Dimitrios G. Goulis

Consensus on infertility treatment related to polycystic ovary syndrome

The treatment of infertile women with polycystic ovary syndrome (PCOS) is surrounded by many controversies. This paper describes, on the basis of the currently available evidence, the consensus reached by a group of experts regarding the therapeutic challenges raised in these women. Before any intervention is initiated, preconceptional counselling should be provided emphasizing the importance of life style, especially weight reduction and exercise in overweight women, smoking and alcohol consumption. The recommended first-line treatment for ovulation induction remains the anti-estrogen clomiphene citrate (CC). Recommended second-line intervention, should CC fail to result in pregnancy, is either exogenous gonadotrophins or laparoscopic ovarian surgery (LOS). The use of exogenous gonadotrophins is associated with increased chances for multiple pregnancy and, therefore, intense monitoring of ovarian response is required. LOS alone is usually effective in <50% of women and additional ovulation induction medication is required under those circumstances. Overall, ovulation induction (representing the CC, gonadotrophin paradigm) is reported to be highly effective with a cumulative singleton live birth rate of 72%. Recommended third-line treatment is in vitro fertilization. More patient-tailored approaches should be developed for ovulation induction based on initial screening characteristics of women with PCOS. Such approaches may result in deviation from the above mentioned first-, second- or third-line ovulation strategies in well-defined subsets of patients. Metformin use in PCOS should be restricted to women with glucose intolerance. Based on recent data available in the literature, the routine use of this drug in ovulation induction is not recommended. Insufficient evidence is currently available to recommend the clinical use of aromatase inhibitors for routine ovulation induction. Even singleton pregnancies in PCOS are associated with increased health risk for both the mother and the fetus.

The complex interaction between obesity, metabolic syndrome and reproductive axis: a narrative review.

The aim of this narrative review is to provide current evidence for the interaction between obesity, metabolic syndrome (MS) and reproductive axis. Gonadotropin-releasing hormone (GnRH) pulses and, consequently, normal function of reproductive (hypothalamus-pituitary-gonadal) axis depend on normal energy balance, which presupposes sufficient food intake, reasonable energy consumption and average thermoregulatory costs. In case of an energy imbalance, reproductive dysfunction may occur. In young women, excessive leanness is accompanied by puberty delay, whereas premature puberty might be a manifestation of obesity. In a similar way, obesity in men affects fertility. Excess adipose tissue results in increased conversion of testosterone to estradiol, which may lead to secondary hypogonadism through reproductive axis suppression. Moreover, oxidative stress at the level of the testicular micro-environment may result in decreased spermatogenesis and sperm damage. Products of the adipocyte, such as leptin, adiponectin and resistin, and gut peptides, such as ghrelin, are considered to be crucial in the interaction between energy balance and reproduction. Finally, an indirect evidence for the interplay between MS and reproductive axis is the fact that when treating components of one, parameters of the other can be improved as well. These therapeutic interventions include lifestyle modifications, pharmacological agents, such as sex hormone replacement therapy, and surgical procedures. Although many issues remain unclear, the elucidation of the complex interaction between MS and reproductive axis will have obvious clinical implications in the therapeutic approach of both entities.

Serum total adiponectin in nonalcoholic fatty liver disease: a systematic review and meta-analysis.

Hypoadiponectinemia might represent a risk factor for nonalcoholic fatty liver disease (NAFLD). We performed a systematic review and meta-analysis to evaluate the serum total adiponectin levels in patients with simple nonalcoholic fatty liver (NAFL), those with nonalcoholic steatohepatitis (NASH), and controls. Data were extracted from PubMed, EMBASE, and Cochrane Central Register of Controlled Trials electronic databases (up to December 2009). The main outcome was the weighted mean differences (WMDs) in adiponectin between comparison groups. Twenty-eight studies were included in the systematic review. A meta-analysis of 27 studies that reported data on 2243 subjects (698 controls and 1545 patients with NAFLD) was performed. Controls had higher serum adiponectin compared with NAFL patients (12 studies, random-effects WMD [95% confidence interval {CI}] = 3.00 [1.57-4.43], I² = 80.4%) or NASH patients (19 studies, random-effects WMD [95% CI] = 4.75 [3.71-5.78], I² = 84.1%). The NASH patients demonstrated lower adiponectin compared with NAFL patients (19 studies, random-effects WMD [95% CI] = 1.81 [1.09-2.53], I² = 71.7%). By performing a meta-regression analysis, body mass index, age, sex, and type 2 diabetes mellitus failed to account for heterogeneity. However, the performance of liver biopsy on controls had significant effect on the outcome and accounted for 76.7%, 85.5%, and 22.8% of the between-study variance for comparisons between controls vs NAFLD, NAFL, and NASH patients, respectively. Based on liver histology, serum adiponectin levels are similar in NAFL patients and controls, but hypoadiponectinemia may play an important pathophysiological role in the progression from NAFL to NASH.

