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Background An efficient method for cryopreservation of human oocytes may offer solutions to legal and ethical problems in routine infertility programs and may also be used for fertility preservation for medical and social reasons. Methods We conducted an observational longitudinal cohort multicentric study to investigate the efficacy and reproducibility of oocyte cryopreservation outcomes in IVF/ICSI cycles. Moreover, the effects of patient and cycle characteristics on the delivery rate (DR) were analyzed. Results In 486 cycles performed in 450 couples, 2721 oocytes were warmed and 2304 of them survived cryopreservation (84.7%). Of the 2182 oocytes subjected to ICSI, the rates of fertilization and development to top-quality embryos were 75.2 and 48.1%, respectively. A total of 128 deliveries were obtained (26.3% per cycle and 29.4% per transfer) for 450 patients (28.4%) and 147 babies were live born from 929 embryos transferred (15.8%). The forward logistic regression analysis on a per patient basis showed that female age [odds ratio (OR): 0.93, 95% confidence interval (CI): 0.88-0.98], number of vitrified oocytes (OR: 1.08, 95% CI: 1.01-1.17) and the day of transfer (OR: 1.97, 95% CI: 1.14-3.42) influenced DR. By recursive partitioning analysis, it can be estimated that more than eight oocytes vitrified are required to improve the outcome (22.6 versus 46.4% DR, respectively). When fewer oocytes are available in women aged >38 years, results are dramatically reduced (12.6 versus 27.5% DR, respectively). Conversely, when >8 oocytes are available, blastocyst culture represents the most efficient policy (62.1% DR; data from one center only). Conclusions Oocyte vitrification is an efficient and reliable approach, with consistent results between centers and predictable DRs. It should be applied routinely for various indications. A predictive model is proposed to help patient counselling and selection.

Objective We have conducted a longitudinal observational study in order to evaluate the prevalence and the incidence of depressive and anxious symptoms in women and men seeking infertility treatment and to analyze associated factors or risk factors for these kinds of disorders. Study design A total of 1000 consecutive couples that visited our center for the first time were asked to join this study. Depressive and anxious symptoms were assessed with self-rating Zung Depression Scale (ZDS) and Zung Anxiety Scale (ZAS) questionnaires. A second assessment was planned at the time of β HCG dosage (or at the moment of cycle suspension). A standard questionnaire was used to investigate socio-demographic information and the psychological aspects of couples undergoing in vitro fertilization (IVF) treatment. The fertility history and outcome of IVF treatment were collected from patients’ medical records. Results 14.7% of women had anxious symptoms and 17.9% depressive symptoms, whereas 4.5% of men had anxious symptoms and 6.9% depressive symptoms. Women with depressive and anxious symptoms were younger, more often had an anxious partner and had a longer history of infertility. Men with depressive and anxious symptoms more frequently had a temporary job, they had an anxious partner and they were more frequently at the first in vitro fertilization (IVF) cycle. The incidence of depressive and/or anxious symptoms was 18.5% in women and 7.4% in men. Age and previous IVF treatments seem not to be associated with incidence of depressive or anxious symptoms. Conclusion Both the prevalence and incidence of depressive and/or anxious symptoms in couples undergoing IVF treatment were worthy of note and should not be underestimated. More attention must be paid to psychological aspects in young women and in couples with a long history of infertility or previous failure treatments. Having an anxious partner was associated with anxious and depressive symptoms. For this reason, both males and females might benefit from psychological intervention, which could also help them to be supportive to each other.

Background A possible and neglected concern in women with endometriosis undergoing IVF is the potential risk of progression of the disease. We set up a prospective study mainly aimed at evaluating the impact of IVF on endometriosis-related symptoms. Materials and methods Women with surgical or echographic diagnosis of endometriosis and selected for IVF were included. In the month preceding the IVF attempt and at a second evaluation 3-6 months after the cycle, women who did not get pregnant underwent clinical assessment and transvaginal ultrasonography. Each patient was requested to complete a questionnaire on the presence, severity and modifications of endometriosis-related symptoms before and after the IVF cycle. Results Overall, 64 patients completed the study protocol. The Biberoglu-Behrman Scores and the Verbal Rate Scales for dysmenorrhea, dispareunia and chronic pelvic pain did not worsen after the procedure. Other endometriosis-related symptoms also did not change. There was no modification in size and number of endometriomas and deep peritoneal nodules. The number (%) of women reporting general improvement and worsening were 14 (22%) and 7 (11%), respectively. Conclusions IVF does not expose women to a consistent risk of endometriosis-related symptoms progression.

