Histone H3 E50K mutation confers oncogenic activity and supports an EMT phenotype.

Sequencing of human patient tumors has identified recurrent missense mutations in genes encoding core histones. We report that mutations that convert histone H3 amino acid 50 from a glutamate to a lysine (H3E50K) support an oncogenic phenotype in human cells. Expression of H3E50K is sufficient to transform human cells as evidenced by a dramatic increase in cell migration and invasion, and a statistically significant increase in proliferation and clonogenicity. H3E50K also increases the invasive phenotype in the context of co-occurring BRAF mutations, which are present in patient tumors characterized by H3E50K. H3E50 lies on the globular domain surface in a region that contacts H4 within the nucleosome. We find that H3E50K perturbs proximal H3 post-translational modifications globally and dysregulates gene expression, activating the epithelial to mesenchymal transition. Functional studies using S. cerevisiae reveal that, while yeast cells that express H3E50K as the sole copy of histone H3 show sensitivity to cellular stressors, including caffeine, H3E50K cells display some genetic interactions that are distinct from the characterized H3K36M oncohistone yeast model. Taken together, these data suggest that additional histone H3 mutations have the potential to be oncogenic drivers and function through distinct mechanisms that dysregulate gene expression.

Retrospective Review of Acute Renal Colic Management in the Emergency Department and Review of Guidelines.

INTRODUCTION: The influence of multispecialty guidelines on practice patterns in the emergency department is unknown. We documented practice patterns in our emergency department among patients presenting with acute renal colic. METHODS: We identified practice patterns in the treatment of nephrolithiasis in our emergency department via a retrospective chart review of 469 patients from 2013 to 2015. We compared practice patterns to available guidelines over the domains of 1) diagnostic and imaging studies, 2) medications and 3) referral to urology. RESULTS: There was a slight preference toward noncontrast computerized tomography (29%) as a single modality imaging study compared to renal ultrasound (26%). Overall 74% of renal ultrasounds were completed at bedside by emergency department physicians. Alpha blockers were used for medical expulsive therapy in 47% of patients. However, 133 patients with ureteral stones did not receive medical expulsive therapy. Only 34% of the total cohort received a urology consultation in the emergency department or subsequent outpatient referral. CONCLUSIONS: We noted variability in practice patterns for patients presenting with nephrolithiasis in the emergency department compared to guidelines provided by several professional organizations. There is inconsistent use of imaging studies, underuse of medical expulsive therapy and underuse of urology, highlighting a need for collaborative standardization of a diagnostic and treatment protocol to enhance quality of care.

Circulating Cd34+ cell count differentiates primary myelofibrosis from other Philadelphia-negative myeloproliferative neoplasms: a pragmatic study.

A high number of circulating CD34+ cells has been advocated to distinguish primary myelofibrosis from other Philadelphia-negative myeloproliferative neoplasms. We re-evaluated the diagnostic interest of measuring circulating CD34+ cells in 26 healthy volunteers and 256 consecutive patients at diagnosis for whom a myeloproliferative neoplasm was suspected. The ROC curve analysis showed that a number of CD34+ <10/µl excludes the diagnosis of primary myelofibrosis with a sensitivity of 97 % and a specificity of 90 % (area under the curve: 0.93 [0.89-0.98]; p < 0.001). Patients with PMF harboring a CALR mutation had more circulating CD34+ cells than patients with either a JAK 2 or MPL mutation (p = 0.02 and p < 0.01, respectively). These results suggest that this fast, simple, non-invasive, and standardized test is of particular interest to exclude the diagnosis of primary myelofibrosis.

Timing of testicular sperm retrieval procedures and in vitro fertilization-intracytoplasmic sperm injection outcome.

