (P-value < 0.05), which was previously linked to a negative impact on semen. Therefore, varying microbiota profiles can influence the abundance of certain metabolites, potentially having an immunomodulatory effect, as seen with urocanate.IMPORTANCEMale infertility is often considered idiopathic since the specific cause of infertility often remains unidentified. Recently, variations in the seminal microbiota composition have been associated with normal and abnormal semen parameters and may, therefore, influence male infertility. Bacteria are known to alter the metabolite composition of their ecological niches, and thus, seminal bacteria might affect the composition of the seminal fluid, crucial in the fertilization process. Our research indicates that distinct seminal microbiota profiles are not associated with widespread changes in the metabolite composition of the seminal fluid. Instead, the presence of particular metabolites with immunomodulatory functions, such as urocanate, could shed light on the interplay between seminal microbiota and variations in semen parameters.

Robotic single-site hysterectomy: feasibility, learning curve and surgical outcome.

BACKGROUND: The field of laparoscopy has undergone several changes to improve the morbidity and cosmesis of laparoscopic surgery. The robotic single-site surgery is the inevitable hybridization of robotic technology with laparoendoscopic single-site surgery. METHODS: Perioperative information of 12 robotic single-site hysterectomies (R-SSH) were collected to evaluate the surgical feasibility and the possible influence of the body mass index (BMI) and the uterine weight on operative times. RESULTS: The mean operative time was 85 ± 33 min (range, 355 to 149 min), the mean docking time was 9 ± 3 min, and the mean console time was 76 ± 33 min. The mean blood loss was 80 ± 18 mL, and the median weight of resected uteri was 220 ± 45 g. No serious postoperative complications occurred. The CUSUM learning curve was observed to consist of two different phases: phase 1 (the initial 6 cases) and phase 2 (the last 6 cases) with significant reduction in operative and console time observed between the two phases. For BMI, no correlation was found with operative times, console times, and docking times, and no correlation was found between uterine weight and operative time. CONCLUSIONS: This series, identifying two different phases of the learning curve and suggesting that the initial learning phase for the procedure can be achieved after six cases, confirms the feasibility and safety of a robotic approach for single-site hysterectomy. However, the limits of this study mainly rely on the limited casuistic and short follow-up, although the preliminary results appear promising. Larger series and prospective studies comparing R-SSH hysterectomy with standard robotic multiport hysterectomy are necessary to define properly the role of this innovative surgical technique.

Advances in neurosteroids: role in clinical practice.

The steroidogenic endocrine glands and local synthesis both contribute to the pool of steroids present in the central nervous system and peripheral nervous system. Although the synthesis of neurosteroids in the nervous system is now well established, the spectrum of respective functions in regulating neuronal and glial functions remains to be fully elucidated. From the concept of neurosteroids derives another treatment strategy: the use of pharmaceutical agents that increase the synthesis of endogenous neurosteroids within the nervous system. This approach has so far been hampered by lack of knowledge concerning the regulation of the biosynthetic pathways of neurosteroids and their relationship with sex steroids produced by the peripheral gland or with exogenous steroids. The present review summarizes some of the available clinical and experimental findings supporting the critical role of neurosteroids during fertile life and reproductive aging and their relationship with endogenous and exogenous sex steroids. The brain metabolism of synthetic progestins and the implications of DHEA treatment in postmenopausal women will also be discussed.

Fertility and endocrine outcome after robot-assisted laparoscopic myomectomy (RALM).

