Schizophrenia and delusional disorder in older age: community prevalence, incidence, comorbidity, and outcome.

The opportunity to assess prevalence, incidence, and outcome of schizophrenia and delusional disorder was provided by an age- and sex-stratified random sample of 5,222 persons age 65 years and over. This sample was chosen from general practitioner lists, and interviewed by psychiatric nurses trained to use the Geriatric Mental State (GMS)-AGECAT computerized diagnostic system. GMS-AGECAT ensured the reliability of the selection of cases between the two waves of the study. A subsample was interviewed by a research psychiatrist. The sample was followed up 2 years later using the same method by interviewers blind to the initial findings. The protocols of all nominated cases and subcases of schizophrenia/paranoid disorder diagnosed by AGECAT were reviewed by a clinician and DSM-III-R diagnoses were made. Refusal rate was 13 percent for initial interviews (wave 1) and 15 percent for reinterview 2 years later (wave 2). The prevalence of DSM-III-R schizophrenia was 0.12 percent (95% confidence interval [CI] 0.04-0.25) and delusional disorder 0.04 percent (95% CI 0.00-0.14). The minimum incidence of schizophrenia for new cases was 3.0 (95% CI 0.00 to 110.70); for new and relapsed cases, 45.0 (95% CI 3.54-186.20); and for delusional disorder, 15.6 (95% CI 0.02-135.10) per 100,000 per year. Two of the five cases with schizophrenia were known to have been first diagnosed before age 65. After 2 years, none of the cases of schizophrenia had recovered fully, but none was deluded at followup. Two had developed dementia. The outcome was bad because they remained cases of some type of psychiatric illness but good because of the improvement in their schizophrenia/delusion disorder symptoms.

Acute dexfenfluramine administration normalizes glucose tolerance in rats with insulin-deficient diabetes.

Dexfenfluramine has been shown to lower blood glucose concentrations independently of its effects in reducing food intake and body weight, in human and animal syndromes of non-insulin dependent diabetes. This study aimed to determine whether dexfenfluramine could also reduce glycaemia in rats with severe insulin-deficient diabetes induced by the beta-cell toxin, streptozotocin (55 mg kg-1). Three weeks after diabetes induction, nine groups (each n = 10) of diabetic and non-diabetic rats underwent oral glucose tolerance tests (1 g kg-1, by gavage). These tests were preceded by 12-18 h of fasting to remove the confounding effects of hyperphagia in diabetic rats, and to stabilize glycaemia. Dexfenfluramine (1.0 mg kg-1), given 2 h before the glucose challenge, significantly reduced basal glycaemia and decreased the post-challenge glycaemic rise (P < 0.01 vs. untreated diabetics). Dexfenfluramine dosages of 2.5 and 5.0 mg kg-1 both further flattened the post-challenge glycaemic profiles (both P < 0.01 vs. untreated diabetics) and achieved levels that did not differ significantly from those in non-diabetics (both P > 0.05). Subsequently, the studies using dexfenfluramine dosages of 2.5 and 5.0 mg kg-1 were repeated to determine whether the drug affected plasma insulin levels 2 h after dosing. In diabetic rats, plasma insulin concentrations were reduced to 10-20% of non-diabetic values, and were not significantly altered by dexfenfluramine. Acute dexfenfluramine administration therefore improves and (at dosages of 2.5 and 5.0 mg kg-1) essentially normalizes glucose tolerance in rats with severe insulin-deficient diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in hypothalamic NPY and CRF in anorexic tumor-bearing rats.

Regional hypothalamic concentrations of neuropeptide Y (NPY) and corticotropin-releasing factor (CRF), respectively a stimulant and an inhibitor of feeding behavior, were investigated in hypothalamic nuclei in rats carrying the Yoshida sarcoma. Tumor-bearing rats (n = 10), non-tumor-bearing controls (n = 10), and food-restricted rats (n = 10), which did not carry tumors but were pair-fed to match the reduced food intake of the tumor-bearing group, were studied after 10 days. NPY concentrations in the arcuate nucleus (ARC, the main site of NPY synthesis) were significantly increased above controls (P < 0.01) in both tumor-bearing and food-restricted groups. However, NPY concentrations in the paraventricular nucleus (PVN, an NPY-sensitive site of NPY release) showed opposing changes, with a 25% decrease (P = 0.052) in the tumor-bearing but a 48% increase (P < 0.01) in the food-restricted group. CRF concentrations in both the PVN and the ARC were significantly reduced (P < 0.01) in the food-restricted group, but remained close to control values in the tumor-bearing group (P not significant). Changes in hypothalamic appetite-regulating neuropeptides in cancer anorexia, which may result from the action of cytokines produced by a host defense response or the tumor itself, may account for reduced feeding. Such changes may include impaired activity of NPY or failure of CRF activity to be suppressed after underfeeding and weight loss.