The aim of the present study was to compare an 'open' vitrification protocol to a 'closed' vitrification protocol for mature human oocytes. A prospective comparison between fresh and sibling vitrified oocytes and a retrospective comparison between the two vitrification protocols were performed. For recruited patients undergoing an IVF cycle, two or three fresh oocytes were inseminated with intracytoplasmic sperm injection (ICSI) and the remaining three or more oocytes were vitrified according to manufacturer's instructions with a 'closed' or an 'open' vitrification system. After an unsuccessful fresh cycle, oocytes were warmed and inseminated with ICSI. Embryological parameters were recorded and compared between fresh and sibling vitrified oocytes (intrapatient) as well as between the two vitrification techniques (interpatient). Oocytes vitrified with the 'closed' system showed significantly lower fertilization and cleavage rates and a reduction in the quantity and quality of obtained embryos compared with fresh sibling oocytes (P

Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease leading to worsening functional status and reduced survival for those patients who cannot undergo pulmonary endarterectomy (PEA). Pharmacotherapy with novel drugs for pulmonary hypertension may be useful in treating patients who are poor candidates for surgery, but there are still few clinical data on medical therapy for CTEPH. The aim of this prospective open-label, multicenter, study is to compare the efficacy of 1-year bosentan treatment to standard drugs in nonoperated patients with CTEPH.Thirty-four nonoperated patients with CTEPH were enrolled. Functional assessment included 6 minute walk test (6MWT), Borg index, WHO classification, arterial blood gases and echocardiography systolic pulmonary artery pressure (sPAP). Seventeen patients received bosentan (62.5 mg b.i.d. for 4 weeks and then 125 mg b.i.d.); 17 patients were treated with standard therapy alone.At admission sPAP was 76.18+/-5.96 mmHg in bosentan group and 71.48+/-3.71 mmHg in controls, p(a)O(2) 64.68+/-2.25 mmHg in bosentan group, and 59.52+/-2.05 mmHg in controls, 6MWT 297.53+/-34.25 mt in bosentan group, and 268.47+/-36.54 mt in controls. After 12 months there were significant differences between the groups in the 6MWT (+57.24+/-22.21 m vs -73.13+/-21.23 m, p0.001), dyspnoea index (Borg score 4.29+/-0.49 vs 7.06+/-0.32, p0.001) and oxygenation (p(a)O(2) 65.93+/-3.76 mmHg vs 48.48+/-1.31 mmHg, p0.001). The sPAP was stable after 12 months of bosentan (76.18+/-5.96 mmHg vs 71.00+/-5.41 mmHg, p=0.221) in contrast to controls (71.48+/-3.71 mmHg vs 80.44+/-4.70 mmHg, p=0.029).The data of this open-label study in nonoperated CTEPH patients suggest an improvement in functional outcomes adding Bosentan to diuretics and oral anticoagulants. No improvement was observed using only standard drugs after 1-year.

To evaluate the influence of IVF on the dimension of leiomyomas, we selected 72 women with small intramural or subserosal leiomyomas and assessed the size of these lesions before and after the treatment cycle. The mean ± SD diameters of the tumors at these two time points were 20.5 ± 9.5 and 20.6 ± 10.2 mm, respectively, thus supporting the conclusion that IVF does not influence the growth of these lesions.

In 2010 a Cochrane review confirmed that folic acid (FA) supplementation prevents the first- and second-time occurrence of neural tube defects (NTDs). At present some evidence from observational studies supports the hypothesis that FA supplementation can reduce the risk of all congenital malformations (CMs) or the risk of a specific and selected group of them, namely cardiac defects and oral clefts. Furthermore, the effects on the prevention of prematurity, foetal growth retardation and pre-eclampsia are unclear. Although the most common recommendation is to take 0.4 mg/day, the problem of the most appropriate dose of FA is still open. The aim of this project is to assess the effect a higher dose of peri-conceptional FA supplementation on reducing the occurrence of all CMs. Other aims include the promotion of pre-conceptional counselling, comparing rates of selected CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age, abruptio placentae. This project is a joint effort by research groups in Italy and the Netherlands. Women of childbearing age, who intend to become pregnant within 12 months are eligible for the studies. Women are randomly assigned to receive 4 mg of FA (treatment in study) or 0.4 mg of FA (referent treatment) daily. Information on pregnancy outcomes are derived from women-and-physician information. We foresee to analyze the data considering all the adverse outcomes of pregnancy taken together in a global end point (e.g.: CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age). A total of about 1,000 pregnancies need to be evaluated to detect an absolute reduction of the frequency of 8%. Since the sample size needed for studying outcomes separately is large, this project also promotes an international prospective meta-analysis. The rationale of these randomized clinical trials (RCTs) is the hypothesis that a higher intake of FA is related to a higher risk reduction of NTDs, other CMs and other adverse pregnancy outcomes. Our hope is that these trials will act as catalysers, and lead to other large RCTs studying the effects of this supplementation on CMs and other infant and maternal outcomes. Italian trial: ClinicalTrials.gov Identifier: NCT01244347 . Dutch trial: Dutch Trial Register ID: NTR3161 .

