Amerigo Vitagliano

“Empiric” inositol supplementation in normal-weight non insulin resistant women with polycystic ovarian disease: from the absence of benefit to the potential adverse effects

We read with great interest the manuscript titled ‘‘Evaluation of ovarian function and metabolic factors in women affected by polycystic ovary syndrome after treatment with D-Chiro-Inositol’’ by Lagana et al. [1] recently published in your prestigious Journal. The authors conducted an interesting prospective cohort study evaluating the effects of D-chiro inositol (DCI) supplementation in non-overweight women affected by polycystic ovarian syndrome (PCOS). Authors demonstrated that normal weight PCOS (BMI \ 25) benefited from a 6 months dietary DCI supplementation with 1 gram daily. They observed menstrual cycle regularization and restoration of ovulation in 62.5 % of cases (30 of 48 patients) most likely due to significant improvements in the metabolic (evaluated by glucose profile and serum glucose to insulin ratio) and hormonal profile (evaluated by LH to FSH ratio and androgen levels) [1]. In our opinion, the manuscript by Lagana et al. is both interesting and innovative as only one other study investigating hormonal and metabolic changes following inositol supplementation in lean women with PCOS phenotype is reported in the literature [2]. Iuorno et al. [2] following 600 mg daily DCI supplementation for a period of 6–8 weeks described metabolic and hormonal improvements strictly comparable with the ones reported by Lagana. Interestingly, both study noted the rate of ovulation restoration after DCI supplementation. Intriguingly, despite both studies being conducted on a very small number of patients (48 women by Lagana et al. and 20 by Iuorno et al.), the rate of ovulation restoration was very similar, at around 60 %. Unfortunately, even if Lagana et al. achieved statistical significance evaluating the endpoint ovulation restoration, Iuorno et al. did not. Certainly our speculation does not take into account the statistical result, probably strongly influenced by methodology and sample size (study protocol by Lagana did not include a control group while Iuorno et al. performed a case–control study on 20 patients) but rather focuses on the possible mechanisms involved and on the different effects that DCI supplementation may have on non-overweight PCOS patients as opposed to the well documented improvements in ovulation restoration in obese PCOS women [3, 4]. Despite further studies with larger sample size are required to confirm evidences of DCI supplementation in lean PCOS patients, we aim to stress the importance this data, which may indirectly explain the differences in the pathophysiological mechanisms (respect to the obese women) responsible for chronic anovulation and open the door for future improvements in terms of treatment. The most accredited theory for anovulation in PCOS women was insulin-resistance directly related with obesity This comment refers to the article available at doi:10.1007/s00404014-3552-6 and an author’s reply to this comment is available at doi:10.1007/s00404-015-3663-8.

Statins as Targeted “Magical Pills” for the Conservative Treatment of Endometriosis May Potential Adverse Effects on Female Fertility Represent the “Dark Side of the Same Coin”? A Systematic Review of Literature

The aim of the study was to analyze all the available evidence from both in vitro and in vivo studies regarding the efficacy of statin therapy in the treatment of endometriosis, evaluating the potential efficacy, side effects, and contraindications of their administration in humans. We focused on defining the potential benefits that the administration of statins may have on patients affected by endometriosis and the possible adverse effects of such a therapy on ovarian function and fertility profile. According to our article selection criteria, we included in the review in vitro and in vivo studies performed on human or animal models. The systematic review of literature identified 24 eligible articles, 12 of which reported evidence regarding the effects of statins on endometrial/endometriotic cells and 12 regarding their effects on ovarian function and fertility. All articles seem to emphasize the utility of statin administration in the treatment of endometriosis due to their anti-proliferative/proapoptotic effects, their ability to reduce cell viability and migration, and the inhibition of angiogenesis and anti-inflammatory activities. Regarding the potential adverse effects on gonadal activities, steroidogenesis and fertility function, no conclusive data were collected in human models (excluding women affected by polycystic ovary syndrome in which significant decline of androgen levels was reported after statin treatment), while contrasting results were reported by studies conducted in in vitro and in vivo in animal models. Despite evidence supporting statins as the potential therapeutic agent for a targeted conservative treatment of endometriosis, the uncertainties regarding their impact on gonadal function may not define them as an appropriate therapy for all young fertile women.