Intense exercise and food restriction cause similar hypothalamic neuropeptide Y increases in rats.

Neuropeptide Y (NPY) is a potent central appetite stimulant whose concentrations rise markedly in hypothalamic appetite-regulating regions in food-deprived rats. To determine whether increased energy expenditure also affects hypothalamic NPY, we studied the effects of intense physical exercise in rats (n = 10) running voluntarily on a large-diameter exercise wheel. Running was initiated by restricting food intake but stabilized at an average of 8 km/day when food intake was matched to that in 11 nonexercised, freely fed controls [23.9 +/- 1.9 (SE) g/day vs. 24.7 +/- 1.3 g/day; P > 0.5]. Running expended approximately 40% of daily energy intake, and weight gain was significantly inhibited. A separate group (n = 10) of nonexercised rats was food restricted (approximately 15 g/day) to match the weights of the exercised rats. The rats were killed after 40 days, when both experimental groups weighed 30% less than controls (P < 0.01). Hypothalamic NPY concentrations showed significant (P < 0.01) increases of 30-70% in specific regions (arcuate and dorsomedial nuclei and medial preoptic and lateral hypothalamic areas) in both the running and food-restricted groups, compared with controls. There were no significant differences between the two experimental groups in NPY concentrations in any hypothalamic region. These findings suggest that negative energy balance, whether caused by reduced energy intake or increased expenditure, increases hypothalamic NPYergic activity. As NPY acts on the hypothalamus to increase body weight, these data support the postulated homeostatic role of NPY in maintaining nutritional state.

Peripheral insulin administration attenuates the increase in neuropeptide Y concentrations in the hypothalamic arcuate nucleus of fasted rats.

Fasting increases neuropeptide Y (NPY) concentrations in the arcuate nucleus (ARC), its site of synthesis, and in other regions of the rat hypothalamus. Neuropeptide Y is a potent central orexigenic agent and may therefore stimulate appetite during fasting. We tested the hypothesis that low plasma insulin levels stimulate ARC levels of NPY in fasted rats. Compared with freely fed controls (n = 8), rats fasted for 72 h (n = 8) showed significantly lower plasma insulin levels (28.9 +/- 1.6 vs. 52.6 +/- 5.7 pmol/l; p < 0.001) and higher ARC NPY concentrations (14.2 +/- 1.8 vs. 8.4 +/- 2.2 fmol/micrograms protein; p < 0.001). Fasted rats treated with subcutaneous insulin (5 U/kg/day; n = 10), which nearly normalized plasma insulin (46.6 +/- 2.8 pmol/l), showed intermediate ARC NPY levels (11.2 +/- 1.4 fmol/micrograms protein; p < 0.01 vs. controls and untreated fasted rats). Insulin administered peripherally, therefore, attenuates fasting-induced NPY increases in the ARC, supporting the hypothesis that hypoinsulinemia stimulates hypothalamic NPY.

Insulin deficiency is a specific stimulus to hypothalamic neuropeptide Y: a comparison of the effects of insulin replacement and food restriction in streptozocin-diabetic rats.

Untreated insulin-deficient diabetes causes hyperphagia and neuroendocrine disturbances that may be partly mediated by increased hypothalamic activity of neuropeptide Y (NPY), a potent central appetite stimulant. The metabolic signal that stimulates hypothalamic NPY is unknown. This study aimed to determine whether insulin deficiency or hyperglycemia was responsible. Regional hypothalamic NPY concentrations were compared in streptozocin-diabetic (STZ-D) rats rendered nearly normoglycemic by either insulin replacement or food restriction. Untreated STZ-D rats were hyperphagic and showed significantly increased (p less than 0.01) hypothalamic NPY concentrations in the arcuate nucleus and lateral hypothalamic area. Once-daily ultralente insulin injections corrected hypoinsulinemia and hyperglycemia, abolished hyperphagia, and normalized NPY concentrations in all hypothalamic regions. By contrast, food restriction effectively lowered glycemia without raising insulin levels. In these underfed diabetic rats, NPY concentrations rose further and were significantly higher than nondiabetic and untreated diabetic levels in most hypothalamic regions. We conclude that insulin deficiency is a major stimulus to hypothalamic NPY in STZ-D, whereas hyperglycemia may exert an inhibitory influence. These findings support the hypothesis that hypothalamic NPY responds to specific metabolic cues and is involved in regulating energy balance and conserving body weight.