The role of non-invasive nocturnal domiciliary ventilation (NNV) in chronic obstructive pulmonary disease (COPD) patients with chronic hypercapnia is still discussed. The aims of this study were to evaluate the long-term survival, the clinical effectiveness and side-effects of NNV in these patients. Forty-nine stable hypercapnic COPD patients on long-term oxygen therapy (LTOT) were assigned to two groups: in Group 1, 28 patients performed NNV by pressure support modality in addition to LTOT; in Group 2, 21 patients continued their usual LTOT regimen. Treatment was assigned according to the compliance to NNV, after an in hospital period. Mortality rate, hospital stay (HS) and ICU admissions (IA) were recorded in the two groups. HS and IA were compared to those recorded in a similar period of follow-back. Lung and respiratory muscle function, dyspnoea, and exercise capacity (by 6-min walk test) were evaluated baseline and every 3-6 months up to 3 yr. Mean follow-up time was 35 +/- 7 months. Mortality rate was not different between the two groups: 16, 33, 46% and 13, 28, 50% at 1, 2 and 3 yr in Groups 1 and 2 respectively. Lung and respiratory muscle function did not significantly change over time. A significant increase in 6-min walk test (from 245 +/- 78 to 250 +/- 88, 291 +/- 75, 284 +/- 89 m after 1, 2 and 3 yr respectively, P < 0.01) was observed only in patients undergoing NNV. In comparison to the follow back HS significantly decreased in both groups (from 37 +/- 29 to 15 +/- 12 and from 32 +/- 18 to 17 +/- 11 days/pt/yr in Groups 1 and 2 respectively, P < 0.001) whereas IA significantly decreased only in patients performing also NNV (from 1.0 +/- 0.7 to 0.2 +/- 0.3/pt/yr, P < 0.0001). Addition of NNV by pressure support modality to LTOT does not improve long term survival but significantly reduces ICU admissions and improves exercise capacity in severe COPD with hypercapnia.

BACKGROUND There is a growing consensus that ovarian endometriomas should not be systematically removed in women selected for IVF. However, some recent evidence suggested that the presence of these cysts may negatively affect the course of pregnancy. METHODS We set up a multicenter retrospective cohort study, including two infertility units. We analyzed data from patients achieving singleton clinical pregnancies through IVF comparing the pregnancy outcome between 78 pregnant women with endometriomas at the time of IVF and 156 patients who achieved pregnancy through IVF without endometriomas. RESULTS The number of live births in women with and without endometriomas were 61 (78%) and 130 (83%), respectively (P = 0.39). The adjusted odds ratio (OR) of live birth in affected cases was 0.79 [95% confidence interval (CI): 0.38-1.68]. No differences were observed in late pregnancy and neonatal outcomes between the two groups. In particular, the rate of preterm birth and small-for-gestational age (SGA) was similar. The adjusted ORs were 0.47 (95% CI: 0.14-1.54) and 0.56 (95% CI: 0.12-2.56), respectively. CONCLUSIONS Women with endometriomas achieving pregnancy through IVF do not seem to be exposed to a significant increased risk of obstetrical complications.

background: The impact of fibroids, not encroaching the endometrial cavity, have on the rate of success of IVF is still controversial. Recent meta-analyses suggest a detrimental effect of intramural lesions but not subserosal lesions. However, they also emphasize the need for further evidence. In order to elucidate this, we designed a prospective cohort study to compare the rate of success of IVF in women with and without fibroids. methods: Exposed women were those with asymptomatic intramural or subserosal fibroids with a diameter below 50 mm and who were selected for IVF. Unexposed women were those free of fibroids, who were matched to cases by age and number of previous IVF cycles. All recruited patients underwent hystero-sonography to rule out intra-cavitary lesions. results: There were 119 cases and 119 controls recruited. The number of clinical pregnancies in women with and without fibroids was 28 (24%) and 22 (19%), respectively (P ¼ 0.43). The adjusted odds ratio (OR) for pregnancy in affected women was 1.38 [95% confidence interval (CI): 0.73 –2.60]. The number of deliveries was 22 (18%) and 16 (13%), respectively (P ¼ 0.38). The adjusted OR was 1.45 (95% CI: 0.71 –2.94). Similar results emerged when focusing exclusively on women carrying intramural lesions (n ¼ 80 couples). There was no significant relationship between clinical outcome and either the number or size of the fibroids. conclusions: In asymptomatic patients selected for IVF, small fibroids not encroaching the endometrial cavity did not impact on the rate of success of the procedure.

