A human iPSC-based in vitro neural network formation assay to investigate neurodevelopmental toxicity of pesticides.

Proper brain development is based on the orchestration of key neurodevelopmental processes (KNDP), including the for­mation and function of neural networks. If at least one KNDP is affected by a chemical, an adverse outcome is expected. To enable a higher testing throughput than the guideline animal experiments, a developmental neurotoxicity (DNT) in vitro testing battery (DNT IVB) comprising a variety of assays that model several KNDPs was set up. Gap analysis revealed the need for a human-based assay to assess neural network formation and function (NNF). Therefore, we established the human NNF (hNNF) assay. A co-culture comprised of human induced pluripotent stem cell (hiPSC)-derived excitatory and inhibitory neurons as well as primary human astroglia was differentiated for 35 days on microelectrode arrays (MEA), and spontaneous electrical activity, together with cytotoxicity, was assessed on a weekly basis after washout of the compounds 24 h prior to measurements. In addition to the characterization of the test system, the assay was challenged with 28 com­pounds, mainly pesticides, identifying their DNT potential by evaluating specific spike-, burst-, and network parameters. This approach confirmed the suitability of the assay for screening environmental chemicals. Comparison of benchmark con­centrations (BMC) with an NNF in vitro assay (rNNF) based on primary rat cortical cells revealed differences in sensitivity. Together with the successful implementation of hNNF data into a postulated stressor-specific adverse outcome pathway (AOP) network associated with a plausible molecular initiating event for deltamethrin, this study suggests the hNNF assay as a useful complement to the DNT IVB.

The impact of hip fracture on health-related quality of life and activities of daily living: the SPARE-HIP prospective cohort study.

PURPOSE: The medical morbidity and mortality associated with neck of femur fractures is well-documented, whereas there is limited data for patient-reported outcomes. The aim of this study was to characterize the impact of neck of femur fractures on activities of daily living and patient-reported health-related quality of life. METHODS: Design and participants: Multicentric prospective cohort study. Consecutive sample patients with fragility hip fracture over 50 years old admitted in 48 hospitals in Spain. OUTCOMES: daily living activity function (Barthel Index) and health-related quality of life (EQ-5D) pre-fracture, admission to hospital and at 1- and 4-month follow-up post-fracture. STATISTICS: Barthel and EQ-5D over time are described as mean (SD) and median (interquartile range). RESULTS: A total of 997 patients were recruited at baseline with 4-month outcomes available for, and 856 patients (89.5%). Barthel Index fell from 78.77 (23.75) at baseline to 43.62 (19.86) on admission to hospital with the fracture. Scores partially recovered to 54.89 (25.40) and 64.09 (21.35) at 1- and 4-month post-fracture, respectively. EQ-5D fell from a median of 0.75 (0.47-0.91) to - 0.01 (- 0.03 to 0.51) on admission. Partial recovery was observed again to (0.51 (- 0.06 to 0.67)) and (0.60 (0.10 to 0.80)) at 1- and 4-month post-fracture, respectively. CONCLUSIONS: Hip fracture results in a large decline in the ability to perform activities of daily living and patient-reported health-related quality of life with only partial recovery amongst survivors 4-month post-fracture.

Eutanasia en el anciano: las cosas lo más claras posibles / Euthanasia in the elderly: making things as clear as possible

No disponible

Lupus eritematoso sistémico en una anciana de 92 años / Systemic lupus erythematosus in a 92-year-old woman

No disponible

Ancianos multiingresadores: no hay peor ciego que quien no quiere ver... ni oír / Elderly patients with multiple admissions: there´s none so blind as the one who does not want to see or hear

No disponible

Sedación terminal: el último recurso ante una "mala muerte" / Terminal sedation: the last resort to avoid a bad death