Hypothalamic neuropeptide Y disturbances in the obese (cp/cp) JCR:LA corpulent rat.

Regional hypothalamic neuropeptide Y (NPY) concentrations were compared between cp/cp JCR:LA corpulent rats, which were grossly obese, hyperphagic, and hyperinsulinemic, and lean (+/+) controls. In freely fed cp/cp rats, NPY levels in the arcuate nucleus (ARC) were 31% higher than in lean rats (p less than 0.001). In lean rats, chronic food restriction significantly raised NPY levels by 22% in the ARC (p less than 0.05) and by 44% in the dorsomedial nucleus (DMH; p less than 0.05). By contrast, food-restricted cp/cp rats showed no change in the ARC, but NPY levels rose in the DMH (by 36%; p less than 0.05) and ventromedial nucleus (31%; p less than 0.05). Increased NPY levels in the ARC, the major site of hypothalamic NPY synthesis, suggests increased NPYergic activity in cp/cp rats; given the central actions of NPY, this could contribute to hyperphagia, obesity, and hyperinsulinemia in this syndrome. Abnormal NPY responses to food deprivation further suggest dysregulation of NPY in cp/cp rats.

The effect of dexamethasone on neuropeptide Y concentrations in specific hypothalamic regions.

Neuropeptide Y (NPY) is a major hypothalamic peptide which is implicated in the regulation of energy balance and in the activation of the hypothalamo-pituitary adrenal axis. This study aimed primarily to determine the effects on regional hypothalamic NPY levels, of catabolism and weight loss induced in rats by the synthetic glucocorticoid, dexamethasone, injected daily at a dose of 0.4 mg/kg for 7 days. NPY concentrations were significantly raised in the paraventricular nucleus (PVN) of male Wistar rats (45%, p = 0.009; n = 10) compared with saline-injected controls (n = 10). Body weight (p less than 0.001) and food intake (p less than 0.001) were significantly reduced, plasma insulin concentrations were increased (p less than 0.001), but there was no change in glucose concentrations. Chronic dexamethasone treatment did not cause the marked NPY increases in the arcuate nucleus (ARC) and other hypothalamic regions which have been observed in other catabolic states causing weight loss. One possible explanation is the high insulin levels induced by dexamethasone, which may have prevented compensatory hyperphagia by suppressing an increase in hypothalamic NPYergic activity. We also examined the acute effects of a single dexamethasone injection on regional hypothalamic levels, to determine whether the drug had a direct action separate from that due to sustained weight loss. In the acute study, groups of rats (n = 7) were examined at 4 h after a single injection of dexamethasone or saline. NPY concentrations were significantly increased in the lateral hypothalamic area (LHA), (60%, p = 0.008) when compared with saline-injected controls, but there was no change in body weight or glucose or insulin concentrations during the 4h interval. Altered transport or release of NPY in the lateral hypothalamic area may be a result of acute feedback regulation by glucocorticoids on the hypothalamus.

Altered neuropeptide Y concentrations in specific hypothalamic regions of obese (fa/fa) Zucker rats. Possible relationship to obesity and neuroendocrine disturbances.

Neuropeptide Y (NPY) concentrations were measured by radioimmunoassay in eight microdissected hypothalamic regions of obese (fa/fa) and lean (Fa/?) Zucker rats. Freely fed obese rats showed significant (40-100%) increases in NPY concentrations in several regions, notably the paraventricular, ventromedial, and dorsomedial nuclei and the arcuate nucleus/median eminence, compared with lean rats. Hypothalamic NPY concentrations were not affected in either obese or lean rats by food restriction, which caused 25% weight loss over 3 wk. Refeeding to initial weight significantly increased NPY levels in the ventromedial and dorsomedial nuclei in lean rats but did not significantly alter NPY concentrations in any hypothalamic region in obese rats. These observations indicate fundamental differences in the regulation of hypothalamic NPY between obese and lean Zucker rats. NPY injected into the paraventricular nucleus and other regions causes hyperphagia, obesity, and increased secretion of insulin, glucagon, ACTH, and corticosterone. These behavioral and neuroendocrine abnormalities all occur in the obese Zucker syndrome and may be due to increased NPY-ergic activity in the hypothalamus.