OBJECTIVE: To compare the outcome of IVF-intracytoplasmic sperm injection (ICSI) using testicular spermatozoa obtained on the day of ovum pick-up (OPU) or on the day before OPU. DESIGN: Retrospective study. SETTING: An IVF clinic in a university hospital. PATIENT(S): Forty-seven IVF-ICSI cycles using testicular spermatozoa in 28 couples with the male partner suffering from nonobstructive azoospermia. INTERVENTION(S): Sperm retrieval was performed either on the OPU day (23 cycles in 19 patients; group A) or on the day before OPU (24 cycles in 15 patients; group B). Testicular sperm aspiration (TESA) was performed and followed by testicular sperm extraction (TESE) if no spermatozoa could be found. MAIN OUTCOME MEASURE(S): The presence of motile spermatozoa at the time of ICSI and fertilization and clinical pregnancy rates. RESULT(S): A similar proportion of motile spermatozoa (60.9% vs. 62.5%), fertilization rate (61.7% vs. 58.9%), and clinical pregnancy rate per transfer (34.8% and 29.2%) were obtained for groups A and B, respectively. CONCLUSION(S): Testicular sperm retrieval can be performed on the day before OPU without compromising success. Considerable medical and practical advantages may be offered by further advancement of testicular sperm retrieval procedures to 48 hours before OPU. This approach should thus be further evaluated.

Poor outcome with round spermatid injection in azoospermic patients with maturation arrest.

OBJECTIVE: To compare the outcome of intracytoplasmic sperm injection (ICSI) and round spermatid injection (ROSI), both obtained by testicular sperm extraction (TESE), and to compare the results of fresh versus frozen ROSI. DESIGN: Retrospective study. SETTING: An IVF unit at a university hospitalPatient(s): Eighteen infertile couples with nonobstructive azoospermia. INTERVENTION(S): TESE with ROSI or ICSI of mature spermatozoa into metaphase II oocytes was performed. The resulting embryos were transferred to female partners. The spare round spermatids were frozen. MAIN OUTCOME MEASURE(S): Fertilization and cleavage rates, embryo quality, and clinical pregnancy rates. RESULT(S): Seventeen ROSI cycles and six ICSI cycles were compared. Fertilization rate following ROSI (44.9%) was significantly lower than with ICSI (69%). A significantly higher rate of cleavage arrest occurred following ROSI (40.8%) as compared to ICSI (8.2%). The morphology of embryos resulting from ROSI was significantly poorer. No pregnancies were achieved following ROSI as compared to a 50% clinical pregnancy rate in the ICSI group. The fertilization and cleavage rates following ROSI with fresh versus frozen-thawed spermatids were comparable. CONCLUSION(S): In azoospermic patients with maturation arrest at the stage of round spermatids the efficiency of ROSI appears to be extremely poor. The role of ROSI in the treatment of nonobstructive azoospermia should be reevaluated.

Zygote intrafallopian transfer in patients with tubal factor infertility after repeated failure of implantation with in vitro fertilization-embryo transfer.

OBJECTIVE: To evaluate the efficacy of zygote intrafallopian transfer (ZIFT) in terms of implantation and pregnancy rates in patients with tubal factor infertility and repeated implantation failure in IVF-ET cycles. DESIGN: Retrospective analysis of ZIFT cycles. SETTING: An IVF unit in a university hospital. PATIENT(S): Criteria for patient selection for ZIFT included at least four failures of implantation in IVF-ET cycles in which at least 3 embryos were replaced per transfer and a cause of infertility diagnosed as male, unexplained, or tubal factor with proof of one patient tube. INTERVENTION(S): Four to six zygotes were transferred by laparoscopy into the fallopian tube 24-26 hours after oocyte retrieval. MAIN OUTCOME MEASURE(S): Implantation and pregnancy rates were determined in 112 ZIFT cycles performed in 81 patients with repeated failure of implantation. Results were further stratified for patients with tubal factor (n = 15) and patients without tubal factor (n = 66). RESULT(S): The pregnancy and implantation rates for all ZIFT cycles were 35.1% and 11.1%, respectively. Pregnancy and implantation rates per cycle in patients with tubal factor versus patients without tubal factor were 26.6% versus 37.1% and 9.4% versus 11.4%, respectively. CONCLUSION(S): ZIFT can be considered as a mode of treatment for patients with repeated failure of implantation in IVF-ET and with tubal factor with proved patency of one tube.