Serum Stem Cell Factor Assay in Elderly Poor Responder Patients Undergoing IVF A New Biomarker to Customize Follicle Aspiration Cycle by Cycle

In humans, stem cell factor (SCF), produced during follicular phase, may reflect a successful stimulation and oocyte maturation and so it may be a predictor of in vitro fertilization (IVF) outcome. An observational cohort study was conducted on 37 poor responders scheduled for fresh nondonor IVF/intracytoplasmic sperm injection treatment with standard controlled ovarian stimulation (COS) using recombinant follicle-stimulating hormone (rFSH; S-COS group). A total of 35 women received a second treatment using both rFSH and recombinant luteinizing hormone (rLH; LH-COS group). From 144 samples collected at pickup day, serum concentration of SCF (s-SCF) and follicular levels of SCF (f-SCF) were measured by enzyme-linked immunosorbent assay (ELISA) kit. No differences were observed between the 2 protocols in terms of both f-SCF and s-SCF levels. The comparison between f-SCF and s-SCF levels showed a strong linear correlation. The comparison between s-SCF levels and clinical outcomes showed a statistically significant correlation between both the number of metaphase II (MII) oocytes retrieved and the embryos obtained after fertilization. Cases with at least 3 MII oocytes showed s-SCF values >800 pg/mL, 2 MII oocytes >600 pg/mL, and 1 MII oocytes >400 pg/mL. In 100% of cases with s-SCF <400 pg/mL, no MII oocytes were recovered. All 5 pregnancies occurred in patients with s-SCF values >1000 pg/mL. The introduction of s-SCF assay in the management of poor-responder patients may contribute to solving the dilemma of whether to cancel or proceed with the stimulation cycle.

Chronic endometritis in patients with unexplained infertility: Prevalence and effects of antibiotic treatment on spontaneous conception.

The correlations between chronic endometritis and unexplained infertility are unexplored.

The Potential Role of GnRH Agonists and Antagonists in Inducing Thyroid Physiopathological Changes During IVF.

We conducted an observational cohort study to evaluate whether drugs used for hypothalamic inhibition may impact thyroid function of infertile women scheduled for fresh nondonor in vitro fertilization/intracytoplasmic sperm injection treatment. We considered eligible for inclusion in the study only women with normal thyroid function (serum thyroid-stimulating hormone [TSH] range: 0.2-4.0 mIU/L, serum thyroxin values: 9-22 pmol/L) and negative personal history for previous thyroid disorders. According to which protocols were implemented to gain hypothalamic inhibition, patients were assigned to group A (70 women treated by long gonadotropin-releasing hormone [GnRH] agonist protocol) or to group B (86 women treated by flexible GnRH antagonist protocol). Before initiating controlled ovarian stimulation (COS), both groups were further stratified into 4 subgroups: A1 (46 of the 70 women) and B1 (61 of the 86 women) in women with a baseline TSH value <2.5 mIU/L, whereas those with a baseline value ≥2.5 mIU/L were assigned to groups A2 (24 of the 70 women) and B2 (25 of the 86 women). Prior to initiating stimulation (T-0), 17-β-estradiol (E2) and TSH serum values were dosed in all women and repeated on T-5 (day 5 of COS) and subsequently every 2 days until T-ov-ind (ovulation induction day) and T-pick-up (oocytes retrieval day). In case of detection of TSH levels above the cutoff, patients were screened for thyroxin and thyroid autoantibody serum values. In group A, E2 at T-ov-ind was significantly increased compared to group B (P < .01), whereas TSH values showed an opposite trend (not significantly modified in group A, whereas significantly increased in group B; P < .001). A total of 64 women were found to have TSH values above the cutoff during COS: 7 in group A (11%) and 57 in group B (89%). Among them, 5 (71.4%) of the 7 in group A displayed hypothyroidism (and 4 of the 5 autoantibody positivity), whereas in group B, 6 (10.5%) of the 57 displayed hypothyroidism (and 2 of the 6 autoantibody positivity; P < .001). No pregnancies were observed in women with hypothyroidism, whereas in the 53 women with “isolated” increased TSH (normal T4, negative antibodies), we reported a 20.7% clinical pregnancy rate and a 54.5% ongoing pregnancy rate. Our preliminary data, despite requiring further confirmation, seem to suggest that the various drugs used for gaining hypothalamic control during COS could interfere through different mechanisms with physiological function of thyroid axis, potentially affecting its regulation.