To develop an experimental model to assess the feasibility of polar body preimplantation genetic diagnosis without requiring oocyte fertilization. First polar body was removed from donated oocytes and second polar body was biopsied after parthenogenetic activation. Molecular analysis on both polar bodies involved a fluorescent multiplex polymerase chain reaction of short-tandem repeat markers, closely linked to genes of interest. Main outcome measures were: allele segregation through polar bodies and haploid nucleus, recombination rates between alleles and frequency of Allele Drop Out. Twenty-six out of 39 oocytes extruded a second polar body after activation. Ninety-two percent of the first polar bodies and 20 out of 26 (77%) second polar bodies were successfully amplified. Eighty percent of first polar bodies were heterozygous for CFTR and 55% for HBB. Analysis of second polar bodies predicted the genotype of the oocytes in case of heterozygous first polar body, and validated results in homozygous cases. Frequency of allele drop out was 4%. Our model confirms that polar body preimplantation genetic diagnosis for single gene disorders can be evaluated using parthenogenetic oocytes and offers an option to set up procedures without requiring oocyte fertilization.

To develop a procedure for the analysis of gene expression in cumulus cells during the interval between ovum pick up and insemination to select the best oocytes for fertilization.Five RNA extraction methods, three reverse transcription procedures followed by Real-time quantitative PCR and one single-step mRNA quantification kit were tested to measure the expression of five genes in cumulus cells.Two RNA extraction kits gave the best combination of efficiency and purity. One reverse transcription procedure gave the best speed and efficiency. The single-step kit required more biological material than would be available from single cumulus oocyte complexes (COCs).Our test identified a combination of RNA extraction and reverse transcription procedures that enables the level measurement of 5 selected cumulus cell transcripts within 4 h. Using this combination it was possible to obtain a reliable quantification of gene expression in 44 out of 46 individual COCs collected from seven patients.

Background/Aims: Limited information is available regarding the quantity of blood loss associated with uncomplicated transvaginal oocyte retrieval. The aim of the present study was evaluating the quantity of such a loss. Methods: One hundred and fifty consecutive women undergoing oocyte retrieval were recruited. They underwent blood test assessment and ultrasonographic transvaginal evaluation at three different times: (1) immediately before initiating oocyte retrieval, (2) 4–6 h later, and (3) 72 h later. Results: At 4–6 h after oocyte retrieval, the red blood cell count and the hemoglobin concentration were significantly reduced, whereas pelvic free fluid had significantly increased. The estimated median (Interquartile range) blood loss was 72 (–8/162) ml. None of the recruited women was found to have a hemoglobin reduction >2 g/day or an increase in the pelvic free fluid >200 ml or a calculated blood loss >500 ml (0.0%, 95% CI: 0.0–2.4%). No significant worsening from baseline was observed at the 72 h evaluation. Conclusions: The quantity of blood loss following oocyte retrieval is clinically unremarkable in the vast majority of women.

Central venous catheters (CVCs) are widely used for therapeutic purposes and to measure hemodynamic variables that cannot be recorded from a peripheral vein. However, the method can involve complications. In cardiac surgery, CVCs are electively placed in the right internal jugular vein but there is little information on deep venous thrombosis (DVT) in catheterized veins (CVC-related DVT) or on secondary pulmonary embolism (PE). The impact of CVC-related DVT and PE in cardiac surgery and measures to prevent PE were assessed. We used ultrasonography (US) to check the point of insertion of CVC in 815 patients in the intensive cardiac rehabilitation unit after heart surgery. In this series, 386 patients (48%) had CVC-related DVT; those already receiving anticoagulant, and considered at low risk, continued that therapy, while those taking an antiplatelet agent (aspirin 100 mg daily) but deemed at high risk of PE from the US findings were given an anticoagulant instead. Only patients with CVC-related DVT at low risk of PE continued taking aspirin. At 3 months, there were no cases of PE among patients receiving an anticoagulant, but six on antiplatelet had non-fatal PE. The prevalence of PE in the whole series of 815 patients was 0.7%. CVC-related DVT is a frequent complication of heart surgery. Anticoagulant therapy started early does not prevent thrombus formation but probably prevents PE, whereas antiplatelet gives no such protection. Sonographic screening of the CVC removal in intensive care unit may be useful for avoiding PE after CVC-related DVT.

