Hyperandrogenism and menstrual imbalance are the best predictors of metformin response in PCOS patients.

BACKGROUND: Moving from the correlation between insulin-resistance and PCOS, metformin has been administered in some PCOS women improving ovulatory and metabolic functions and decreasing androgen levels. Inconsistency and unpredictability of response to metformin limit its extensive use. Aim of this study was to identify reliable predictors of response to metformin therapy for weight loss and reduction in plasma androgen levels using ANNs (artificial neural networks). METHODS: One hundred eight consecutive women with PCOS (ESHRE/ASRM 2003 Rotterdam criteria) treated with metformin 1500 mg/day, at inclusion and every 6 months underwent to a complete clinical, endocrine/metabolic assessment and ultrasonographic evaluation. Therapy outcomes were BMI reduction (≥1 kg/m2) in overweight/obese and free-androgen-index (FAI) decrease (≥1%) in hyperandrogenemic women. Semantic connectivity maps (SCMs) were obtained through Auto-CM, a fourth generation ANN, to compare patients' baseline clinical features to the treatment outcomes. Multivariate logistic regression analysis was used to assess the major predictor in drop-out patients and the associated risk. RESULTS: At 6 months 54 out of 103 (52,4%) obese patients showed BMI reduction and 45 out of 89 (50,6%) hyperandrogenemic women showed FAI decrease. The further response rates at 12 months were 30,6 and 47%, respectively. SCMs showed a clear polarization for both the outcomes with elevated accuracy. Treatment responsiveness resulted strictly related to oligo-amenorrhea and hyperandrogenemia at baseline. In addition, lower serum testosterone levels at baseline were found to be the major predictor of treatment discontinuation. CONCLUSIONS: In women with PCOS, menstrual pattern imbalance and ovarian androgens excess are the best predictors of metformin response. They may pave the way for a rethinking of the criteria for evaluating hyperandrogenism in order to better define the large population included in the diagnosis of PCOS. Baseline plasma testosterone level can serve as a sensitive marker to predict treatment compliance.

Basal serum level of Δ4-androstenedione reflects the ovaries' ability to respond to stimulation in IVF cycles: setting up a new reliable index of both ovarian reserve and response.

PURPOSE: Adequate androgen levels are necessary for regular follicular growth, progression beyond the pre-antral stage, and prevention of follicular atresia. The main purpose of this study was to investigate whether baseline androgen levels had a predictive value on stimulation outcomes in IVF cycles. The secondary purpose was to compare the possible predictive value of androgens with that of already known markers. METHODS: The study included 91 infertile patients aged 30-45 years awaiting the first IVF cycle. All women underwent the same stimulation protocol and the same starting dose of recombinant FSH. As stimulation outcomes, the number of follicles recruited, estradiol and progesterone levels on the day of trigger, the total dose of gonadotropins administered, and the number of oocytes collected were recorded. Multiple linear regression and multivariate logistic regression were used to evaluate the significant predictive value of the variables for response to controlled ovarian stimulation (COS). By studying the reliability of different markers, an attempt was made to develop a single index with the highest predictive value. RESULTS: Pearson's correlation revealed a statistically significant inverse correlation between oocytes collected and age (r = - 0.333, p < 0.001) and a positive correlation with AMH (anti-müllerian hormone) (r = 0.360, p < 0.001), antral follicle count (AFC) (r = 0.639, p < 0.001), and androstenedione (Δ4-A) (r = 0.359, p < 0.001). No significant correlation was reported with FSH (r = - 0.133, p = 0.207) and total testosterone (r = 0.180, p = 0.088). In COS good responders, the G-index (= AMH ng/mL*AFC/Δ4-A ng/dL) revealed a significantly higher level (p < 0.001) than AMH, AFC, and Δ4-A alone. CONCLUSION: Baseline serum Δ4-A, presumably crucial for ensuring a regular follicular growth, is a reliable marker of ovarian response to stimulation. Since the ovarian capacity to respond to gonadotropins does not depend exclusively on the presence of follicles, we suggest a new index, the G-index, able to contemplate both the ovarian reserve and the Δ4-A level.

Cord blood androgen levels of females from same sex and opposite sex twins - A pilot study.