Estradiol supplementation during the luteal phase may improve the pregnancy rate in patients undergoing in vitro fertilization-embryo transfer cycles.

OBJECTIVE: To evaluate the effect of adding E(2) to progestin supplementation during the luteal phase on pregnancy and implantation rates in patients undergoing IVF cycles. DESIGN: Prospective, randomized study. SETTING: An IVF unit in a university hospital. PATIENT(S): Patients who were undergoing IVF with controlled ovarian hyperstimulation using a GnRH analog and who had E(2)2,500 pg/dL at the time of hCG administration. INTERVENTION(S): Serum concentrations of E(2) and progesterone were measured in all patients on days 7, 10, and 12 after ET. MAIN OUTCOME MEASURE(S): The E(2) and progesterone profiles of the luteal phase and the pregnancy and implantation rates were documented. Data were analyzed for the entire study population and further stratified according to the GnRH analog protocol used (short or long). RESULT(S): Significantly higher E(2) levels were found during the luteal phase in the group that received E(2) supplementation. This effect was more pronounced in the patients who were treated with the long GnRH analog protocol. Significantly higher pregnancy and implantation rates were recorded in the patients who received E(2) supplementation and were treated with the long GnRH analog protocol. CONCLUSION(S): For patients who are treated with the long GnRH analog protocol for controlled ovarian hyperstimulation and for whom luteal support with hCG is contraindicated, the addition of E(2) to the progestin support regimen may have a beneficial effect on pregnancy and implantation rates.

Follicle-stimulating hormone treatment for men with idiopathic oligoteratoasthenozoospermia before in vitro fertilization: the impact on sperm microstructure and fertilization potential.

OBJECTIVE: To assess the effect of FSH on sperm fertilization potential and sperm intracellular structure in men with oligoteratoasthenozoospermia and a proven low fertilization rate in IVF. DESIGN: Prospective, randomized, partial crossover study. SETTING: IVF Unit, Golda Campus, Rabin Medical Center, Petah Tikva, Israel. PATIENT(S): Forty normogonadotropic, normogonadal men with oligoteratoasthenozoospermia and at least one previous IVF attempt in which fertilization failed or the fertilization rate was <30%. INTERVENTION(S): The men were randomly assigned to treatment with daily injections of 75 IU of FSH or 150 IU of FSH for at least 60 days before IVF treatment. A control group of men underwent an IVF cycle without treatment and then were randomly assigned tojoin group 1A or 1B for an additional IVF cycle with treatment. MAIN OUTCOME MEASURE(S): LH, FSH, and testosterone levels during FSH treatment, evaluation of ultramorphologic changes in sperm by electron microscopy, and comparison of fertilization rates in the control and study groups. RESULT(S): After treatment with 75 IU or 150 IU of FSH, the mean fertilization rates were 19.7% and 20.5%, respectively, compared with a 5.8% fertilization rate in the study control cycles. CONCLUSION(S): Prolonged treatment with FSH results in a significant increase in fertilization rates. This effect may be related to improvements in subcellular components of the sperm.

The role of purified follicle stimulating hormone therapy in the male partner before intracytoplasmic sperm injection.