Unchanged hypothalamic neuropeptide Y concentrations in hyperphagic, hypoglycemic rats: evidence for specific metabolic regulation of hypothalamic NPY.

Hypothalamic concentrations of neuropeptide Y (NPY), a potent central appetite stimulant, increase dramatically in food-restricted and insulin-deficient diabetic rats. This suggest that NPY may drive hyperphagia in these conditions, which are characterized by weight loss and insulin deficiency. To test the hypothesis that insulin deficiency and weight loss are specific stimuli to hypothalamic NPY, we measured NPY concentrations in individual hypothalamic regions in rats with hyperphagia caused by insulin-induced hypoglycemia. Groups of 8 male Wistar rats were injected with ultralente insulin (20-60 U/kg) to induce either acute hypoglycemia (7 h after a single injection) or chronic hypoglycemia (8 days with daily injections). In hypoglycemic rats, plasma insulin concentrations were increased 6- to 7-fold compared with saline-injected controls; food intake was significantly increased with acute and chronic hypoglycemia and weight gain was significantly increased in the chronically hypoglycemic group. NPY concentrations were measured by radioimmunoassay in 8 hypothalamic regions microdissected from fresh brain slices. NPY concentrations were not increased in any region in either acute or chronic hypoglycemia. NPY therefore seems unlikely to mediate hyperphagia in hyperinsulinemia-induced hypoglycemia, supporting the hypothesis that weight loss is a specific stimulus to hypothalamic NPY and that insulin deficiency may be the metabolic signal responsible.

Acute fenfluramine administration reduces neuropeptide Y concentrations in specific hypothalamic regions of the rat: possible implications for the anorectic effect of fenfluramine.

Neuropeptide Y (NPY), a powerful central appetite stimulant, coexists in several hypothalamic areas with serotonin, which suppresses feeding. This study investigated the effect of acute administration of the serotonergic drug, fenfluramine, on NPY concentrations in microdissected hypothalamic nuclei. Adult male Wistar rats were given fenfluramine (10 mg/kg, n = 7) or saline (n = 7), intraperitoneally 1 h before darkness. Food was presented immediately before darkness and the rats were killed during the first 4 h of darkness. Fenfluramine injection significantly reduced food intake. In fenfluramine-injected animals, NPY levels in the ventromedial and dorsomedial nuclei and in the lateral hypothalamic and lateral preoptic areas were significantly lower than in saline-injected controls. The ventromedial and dorsomedial nuclei and the lateral hypothalamic area are sites which mediate the hyperphagic action of centrally injected NPY. Selective NPY changes in specific nuclei after fenfluramine injection suggest functional interaction between NPYergic and serotonergic systems, and may indicate that NPY is involved in mediating the anorectic effect of serotonergic agents.

Hypothalamic neuropeptide Y receptor characteristics and NPY-induced feeding responses in lean and obese Zucker rats.

Increased hypothalamic neuropeptide Y levels have previously been demonstrated in several hypothalamic nuclei of the (fa/fa) Zucker rat. This study set out to characterise hypothalamic NPY receptors in both genotypres and to study the effect of exogenous NPY on feeding behavior in these rats. Spontaneous daytime food intake was raised in the obese rat (p less than 0.05). Total hypothalamic receptor density (Bmax) was reduced in the obese rat compared with the lean rat (by 56%, p less than 0.005), but affinity remained unaltered. The lowest dose of NPY tested (23.5 pmol) stimulated daytime feeding in lean rats after 1, 2 and 3 hours but was inaffective in the obese rat (p less than 0.05). At two higher doses (235 pmol and 2.35 nmol), NPY was equipotent in both genotypes over 1 and 2 hours but NPY-induced feeding was attenuated over 3 hours in the obese rat. These results suggest an overactive endogenous NPYergic system in the obese (fa/fa) rat which might contribute to hyperphagia and obesity in this strain.

Increased neuropeptide Y concentrations in the lateral hypothalamic area of the rat after the onset of darkness: possible relevance to the circadian periodicity of feeding behavior.

