PET imaging of steroid receptor expression in breast and prostate cancer.

The vast majority of breast and prostate cancers express specific receptors for steroid hormones, which play a pivotal role in tumor progression. Because of the efficacy of endocrine therapy combined with its relatively mild side-effects, this intervention has nowadays become the treatment of choice for patients with advanced breast and prostate cancer, provided that their tumors express hormone receptors. However, in case of breast cancer it is well known that part of the patients have hormone receptor-negative tumors at diagnosis, whereas other patients have discordant receptor expression across lesions. In addition, receptor expression can change during therapy and result in resistance to this therapy. Besides several lines of hormonal treatments, also other strategies to affect the hormone receptors are currently under investigation, namely histone deacetylases (HDAC) and heat shock protein (HSP) inhibitors. Knowledge of the actual receptor status can support optimal treatment decision-making and the evaluation of new drugs. Positron emission tomography (PET) is a non-invasive nuclear imaging technique that allows monitoring and quantification of hormone receptor expression across lesions throughout the body. Several PET tracers have been developed for imaging of the most relevant hormone receptors in breast and prostate cancer: i.e. the estrogen, progesterone and androgen receptors. Some of these PET tracers have been successfully applied in early clinical studies. This review will give an overview of the current status of PET imaging of hormone receptors in breast and prostate cancer.

Tibolone relieves climacteric symptoms in highly symptomatic women with at least seven hot flushes and sweats per day.

OBJECTIVE: To establish the potency of four dose levels of tibolone, a tissue selective estrogenic activity regulator (STEAR), to relieve climacteric symptoms in a subgroup of highly symptomatic women experiencing a minimum of seven hot flushes and sweats per day. METHODS: In a group of 770 women receiving tibolone 0.625, 1.25, 2.5 or 5.0 mg or placebo for 12 weeks, a total of 317 women experienced at least seven hot flushes and sweats per day. Frequency and intensity of climacteric symptoms were assessed at baseline and after 4, 8 and 12 weeks of treatment. Vaginal bleeding/spotting was studied using diary cards. Occurrence of adverse events was determined by active questioning. RESULTS: Tibolone induced a decrease in the frequency and intensity of climacteric symptoms, leading to statistically significant differences compared to placebo for dose levels of 1.25 mg and higher. The incidence of vaginal bleeding/spotting and of drug-related adverse events was similar in all tibolone dose groups, except for the 5.0 mg group, where the incidence was about twice as high. Dropout rate due to insufficient therapeutic effect is substantially higher in the 0.625 and 1.25 mg group (about 10%) compared to the 2.5 and 5.0 mg group (about 1%). These results are consistent with what occurred in the total study population published previously. CONCLUSION: The effects of tibolone in highly symptomatic women experiencing at least seven hot flushes and sweats per day do not differ much from that in the total study population. A daily dose of 2.5 mg is the optimal dose for both the total study population and the subgroup of highly symptomatic women. However, in order to optimise individual treatment, the 1.25 mg dose might also be taken into consideration.

The effect of tibolone in postmenopausal women receiving tamoxifen after surgery for breast cancer: a randomised, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the effects of tibolone on climacteric symptoms, endometrium and serum lipid/lipoproteins in postmenopausal women receiving tamoxifen after surgery for breast cancer. DESIGN: Double-blind, randomised, placebo-controlled, multicentre pilot study. SETTING: Hospital outpatient clinic. SAMPLE: Seventy postmenopausal women receiving tamoxifen following surgery for early breast cancer. METHODS: Women received 20 mg/day oral tamoxifen plus either 2.5 mg/day oral tibolone or placebo for 12 months. MAIN OUTCOME MEASURES: Frequency and severity of hot flushes (diary cards); intensity of hot flushes and sweats (Landgren scale); interference of hot flushes and sweats with normal life; frequency and intensity of other climacteric symptoms; endometrial thickness and histology; vaginal bleeding; breast cancer recurrence and serum lipid/lipoproteins. RESULTS: Daily card data showed no change in the daily number of hot flushes with either tibolone or placebo (P= 0.219) after three months. There was a significant reduction in the severity of flushes with tibolone compared with placebo (-0.4 vs 0.2, P= 0.031). The Landgren scale showed a mean change in the number of hot flushes of -0.6 with tibolone and +1.1 with placebo after 12 months (P= 0.022). Endometrial biopsies were normal and vaginal bleeding was similar in both groups. A significant decrease in triglycerides (-23% vs 1.4%) and HDL (-12% vs 19%) was seen with tibolone compared with placebo after 12 months. CONCLUSIONS: Tibolone prevented an increase in hot flushes in postmenopausal women given tamoxifen following surgery for breast cancer without untoward effects on the endometrium. Beneficial effects on serum lipid profile were noted.