INTRODUCTION: Laparoscopic myomectomy has recently gained wide acceptance but this procedure remains technically highly demanding and concerns have been raised about the increased blood loss and an higher risk of postoperative uterine rupture of the pregnant uterus. OBJECTIVE: The aim of the present study is to evaluate the fertility and endocrine outcome in women underwent robot-assisted laparoscopic myomectomy (RALM). METHODS: Data from 48 RALM performed in our department between the years 2007 and 2011 have been collected. Conception rate, abortion rate, incidence of feto-maternal morbidity or severe pregnancy and labor-related complications were reported; FSH and AMH levels and ultrasound valuation of AFC has been made before and 6 months after operation. Number of cesarean sections and vaginal deliveries were described. RESULTS: The average age of the patients was 35 years and median Body Mass Index was 23 kg/m(2) (range 18-35 kg/m(2)). Seven women (13%) became pregnant after RALM with eight pregnancies. One pregnancy is actually on going; there were six deliveries with caesarian section and one spontaneous delivery. No spontaneous abortions. No uterine ruptures occurred. No significant modification of ovarian function was found after myomectomy. CONCLUSION: RALM seems to have a favorable impact on the reproductive outcome of young patients with no impact on the ovarian function.

Efficacy of a topical cosmetic slimming treatment for postmenopausal women: a randomized, double-blind, placebo controlled trial.

AIM: The aim of this paper was to evaluate by clinical and non-invasive instrumental evaluations, the efficacy and the tolerance of a cosmetic slimming treatment for menopausal women used topically (for at least 3 years) under dermatological control. METHODS: A controlled double blind, randomised study was performed to compare the slimming efficacy of the cosmetic slimming treatment versus placebo after 4 weeks of treatment. RESULTS: Cosmetic slimming treatment twice a day for 4 weeks reduced abdomen and hips fat, with no significant variation in body weight in comparison with the placebo. CONCLUSION: The present study evidenced the clinical effectiveness and women satisfaction of a slimming treatment specifically studies for postmenopausal adipose tissue with potential interesting consequences on measures of quality of life and on health-care programs.

Evaluation of adhesions after laparoscopic myomectomy using the Harmonic Ace and the auto-crosslinked hyaluronan gel vs Ringer's lactate solution.

OBJECTIVE: To evaluate the efficacy of a crosslinked hyaluronic acid (HA) for the prevention of postsurgical adhesions after laparoscopic myomectomy using the Harmonic Ace. MATERIALS AND METHODS: Women 23-42 years of age who wished to conceive underwent laparoscopic myomectomy. As adhesion preventing agents, crosslinked HA gel was applied on the myometrial scar at the end of the surgery in Group A, whereas in Group B a Ringer's lactate solution was used in a prospective, observational study. Second-look mini-laparoscopy was performed 45-60 days after surgery and the adhesions were assessed according to a site-specific modified scoring. RESULTS: The incidence of postoperative adhesions was the same in both groups, but anatomically significant adhesions and site-specific modified score was significantly reduced in Group A compared to Group B control group (31.8% vs 54.6% and 1.05 +/- 1 vs 2.27 +/- 2.5, respectively). CONCLUSION: The use of auto-cross-linked HA gel confirms a protection on adhesion formation on myometrial wounds, although the degree of this effect appears to be weak. The absence of adnexa adhesions using the HA and a different uterine incision appear remarkable, although a larger number of patients is required to confirm the present findings.

Polycystic ovary syndrome: brain-derived neurotrophic factor (BDNF) plasma and follicular fluid levels.

Polycystic ovary syndrome is one of the most common endocrine disorders in women of reproductive age. Features of PCOS are hyperandrogenism, chronic anovulation and polycystic ovaries on ultrasonography. Follicle development is a complex and carefully orchestrated phenomenon, involving gonadotropins and a rapidly expanding list of other intraovarian regulators, such as brain-derived neurotrophic factor (BDNF). The aim of this study is to evaluate BDNF in plasma and in follicular fluid in women affected by PCOS and in normal menstruating women. In PCOS patients the BDNF levels in plasma and in follicular fluid are higher than values obtained in healthy controls. Therefore we can hypothsize that high levels of luteinizing hormone, probably increase the secretion of BDNF in PCOS patients.

Evaluation of brain-derived neurotrophic factor in menstrual blood and its identification in human endometrium.