OBJETIVOS: Una "mala muerte" es siempre una emergencia médica, y la asistencia al moribundo una obligación clínica ineludible. Nuestro propósito claro fue demostrar empíricamente que esto es posible en el ámbito clínico de un hospital general. MÉTODO: Investigación clínica observacional y prospectiva, que describe los efectos de la intervención clínica "sedación terminal" en una serie de pacientes asistidos y en tiempo real. RESULTADOS: Un total de 36 enfermos moribundos (20 varones [55,5 por ciento] y 16 mujeres [44,6 por ciento], con una edad media ñ desviación estándar [DE] de 70,47 ñ 13,7 años), que presentaban una diversidad de afecciones médicas avanzadas e irreversibles (fallo respiratorio, 30 por ciento; neoplasia extensa, 23,3 por ciento; fallo cardíaco, 11 por ciento; fallo renal, 11,6 por ciento, etc.), recibieron como intervención de sedación, destinada a superar el último y extremo sufrimiento, uno de los siguientes fármacos por vía parenteral: propofol (5 pacientes [13 por ciento], con un rango de dosis de 8-480 mg; dosis media, 164 mg), midazolam (13 pacientes [36,1 por ciento], 2-100 mg; dosis media, 19,6 mg) y/o cloruro mórfico (23 pacientes [64 por ciento], 5-600 mg; dosis media, 156 mg).Todos los pacientes contaron con garantías sistemáticas, que incluyeron tanto el consentimiento informado (autonomía) como la proporcionalidad, la segunda opinión y un registro sistemático documentado según el protocolo escrito. Se obtuvo el consentimiento de 25 (69,4 por ciento) pacientes a través de un familiar de primer grado, 8 (22,2 por ciento) mediante directiva verbal avanzada, y 3 (8,3 por ciento) directamente por el propio paciente aún lúcido.El intervalo desde el inicio de la sedación y la muerte fue (media ñ DE) de 39,56 ñ 17,32 h. La moda fue de 12 h, la mediana de 22,5 h, y el rango de 1-216 h. En todos los casos se alcanzó el bienestar necesario. CONCLUSIONES: La asistencia que han recibido los pacientes de nuestro estudio facilitó el derecho a no sufrir inútilmente, y lo hemos probado empíricamente en el ámbito de un hospital general. Sugerimos que éste es un objetivo alcanzable y digno del mayor respeto, algo sustantivo, no propiamente retórico (AU)

Effects of 15 months of 17 beta-estradiol and dydrogesterone on systolic cardiac function according to quantitative and Doppler echocardiography in healthy postmenopausal women.

OBJECTIVE: Our goal was to investigate the short-term and intermediate effects of low-dose hormone replacement therapy on echocardiographic parameters of cardiac function in healthy postmenopausal women. STUDY DESIGN: In a prospective, controlled study 30 healthy postmenopausal women (mean age, 52 +/- 3 years) were randomly assigned to 2 groups. Women in the hormone replacement therapy group (n = 15) received 1 mg micronized 17 beta-estradiol daily sequentially combined with 5 or 10 mg dydrogesterone for 14 days of each 28-day cycle during 12 months and thereafter 2 mg 17 beta-estradiol combined with 10 mg dydrogesterone for a period of 3 months. The control group (n = 15) received no treatment. M-mode, quantitative 2-dimensional, and Doppler echocardiographic measurements were performed at baseline and within the 17 beta-estradiol phase at 3, 12, and 15 months. RESULTS: After 12 months significant differences in change between the 2 groups were found for left ventricular end-diastolic and left ventricular end-systolic diameters, left ventricular mass index, and stroke volume index. These differences were caused by changes in the control group rather than in the hormone replacement therapy group, in which no significant within-group changes were found. All other parameters measured showed no effect. CONCLUSION: Within 15 months of 17 beta-estradiol and dydrogesterone treatment no clinically relevant differences were found in the M-mode, quantitative 2-dimensional, and Doppler echocardiographic parameters measured in this study. It is suggested that 15 months of treatment probably is too short a period for detection of direct effects on the heart itself.

Impaired procoagulant-anticoagulant balance during hormone replacement therapy? A randomised, placebo-controlled 12-week study.