Dose-response analysis of effects of tibolone on climacteric symptoms.

OBJECTIVE: To assess the clinically optimal tibolone dose for the relief of climacteric complaints. DESIGN: A randomised, double blind, placebo-controlled trial. SETTING: Twenty-eight centres in Norway, The Netherlands, Sweden and Finland. POPULATION: Seven hundred and seventy-five healthy postmenopausal women were randomised to tibolone in a daily dose of 0.625, 1.25, 2.5 or 5.0 mg or placebo for 12 weeks. METHODS: At baseline, and after 4, 8 and 12 weeks, hot flushes, sweating, vaginal bleeding and adverse experiences were recorded. MAIN OUTCOME MEASURES: Change in frequency and intensity of hot flushes and sweating over 12 weeks. RESULTS: From week four onwards, 2.5 and 5.0 mg tibolone were significantly more effective than placebo, regarding the frequency of hot flushes and sweating (P < 0.001), whereas the 0.625 mg dose was not significantly different from placebo during the study. The frequency of hot flushes with the 1.25 mg dose was statistically significantly different from placebo, only from week eight onwards. The incidence of dropouts due to insufficient therapeutic effect was much higher in the tibolone 1.25 mg group (9.5%) than in the 2.5 (1.9%) and 5.0 mg (1.3%) groups. A dose-related increase in incidence of vaginal bleeding or spotting was observed (P < 0.0001). Bleeding incidence in the 5.0 mg dose group was about twice as high as in the 2.5 mg dose group. There was no difference in incidence of adverse experiences between the 2.5- and the 1.25 mg dose group. CONCLUSION: A daily dose of 2.5 mg tibolone is the clinically optimal dose for the treatment of climacteric complaints in postmenopausal women.

Effects of tibolone on the endometrium.

OBJECTIVE: To investigate the effects of 24 months of tibolone treatment on the endometrium in postmenopausal women. DESIGN: An open, prospective, multicenter study with a treatment duration of 24 months. POPULATION: One hundred and fifty healthy postmenopausal women. METHODS: Women were treated with one tablet of tibolone (2.5 mg Org OD14) daily. Endometrial biopsies were taken at baseline, 12 months (n = 112) and 24 months (n = 62) to investigate endometrial histology by means of light microscopy. RESULTS: No stimulation of atrophic endometrium was observed in 98.2% and 91.9% of the analyzed women after 12 and 24 months, respectively. A change from an atrophic endometrial pattern to a weakly proliferative pattern was seen in 1.8% (95% confidence interval (CI) 0.22-6.45) and 6.5% (95% CI 1.20-7.51) of the women after 12 and 24 months, respectively. In one woman, the endometrial pattern after 24 months was classified as simple hyperplasia (1.6%; 95% CI 0.01-3.20). The low incidence of proliferation and/or hyperplasia corresponds to that seen in other clinical trials in which women have been treated with placebo. Vaginal bleeding and/or spotting was reported by 18 women (12%), all showing an atrophic endometrium at all assessments, except for one woman with a proliferative endometrium at 24 months. CONCLUSION: In the majority of women (92%), the endometrium remained atrophic during 24 months of tibolone treatment.

Effects of tibolone and continuous combined hormone replacement therapy on parameters in the clotting cascade: a multicenter, double-blind, randomized study.

OBJECTIVE: To determine the effects of tibolone and continuous combined HRT (ccHRT) on parameters in the clotting cascade. DESIGN: Randomized, double-blind study. SETTING: Hemostasis unit of a university hospital clinic in Germany. PATIENT(S): Sixty healthy postmenopausal women. INTERVENTION(S): Twenty-nine subjects were treated with tibolone (2.5 mg/d) and 31 with oral ccHRT containing estradiol (2 mg/d) + estriol (1 mg/d) + norethindrone acetate (1 mg/d). MAIN OUTCOME MEASURE(S): Effects on parameters in the clotting cascade at baseline and after 12 and 24 weeks of treatment. RESULT(S): Tibolone increased fibrinolysis parameters without significantly altering coagulation parameters. Treatment with ccHRT resulted in a stimulating effect on parameters of both fibrinolysis and coagulation. Tibolone showed a stronger reduction of factor VII activity; less reduction of AT-III, protein C activity, and protein S activity; stronger increase of the activated partial thromboplastin time, plasminogen and plasminogen-antiplasminogen complexes; and less increase of D-Dimer than ccHRT. Both preparations similarly reduced climacteric complaints, whereas tibolone showed less breast complaints than ccHRT. CONCLUSION(S): This study confirms that tibolone, and to a lesser extent also ccHRT, changes hemostasis parameters toward a more fibrinolytic profile, which may diminish the risk of venous thrombosis.