Objective The rationale of the clomiphene citrate challenge test (CCCT) is that day 10 serum FSH is influenced by the quality of the recruited oocytes. Biological evidence supporting this assumption is, however, lacking. The aim of this study is to investigate the relationship between results from the CCCT and the quantity and the quality of the recruited oocytes. Study design Patients selected for in vitro fertilization (IVF) and who were found to have elevated basal FSH (n = 114) underwent an IVF cycle using follicles developing during CCCT. Subsequently, a subgroup of patients (n = 89) underwent a second cycle receiving high doses of gonadotropins. The main outcome considered was the transfer of viable embryos. Results During the CCCT cycle, the area under the receiver operating characteristics (ROC) curves for day 3 and day 10 serum FSH to predict embryo-transfer was 0.48 (95% CI, 0.37–0.60) and 0.74 (95% CI, 0.63–0.82), respectively. In the subsequent cycle, the area under the ROC curves for the two variables was 0.58 (0.43–0.72) and 0.58 (0.43–0.72), respectively. Conclusions CCCT effectively mirrors the quantity and the quality of the recruited oocytes but its predictive value is low.

Cardiovascular complications are frequently observed in patients with chronic obstructive pulmonary disease (COPD) admitted to respiratory intensive care units and may affect the prognosis. The aims of this study were to evaluate a) the prevalence of cardiovascular complications in patients with COPD exacerbation admitted to respiratory intensive care units, b) which parameters detected at admission were predictive of cardiovascular complications, and c) the prognostic role of cardiovascular complications.A series of 278 consecutive patients with COPD admitted to 11 Italian respiratory intensive care units between November 1997 and January 1998 has been retrospectively analyzed. All cardiovascular complications were recorded.One hundred and ten patients (39.6%) developed cardiovascular complications: congestive heart failure 49 (17.6%), arrhythmias 40 (14.4%), shock 13 (4.7%), and hypotension 11 (4%). Multivariate analysis showed that the APACHE II score, ECG abnormalities (supraventricular ectopic beats, right and/or left ventricular hypertrophy) and digoxin therapy were independent predictors of cardiovascular complications. The overall mortality was 9% being 4.7% in patients without and 15.5% in patients with cardiovascular complications (p = 0.0044). Multivariate analysis showed that the APACHE II score, respiratory rate, pneumonia and end-stage respiratory diseases were independent predictors of mortality.Cardiovascular complications occurred in many patients with COPD exacerbation admitted to respiratory intensive care units, and identify a subset of patients with higher mortality.

BACKGROUND Oesophageal leiomyomas are usually so easily removed that thoracotomy seems out of proportion and thoracoscopic removal is therefore highly desirable. METHODS Out of a total of 1003 thoracoscopic operations undertaken between July 1991 and December 1996, seven patients underwent thoracoscopic removal of oesophageal leiomyoma. All of them had been preoperatively studied by oesophagogastroscopy and computed tomographic scanning of the chest which had confirmed the presence of a lesion with benign features. The surgical technique required intubation with a double lumen tube. Operative access was gained through the right chest via three ports and a small utility thoracotomy in the inframammary sulcus. The mean operating time was 120 minutes. RESULTS Conversion to open thoracotomy was necessary in one case with a very large horseshoe-shaped leiomyoma which was firmly adherent. The mean postoperative hospital stay was seven days. No intraoperative deaths or postoperative complications occurred. CONCLUSIONS The simplicity and safety of the thoracoscopic approach, combined with reduced surgical trauma and postoperative pain and functional and cosmetic advantages, make this technique the approach of choice for the removal of oesophageal leiomyomas.