Preventive and Therapeutic Role of Dietary Inositol Supplementation in Periconceptional Period and During Pregnancy: A Summary of Evidences and Future Applications

Although inositol dietary deficiency in the general population has not been demonstrated at the serum level, several findings are emerging regarding the impact of inositol supplementation in periconceptional period and in early phases of pregnancy. We are aimed to summarize all experimental (murine in vivo and in vitro murine embryo studies) and clinical (human) evidences regarding the role of inositol in the prevention and treatment of folate-resistant embryo neural tube defects (FR-NTDs) and gestational diabetes mellitus (GDM). We also collected all information regarding the effect that inositol supplementation may have in the metabolic reassessment of early and late pregnancy in order to draw evidence-based conclusions and suggest further studies defining the potential therapeutic role of this molecule in human reproduction. The systematic review of literature clearly showed that inositol supplementation in preconceptional period and in early phase of pregnancy reduces the risk of developing GDM in patients at increased risk. Furthermore, continued intake during pregnancy improves the metabolic status of affected patients, but further studies are needed to confirm this end point. All women at risk of FR-NTDs assuming inositol from the periconceptional period until late pregnancy are reported to have healthy newborns without any significant complications linked to inositol supplementation.

Emerging evidence regarding statins use as novel endometriosis targeted treatment: real “magic pills” or “trendy” drugs? Some considerations

We read with great interest the recent review by Gibran et al. concerning the evidence of pleiotropic effects of statins in conservative treatment of endometriosis disease [1]. The authors performed an exhaustive review of the literature investigating all the possible molecular mechanisms through which statins may interfere with cellular and tissue pathways involved in development, establishment and progression of endometriosis. To date, several drugs have been proposed and administered with the intention of treating endometriosis conservatively but many of these drugs are affected by time-limited administration and several side effects, with the result that they are frequently useful only for symptom reduction with little benefit on disease severity and/or on restoration of fertility [2]. Unexpectedly, from 2006 to the present, encouraging results derived from in vitro human-cell studies and in vivo murine studies seem to strongly nominate statins as ‘‘magic pills’’ for long term conservative treatment of endometriosis, due to their low cost, safe pharmacological profile and apparent neutrality on the hormonal profile of women of childbearing age [1]. This is new exciting evidence, especially because it was collected during research on conservative treatment for a disease whose etiopathological mechanisms are not well understood and to date without any curative treatment, but it may erroneously result in a ‘‘reassuring and optimistic message’’ for both scientists and clinicians. Much of the data demonstrating the dose-dependent effective reduction in number and volume of endometriotic lesions after administration of statins was collected in murine models or in vitro studies. To date only one study, by Almassinokiani et al. [3], has reported data from the in vivo human model, and the endpoint was focused on post-surgical pain reduction. The authors observed that, after adequate surgical treatment, therapy with atorvastatin (20 mg/day) was comparable to gonadotropin-releasing hormone agonists (3.75 mg/IM/month) in reducing post-surgical pain due to endometriosis. Though encouraging, however, this study was affected by several biases such as small sample size (60 patients), short term follow-up (16 weeks), and absence of an untreated control group (making it impossible to prove whether the observed benefits were due to surgical treatment or to post-operative medical therapy). In addition, Almassinokiani et al. administered statins to women who were trying to conceive, apparently underestimating the possible risks associated with the administration of therapy in the pre-conceptional and early pregnancy period.

Surgery, endometriosis-related infertility and negative impact on ovarian reserve: “which came first, the hen or the egg?” An unresolved dilemma

We greatly appreciate the opportunity to reply to the interesting comments by Coccia et al. [1] regarding our manuscript titled ‘‘Could surgeon’s expertise resolve the debate about surgery effectiveness in treatment of endometriosis-related infertility?’’ recently published in your prestigious journal [2]. In the recent past, great strides have been made in the clinical management of patients affected by endometriosis. The proposal of innovative diagnostic techniques in association with the discovery of new targeted conservative treatments allows clinicians a narrow selection of patients who may benefit from surgery [3–7]. Unfortunately, when considering patients affected by endometriosis-related infertility, the dilemma regarding the real advantages of surgery with the intent to improve fertility by removing endometriosis and restoring normal anatomy remains a debate yet unresolved [2]. Despite that the end goal of surgical intervention in patients suffering from endometriosis-related infertility is re-establishment of correct anatomical relationship among pelvic organs and preservation of function, evidences reporting severe reductions in ovarian reserve after surgery in addition to an absence of spontaneous fertility restoration have fuelled doubts and debates regarding the real sense of surgery [8]. Similar to the unresolved paradox of ‘‘Whether the hen or the egg came first’’, it is still unclear whether the ovarian reserve of patients affected by ovarian endometriosis is more impaired by the persistence of endometriomas or by the surgical excision of those lesions. Contrasting evidences on fertility outcome following surgery augment the ongoing debate. On one hand, we can find data reporting a significant increase in spontaneous conception after surgery when compared with expectant management (considering all AFS/ASRM stages) while on the other hand, a great deal of literature underlines the absence of benefits even in terms of an increased success rate in assisted reproduction [9, 10]. We are in full agreement with what was stated by Coccia et al. regarding the fundamental role that ‘‘wellexperienced’’ surgeons have in the surgical treatment of endometriosis-related infertility. However, our manuscript introduced the idea of ‘‘dedicated’’ well-experienced surgeons and reported significant improvements in both spontaneous fertility and assisted reproduction outcomes (despite time limited) following surgical treatment. In fact, what Coccia et al. defined as ‘‘ideal’’ (ideally, surgeon dedicated to endometriosis-related infertility should also have a know-how in reproductive medicine to adopt a very conservative and anatomical–functional approach to preserve function of reproductive organs) was routine clinical practice in our setting. Our pioneeristic results suggest that this approach should be ‘‘the way everyone should do it’’. Only data collected from dedicated and highly-skilled specialist settings may contribute to divulgate bias-free This reply refers tothe comment available at doi:10.1007/s00404-015-3791-1.