UNLABELLED: In this randomised, placebo-controlled 12-week study, sixty healthy postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or combined with a progestagen for 14 days of each cycle (N = 28, E2+P group). RESULTS: As compared to placebo, plasma levels of AT III were reduced only in the E2 group (approximately 28%), plasma levels of protein C decreased only in the E2+P group (approximately 4%) and plasma levels of protein S decreased in both the E2 and E2+P group (approximately 21%). In both the E2 and E2+P groups, the plasma levels of factor VII (antigen and activity) showed a borderline significant increase (approximately 10%), whereas no significant change was observed in active factor VII. Plasma levels of tissue-type plasminogen activator (approximately 22%), urokinase plasminogen activator (approximately 25%) and plasminogen activator inhibitor type-1 (approximately 43%) decreased in the E2 and E2+P groups, whereas those of plasminogen increased (approximately 12%). Treatment was associated with an increase in levels of prothrombin fragment 1+2 (approximately 31%), but levels of thrombin-antithrombin III complexes, and of plasmin-alpha2-antiplasmin complexes and total fibrin(ogen) degradation products did not change significantly. CONCLUSION: Short-term E2 and E2+P treatment is associated with a shift in the procoagulant-anticoagulant balance towards a procoagulant state. A substantial proportion of women do not have a net increase in fibrinolytic activity. These data may be relevant in explaining the increased risk of venous thromboembolism associated with ERT and HRT, and possibly also in explaining the negative results of the Heart and Estrogen/progestin Replacement Study.

Ultrasound assessment of the endometrium in healthy, asymptomatic early post-menopausal women: saline infusion sonohysterography versus transvaginal ultrasound.

OBJECTIVE: To exclude pre-existing endometrial pathology in asymptomatic early post-menopausal women before starting hormone replacement therapy by transvaginal ultrasound (TVS) and saline infusion sonohysterography (SIS). METHODS: In a cross-sectional study, 148 healthy women (mean age, 51.1 years; range, 46-59 years) underwent ultrasound evaluation of the endometrium before participation in a clinical trial. TVS was used to measure double-layer endometrial thickness. SIS was performed at the same visit to measure anterior and posterior single-layer endometrial thickness, and to identify endometrial abnormalities when present. Ultrasound results were defined as informative if the endometrium could be adequately visualized. Findings on TVSs were defined as abnormal if a double-layer endometrial measurement > 5.0 mm was obtained. Findings on SIS were defined as abnormal if one or both single layers of the endometrium measured > 2.5 mm, or if focal endometrial thickening or a polyp was present. RESULTS: Of the 148 eligible women, informative TVS results were obtained from 134 women, SIS results from 133 women and both procedures combined from 119 women. TVS scans gave abnormal results in 8.2% of women (11 of 134) and SIS gave abnormal results in 36.8% of women (49 of 133). Of the 14 women with a non-informative TVS, eight had abnormal SIS results. Of the 15 women with a non-informative SIS, three had abnormal TVS results. In the 119 women with both informative TVS and SIS, abnormal TVS scans were found in 6.7% of women (eight of 119) and abnormal SIS in 34.5% of women (41 of 119). All eight women with abnormal TVS had an abnormal SIS, whereas 29.7% (33 of 111) of the women with a normal TVS had an abnormal SIS. CONCLUSIONS: Ultrasound evaluation demonstrated endometrial abnormalities in 34.5% (41 of 119) of asymptomatic post-menopausal women. SIS is more accurate than TVS in the detection of endometrial abnormalities.

Short-term hormone replacement therapy: reduced plasma levels of soluble adhesion molecules.

BACKGROUND: Epidemiological data have suggested that the use of hormone replacement therapy (HRT) is associated with a decreased risk of cardiovascular disease. Vascular endothelium and adhesion molecules play an important role in the initiation and progression of atherosclerosis. MATERIAL AND METHODS: Prospective, randomized, placebo-controlled 12-week study. Sixty healthy, normotensive postmenopausal women received either micronised oestradiol 2 mg alone (n = 16, E2 group), or sequentially combined with a progestagen; E2 + P groups trimegestone 0.5 mg (E2 + T, n = 14) or dydrogesterone 10 mg (E2 + D group, n = 14) or placebo (n = 16). Data were collected at baseline and at 4 and 12 weeks. RESULTS: Twelve weeks of treatment with E2 or E2 + P was associated with a significant decrease in the plasma concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and thrombomodulin (sTM). The average decrease in these markers was about 9%. In women treated with trimegestone the decreases were larger than in those treated with dydrogesterone; for sICAM-1 (-15% vs. -2%; P < 0.0001), sVCAM-1 (-15% vs. +3%; P = 0. 003) and sTM (-9% vs. -4%; P = 0.11). Plasma levels of endothelin-1 (ET-1) decreased (by 13%) only in women treated with E2 + P. In the E2 group, flow-mediated, endothelium-dependent vasodilatation increased by 6 percentage points after 12 weeks (P = 0.07 vs. baseline, P = 0.02 vs. E2 + P, and P = 0.17 vs. placebo). CONCLUSION: Short-term treatment with E2 or E2 + trimegestone reduces plasma levels of sICAM-1, sVCAM-1 and sTM. ET-1 decreased only in the E2 + P groups. Different types of progestagens may differentially affect sICAM-1, sVCAM-1 and sTM levels, which may be relevant for the choice of type HRT.

Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women.

OBJECTIVE: To study the short-term effect of unopposed oestradiol (E2) and sequentially combined hormone replacement therapy (E2 + P) on C-reactive protein (CRP) in healthy postmenopausal women. DESIGN: Prospective, randomised, placebo-controlled 12-week study. Sixty healthy. normotensive, non-hysterectomised postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or sequentially combined with a progestagen on 14 days of each cycle (N = 28, E2+P group). Data were collected at baseline and at 4 and 12 weeks. RESULTS: CRP levels increased significantly during the 12 weeks in the E2 and the E2+P groups compared to placebo. No differences were found between the E2 group and the E2+P group [E2 and E2+P group together (N = 44) versus placebo: P = 0.01; E2 versus E2+P: P = 0.75]. To give a quantitative estimate of the increase, the median change calculated from baseline in both treatment groups together was +87% (P = 0.02) at 4 weeks, and +114% (P = 0.08) at 12 weeks, as compared to the placebo group. CONCLUSION: In healthy postmenopausal women, short-term treatment with E2 or E2+P was associated with a rapid rise in CRP concentrations. These observations raise the possibility that the increased risk of cardiovascular events is related to an initial increase in CRP levels after starting hormone replacement therapy.

[An unusual bone scintigram in osteomyelitis. A case report]. / Ungewöhnliches Knochenszintigramm bei Osteomyelitis. Kasuistischer Beitrag.

Despite hyperemia in the blood-pool phase of bone scintigraphy with 99mTc-MDP there was an decreased concentration of the nuclide in a 7-year-old boy with acute osteomyelitis of the femur. In addition to inflammatory destruction of the bone tissue, the other reason for this surprising scintigraphic finding might be a reduced blood flow because of thrombotic occlusion or compression of bone-supplying vessels.

[Malignant hyperthermia during cataract extraction in an elderly patient]. / Hipertermia maligna durante la extracción de catarata en un anciano.

The case of a 67-year-old patient who suffered an episode of malignant hyperthermia during the extraction of a cataract is described. The outcome was favourable in spite of the lack of sodium dantrolene. Twenty months later the patient was operated on the contralateral eye with local anesthesia presenting no complications. It is worthy of note that the rareness of the syndrome in this age group and in this type of surgery, as well as the probable safeness of local anesthetics in susceptible patients. We also comment on the lack of sodium dantrolene and the nonexistence of a center facilitating information and diagnosis of malignant hyperthermia in our country.

Clinical follow-up after surgery of lumbar disc prolapses. A critical analysis.

A retrospective clinical study was made on 987 patients with lumbar disc disease treated by discectomy. All patients had been operated on in the Department of Neurosurgery (University-Hospital Mainz). 545 patients were males, and 442 females (1.2:1). Patients in the 4th decade of life were affected most often (33.5%). Perioperative complications occurred in 5.4%, with discitis as the single major complication (1.9%). 83% of all patients who underwent discectomy could return to their normal occupation.

The effects of long term testosterone administration on pulsatile luteinizing hormone secretion and on ovarian histology in eugonadal female to male transsexual subjects.