Poor rearing conditions and social stress in pigs: repeated social challenge and the effect on behavioural and physiological responses to stressors.

Effects of rearing condition on behavioural and physiological reaction to social confrontations and to social and non-social stressors were studied in female pigs. The pigs were reared under either poor (the standard farrowing crate) or enriched (group of free-ranging sows with piglets) conditions. At the age of 14-17 weeks, the pigs were exposed to a series of social confrontations where an intruder was introduced into the home pen of a resident. The results show the presence of a clear difference in terms of aggressive behaviour between residents and intruders from enriched but not from poor rearing conditions. Furthermore pigs reared under poor conditions inflicted more wounds on each other. We suggest that this reflects a difficulty in establishing a dominance relationship in poorly reared pigs, caused by impaired development of social skills in these pigs. Subsequently, reaction to novel object, non-social and social stress was measured in adult age, showing that the effects of rearing conditions are long-lasting, and give rise to differences in reaction to challenges in that pigs from enriched rearing conditions showed more avoidance behaviour than pigs from poor rearing conditions.

Psychoendocrinological assessment of the menstrual cycle: the relationship between hormones, sexuality, and mood.

The role of sex hormones in sexuality and mood across the menstrual cycle was investigated. Twenty-one normal health women were followed for one menstrual cycle. Blood samples were taken frequently, and analyzed for estradiol, progesterone, testosterone, androstenedione, dehydroepiandrosterone sulfate, cortisol, and sex hormone-binding globulin. A diary concerning sexual interest and behavior, and different moods, was completed daily. Although the sample was not large, a clear effect of menstrual cycle phase on levels of testosterone and the free testosterone index was demonstrated. In a preliminary screening interview, 11 of the 21 women had reported that they suffered from premenstrual complaints (PC), the other 10 had reported no complaints in the premenstrual phase (NPC). Significant differences between the two groups were established in estradiol and the estradiol-progesterone ratio, with the NPC group having higher levels of both endocrine parameters across different menstrual samples. Psychologically, a cycle effect on tension and sexual interest was demonstrated. The NPC group reported a peak in sexual interest in the premenstrual phase, whereas the PC group reported a peak in the ovulatory phase. There was a difference between the two groups in feelings of fatigue but not in other moods across the menstrual cycle. The study provides further evidence of the importance of androgen levels in women's sexuality and shows again that the relationship between menstrual cycle phase and sexuality is much clearer than between phase and mood.

Oestrus, ovulation and peri-ovulatory hormone profiles in tethered and loose-housed sows.

Multiparous sows that had been tethered during lactation were put in two different housing conditions after weaning (Day 0); the sows were either tethered by neck chain, or individually housed in a pen of approximately 6 m2. After two months, ten tethered and eleven loose housed sows were used to assess stress and reproductive parameters. Stereotypic behaviour after the afternoon feeding was assessed from Day 18 onwards; at Day 53 stereotypic behaviour tended to occur during a higher percentage of time in the tethered sows (P = 0.11) and at Day 66, the differences were significant (tethered, 78 +/- 5 vs. loose-housed, 40 +/- 10% of time (mean +/- sem); P = 0.03). At Day 35 and 55, cortisol profiles after afternoon feeding were similar for the two groups of sows (P > 0.10). Around oestrus (approximately Day 64), the profiles of oestradiol-17 beta, luteinizing hormone and progesterone were measured and proved to be similar for both treatment groups (P > 0.10). The duration of oestrus was shorter in the tethered sows (42 +/- 4 vs. 63 +/- 2 h; P < 0.001) and, consequently, the timing of ovulation during oestrus (h after onset of oestrus) was advanced in the tethered sows (28 +/- 2 vs. 41 +/- 2; P < 0.001). The duration of ovulation did not differ (tethered, 2.9 +/- 0.5 vs. loose-housed, 2.1 +/- 0.2 h; P = 0.16). The sows were sacrificed at Day 5 after ovulation; ovulation rate, fertilization rate, embryo development and embryo diversity were similar for the two groups, as were adrenal weight and size of adrenal cortex. Duration of oestrus and the levels of stereotypies at Day 60 tended to be negatively related in the tethered sows (P = 0.07), but not in the loose-housed sows (P = 0.65). In conclusion, sows that had been tethered during pregnancy and lactation, and were housed loose or were tethered again at weaning within two months differed both in stereotypic behaviour and in duration of oestrus, without apparent effects on reproductive hormones.