Neuropeptide Y (NPY) is a major hypothalamic peptide which powerfully stimulates feeding when injected into the hypothalamus and is implicated in circadian rhythmicity. To investigate whether NPY is involved in the increased feeding that follows the onset of darkness in rats, NPY levels were measured in discrete hypothalamic areas before and after darkness. Four groups of eight adult female Wistar rats were habituated to a 12:12 hour light:dark cycle, with food presented at the onset of darkness (19.00 hours). One group was sacrificed during the 3 hours before darkness and another in the first 2.5 hours after darkness, with food provided as usual. To distinguish any effects of feeding itself, the study was repeated with two further groups, but food was not provided after darkness. Seven hypothalamic regions were microdissected from slices of fresh brain and acid-extracted for radioimmunoassay of NPY. NPY levels (fmol/microgram protein) were significantly higher (p less than 0.01) in the lateral hypothalamic area (LHA) of the dark-phase group in both studies. In the other six regions, NPY levels did not differ between light and dark phases. The LHA regulates the circadian rhythmicity of feeding and NPY injection here stimulates feeding. Alterations in NPY in the LHA around the onset of darkness may be related to the initiation of dark-phase feeding.

Prolonged pulsatile release of gonadotropin-releasing hormone from the guinea pig hypothalamus in vitro.

The sexually mature mammal secretes luteinizing hormone in a pulsatile fashion. This is presumed to depend on the intermittent release of hypothalamic gonadotropin- releasing hormone (GnRH). The isolated guinea pig hypothalamus has been studied because, in this species, as in primates, the pulse generator appears to reside within the medial basal hypothalamus. The basal 2 mm of guinea pig hypothalami were rapidly removed and perifused at 37 degrees C with Krebs-Ringer solution containing 20 mM bacitracin gassed with 95% O2, 5% CO2. The eluates were sampled at 15 and 5 min intervals and pulsatile patterns of GnRH were consistently observed for periods up to 72 h. There was no difference in GnRH levels from hypothalami of intact and ovariectomized animals. Simultaneous measurement of TRH and somatostatin disclosed independent pulses of both neurohormones which did not coincide with GnRH, indicating that the peaks were secretory episodes not artefacts generated by varying perifusion rates. The hypothalami disclosed no histologic evidence of necrosis when examined after 20 h perifusion.

The effects of hypophysectomy and administration of pituitary hormones on luteal function and uptake of high density lipoproteins by luteinized ovaries and adrenals of the rat.

The role of plasma lipoproteins and hypophyseal hormones in the maintenance of progesterone secretion by the rat corpus luteum was investigated. In the first experiment, rats were treated daily from days 1-6 of pregnancy with 5 mg/kg 4-aminopyrozolopyramidine (4APP), a blocker of hepatic lipoprotein secretion, or with 5 mg/kg 4APP and 1 or 2 mg ovine PRL or 0.1 ml 0.5% phosphoric acid (4APP vehicle). The administration of 4APP reduced serum cholesterol and progesterone levels on days 2-6 of pregnancy and ovarian progesterone on day 6. The reduced progesterone secretion had no effect on embryo implantation. PRL, in the doses used, was incapable of abrogating the effects of 4APP on circulating or ovarian progesterone levels. Ovaries and adrenals, but not kidneys, of pseudopregnant rats exhibited specific and saturable uptake of porcine high density lipoprotein (HDL). Time-course studies indicated that the uptake of HDL was rapid in ovaries compared to that in adrenals. Ovaries from rats not only exhibited uptake of porcine HDL, but also were capable of using it for progesterone synthesis. Immature rats were assigned to 7 groups of 16 rats each; 8 rats from each group received 4 mg/kg 4APP, and 8 received 4APP vehicle from day 1 of pseudopregnancy. Four groups underwent hypophysectomy on day 1 and received one of the following: 0.1 mg (30 IU/mg) ovine PRL, 0.1 mg ovine LH or 0.1 mg synthetic ACTH daily, or no replacement therapy. Three sham-hypophysectomized groups received 0.1 mg PRL or LH twice daily or no hormone treatment. On day 5 of pseudopregnancy, rats received intravascular HDL, as described above, and were killed 1 h later. Treatment with 4APP increased the adrenal uptake of HDL, but ovarian uptake was not different from that in the control group. Hypophysectomy reduced both adrenal and ovarian uptake of HDL. In adrenals only ACTH at the dose employed ameliorated reduction of HDL uptake induced by hypophysectomy, while in the ovaries, both PRL and LH reversed the effect of hypophysectomy. The effect of PRL on uptake was specific to [125I]HDL and did not alter [125I]albumin uptake. It is concluded that: 1) hypophysectomy reduces HDL uptake in the luteinized rat ovary; and 2) PRL and LH replacement therapy maintain ovarian uptake of HDL, suggesting a direct effect of these luteotropins on lipoprotein uptake.