Laparoscopic cholecystectomy is considered the gold standard for cholelithiasis. Nevertheless possible complications must not be underestimated. In this department, from 1 July 1991 to 30 November 1995, 1005 patients with cholelithiasis underwent videocholecystectomy. There was no peri-operative mortality. In 36 cases (3.6%) the procedure was changed to laparotomy. In four cases (0.4%) conversion was mandatory due to severe complications: in three patients while introducing a trocar (one aortic lesion, one middle colic vein injury and one visceral perforation) and in one patient due to bleeding in the hepatic hilar region. In 32 cases (3.2%) conversion was carried out electively. This was due to technical difficulties or to choledocholithiasis (22 patients), anaesthesiological problems (three cases), biliodigestive fistula (one), bile spillage from accessory hepatic ducts (three), unexpected colonic cancer (one), instrument malfunction (two cases). Twenty-four patients (2.4%) experienced post-operative complications: one with pneumothorax, two with bile leakage (one bile duct damage, and one cystic duct leakage), eight with haemoperitoneum, five with subphrenic abscess, three with anaemia, three with intraparietal collections, one with bilateral basal bronchopneumonia, one with perforated duodenal stress ulcer. Of these, 11 patients (1%) underwent reintervention: five re-laparoscopies, three conversions, and three open laparotomies. This study demonstrates the safety of videolaparocholecystectomy. Complications are relatively rare and can be often dealt with conservative treatment or re-laparoscopy. Complications are often linked to insertion of a blind trocar or to the induction of a closed pneumoperitoneum. Meticulous technique or open laparoscopy minimize these risks. Conversion must not be considered a defeat but a wise decision in the face of major difficulties. Under these principles, videocholecystectomy is safe and represents the best treatment of gallbladder stones.

The complications of endotracheal intubation are particularly frequent in patients with obstructive sleep apnoea syndrome (OSAS). We prospectively tested nasal ventilation in such patients admitted for acute respiratory failure. Six consecutive patients, aged 17-70 yrs, were selected for the study. All patients were confused or severely obtunded, Glasgow Coma Score (GCS) 10 (SD 2). With nasal bi-level positive airways pressure (BiPAP) all these patients improved clinical status and arterial blood gas values, avoiding intubation and invasive mechanical ventilation. The median pH increased from 7.26 (SD 0.06) to 7.36 (0.01) and to 7.43 (0.02) after, 1-3 and 24 h of nasal ventilation, respectively. Nasal ventilation lasted an average of 21 (3) h on the first day. All patients were discharged home after a median hospital stay of 28 (11) days.

Echoguided transvaginal oocyte retrieval gives good results even when carried out after a short training course. This study compares the results obtained by a group of physicians with long experience and a newly-trained group. No significant differences were found in the percentages of follicles punctured (87.9% vs 91.9%), of oocytes recovered (62.8 vs 70.6%), in the mean number of follicles aspirated (4.5 vs 4.1) or in duration of the procedure (33.9 min vs 34.2 min). No complications occurred in the retrieval and the patients, pain was very slight.

One hundred ninety-one hyperprolactinemic patients (178 women and 13 men; 54 with pituitary macroadenoma, 53 with microadenoma, and 84 with idiopathic disease) were treated for 2 to 48 months with one or two of the following prolactin (PRL)-lowering drugs: bromocriptine, metergoline, and lisuride. All of the three drugs used were highly effective in lowering PRL levels and restoring gonadal function both in females and in males in the majority of patients with either idiopathic or tumorous disease. In poorly responsive patients, increasing the drug doses resulted in further PRL lowering for all the three drugs. Mild side effects were frequently encountered with initiation of drug treatment but spontaneously subsided in most cases; severe side effects, necessitating stopping of the treatment, occurred in only 12 instances, but changing of the drug allowed PRL-lowering treatment to be continued in 11 of them.

29 pregnancies occurred spontaneously in 28 women with mild to moderate hyperprolactinemia (prolactin levels up to 100 ng/ml). Only 4 of them showed tomographic evidence of microprolactinoma; 1 of the prolactinoma patients experienced a visual field defect at week 30, which was quickly controlled by bromocriptine treatment. Pregnancy was uneventful in the rest of the patients. Subjects who wished to lactate successfully breast-fed their babies. Of 22 women in whom prolactin levels were reevaluated at least 1 month after delivery and/or lactation, normal values were found in 9.

To investigate the effect of dopaminergic stimulation on gonadotrophin release, serum LH and FSH concentrations were measured during dopamine infusion (5 μg/kg/min for 120 min) in 8 healthy women in the early follicular phase, in 12 patients with hyperprolactinaemic amenorrhoea, in 5 subjects with premature ovarian failure and in 8 with polycystic ovarian disease and raised serum LH levels. Dopamine infusion produced a significant LH decrease compared with a control study using saline in all groups; there were no significant changes in FSH concentration. Between groups analysis showed a significantly greater LH fall in patients with polycystic ovarian disease than in the other groups. Dopamine inhibits LH release in healthy women and patients with anovulatory states of varying aetiology, and enhanced sensitivity to this inhibitory mechanism exists in polycystic ovarian disease. This finding suggests reduced dopamine activity at the median eminence level in this condition.