OBJECTIVE: Opposite-sex twins have shown behavioural and reproductive differences between females and males. These differences may be determined by higher intrauterine levels of androgens among females that were exposed to a male co-twin. The aim of this study was to compare cord blood androgen levels in females from same-sex and opposite-sex twins. DESIGN: A prospective study. In this pilot study, we compared cord blood androgens (DHEA-S, Δ-4 androstenedione, total testosterone-TT) and sex hormone-binding globulin (SHBG) levels in 20 females from same sex and 20 females from opposite-sex dichorionic diamniotic twins. We used generalized estimating equation (GEE) modelling to assess differences in cord blood androgens between females from same-sex twin pregnancies and females from opposite-sex twin pregnancies. PATIENTS: Twenty opposite-sex twin pairs (female-male twins) and 20 same-sex twin pairs (female-female). MEASUREMENTS: Cord blood total testosterone, Δ-4 androstenedione, DHEA-S and sex hormone-binding globulin (SHBG) levels. RESULTS: No difference in the levels of androgens as Δ-4 androstenedione, total testosterone and SHBG was identified between females that were exposed to a female co-twin compared with females that were exposed to a male co-twin. DHEA-S levels were significantly lower among females from opposite-sex twins compared with females from same-sex twins. CONCLUSIONS: Our preliminary data do not support the hypothesis that females exposed to male co-twins are exposed to higher levels of androgens in utero compared with females exposed to female co-twins. Further studies are needed to explain the reported behavioural and reproductive differences among opposite-sex twins.

Stop GnRH-Agonist Combined with Multiple-Dose GnRH-Antagonist for Patients with Elevated Peak Serum Progesterone Levels Undergoing Ovarian Stimulation for IVF: A Proof of Concept.

AIM: The aim of the study was to examine whether the Stop GnRH-agonist combined with multiple-dose GnRH-antagonist protocol may overcome progesterone elevation during the late follicular phase. PATIENTS AND METHODS: A cohort historical, proof of concept study consisting of 11 patients with progesterone elevation (>3.1 nmol/L) during conventional IVF/intracytoplasmic sperm injection (ICSI), who underwent a subsequent Stop GnRH-agonist combined with multiple-dose GnRH-antagonist ovarian stimulation (OS) protocol, within 3 months of the previous failed conventional IVF/ICSI cycle. RESULTS: The Stop GnRH-agonist combined with multiple-dose GnRH-antagonist COH protocol revealed significantly lower peak progesterone levels, with significantly higher numbers of follicles >13 mm in diameter on the day of hCG administration, oocytes retrieved, mature oocytes, and top-quality embryos, with an acceptable clinical pregnancy rate (18.2%). CONCLUSIONS: The combined Stop GnRH-ag/GnRH-ant OS protocol is a valuable tool in the armamentarium for treating patients with progesterone elevation during the late follicular phase. Further large prospective studies are needed to validate our observation and to characterize the appropriate patients' subgroup, which might benefit from the combined Stop GnRH-ag/GnRH-ant COH protocol.

Asymptomatic 39 Weeks Abdominal Pregnancy - Video Report of a Case Occurred in Ivory Coast Resulting in a Live Birth.

BACKGROUND: Despite the current advances in antenatal care and imaging methodologies in obstetrics, cases of advanced abdominal pregnancies are still reported, mostly in low- and middle-income countries where frequently only a few perinatal checks are performed and where these methodologies are sometimes not adopted in obstetrical outpatient settings. CASE PRESENTATION: We report the video of a case of a 20-year-old I gravida Ivorian patient, sent to CHU de T reichville in Abidjan, Ivory Coast, for management of abdominal 39 weeks pregnancy after routine antenatal care. She was asymptomatic with a live foetus in transverse lie position. The anamnesis revealed four prenatal checks without ultrasound evaluation, the first one at 24 weeks of pregnancy. Emergency median longitudinal sub-umbilical laparotomy incision was performed. Foetal extraction was realized by transplacental incision due to omental placental implantation. A live female baby weighting 3350 grams was delivered, presenting bilateral clubfeet and an enlarged neck. The release of the adherent placenta required a partial omentectomy and left adnexectomy and was carefully removed following active bleeding from its detached margins. The newborn died of respiratory distress on the first day after birth. No autopsy was performed. Postoperative morbidity for the woman was minimal and she was discharged on the seventh post-operative day in good general condition. CONCLUSION: Abdominal pregnancies with a normal live foetus at such an advanced gestational age are extremely rare, and there are no available videos in the extant literature of the surgical procedure performed. Standardization of treatment principles, pre-operative preparation with imaging techniques (MRI, embolization of placental vessels) and adequately equipped and staffed neonatal units are necessary to optimize the foetus-maternal outcomes.

Emotional and autonomic response to visual erotic stimulation in patients with functional hypothalamic amenorrhea.