OBJECTIVE: To evaluate the impact of long-term purified FSH (pFSH) therapy in male partners before intracytoplasmic sperm injection (ICSI). DESIGN: Prospective, randomized, controlled study. SETTING: Large university-based IVF unit. PATIENT(S): Seventy-eight patients made up the study and control groups (39 patients each). All patients had severe male factor infertility. INTERVENTION(S): Induction of ovulation, oocyte retrieval, ICSI, and ET were carried out in both groups. In the study group, male partners received pFSH (75 IU FSH, <1 IU LH) for > or = 50 days before oocyte retrieval. MAIN OUTCOME MEASURE(S): Fertilization rate, embryo quality, implantation and pregnancy rates. RESULT(S): Fertilization and pregnancy rates were higher in the study group (68% and 35.9%, respectively) were higher than in the control group (59% and 17.9%, respectively), although the differences did not reach statistical significance. The implantation rate was significantly higher in the study group (15.5% versus 6.5%). The study group showed a trend toward a higher number of better-quality embryos per transfer (mean +/- SD, 2.2 +/- 1.6 versus 1.6 +/- 1.6). CONCLUSION(S): Purified FSH therapy in male partners before ICSI improves implantation rate. Improved embryo quality may be a contributory factor.

ART success and in vivo sperm cell selection depend on the ultramorphological status of spermatozoa.

Management of male infertility has recently shifted from treatment of the subfertile man towards techniques of assisted reproduction (ART). This study aimed to evaluate the possible role of the ultramorphological status of the spermatozoon with respect to sperm selection in vivo and prediction of ART success. Ultramorphological sperm parameters were assessed retrospectively for 92 males with sufficient sperm density (10(7) spermatozoa ejaculate-1) whose wives conceived following a stepwise discarding of the female genital tract barriers, using intra-uterine insemination (IUI) (n = 26), in vitro fertilization (IVF) (n = 45) or intracytoplasmic sperm injection (ICSI) (n = 21). In parallel, sperm samples of 71 fertile males were examined. Normal ultramorphology of all head and tail subcellular organelles was found to be essential for the ability of spermatozoa to pass the lower female genital tract. The ultramorphological migration threshold for this barrier is apparently higher than that essential for oocyte fertilization. No specific indication associated with passage through the upper genital tract was found. A high prevalence of axonema defects was found to impair the ability of sperm cells to penetrate the oocyte investment. The natural fertility index, based on routine sperm parameters and the ultrastructural status of the spermatozoon's subcellular organelles was confirmed to be beneficial for directing patients to ART. A discriminative score based on axonema integrity was found to contribute additional information for the first choice decision between conventional ART and ICSI (75% prediction ability). Thus it may be helpful in finding the simplest and least expensive procedure with the greatest long-term chance for pregnancy.

Diagnosis of ruptured fetal membranes in pregnancy with the use of urograffin.

The objective of our study was to assess the value of intraamniotic injection of urograffin in the diagnosis of premature rupture of membranes (PROM). Intra-amniotic injection of urograffin with the concomitant insertion of a vaginal tampon was performed in 30 consecutive patients who were admitted because of suspected PROM and the presence of a heavy bloody vaginal secretion. The vaginal tampons were X-rayed for the presence of radio-opacity. In 23 patients, traces of urograffin were found in the vaginal tampons by X-ray. No fetal or maternal complications were observed during delivery and puerperium. We suggest the use of intraamniotic injection of urograffin for the diagnosis of PROM in cases where heavy bloody vaginal discharge is present.

Pre-operative ultrasonographic evaluation of nongravid, enlarged uteri--correlation with bimanual examination.

OBJECTIVE: To correlate the size of the nongravid uterus measured by ultrasound and bimanual examination before hysterectomy, with the actual size of the specimens. PATIENTS AND METHODS: Uterine size of 49 consecutive patients, who underwent elective hysterectomy, was assessed by bimanual pelvic examination, preoperative ultrasonographic evaluation and actual postoperative size. RESULTS: All preoperative ultrasonographic uterine dimensions significantly correlated with the corresponding actual dimensions of the uterine specimens. Furthermore, ultrasonographic uterine length had the best correlation with uterine size estimation by bimanual examination. A formula was established in an attempt to calculate clinical uterine size by gestational week, using preoperative ultrasonographic dimensions. CONCLUSIONS: By using the aforementioned formula, ultrasonographic uterine dimensions can be extrapolated to uterine size in terms of gestational week, and therefore, be applicable to traditional clinical practice.