All IVF programs have a consistent rate of failure in inducing ovulations. Pharmacological induction of ovulation is otherwise crucial for an IVF program because of the need for more than one ovum. Since it is well known that the best candidates for HMG treatment are hypogonadotropic women a short reversible hypogonadotropic state was induced in IVF patients by LH-RH agonist (Buserelin). Superovulation was then achieved with very high initial doses of FSH (Metrodin) in order to maximize the ovarian response. This technique used in 116 IVF women induced a satisfactory follicle growth even in 70% of the patients already poorly responsive to HMG stimulation.

Multiple ovulation was induced in 122 hypogonadotrophic IVF patients with large doses of HMG. The hypogonadotrophic state, short and reversible, was obtained by nasal administration of a GnRH agonist (200 micrograms, five times per day). In the 97 induced cycles, a mean of 9.1 follicles was recorded. A comparison of the results obtained for 36 patients who had already been treated with clomiphene and HMG showed both significantly more follicles per cycle (8.5 versus 3.0) and an increase in oocytes retrieved (6.7 versus 1.3) when treated with the agonist and HMG. In addition 11 of 18 already poorly responsive patients had normal responses. The luteal phase was supported by either HCG or progesterone injection. Plasma progesterone profiles were satisfactory and, as expected, the highest progesterone concentrations were associated with HCG treatment.

This paper reports the changes in prolactin levels after 12 spontaneous and 52 induced pregnancies in 54 women with unambiguous hyperprolactinaemia (median plasma prolactin levels 67.5 ng/ml, range 40-400). Twenty-three of the patients showed radiological evidence of prolactinoma. The pregnancies were induced in 37 patients by bromocriptine, in nine by metergoline, in two by lisuride and in four by other treatments. Of the 64 pregnancies, 16 ended in spontaneous abortion, while 48 went to term. Follow-up was continued for at least 6 months after delivery or until the end of lactation. In a control group of 32 hyperprolactinaemic women (median prolactin 70 ng/ml, range 40-400) not wishing to become pregnant, prolactin changes were similarly registered over a mean period of 15 months without any treatment (range 6-38 months). After pregnancy, a significant downward trend of plasma prolactin was observed in the puerperal women with a 'normalization' rate of 17%. No changes were observed in the 32 controls who did not become pregnant.

The PRL response to the dopamine antagonists sulpiride (100 mg i.m.) or domperidone (2 or 8 mg i.v.) was evaluated in healthy controls and in 148 patients with different hyperprolactinemic disorders (50 with idiopathic hyperprolactinemia, 58 with microprolactinoma, 19 with macroprolactinoma, 2 with empty sella, 8 with acromegaly, 7 with organic lesions of the hypothalamus, and 4 with idiopathic hypopituitarism of presumed hypothalamic origin). Mean PRL response to both drugs was significantly lower in all groups of patients than in controls, and significantly higher in subjects with idiopathic hyperprolactinemia than in those with pituitary adenomas or hypothalamic disease. Absent or impaired PRL responses were found in 38% of idiopathic patients, in 91.5% of microprolactinomas and in all of the patients with either macroprolactinoma, acromegaly, or hypothalamic disorders. Since the PRL response to dopamine antagonists depends on the presence of an endogenous dopaminergic tone, it is suggested that these figures reflect the incidence of major dopamine deficiency at pituitary lactotrophs in different hyperprolactinemic states. These data suggest that the pathophysiology of hyperprolactinemia in many patients with idiopathic disease is different from that of microprolactinoma. However, the finding of a normal PRL response to sulpiride in some subjects with radiologically or surgically proven microprolactinoma indicates that this test has no diagnostic value in the individual case.

Sixty-nine pregnancies were observed in 57 hyperprolactinemic women (5 with pituitary macroadenoma, 20 with microadenoma, and 32 with normal tomography of the sella turcica). Ten of these pregnancies took place spontaneously in women with mild to moderate hyperprolactinemia (up to 70 ng/ml); 2 were induced by exogenous gonadotropins, 2 by clomiphene, 42 by bromocriptine, and 9 by metergoline; and 4 occurred after pituitary selective adenomectomy. The observed complications included spontaneous abortion (10 cases); headache (7 cases); sellar enlargement (5 cases); and bitemporal hemianopsia (1 subject with macroadenoma). Among 24 women in whom prolactin levels were reevaluated at least 1 month after parturition and/or lactation, 8 showed a decrease in prolactin concentration (less than 50% of pregestational levels), with actual prolactin normalization in 3 and resumption of cyclic menses in 2 previously amenorrheic women. In contrast, no changes in prolactin levels occurred after pregnancies that ended in abortion. These data suggest the following: 1) conception is not uncommon in women with moderate hyperprolactinemia; and 2) pregnancy may be safely induced without prior surgery and/or radiotherapy in hyperprolactinemic women, except those with large pituitary adenomas, and a considerable number of these patients even show a clinical and biochemical improvement after pregnancy.