Ectopic thyroid tissue: anatomical, clinical, and surgical implications of a rare entity

Ectopic thyroid tissue is a rare entity resulting from developmental defects at early stages of thyroid gland embryogenesis, during its passage from the floor of the primitive foregut to its final pre-tracheal position. It is frequently found around the course of the thyroglossal duct or laterally in the neck, as well as in distant places such as the mediastinum and the subdiaphragmatic organs. Although most cases are asymptomatic, symptoms related to tumor size and its relationship with surrounding tissues may also appear. Any disease affecting the thyroid gland may also involve the ectopic thyroid, including malignancy. The clinician must distinguish between ectopic thyroid and metastatic deposits emerging from an orthotopic gland, as well as other benign or malignant masses. Thyroid scintigraphy plays the most important role in diagnosing ectopy, but ultrasonography contributes as well. In cases of symptomatic disease, surgery is the treatment of choice, followed by radioiodine ablation and levothyroxine suppression therapy in more refractory cases. This review provides current understanding about the wide clinical spectrum of this rare condition, also referring to optimal diagnostic approach, differential diagnosis, and management strategies.

Meta-analysis of cardiovascular disease risk markers in women with polycystic ovary syndrome

BACKGROUND The relation between polycystic ovary syndrome (PCOS) and cardiovascular disease (CVD) remains unclear. In an attempt to provide high-quality evidence on the relation between PCOS and CVD, relevant literature for CVD risk markers [C-reactive protein (CRP), homocysteine (Hcy), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1), lipoprotein (a) [Lp(a)], advanced glycation end-products (AGEs), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), asymmetric dimethylarginine (ADMA), endothelin-1 (ET-1) and fibrinogen] in women with PCOS was reviewed and analyzed. METHODS A systematic search was conducted electronically using specific eligibility criteria. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated and combined appropriately. To ensure synthesis of the best available evidence, sensitivity analyses were performed. RESULTS A total of 130 data sets were included in 11 different outcomes, involving 7174 and 5076 CVD markers in women with PCOS and controls, respectively. Women with PCOS demonstrated significantly elevated CRP [WMD (95% CI) 0.99 (0.77-1.21)], Hcy [2.25 (1.46-3.03)], PAI-1 antigen [16.96 (7.25-26.28)], PAI-1 activity [0.71 (0.18-1.23)], VEGF [1.72 (0.96-2.48)], ADMA [0.19 (0.08-0.3)], AGEs [3.91 (2.36-5.45)] and Lp(a) [0.81 (0.58-1.04)] concentrations compared with controls, yet with significant between-study heterogeneity. Borderline significance (not robust in the sensitivity analyses) was detected for TNF-α [0.75 (0.07-1.44)], ET-1 [1.06 (0.52-1.59)] and fibrinogen [0.20 (0.01-0.39)], whereas no difference was detected for IL-6 [0.71 (-0.16 to 1.59)]. CONCLUSIONS Women with PCOS have increased serum concentrations of CVD risk markers compared with controls. Whether this apparent risk is translated into increased incidence of CVD in later life remains to be elucidated.

Risk of spontaneous miscarriage in euthyroid women with thyroid autoimmunity undergoing IVF: a meta-analysis.

OBJECTIVE To investigate whether thyroid autoimmunity (TAI) is associated with increased risk for spontaneous miscarriage in subfertile, euthyroid women undergoing IVF. DESIGN Meta-analysis of observational studies. PATIENT(S) Four prospective studies that reported data on 1098 subfertile women undergoing IVF (141 with TAI and 957 controls) were included in the meta-analysis. MAIN OUTCOME MEASURE Miscarriage risk ratio (RR). SECONDARY OUTCOME MEASURES Clinical pregnancy rate and delivery rate. RESULT(S) Euthyroid, subfertile women with TAI undergoing IVF demonstrated significantly higher risk for miscarriage compared with controls (four studies-fixed effects RR: 1.99, 95% confidence interval: 1.42- 2.79, P<0.001). No significant difference in clinical pregnancy and delivery rates was detected between groups. CONCLUSION Based on the currently available evidence, it appears that the presence of TAI is associated with an increased risk for spontaneous miscarriage in subfertile women achieving a pregnancy through an IVF procedure.