Zygote intrafallopian transfer may improve pregnancy rate in patients with repeated failure of implantation.

OBJECTIVE: To evaluate the efficacy of zygote intrafallopian transfer (ZIFT) on implantation rates and pregnancy rates (PRs) in patients with repeated failure of implantation in IVF-ET cycles. DESIGN: A case-control study. PATIENT(S): Criteria for patient selection included male factor or unexplained infertility, normal uterine cavity, and at least three failures of implantation in IVF-ET cycles in which at least three embryos were placed per transfer. Data on 70 patients who underwent 92 ZIFT cycles are presented. A control group consisted of patients with the same selection criteria who underwent an additional standard IVF-ET cycle during the same time period. INTERVENTION(S): Ovulation induction consisted of down-regulation with GnRH analogue followed by ovarian stimulation with FSH and hMG. Intracytoplasmic sperm injection was performed on the oocytes of all patients with male factor infertility. Zygotes were transferred by laparoscopy into the fallopian tube 24-26 hours after oocyte retrieval. MAIN OUTCOME MEASURE(S): Implantation rates and PRs in the ZIFT and control groups were compared. RESULT(S): The PRs and implantation rates were significantly higher in the ZIFT group than in the control group: 34.2% (24/70) and 8.7% (29/333) versus 17.1% (12/70) and 4.4% (13/289), respectively (P = 0.002 and P = 0.04). The cumulative conception rate for two ZIFT cycles was 59.3%. CONCLUSION(S): Zygote intrafallopian transfer should be considered a beneficial mode of treatment for patients with repeated failure of implantation in IVF and transcervical ET. More prospective randomized studies are needed to support this observation.

Incubation with sperm enhances in vitro maturation of the oocyte from the germinal vesicle to the M2 stage.

OBJECTIVE: To evaluate the effect of sperm in the culture medium on the rate of oocyte maturation in vitro from the germinal vesicle to the M2 stage. DESIGN: Prospective randomized controlled study. SETTING: The IVF Unit, Wolfson Medical Center, Holon, Israel. PATIENT(S): All women in whom oocytes were retrieved at the germinal vesicle stage between December 1995 and March 1996. INTERVENTION(S): Oocytes retrieved at the germinal vesicle stage were divided prospectively and randomly into four groups of incubation conditions: group 1, intact germinal vesicle with cumulus; group 2, intact germinal vesicle with sperm cells in the culture medium; group 3, stripped germinal vesicle; and group 4, stripped germinal vesicle with sperm cells. Oocytes were observed 24 hours after retrieval, and the stage of maturation was recorded. Oocytes that reached the M2 stage underwent the intracytoplasmic injection procedure, and the fertilization rate in each group was recorded at 48 hours. MAIN OUTCOME MEASURE(S): Maturation rate from the germinal vesicle to M2 stage and fertilization rate. RESULT(S): Each group contained 20 germinal vesicle oocytes. In groups 1 and 2, 2 (10%) and 9 (45%) oocytes, respectively, reached the M2 stage at 24 hours; at 48 hours, 1 (5%) and 8 (40%) embryos developed, respectively. The results in group 2 were significantly higher than in group 1. In groups 3 and 4, 6 (30%) and 16 (80%) oocytes, respectively, reached the M2 stage at 24 hours; at 48 hours, 5 (25%) and 14 (70%) embryos developed, respectively. Results in group 4 were significantly higher than those in groups 1, 2, and 3. CONCLUSION(S): Both methods of oocyte activation (i.e., addition of sperm to the culture medium or removal of the cumulus) enhance oocyte maturation in vitro, but the sperm-incubation method has a more pronounced effect. A combination of both methods leads to an exceptionally high rate of oocyte maturation, followed by a high fertilization rate.