Epigenetic and genetic landscape of uterine leiomyomas: a current view over a common gynecological disease

PurposeDespite the numerous studies on the factors involved in the genesis and growth of uterine leiomyomas, the pathogenesis of these tumors remains unknown. Intrinsic abnormalities of the myometrium, abnormal myometrial receptors for estrogen, and hormonal changes or altered responses to ischemic damage during the menstrual period may be responsible for the initiation of (epi)genetic changes found in these tumors. Considering these elements, we aimed to offer an overview about epigenetic and genetic landscape of uterine leiomyomas.MethodsNarrative overview, synthesizing the findings of literature retrieved from searches of computerized databases.ResultsSeveral studies showed that leiomyomas have a monoclonal origin. Accumulating evidence converges on the risk factors and mechanisms of tumorigenesis: the translocation t (12;14) and deletion of 7q were found in the highest percentages of recurrence; dysregulation of the HMGA2 gene has been mapped within the critical 12q14–q15 locus. Estrogen and progesterone are recognized as promoters of tumor growth, and the potential role of environmental estrogens has been poorly explored. The growth factors with mitogenic activity, such as transforming growth factor-β3, fibroblast growth factor, epidermal growth factor, and insulin-like growth factor-I are elevated in fibroids and may have a role as effectors of the tumor promotion.ConclusionThe new clues on genetics and epigenetics, as well as about the growth factors that control normal and pathological myometrial cellular biology may be of great help for the development of new effective and less invasive therapeutic strategies in the near future.

An Update on Maternal Hydration Strategies for Amniotic Fluid Improvement in Isolated Oligohydramnios and Normohydramnios: Evidence from a Systematic Review of Literature and Meta-Analysis.

Objective Several trials aimed at evaluating the efficacy of maternal hydration (MH) in increasing amniotic-fluid-volume (AFV) in pregnancies with isolated oligohydramnios or normohydramnos have been conducted. Unfortunately, no evidences support this intervention in routine-clinical-practice. The aim of this systematic-literature-review and meta-analysis was to collect all data regarding proposed strategies and their efficacy in relation to each clinical condition for which MH-therapy was performed with the aim of increasing amniotic-fluid (AF) and improving perinatal outcomes. Materials and Methods A systematic literature search was conducted in electronic-database MEDLINE, EMBASE, ScienceDirect and the Cochrane-Library in the time interval between 1991 and 2014. Following the identification of eligible trials, we estimated the methodological quality of each study (using QADAS-2) and clustered patients according to the following outcome measures: route of administration (oral versus intravenous versus combined), total daily dose of fluids administered (<2000 versus >2000), duration of hydration therapy: (1 day, >1 day but <1 week, >1 week), type of fluid administered (isotonic versus hypotonic versus combination). Results In isolated-oligohydramnios (IO), maternal oral hydration is more effective than intravenous hydration and hypotonic solutions superior to isotonic solutions. The improvement in AFV appears to be time-dependent rather than daily-dose dependent. Regarding normohydramnios pregnancies, all strategies seem equivalent though the administration of hypotonic-fluid appears to have a slightly greater effect than isotonic-fluid. Regarding perinatal outcomes, data is fragmentary and heterogeneous and does not allow us to define the real clinical utility of MH. Conclusions Available data suggests that MH may be a safe, well-tolerated and useful strategy to improve AFV especially in cases of IO. In view of the numerous obstetric situations in which a reduced AFV may pose a threat, particularly to the fetus, the possibility of increasing AFV with a simple and inexpensive practice like MH-therapy may have potential clinical applications. Considering the various strategies of maternal hydration implemented in the treatment of IO, better results were observed when treatment was based on a combination of intravenous (for a period of 1 day) and oral (for a period of at least 14 days) hypotonic fluids (≥2000ml).