Introduction: Functional hypothalamic amenorrhea (FHA) is a clinical condition associated with high levels of physiological and psychological stress ranging from weight loss to maladaptive behavior and coping skills. A reliable measure of the psychophysiological response to stress and the ability to cope with stimuli is heart rate variability (HRV). Through the sympathetic (SNS) and parasympathetic nervous system (PNS), the autonomic nervous system (ANS) promotes various changes in HRV that reflect the individual's psychophysiological response to stress. FHA patients are characterized by high levels of PNS activation during psychological load, suggesting that parasympathetic hyperactivation could be a pathology marker. Methods: In the present study, we examine changes in HRV during observation of erotic, neutral, and disgusting images in 10 patients with FHA [(mean ± S.D.) age: 26.8 ± 5.9] and in 9 controls (age: 25.4 ± 6.4; BMI: 22.47 ± 2.97) to assess the differential activation of PNS and SNS between FHA patients and controls matched for age and without other clinical conditions. Results: Our results showed that FHA patients had significantly higher HRV activation while observing high emotional value images and not during the observation of neutral images confirming a parasympathetic hyperactivation. Discussion: HRV and cognitive and psychological testing, could provide new insights into understanding such a clinically understudied condition and provide further tools for clinical diagnosis and treatment.

Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics.

BACKGROUND: Glioblastoma is the most aggressive primary brain malignancy in adults, with a poor prognosis of about 14 months. Recent evidence ascribed to metformin (MET), an antihyperglycemic drug, the potential to reduce cancer incidence and progression, but the molecular mechanisms underlying these effects need to be better investigated. METHODS: Here, we tested the efficacy of MET on n = 10 primary glioblastoma endothelial cells (GECs), by viability and proliferation tests, as MTT and Live/Dead assays, apoptosis tests, as annexin V assay and caspase 3/7 activity, functional tests as tube-like structure formation and migration assay and by mRNA and protein expression performed by quantitative real-time PCR analysis (qRT-PCR) and Western Blot, respectively. RESULTS: Data resulting revealed a time- and µ-dependent ability of MET to decrease cell viability and proliferation, increasing pro-apoptotic mechanisms mediated by caspases 3/7. Also, MET impacted GEC functionality with a significant decrease of angiogenesis and invasiveness potential. Mechanistically, MET was able to interfere with sphingolipid metabolism, weakening the oncopromoter signaling promoted by sphingosine-1-phosphate (S1P) and shifting the balance toward the production of the pro-apoptotic ceramide. CONCLUSIONS: These observations ascribed to MET the potential to serve as add-on therapy against glioblastoma, suggesting a repurposing of an old, totally safe and tolerable drug for novel oncology therapeutics.

Diagnostic Complexities in a Case of Ovarian Hyperstimulation Syndrome Presented Solely as a Unilateral Massive Hydrothorax.

To describe a rare case of unilateral massive hydrothorax after controlled ovarian stimulation for IVF and to analyze the diagnostic complexities in a patient lacking both risk factors and typical features of ovarian hyperstimulation syndrome (OHSS). We present a case of a 35-year-old woman suffering from primary infertility due to a severe male factor. Admitted to hospital for dyspnea, the patient initially underwent a thoracentesis. Later, due to the recurrence of massive hydrothorax, permanent pleural drainage was placed. Recognized as a severe manifestation of the OHSS, it was treated by pleural drainage, hydration, albumin perfusion, and management of the intercurrent pregnancy, up to improvement in clinical and hematological laboratory parameters and resolution of pleural effusion and respiratory symptoms. A total of 42 l of pleural fluid was drained during the 40 days of hospitalization. Since the pathogenesis of isolated acute hydrothorax in ovarian stimulation probably lies in the presence of anatomical defects of the diaphragm, this may justify that the relationship between this pathology and the OHSS risk factors may be less close. Massive pleural effusion may exceptionally be the only clinical presentation of OHSS. A high index of suspicion is necessary to make the correct diagnosis and to promptly administer treatment.

"Add-Ons" for Assisted Reproductive Technology: Do Patients Get Honest Information from Fertility Clinics' Websites?

"Add-on" procedures are actively promoted on some fertility clinic websites as proven means to improve IVF success rates, especially for couples with repeated implantation/IVF failures. However, the actual contribution of these interventions to live birth rates remains inconclusive. At present, little is known about the type and quality of the information provided on the IVF clinics' websites regarding the merits of "add-ons." A systematic evaluation of the quality of information on "add-on" procedures in fertility clinic websites was performed using 10-criteria structured questionnaire. We included English language websites that presented in the Google.com search engine after typing the following key-words:"endometrial scratching"(ES), "intralipid infusions"(ILI), "assisted hatching"(AHA), "PGT-A," or "PGS". In total, 254 websites were evaluated. In most cases, an accurate description of the "add-on" procedures was provided (78.8%). However, only a minority (12%) reported their undetermined effectiveness. The use of PGT-A was more often encouraged (52.8%) than ES (23.6%) and AHA (16%). The cost was infrequently presented (6.9%). Scientific references were only rarely provided for ILI, versus 12.7% for ES, 4.0% for AHA, and 5.6% for PGT-A. The information entry date was often missing. None of the websites reported the clinic's pregnancy-rate following the "add-on" procedures. Information on "add-ons" available to patients from IVF clinic websites is often inaccurate. This could perpetuate false myths among infertile patients about these procedures and raises concern regarding possible commercial bias. It is imperative that IVF clinic websites will better communicate the associated risks and uncertainties of "add-ons" to prospective patients.

