Carlo Alviggi

Pathogenesis of endometriosis: natural immunity dysfunction or autoimmune disease?

Endometriosis is a chronic inflammatory disease, characterized by implantation and growth of endometrial tissue outside the uterine cavity. This disabling condition is considered one of the most frequent diseases in gynecology, affecting 15-20% of women in their reproductive life. Pelvic endometriosis, the most common form of the disease, is associated with increased secretion of pro-inflammatory cytokines, neo-angiogenesis, intrinsic anomalies of the refluxed endometrium and impaired function of cell-mediated natural immunity. Recently, endometriosis has also been considered to be an autoimmune disease, owing to the presence of autoantibodies, the association with other autoimmune diseases and recurrent immune-mediated abortion. These findings are in apparent contradiction with the reduced cell-mediated natural immunity observed during the disease. In this review, we focus on the multiple processes underlying the complex pathogenesis of endometriosis, with particular emphasis on the role played by the immune system with the induction of autoimmunity.

Unraveling the multiple roles of leptin in inflammation and autoimmunity

Initially described as an antiobesity hormone, leptin has subsequently been shown also to influence hematopoiesis, thermogenesis, reproduction, angiogenesis, and immune homeostasis. Leptin links nutritional status and proinflammatory T helper 1 immune responses, and the decrease in leptin plasma concentration during food deprivation leads to impaired immune function. This review focuses on the multiple roles of leptin in chronic inflammation and autoimmunity and suggests new possible therapeutic implications for leptin modulators.

Hysteroscopic resection of the septum improves the pregnancy rate of women with unexplained infertility: a prospective controlled trial.

OBJECTIVE To assess fecundity of infertile women after surgical correction of uterine septum. DESIGN Prospective controlled trial. SETTING Three academic infertility clinics. PATIENT(S) Forty-four women affected by septate uterus and otherwise unexplained infertility represented the study group (group A), and 132 women with unexplained infertility were enrolled as control subjects (group B). INTERVENTION(S) Hysteroscopic metroplasty was performed in group A, and group B was managed expectantly. All women were followed-up for 1 year without any other intervention. MAIN OUTCOME MEASURE(S) Fecundity rate was calculated as the number of pregnancies per 100 person-months. RESULT(S) Pregnancy rate (38.6% vs. 20.4%) and live birth rate (34.1% and 18.9%) were significantly higher in group A than in group B. The survival analysis showed that the probability of a pregnancy in the twelve-months follow up was significantly higher in patients who had undergone metroplasty than in women with unexplained infertility. The corresponding fecundity (10-week pregnancy) rates were 4.27 and 1.92 person-months in women who had undergone metroplasty and in women with unexplained infertility, respectively. CONCLUSION(S) Hysteroscopic resection of the septum improves fecundity of women with septate uterus and otherwise unexplained infertility. Patients with septate uterus and no other cause of sterility have a significantly higher probability of conceiving after removal of the septum than patients affected by idiopathic sterility.

Chaotic mosaicism in human preimplantation embryos is correlated with a low mitochondrial membrane potential.

OBJECTIVE To determine the relationship between the intrinsic mitochondrial deltapsi of human embryos and the embryo karyotype. DESIGN Analysis of mitochondrial deltapsi of living embryos followed by chromosomal enumeration with fluorescence in situ hybridization. A tertiary center for assisted reproduction technology. PATIENT(S) Fifty-two patients attending the fertility center for assisted reproduction. INTERVENTION(S) Donated embryos were loaded with a mitochondrial deltapsi-sensitive fluorescence dye. MAIN OUTCOME MEASURE(S) Mitochondrial deltapsi was measured by confocal microscopy. Subsequently, embryos were fixed and fluorescence in situ hybridization analysis was used to denote embryo karyotype. MAIN OUTCOME MEASURE(S) Mitochondrial deltapsi and embryo karyotype. RESULT(S) An association was observed between low mitochondrial deltapsi and the detection of chaotic mosaicism. Analysis of oocytes suggested that this was due to the effect of low mitochondrial deltapsi on the morphology of the meiotic apparatus. CONCLUSION(S) The data suggest that the intrinsic mitochondrial deltapsi of human oocytes programs the developmental fate of embryos through an effect on the ability of oocytes to form a normal meiotic apparatus and not through nondisjunction.

Effects of recombinant LH (rLH) supplementation during controlled ovarian hyperstimulation (COH) in normogonadotrophic women with an initial inadequate response to recombinant FSH (rFSH) after pituitary downregulation

background  This study was aimed to evaluate the effect of different recombinant LH (rLH) doses on the ovarian outcome of normogonadotrophic women with an initial inadequate response to recombinant FSH (rFSH) after pituitary downregulation.

Suboptimal response to GnRHa long protocol is associated with a common LH polymorphism

The aim of this observational preliminary trial was to estimate the association between the most common polymorphism of LH (LH-β variant: v-βLH), with different profiles of ovarian response to recombinant human FSH (rhFSH). A total of 60 normogonadotrophic patients undergoing a gonadotrophin-releasing hormone analogue long down-regulation protocol followed by stimulation with recombinant human FSH (rhFSH) for IVF/intracytoplasmic sperm injection, and in whom at least five oocytes were retrieved were retrospectively included. On the basis of the total rhFSH consumption, patients were divided into three groups: Group A: 22 women requiring a cumulative dose of rhFSH >3500 IU; Group B: 15 patients requiring 2000-3500 IU; Group C (control): 23 women requiring <2000 IU. The presence of v-βLH was evaluated using specific immunoassays. Peak oestradiol concentrations were significantly lower in Group A when compared with both groups B (P < 0.05) and C (P < 0.001). Group A had a significantly lower (P < 0.05) number of oocytes retrieved (7.3 ± 1.5, 11.7 ± 2.4 and 14.7 ± 4.1 in the three groups, respectively). Seven carriers (31.8%) of v-βLH were found in Group A, whereas only one variant (6.7%) was observed in Group B; no variant was detected in Group C. These preliminary results suggest that v-βLH is more frequent in women with ovarian resistance to rhFSH.