PRL secretory dynamics were evaluated by several stimulation and suppression tests in nine patients with hyperprolactinemia due to organic hypothalamic disease. Basal PRL levels ranged between 20-63 ng/ml. There was a normal PRL response to TRH in eight cases (i.e. doubling of basal levels), whereas none of the seven tested subjects responded to sulpiride. The same dissociation of responses was not observed in any of the patients who were still hyperprolactinemic after surgery. Concomitant dopamine infusion resulted in sulpiride-induced PRL release in the four subjects so studied. None of 50 other hyperprolactinemic patients (11 with macroprolactinoma, 18 with microprolactinoma, and 21 with idiopathic hyperprolactinemia) showed PRL response to TRH but not to sulpiride. The TRH-induced PRL increase was significantly higher than that induced by sulpiride in hypothalamic hyperprolactinemia and significantly lower in idiopathic disease as well as in healthy controls; no differences were found in prolactinoma patients. The administration of substances resulting in stimulation of pituitary dopamine receptors, such as dopamine and L-dopa, induced a normal PRL suppression in 7 patients with hypothalamic disease so tested, whereas central nervous system-acting dopaminergic drugs, such as carbidopa plus L-dopa and nomifensine, failed to lower PRL levels in most cases (even when normoprolactinemic after surgery). These data suggest that the mild to moderate hyperprolactinemia found in many patients with hypothalamic lesions is due to dopamine deficiency at the pituitary level, that TRH and dopamine receptors at the lactotropes are intact in this condition, and that paired TRH and sulpiride tests may be of some diagnostic utility in hyperprolactinemic patients. They further suggest that subjects with so-called idiopathic hyperprolactinemia do not suffer from the type of hypothalamic derangement exhibited by patients with organic lesions of the hypothalamus.

The effects of two different doses (40 and 80 mg orally) of fenfluramine on serum prolactin (PRL) levels have been evaluated in healthy and hyperprolactinemic women and compared with those of the potent dopamine antagonist sulpiride (100 mg i.m.). The lower fenfluramine dose resulted in a significant PRL rise in healthy women (n = 16) but not in hyperprolactinemics (n = 14). A dose-response effect was shown between 40 and 80 mg in control subjects (n = 7); in 4 hyperprolactinemics the higher dose also failed to increase PRL levels. Sulpiride resulted in a much greater PRL response. Since fenfluramine at the low doses used does not seem to exert antidopaminergic action, it is suggested that the mild PRL stimulation observed be mediated by the known brain serotoninergic activation induced by the drug.

Background The aim of the present randomised controlled non-inferiority trial is to test whether in women with compromised ovarian reserve requiring in vitro fertilisation, a protocol of ovarian stimulation using exclusively clomiphene citrate performs similarly to a regimen with high doses of gonadotropins. Methods Women with day 3 serum FSH > 12 IU/ml on at least two occasions or previous poor response to hyper-stimulation were recruited at four Italian infertility units. Selected women were allocated to clomiphene citrate 150 mg/day from day 3 to day 7 of the cycle (n=145) or to a short protocol with GnRH agonist 0.1 mg and recombinant FSH 450 IU daily (n=146). They were randomised by means of a computer-generated list into two groups. The study was not blinded. The main outcome of the study was the delivery rate per started cycle. Results The study was interrupted after the scheduled two years of recruitment before reaching the sample size. 148 women were allocated to clomiphene citrate and 156 to the short protocol with high doses of gonadotropins; 124 and 125 participants were analysed in the groups, respectively. Women allocated to high doses of gonadotropins retrieved more oocytes and had a higher probability to perform embryo-transfer. However, the chances of success were similar. The delivery rate per started cycle in women receiving clomiphene citrate and high-dose gonadotropins was 3% (n=5) and 5% (n=7), respectively (p=0.77). The mean estimated cost per delivery in the two groups was 81,294 and 113,107 Euros, respectively. No side-effects or adverse events were observed. Conclusions In women with compromised ovarian reserve selected for in vitro fertilisation, ovarian stimulation with clomiphene citrate or high-dose gonadotropins led to similar chances of pregnancy but the former is less expensive. Trial registration Trial registered on http://www.clinicaltrials.gov (NCT01389713)