Early prediction of ovarian multifollicular response during ovulation induction in patients with polycystic ovary syndrome.

OBJECTIVE: To examine the association between the midfollicular FSH-LH ratio and the number of follicles, and the multifollicular ovarian response to gonadotropin stimulation in patients with polycystic ovary syndrome (PCOS) with normal basal LH and FSH levels. SUBJECT(S): Eighteen patients who had an abandoned treatment cycle because of multifollicular ovarian response. For comparison, all other completed treatment cycles in the same group of patients were used. MAIN OUTCOME MEASURE(S): The dose of hMG or FSH, daily effective dose, day 8 serum FSH and LH concentration, day 8 number of follicles > or = 8 mm, E2 and number of follicles on hCG day or day of cycle was abandoned. RESULT(S): In the abandoned cycles, day 8 serum LH concentrations were significantly lower and day 8 number of follicles and FSH-LH ratios were significantly higher compared with the completed cycles. A high predictive power (> 90%) for multifollicular response was established by using a set of two criteria: a FSH-LH ratio > or = 1.6 and the number follicles > or = 7 as the cutoff point. CONCLUSION(S): When aiming for a monofollicular response in women with PCOS and normal basal FSH and LH levels, cycles with high midfollicular FSH-LH ratios (> or = 1.6) and a high number of follicles (> or = 7) are those prone to develop a multifollicular ovarian response.

Non-response to ovarian stimulation in normogonadotrophic, normogonadal women: a clinical sign of impending onset of ovarian failure pre-empting the rise in basal follicle stimulating hormone levels.

The most important aspect of diminished ovarian reserve is the associated decline in reproductive potential. Assessment of ovarian reserve is mainly based on measurement of early follicular phase follicle stimulating hormone (FSH) concentration. The objective of this study was to report the identification of a group of 12 infertile women initially diagnosed as having unexplained or anovulatory infertility, who had a normal baseline hormonal profile and did not respond to repeated ovarian stimulation with gonadotrophins. All developed ovarian failure within a relatively short time span. Non-response to ovarian stimulation was defined by failure to achieve development of follicles >12 mm and failure to raise oestradiol concentration >350 pmol/l in two successive cycles of human menopausal gonadotrophin (HMG) doses of up to five ampoules per day for 5-8 days. Within a mean of 9 months following the failed attempts of ovarian stimulation the mean day 3 FSH concentrations rose from 5.4 +/- 2.7 IU/l to 53.5 +/- 19.7 IU/l. In these patients, day 3 FSH concentration failed to indicate the low ovarian reserve manifested only by lack of clinical response to treatment with gonadotrophins which was the first sign of impending ovarian failure. We conclude that women with normal early follicular phase serum FSH concentrations who do not respond to ovarian stimulation by HMG are at risk of developing ovarian failure within several months.

A new concept of cotreatment with human growth hormone and menotropins in ovulation induction protocols.

Follicular development in the primordial and preantral stages is almost completely independent of gonadotrophins or steroids and is mainly dependent on growth factors and local regulators. Since human growth hormone (hGH) was found to facilitate ovarian response to gonadotrophin stimulation, we hypothesized that the administration of hGH in an hypogonadotrophic state and prior to ovarian stimulation with menotropins, may initiate or facilitate the propagation of the primordial and preantral follicles to the gonadotrophin-dependent stages. We suggest that treatment with hGH prior to menotropin administration may be useful to improve results for poor responders to gonadotrophins.

Induction of ovulation in clomiphene-resistant polycystic ovary syndrome with pulsatile GnRH.