Home care delivery through the mobile telecommunications platform: The Citizen Health System (CHS) perspective

Health delivery practices are shifting towards home care. The reasons are the better possibilities for managing chronic care, controlling health delivery costs, increasing quality of life and quality of health services and the distinct possibility of predicting and thus avoiding serious complications. For the above goals to become routine, new telemedicine and information technology (IT) solutions need to be implemented and integrated in the health delivery scene, and these solutions need to be assessed through evidence-based medicine in order to provide solid proof for their usefulness. Thus, the concept of contact or call centers has emerged as a new and viable reality in the field of IT for health and telemedicine. In this paper we describe a generic contact center that was designed in the context of an EU funded IST for health project with acronym Citizen Health System (CHS). Since the generic contact center is composed by a number of modules, we shall concentrate in the modules dealing with the communication between the patient and the contact center using mobile telecommunications solutions, which can act as link between the internet and the classical computer telephony communication means. We further elaborate on the development tools of such solutions, the interface problems we face, and on the means to convey information from and to the patient in an efficient and medically acceptable way. This application proves the usefulness of wireless technology in providing health care services all around the clock and everywhere the citizen is located, it proves the necessity for restructuring the medical knowledge for education delivery to the patient, and it shows the virtue of interactivity by means of using the limited, yet useful browsing capabilities of the wireless application protocol (WAP) technology.

The use of androgens or androgen-modulating agents in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis

BACKGROUND The aim of this meta-analysis was to evaluate the role of androgens or androgen-modulating agents on the probability of pregnancy achievement in poor responders undergoing IVF. METHODS Medline, EMBASE, CENTRAL, Scopus and Web of Science databases were searched for the identification of randomized controlled trials evaluating the administration of testosterone, dehydroepiandrosterone (DHEA), aromatase inhibitors, recombinant luteinizing hormone (rLH) and recombinant human chorionic gonadotrophin (rhCG) before or during ovarian stimulation of poor responders. RESULTS In two trials involving 163 patients, pretreatment with transdermal testosterone was associated with an increase in clinical pregnancy [risk difference (RD): +15%, 95% confidence interval (CI): +3 to +26%] and live birth rates (RD: +11%, 95% CI: +0.3 to +22%) in poor responders undergoing ovarian stimulation for IVF. No significant differences in clinical pregnancy and live birth rates were observed between patients who received DHEA and those who did not. Similarly, (i) the use of aromatase inhibitors, (ii) addition of rLH and (iii) addition of rhCG in poor responders stimulated with rFSH for IVF were not associated with increased clinical pregnancy rates. In the only eligible study that provided data, live birth rate was increased in patients who received rLH when compared with those who did not (RD: +19%, 95% CI:+1 to +36%). CONCLUSIONS Based on the limited available evidence, transdermal testosterone pretreatment seems to increase clinical pregnancy and live birth rates in poor responders undergoing ovarian stimulation for IVF. There is insufficient data to support a beneficial role of rLH, hCG, DHEA or letrozole administration in the probability of pregnancy in poor responders undergoing ovarian stimulation for IVF.

Gabapentin and pregabalin in the treatment of fibromyalgia: a systematic review and a meta-analysis

What is known and Objectives:  Fibromyalgia (FBM) is a common chronic pain disorder affecting up to 2% of the general population. Current treatment options are mostly symptom‐based and limited both in efficacy and number. Two promising alternatives are gabapentin (GP) and pregabalin (PB). We aimed to estimate the efficacy and safety/tolerability of the two compounds in FBM through a systematic review and a meta‐analysis of relevant randomized double‐blind placebo‐controlled (RCT) were performed.

Risk of gestational diabetes mellitus in women with polycystic ovary syndrome: a systematic review and a meta-analysis

OBJECTIVE To evaluate the risk of gestational diabetes mellitus (GDM) in women with polycystic ovary syndrome (PCOS). DESIGN Systematic review and meta-analysis of observational studies. SETTING Tertiary Department of Reproductive Endocrinology. PATIENT(S) Five thousand two hundred ninety-three pregnant women (721 with PCOS and 4,572 controls without PCOS). INTERVENTION(S) Literature search in the electronic databases MEDLINE, EMBASE, and CENTRAL, study of the references of all relevant trials or reviews, and manual search of the abstracts from the major meetings in the field of human reproduction. MAIN OUTCOME MEASURE(S) Gestational diabetes mellitus odds ratio. RESULT(S) Women with PCOS demonstrated a significantly higher risk for the development of GDM as compared with women without PCOS (odds ratio 2.89, 95% confidence interval [CI] 1.68-4.98), yet with significant statistical heterogeneity (I(2) = 59.3%), durable to sensitivity analysis. In the subgroup of cohort studies, this finding remained robust (7.11, 95% CI 2.95-17.12), whereas in the subgroup of case-control studies, it did not (0.89, 95% CI 0.38-2.06). Metaregression modeling revealed a linear dependence of the outcome on study type and baseline risk (post hoc). CONCLUSION(S) Significant heterogeneity among studies and dependence of the outcome on study type make the higher risk of GDM in women with PCOS a questionable finding. The conduction of properly designed studies should precede any recommendation to pregnant women with PCOS in regard to the risk of GDM.