The presence of high-affinity brain-derived neurotrophic factor receptor Trk B in mouse and in human fetal oocytes, together with the presence of neurotrophins in human follicular fluid suggests a paracrine role for brain-derived neurotrophic factor (BDNF) in female biology. This study aims to evaluate if BDNF is present and quantitatively determined in human menstrual blood and endometrium. Twenty-one women were studied and subdivided in two groups: A, 11 fertile women (27 ± 2 days cycle length) and B, 10 anovulatory women and/or women with inadequate luteal phase (36 ± 2 days cycle length). In fertile women menstrual BDNF levels was higher than plasma (679.3 ± 92.2 vs 301.9 ± 46.7 pg/ml p <0.001). Similarly, in Group B, BDNF in menstrual blood was higher than plasma (386.1 ± 85.2 vs 166.8 ± 24.1 pg/ml p < 0.001). Moreover, both menstrual and plasma BDNF concentrations in Group A were significantly higher respect to Group B (679.3 ± 92.2 vs 386.1 ± 85.2 pg/ml p < 0.001; 301.9 ± 46.7 vs 166.8 ± 24.1 pg/ml p < 0.001). Immunohistochemistry evidence of BDNF in endometrium, during follicular and luteal phase, was also shown. The detection of BDNF in the human menstrual blood and endometrium further supports the role of this neurotrophin in female reproductive function.

Effect of 1-year, low-dose DHEA therapy on climacteric symptoms and female sexuality.

BACKGROUND: Sexual desire is affected by endocrine and psychosocial factors. Menopausal hormonal changes are relevant to the causes of sexual dysfunction during reproductive aging. AIM: To evaluate the effects of different types of hormonal replacement therapy (HRT) on sexual function, frequency of sexual intercourse, and quality of relationship in early postmenopausal women. We recruited 48 healthy postmenopausal women aged 50-60 years (mean age 54.5 ± 3.3 years). Women with climacteric symptoms were uniformly randomized into three groups receiving either dehydroepiandrosterone (DHEA 10 mg) daily, or daily oral estradiol (1 mg) plus dihydrogesterone (5 mg), or daily oral tibolone (2.5 mg) for 12 months. Women who refused hormonal therapy were treated with oral vitamin D (400 IU). Efficacy was evaluated using the McCoy Female Sexuality Questionnaire before treatment and after 12 months. We evaluated the hormonal profile before treatment and after 3, 6 and 12 months. RESULTS: The groups receiving DHEA or HRT reported a significant improvement in sexual function compared to baseline (p < 0.001 and p < 0.01, respectively) using the McCoy total score. The quality of relationship was similar at baseline and after 3, 6 and 12 months of treatment. There were significant increases in the numbers of episodes of sexual intercourse in the previous 4 weeks in women treated with DHEA, HRT and tibolone in comparison with the baseline value (p < 0.01, p < 0.05, p < 0.01, respectively). No changes in the McCoy score occurred in women receiving vitamin D. CONCLUSIONS: Daily oral DHEA therapy at the dose of 10 mg, HRT and tibolone all provided a significant improvement in comparison with vitamin D in sexual function and in frequency of sexual intercourse in early postmenopausal women.

DHEA therapy in postmenopausal women: the need to move forward beyond the lack of evidence.

The marked age-related decline in serum dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) has suggested that a deficiency of these steroids may be causally related to the development of a series of diseases that are generally associated with aging. Postulated consequences of low DHEA levels include insulin resistance, obesity, cardiovascular disease, cancer, reduction of the immune defence system as well as psychosocial problems such as depression and a general deterioration in the sensation of well-being and cognitive function. Clinically, the spectrum of women that would benefit from DHEA therapy is not clearly defined and nor is the dosage of hormone treatment. Whether DHEA therapy could be prescribed as a general anti-aging therapy or could be an alternative treatment for women suffering from androgen deficiency syndrome remains uncertain across studies. The lack of definitive evidence for biological mechanisms and the presence of only a few studies that address these emerging issues of DHEA therapy in postmenopausal women might encourage a new critical analysis of the available literature, evidencing current limits and incongruities.