Stop GnRH-Agonist Combined With Multiple-Dose GnRH-Antagonist Protocol for Patients With "Genuine" Poor Response Undergoing Controlled Ovarian Hyperstimulation for IVF.

Objective: To examine whether the Stop GnRH-agonist combined with multiple-dose GnRH-antagonist protocol may improve conventional IVF/intracytoplasmic sperm injection (ICSI) cycle in poor ovarian response (POR) patients. Design: Cohort historical, proof of concept study. Setting: Tertiary, University affiliated Medical Center. Patient(s): Thirty POR patients, defined according to the Bologna criteria, who underwent a subsequent Stop GnRH-agonist combined with multiple-dose GnRH-antagonist controlled ovarian hyperstimulation (COH) protocol, within 3 months of the previous failed conventional IVF/ICSI cycle, were included. For the purposes of this study, we eliminated a bias in this selection by including only "genuine" poor responder patients, defined as those who yielded up to 3 oocytes following COH with a minimal gonadotropin daily dose of 300 IU. Main Outcome Measure(s): Number of oocytes retrieved, number of top-quality embryos, COH variables. Result(s): The Stop GnRH-agonist combined with multiple-dose GnRH-antagonist COH protocol revealed significantly higher numbers of follicles >13 mm on the day of hCG administration, higher numbers of oocytes retrieved, and top-quality embryos (TQE) with an acceptable clinical pregnancy rate (16.6%). Moreover, as expected, patients undergoing the Stop GnRH-agonist combined with multiple-dose GnRH-antagonist COH protocol required significantly higher doses and a longer duration of gonadotropins stimulation. Conclusion(s): The combined Stop GnRH-ag/GnRH-ant COH protocol is a valuable tool in the armamentarium for treating "genuine" poor ovarian responders. Further, large prospective studies are needed to elucidate its role in POR and to characterize the appropriate patients subgroup (before initiating ovarian stimulation) that may benefit from the combined Stop GnRH-ag/GnRH-ant COH protocol.

Psychological distress, anger and quality of life in polycystic ovary syndrome: associations with biochemical, phenotypical andsocio-demographic factors.

OBJECTIVE: To investigate the association between polycystic ovary syndrome (PCOS) and psychological disturbances, including anger. To analyze whether the biochemical/phenotypical features of PCOS play a role in the type and severity of psychological disorders. MATERIAL AND METHODS: This case-control study included 30 PCOS patients meeting NIH criteria and 30 non-PCOS women referring to Reproductive Medicine Unit for infertility. Complete clinical and biochemical screening and the self-reported psychological data [Symptom Check List 90-R (SCL-90-R); Short-Form Health Survey 36 (SF-36); and State-Trait Anger Expression Inventory-2 (STAXI-2)] were collected. Statistical analyses were performed with SPSS-21. RESULTS: Compared with control women, women with PCOS reported significantly higher scores on SCL-90-R scales of somatization, anxiety, hostility, psychoticism, overall psychological distress and a number of symptoms. At STAXI-2, patients with PCOS scored higher in trait-anger and in the outward expression of anger, while lower in outward anger-control; PCOS patients had significantly lower scores on SF-36 scales of physical functioning and bodily pain. Hirsutism was directly associated with anxiety. Regarding the associations between phenotypical/biochemical features and psychological distress in PCOS patients, results showed that waist-to-hip ratio is inversely related to anxiety, psychoticism, hostility and to the indexes of psychological distress; such inverse relationship was also seen between plasmatic levels of testosterone and trait-anger, and between total cholesterol and hostility. CONCLUSIONS: Results were consistent with the previous literature on the well-being of PCOS women (in particular for anxiety and quality of life [QoL]) but failed to find evidence for depression. The relationship between psychological distress and the features of the syndrome highlighted the role of hirsutism. With respect to hyperandrogenemia, our data rejected its involvement in the elevated negative mood states and affects. Adopting an interdisciplinary approach in the PCOS patients' care, anger showed to be common and deserves major consideration.