Polycystic ovarian disease (PCOD) is associated with elevated serum LH and (sub)normal FSH levels, while serum androgen levels are often elevated. To clarify the role of androgens in this abnormal pattern of gonadotropin secretion, LH secretion was studied in 1) 9 eugonadal female to male transsexual subjects before and during long term (6 months) testosterone (T) administration (250 mg/2 weeks, im), and 2) in a woman with an androgen-secreting ovarian tumor both before and after surgical removal of the tumor. Finally, we studied the effects of high serum androgen levels on ovarian histology in 3) 26 transsexual subjects after long term (9-36 months) T administration (250 mg/2 weeks, im) to assess whether T-induced ovarian abnormalities are similar to those that occur in women with PCOD. Long term T treatment in the nine female to male transsexual subjects resulted in increases in the mean serum T level from 1.7 +/- 0.8 (+/- SD) to 40.8 +/- 31.9 nmol/L (P less than 0.01), the mean serum dihydrotestosterone level from 0.6 +/- 0.2 to 3.3 +/- 1.5 nmol/L (P less than 0.02), and the mean serum free T level from 9.5 +/- 5.2 to 149 +/- 46 pmol/L (P less than 0.02). Mean serum estrone and estradiol levels were similar before and during T treatment. The mean serum LH level decreased from 6.3 +/- 2.0 to 2.9 +/- 1.1 U/L (P less than 0.01), and the mean FSH levels decreased from 6.6 +/- 2.0 to 3.7 +/- 2.2 U/L (P less than 0.02). Pulsatile LH secretion before and during T treatment was studied in five subjects. Neither the mean nadir LH interval nor the LH pulse amplitude changed significantly in these five subjects. The serum T level in the woman with the androgen-secreting ovarian tumor was 9.6 nmol/L, and it declined to normal after removal of the tumor. Her mean serum LH and FSH levels, the mean nadir LH interval, and LH pulse amplitude were in the normal range before and after removal of the tumor. Studies of ovarian histopathology in 26 transsexual subjects after long term androgen treatment revealed multiple cystic follicles in 18 subjects (69.2%), diffuse ovarian stromal hyperplasia in 21 subjects (80.8%), collagenization of the tunica albuginea in 25 subjects (96.2%), and luteinization of stromal cells in 7 subjects (26.9%). Findings consistent with criteria for the pathological diagnosis of polycystic ovaries, that is 3 of the 4 findings listed above, were present in 18 of the 26 subjects (69.2%).(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of long-term testosterone administration on gonadotropin secretion in agonadal female to male transsexuals compared with hypogonadal and normal women.

We investigated the effects of long term testosterone (T) administration on pulsatile gonadotropin secretion in agonadal women and the effects of estradiol (E2) on gonadotropin secretion in eugonadal women in the follicular phase of the menstrual cycle. We studied 4 groups: A) 28 eugonadal women in the early follicular phase of the menstrual cycle, B) 11 hypogonadal women, C) 13 agonadal female to male (f-t-m) transsexuals treated for at least 3 months with 120-160 mg T undecanoate (TU)/day, orally, and D) 5 agonadal f-to-m transsexuals treated for at least 6 months with 250 mg of a mixture of testosterone esters, im (im T-esters), every 2 weeks. The eugonadal women in the early follicular phase had a mean serum E2 level of 193 +/- 94 (+/- SD) pmol/L, significantly higher (P less than 0.01) than that in the hypogonadal women (60 +/- 24 pmol/L), whereas there was no difference in the mean serum T levels (1.8 +/- 0.7 vs. 2.3 +/- 1.5 nmol/L). the higher serum E2 level in the eugonadal women was associated with a significantly lower mean serum LH level (6.9 +/- 2.6 vs. 44.6 +/- 17.6 U/L; P less than 0.01) and LH pulse amplitude (2.8 +/- 1.0 vs. 12.6 +/- 4.8 U/L; P less than 0.01), whereas the mean nadir LH interval did not differ between the two groups (75 +/- 29 vs. 81 +/- 49 min). The mean serum T level in the agonadal f-to-m transsexuals treated with oral TU was significantly higher (P less than 0.01) than that in the hypogonadal women (9.7 +/- 4.7 vs. 2.3 +/- 1.5 nmol/L). In spite of this elevated T level there was no difference in the mean serum LH level (38.4 +/- 14.7 vs. 44.6 +/- 17.6 U/L), LH pulse amplitude (14.3 +/- 5.7 vs. 12.6 +/- 4.8 U/L), or nadir LH interval (72 +/- 27 vs. 81 +/- 49 min) in these groups. Also, the mean serum E2 (64 +/- 16 vs. 60 +/- 24 pmol/L and FSH levels (62 +/- 17 vs. 64 +/- 28 U/L) did not differ between these groups. Treatment of the agonadal f-to-m transsexuals with im T-esters resulted in mean serum T and E2 levels of 34.4 +/- 27.0 nmol/L and 121 +/- 54 pmol/L, respectively, both significantly higher (P less than 0.01) than those in groups B and C.(ABSTRACT TRUNCATED AT 400 WORDS)

Luteinizing hormone secretion patterns in boys at the onset of puberty measured using a highly sensitive immunoradiometric assay.