Hormonal, functional and genetic biomarkers in controlled ovarian stimulation: tools for matching patients and protocols

Variability in the subfertile patient population excludes the possibility of a single approach to controlled ovarian stimulation (COS) covering all the requirements of a patient. Modern technology has led to the development of new drugs, treatment options and quantitative methods that can identify single patient characteristics. These could potentially be used to match patients with the right treatment options to optimise efficacy, safety and tolerability during COS. Currently, age and follicle-stimulating hormone (FSH) level remain the most commonly used single patient characteristics in clinical practice. These variables only provide a basic prognosis for success and indications for standard COS treatment based on gross patient categorisation. In contrast, the anti-Müllerian hormone level appears to be an accurate predictor of ovarian reserve and response to COS, and could be used successfully to guide COS. The antral follicle count is a functional biomarker that could be useful in determining the dose of FSH necessary during stimulation and the success of treatment. Finally, in the future, genetic screening may allow an individual patients response to stimulation during COS to be predicted based on genotype. Unfortunately, despite the predictive power of these measures, no single biomarker can stand alone as a guide to determine the best treatment option. In the future, hormonal, functional and genetic biomarkers will be used together to personalise COS.

A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept

The management of patients with impaired or poor ovarian response (POR) remains a controversial and complex clinical issue. A systematic review of 47 randomized controlled trials revealed 41 different definitions of POR (1). Notably, the number of oocytes retrieved was adopted as a criterion of POR in 40% of the trials, although the threshold number differed considerably among studies (1). To standardize the definition of POR, Ferraretti et al. (2) proposed new criteria, known as the ‘‘Bologna criteria,’’ based on three conditions: 1) advanced maternal age (R40 years) or any other POR risk factor; 2) a previous incident of POR; and 3) a low ovarian reserve test in terms of antim€ ullerian hormone (AMH) and antral follicle count (AFC). Two of these three criteria are required for a POR diagnosis. In addition, two cycles with POR after maximal stimulation are sufficient to classify a patient as a poor responder even in the absence of the other criteria mentioned. Although the Bologna criteria were found to be useful in predicting the outcome of IVF and for counseling purposes, their use in clinical trials has been questioned because they entail the risk of grouping together women who differ significantly in biologic characteristics (3). For example, according to the Bologna criteria, young women with a low ovarian reserve associated with a previous episode of POR, young women with a normal ovarian reserve and two POR episodes, and older women (R40 years) with a normal ovarian reserve and a previous episode of POR would be included in the same category even though the clinical management of these patients requires different strategies. In clinical terms, apart from the number of oocytes retrieved, various features that may affect treatment outcomes must be considered in the management of patients, namely: 1) the age-related embryo/blastocyst aneuploidy rate, which could dramatically change the prognosis in women that have the same oocyte yield; and 2) ovarian ‘‘sensitivity’’ to exogenous gonadotropins, which could be related to a specific genetic profile. To introduce a more nuanced picture of POR, we here propose clinically relevant criteria that can help to guide the physician in the management of patients. In detail, we suggest a more specific new definition of ‘‘low prognosis’’ patients that:

Intra-follicular leptin concentration as a predictive factor for in vitro oocyte fertilization in assisted reproductive techniques

Background: Granulosa-cells are able to produce and store leptin, suggesting that this hormone is locally involved in the regulation of follicular growth. In this study, the role of follicular fluid (FF) leptin concentration in predicting oocyte fertilization and embryo quality was evaluated in 35 normogonadotrophic women undergoing controlled ovarian stimulation (COS) for assisted reproductive techniques. Materials and Methods: Leptin concentration was measured in 47 consecutively collected FF in which a mature oocyte had been found during the ovum pick-up. Embryos deriving from fertilized oocytes were submitted to quality scoring systems. Results: Mean leptin concentration was significantly higher in FF whose oocytes showed 2 pronuclei (no. 25) when compared with those with no evidence of fertilization (no. 22) at the 16–18 h check (26.0±6.1 vs 15.3±10.6 ng/ml, respectively, p<0.01). Follicular mean diameters were similar in the two groups (21.4±3.4 and 21.0±5.1 mm, respectively). Logistic regression analysis identified FF leptin levels as the best predictive parameter for oocyte fertilization (p<0.001). When receiving operating characteristics curve was employed, a FF leptin concentration of 20.25 ng/ml was the most reliable cut-off in predicting fertilization of oocytes. FF with leptin concentrations higher than this value (no. 27) had an oocyte fertilization rate of 85.7%. In contrast, FF levels ≤20.25 ng/ml (no. 20) were associated with a rate of 16.7% (p<0.05). No correlation emerged between FF leptin and the score attributed to 15 valuable embryos at the zygote stage (r=−0.01) and at 48 h after insemination (r=0.1). Conclusions: FF leptin levels are a better predictor of oocyte fertilization success rates than follicular diameter. These results underline the relevance of FF variables in developing methods for oocyte selection.

The management of Asherman syndrome: a review of literature

Asherman syndrome is a debatable topic in gynaecological field and there is no clear consensus about management and treatment. It is characterized by variable scarring inside the uterine cavity and it is also cause of menstrual disturbances, infertility and placental abnormalities. The advent of hysteroscopy has revolutionized its diagnosis and management and is therefore considered the most valuable tool in diagnosis and management. The aim of this review is to explore the most recent evidence related to this condition with regards to aetiology, diagnosis management and follow up strategies.