Role of lipoproteins and prolactin in luteal function in the ferret.

This study investigated luteal function in vitro during early pregnancy and pseudopregnancy in the ferret. Corpora lutea taken from animals on Day 13 following the ovulatory stimulus (mating or gonadotropin treatment) were dissociated with collagenase and incubated with ovine prolactin (Prl), ovine luteinizing hormone (LH), total lipoprotein fraction from canine serum, canine high-density lipoproteins (HDL), canine low-density lipoproteins (LDL) or combinations of Prl, LH, HDL, and LDL. Total lipoproteins produced statistically definable increases in progesterone accumulation in incubation media at 5 microliter (approx. 50 micrograms protein) through 25 microliter (250 micrograms protein) of the total lipoprotein solution. LDL in doses of 1 or more microgram protein stimulated progesterone accumulation in 2-h incubations and a similar stimulation was observed in the presence of 60 or more micrograms HDL. Prl, LH or the combination of Prl and LH had no apparent stimulatory influence on progesterone accumulation in vitro. Prl in combination with LDL further stimulated progesterone output by luteal cells in short-term incubation relative to LDL alone. Prl and LH together with LDL produced an increase in stimulation over LDL alone, but, for the most part, this augmentation did not exceed that recorded in the presence of the combination of Prl and LDL. No interactions between HDL and luteotropic hormones were present. The results indicate that lipoproteins increase progesterone output from ferret luteal cells, presumably by providing substrate for steroid hormone synthesis. No direct role for LH in ferret luteal function emerged from these experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Luteal contribution to the termination of preimplantation delay in mink.

Five groups of mink were mated once between March 17-19 (Day O), Group 1, designated intact controls, received no further treatment. The remaining four groups of mink underwent unilateral ovariectomy on the day following mating. At that time, preovulatory follicles were transplanted to the ipsilateral kidney capsule of two groups (3 and 5) to become ectopic corpora lutea (CL). The second ovary was removed from all of the animals in Groups 2-5 on Day 8 after mating. At that time animals in Groups 4 (ovariectomized) and 5 (ovariectomized + ectopic CL) received 1-g Silastic implants releasing progesterone. Similar Silastic implants without progesterone were administered to Groups 2 (ovariectomized only) and 3 (ovariectomized + ectopic CL). Blood samples were taken for progesterone analysis and laparotomies performed on all mink through Day 44 of the experiment. Embryos implanted in all (7/7) of the animals in Group 1 (intact controls) at an average of 23.7 days after mating. In Group 5 (ectopic CL + progesterone implant) 6/8 mink were found to have embryos which were calculated to have implanted at an average of 36.3 days after mating. No embryo implantation occurred in Groups 2, 3 and 4 although some unattached blastocysts were recovered from the uteri of the latter two groups. Progesterone was elevated by implants to levels typical of mink gestation. Ectopic corpora lutea further increased progesterone levels in the presence of a progesterone-releasing Silastic implant. The results demonstrate the absolute necessity of the ovary for embryo implantation in mink. Further, the hormonal requirements for implantation consist of progesterone as well as some other factor or factors of luteal origin.

Effect of a progesterone-releasing intravaginal device on the milk progesterone levels, vaginal flora, milk yield and fertility of cyclic and non-cyclic dairy cows.

A progesterone-releasing intravaginal device (PRID) was inserted for 14 days into 10 lactating dairy cows at least 50 days after calving. Synchronization of oestrus was good and 5 of the cows conceived to a double insemination 48 and 72 h after PRID removal. In 9 cows vaginal infection was present when the PRID was removed but resolved spontaneously. The level of progesterone in the milk and the milk yield were similar to those in the 10 control animals. PRID treatment of 9 cows whose ovaries had remained inactive for at least 50 days after calving was followed by ovulation, as judged by the milk progesterone profile, in 8 animals after removal of the device.