A web-based survey of reproductive awareness and choices in women with endometriosis.

OBJECTIVE: Our aim was to study fertility issues, attitudes towards reproductive techniques and fertility preservation options in women of reproductive age with endometriosis. STUDY DESIGN: In 2018 we conducted a web-based survey on fertility issues in women aged 18-40 years with endometriosis. Participants were recruited via advertisements on social media and local endometriosis support groups. Participants completed a self-developed online questionnaire evaluating the following dimensions: sociodemographic, medical data, parental project, knowledge and attitudes toward endometriosis and fertility, means used to access information, and reproductive choices. RESULTS: The majority of women (96 %) worried about the impact of endometriosis on their fertility. Approximately half of them (52 %) reported having received sufficient information concerning the effect of endometriosis on fertility from their doctor, whereas 31 % had discussed fertility issues with their doctor but desired further information. In contrast, only a minority (27 %) of women considered themselves well-informed on fertility preservation options. Information given by specialists on endometriosis and reproduction was considered most useful. Information mediated through patient support groups was also highly rated, whereas information given by the general gynecologist was less highly rated. The majority of women would consider assisted reproductive techniques (74 %) or adoption (70 %) in case of infertility. Interestingly, 72 % of women would undergo oocyte vitrification for fertility preservation, whereas only 37 % would resort to oocyte donation. CONCLUSION: This is the first survey to address the topic of fertility issues from the patient's perspective in women with endometriosis. The vast majority of women attach great importance to a discussion about fertility possibilities and only a minority of women consider themselves well-informed. Our results highlight the importance of addressing the issue of fertility in women with endometriosis. Special attention should be given to information and counselling about fertility preservation options since most women consider their knowledge on the topic insufficient. Knowledge and attitudes to counsel endometriosis patients on fertility issues and fertility preservation options should be included in the training curricula of gynecologists. Adequate information on reproductive aging, risk factors for infertility, and reproductive choices, including oocyte vitrification, should be incorporated into follow-up visits for endometriosis patients.

Daily variation of brain-derived neurotrophic factor and cortisol in women with normal menstrual cycles, undergoing oral contraception and in postmenopause.

BACKGROUND: Plasma brain-derived neurotrophic factor (BDNF) levels are associated with the hormonal status of women. Moreover, the suprachiasmatic nucleus appears to be implicated in the modulation of BDNF central levels. We aimed to investigate whether BDNF circadian rhythms exist in women and if there is a relationship with cortisol circadian rhythmicity. Moreover, we aimed to establish whether the hormonal status influences BDNF diurnal variations. METHODS: A total of 30 women were studied: 10 fertile ovulatory women, 10 women undergoing oral contraceptive (OC) therapy and 10 post-menopausal women. Basal BDNF and estradiol levels were assayed in blood samples collected after overnight fasting at regular intervals (08:00, 12:00, 16:00, 20:00, 24:00). BDNF and cortisol levels were measured in samples collected during the follicular and luteal phases in ovulatory women and once a month in OC and post-menopausal women. RESULTS: Luteal BDNF levels were significantly higher than follicular levels in fertile women (P < 0.001). In OC women, BDNF levels were similar to the follicular BDNF levels, whereas in post-menopausal women, they were significantly lower (P < 0.001). BDNF showed a diurnal rhythm in the follicular phase and in women undergoing OC, although the diurnal rhythm was blunted in the luteal phase. In post-menopausal women, BDNF and cortisol levels significantly decreased during the day. CONCLUSIONS: BDNF has a diurnal variation in women that is somewhat analogous to cortisol variation; however, the amplitude of the variation in BDNF levels appears to be influenced by ovarian function. Interactions between BDNF, the hypothalamus-pituitary-adrenal axis and sex steroids might play a critical role in the human homeostasis and adaptation.