OBJECTIVE: To determine the efficacy of pulsatile GnRH alone and in combination with clomiphene citrate or gonadotropins in a stepwise approach for inducing ovulation in women with clomiphene-resistant polycystic ovary syndrome (PCOS). METHODS: Eighty women with clomiphene-resistant anovulatory infertility and PCOS were given subcutaneous pulsatile GnRH (15 micrograms every 90 minutes) using a portable infusion pump. If no follicular development was seen, clomiphene citrate (100 mg/day for 5 days) was given concurrently with the hormone in the next cycle of treatment. Those who still failed to ovulate regularly were treated with combined pulsatile GnRH with intramuscular gonadotropins (one ampule per day for 5-7 days). RESULTS. Sixty-six of 131 (50%) pulsatile GnRH cycles, 94 of 142 (66%) pulsatile GnRH with clomiphene cycles, and 48 of 69 (70%) pulsatile GnRH with gonadotropin cycles were ovulatory. Monofollicular response (one follicle at least 14 mm on the day of ovulation) occurred in 80.6, 83.9, and 53.6% of cycles, and multifollicular response occurred in 4.8, 3.1, and 21.6% of cycles in the three groups, respectively. Mild ovarian hyperstimulation occurred in one of the 342 cycles. The cumulative conception rate was 30% after three cycles, 60% after six cycles, and 73% after nine cycles. The miscarriage rate was 22% (ten of 45 pregnancies), and 35 women (78%) had live births (33 singletons and two sets of twins). CONCLUSION: The use of subcutaneous pulsatile GnRH alone and in combination with clomiphene citrate or gonadotropins for induction of ovulation in clomiphene-resistant PCOS in a stepwise approach produces a high cumulative conception rate associated with a low rate of multiple pregnancy and ovarian hyperstimulation syndrome.

The outcome of hypophysectomy for prolactinomas in the era of dopamine agonist therapy.

OBJECTIVE: Dopamine agonists are the primary therapeutic modality for the majority of patients with prolactinomas, with pituitary surgery reserved for those patients intolerant of or resistant to these agents. Most published surgical series, however, contain patients treated by surgery as the primary therapeutic modality. Previous exposure to dopamine agonists or the selection of patients with prolactinomas resistant to conventional therapy may potentially compromise the surgical success rate. The purpose of this study was to evaluate the efficacy and safety of pituitary surgery for prolactinomas in a tertiary referral centre where the majority of patients were operated on after treatment with dopamine agonists. DESIGN: A retrospective review of the outcome of pituitary surgery for prolactinomas performed at a tertiary neurosurgical centre by a single neurosurgeon. PATIENTS: Twenty-three patients underwent excision of a macro and 11 excision of a micro-prolactinoma. MEASUREMENTS: Pituitary tumour diameter was determined by CT or MRI imaging. Pre and post-operative measurements were made of serum PRL concentration (off dopamine agonist therapy), free T4, free T3, LH and testosterone (males). Post-operative restoration of a menstrual cycle was taken to indicate resolution of hypogonadism in female patients. RESULTS: The majority (73.9%) of the patients with macro and all with micro-prolactinomas had received dopamine agonists preoperatively. Of the 23 patients with macroprolactinomas, in whom the median preoperative PRL concentration was 13255 mU/l, 17 (73.9%) had radiological evidence of suprasellar extension and 5 (21.7%) cavernous sinus invasion. Only 4 (17.4%) of the patients with macroprolactinomas had a normal serum PRL post-operatively, although there was an improvement in visual fields in 66% of those with preoperative defects. The median preoperative PRL concentration was 4309 mU/l in the patients with microprolactinomas, significantly lower than in the macroprolactinoma group (P = 0.02). Despite a significant fall in serum PRL postoperatively (median PRL 860 mU/l, P = 0.0001), only 45.5% of patients had a normal serum PRL concentration after surgery. CONCLUSIONS: The cure rate following pituitary surgery for prolactinomas in a tertiary referral centre was low when compared with previous series in which surgery was used as the primary therapeutic modality. We suggest this may result both from dopamine agonist pretreatment and the referral of prolactinomas resistant to conventional therapy. The outcome is probably a more realistic reflection of the results of pituitary surgery for prolactinomas as currently practised in the majority of neuroendocrine centres.