Pulsatile LH secretion was studied in 3 prepubertal and 11 early pubertal boys by measuring plasma LH concentrations at 10-min intervals from 1200-1800 h and from 2400-0600 h using an immunoradiometric assay with a lower limit of detection of 0.10 IU/L. Plasma testosterone (T) was measured hourly. In the prepubertal boys plasma LH was not detectable during the daytime but at night 20- to 300-min periods of detectable, but low (less than 0.5 IU/L) plasma LH values occurred. A discrete episodic LH pattern was discernible, and the median number of pulses was 2 during the 6-h nocturnal sampling periods. Plasma T was not detectable (less than 1.0 nmol/L). In the pubertal boys most daytime plasma LH values were greater than 0.3 IU/L, with periods of values of 0.1-0.3 IU/L and short periods of undetectable levels as well. At night definite pulses, up to 4.7 IU/L, were found in all boys. The median number of pulses was 4 during the 6-h nocturnal sampling period. Plasma T was detectable at night in 5 of these 11 boys. The results strongly suggest that at the onset of puberty prepubertal boys (G1) have no LH secretion during the day but intermittent gonadotrophic activity during the night. In early puberty LH secretion increases in amplitude as well as frequency to a clear pulsatile pattern during the night, sometimes with pulses during the day as well.

Effects of opiate receptor blockade on gonadotrophin secretion before and after administration of the oestrogen receptor blocker tamoxifen in eugonadal men.

Both gonadal steroids and endogenous opioid peptides (EOPs) exert an inhibitory effect on gonadotrophin secretion. It is thought that the negative feedback action of the gonadal steroids, testosterone (T) and oestradiol (E2), on the gonadotrophin secretion is mediated by EOPs. To assess the effects of EOPs and oestrogen and their interrelationship on pulsatile LH secretion we studied two groups of eugonadal men. The subjects of the first group were tested on three different occasions, firstly under basal conditions, secondly during infusion of the opiate receptor blocker naloxone (NAL) (bolus 5 mg + 2.1 mg/h for 7 h), and finally during NAL infusion after 6 weeks administration of the oestrogen receptor blocker tamoxifen (10 mg twice daily). The subjects of the second group were studied before and after 6 weeks administration of tamoxifen. NAL infusion produced a significant increase in mean serum LH levels (4.8 +/- SD 1.5 to 6.2 +/- 1.8 U/l) and LH pulse frequency (3.7 +/- 1.6 to 5.3 +/- 1.2 pulses/7 h). No change was seen in mean LH pulse amplitudes (3.5 +/- 1.5 vs 3.4 +/- 1.0 U/l). After tamoxifen administration alone there was a significant increase in mean LH level (from 5.7 +/- 1.3 to 10.1 +/- 2.4 U/l), LH pulse amplitude (from 3.8 +/- 0.9 to 4.6 +/- 0.9 U/l) and LH pulse frequency (from 4.2 +/- 1.5 to 5.8 +/- 1.7 pulses/7 h). A significant rise in mean serum LH levels was observed during NAL infusion after previous tamoxifen administration in comparison to the infusion of NAL alone (from 6.2 +/- 1.8 to 10.5 +/- 6.2 U/l). LH pulse frequency (5.3 +/- 1.2 vs 6.3 +/- 1.3 pulses/7h) and amplitude (3.4 +/- 1.0 vs 3.6 +/- 1.5 U/l) however, did not change. Mean serum LH level and LH pulse frequency after opiate receptor and oestrogen receptor blockade together did not differ from the results obtained after oestrogen receptor blockade alone. NAL however was expected not only to block opioid-mediated oestrogen action but also androgen action and therefore to have additional effect on LH secretion, whereas tamoxifen was supposed to block only oestrogen action. From these data we conclude that EOPs exert a negative feedback effect on LH secretion by slowing the GnRH pulse generator. Because there was no additional effect of opiate receptor blockade after oestrogen receptor blockade on pulsatile LH secretion we infer that androgens may be impeded in their negative feedback action in the presence of the antioestrogen tamoxifen.