Androgen replacement therapy and cardiovascular function.

Androgens play a primary role in female physiopathology. The age-related decline in the production of ovarian and adrenal androgens may significantly affect women's health. Scanty studies have been designed to establish whether androgen deficiency might directly affect cardiovascular biology and whether it might be a risk factor for cardiovascular disease in women during reproductive aging. The present short review examines the effect of androgen on the cardiovascular system, with particular regard to dehydroepiandrosterone and testosterone replacement in postmenopausal women.

Progesterone and progestins: effects on brain, allopregnanolone and beta-endorphin.

The increased use of hormonal therapies over the last years has led to improve the knowledge of pharmacological, biochemical and metabolic properties of several progestins and their effects in target tissues, such as the central nervous system. Progesterone and synthetic progestational agents are able to modulate the synthesis and release of several neurotransmitters and neuropeptides in response to specific physiological and pathological stimuli. While these actions may relay on differential activation of progesterone receptor or recruitment of intracellular pathways, some of the differences found between synthetic progestins may depend on the specific conversion to neuroactive steroids, such as the 3-alpha, 5-alpha reduced metabolite, allopregnanolone. This is a potent endogenous steroid that rapidly affects the excitability of neurons and glia cells through direct modulation of the GABA-A receptors activity exerting hypnotic/sedative, anxiolytic, anaesthetic and anticonvulsive properties. Estrogens increase the CNS and serum levels of allopregnanolone and the addition of certain but not all synthetic progestins determines a further increase in allopregnanolone levels, suggesting that the metabolism into this reduced product is related to the chemical structure of progestin molecule used. In addition, depending on specific progestin molecule used, different interaction are found with the estradiol-induced beta-endorphin synthesis and release, showing that diverse progestins have specific and divergent actions on the opiatergic system. These results highlight the concept that natural and synthetic progesterone receptor agonists may systematically induce different biological actions in CNS. This may have far-reaching implications for the clinical effects and related indications of each compound.

Effect of estetrol on Beta-Endorphin level in female rats.

INTRODUCTION: Estetrol (E4), a naturally occurring estrogen produced exclusively by human fetal liver, is currently being evaluated for potential use in contraception and menopausal care in humans. The present study was designed to profile E4 effects on the central nervous system, to assess the in vivo effects of E4 administration on Beta-Endorphin (ß-END) release in specific brain structures and to evaluate whether E4 has synergic or antagonistic effects on estradiol-mediated ß-END synthesis. EXPERIMENTAL: Intact female adult rats received different doses of E4 and ovariectomized (OVX) rats received different doses of E4 or E2V or combinations of both drugs. The concentrations of ß-END were assessed in the frontal and parietal cortex, hippocampus, hypothalamus, neurointermediate lobe, anterior pituitary and plasma. RESULTS: E4 at the dose of 1mg/kg/day did not alter ß-END content in most brain areas, as well as, plasma levels of intact animals E4 administered at a dose of 5mg/kg/day decreased ß-END content in the hippocampus, hypothalamus, and in the neurointermediate lobe, as well as, plasma levels, compared to intact animals receiving vehicle. E4 increased ß-END values in the frontal cortex, but not in the plasma, following the administration of 1mg/kg/day in OVX rats, whereas treatment with 5mg/kg/day in OVX rats induced a significant increase in ß-END levels in most brain areas and in the plasma. However, in the presence of estradiol, E4 showed an estrogen-antagonistic effect in selected brain structures at the dose of 5mg/kg/day and in plasma levels of ß-END at the dose of 1mg/kg/day and 5mg/kg/day. CONCLUSION: In OVX rats, E4 increases CNS and peripheral levels of ß-END, behaving as a weak estrogen-agonist. The antagonistic effect observed after combined estradiol and E4 administration further profiles E4 as a natural SERM.