Rearing piglets in a poor environment: developmental aspects of social stress in pigs.

Effects of rearing conditions on the development of social relationships were investigated in female pigs. For that purpose, one group of piglets was reared in a poor environment (i.e., a commercially used indoor 4.2-m2 standard farrowing crate) and the other in an enriched environment (i.e., 0.5-ha outdoor pasture with half-open farrowing crates). After weaning, all piglets were housed in pairs under standard conditions. Dominant and subordinate individuals were distinguished within pairs and social relationships between members of a pair were studied in adulthood. The results show that pairs reared in a poor environment behave more aggressively. The subordinates of these pairs also develop symptoms indicative of chronic social stress exposure: i.e., they show a delayed onset of puberty, a smaller daily weight gain, and elevated basal cortisol levels that are also higher 5 h after an acute restraint stressor (tethering stress). No such deviations were found in subordinates reared in an enriched environment. It is concluded that rearing piglets in a poor environment may facilitate the development of social stress in adult (subordinate) pigs. Two underlying mechanisms may be proposed: a) deteriorated social skills lead to increased social stress, or b) a failure to cope with stressors in general, and the stress of being subordinate in particular, occurs in animals reared under poor conditions.

Glucose tolerance of pregnant sows is related to postnatal pig mortality.

An experiment was conducted on three farms to study the relationship between the results of an oral glucose tolerance test on d 104 +/- 4 of pregnancy and subsequent reproductive performance of 104 multiparous sows. After an overnight period without feed, sows were fed (3 g/kg BW.75) glucose, and blood samples were taken for analyses of glucose at -10, 10, 20, 30, 40, 50, 60 70, 80, 90, 105, and 120 min after administration of glucose. Glucose concentrations before glucose administration ranged from 2.0 to 3.6 mmol/L. Sows with lesser pretest glucose concentrations had longer (P < .01) durations of pregnancy (corrected for number of live pigs born) and heavier (P < .05) pigs at birth (corrected for farm and number of live pigs born). Peak glucose concentrations and areas under the curves (i.e., first 70 min and entire 120 min) ranged from .1 to 4.4 mmol/L, -40 to 211 (mmol/L).min, and -95 to 247 (mmol/L).min, respectively. Sows with greater (P < .01) peak concentration of glucose and greater area under the curve (first 70 min [P < .01] and entire 120 min [P < .01]) had increased pig mortality during the first 7 d after farrowing (corrected for live weight of the sows). In 83 sows, a sample of morning urine (before feeding) was collected and tested for glucose and ketone bodies. Neither glucose nor the ketone body acetoacetic acid was detected in the urine. The results indicate that sows that are less glucose-tolerant have greater pig mortality.

Effects of energy source in the diet on reproductive hormones and insulin during lactation and subsequent estrus in multiparous sows.

Two experiments were performed. The first experiment was done to study the effects of dietary energy source on plasma insulin concentration using five gilts in a Latin square design with two diets over two periods. The diets contained either 200 g/kg of cornstarch (Starch) or soybean oil (Fat) as energy sources. Results indicate that insulin response was greater in the Starch-fed than in the Fat-fed gilts. A second experiment was performed in which 18 multiparous sows were fed one of the two experimental diets from farrowing until slaughter at d 35 of subsequent pregnancy. All sows nursed nine pigs. Blood samples were taken from a permanent jugular vein catheter every 12 min during a 12-h period on d 109 +/- 1 of pregnancy, on d 7 +/- 1, 14 +/- 1, and 21 +/- 1 of lactation, and on the day of weaning ( d 22 +/- 1). From 48 h after weaning, blood samples were taken every 4 h until 24 h after ovulation. After that, blood samples were taken at 12-h intervals until d 10 after ovulation. Differences between diets in insulin response were not significant. In Starch-fed sows, LH pulsatility at d 7 of lactation was greater (P < .05), the preovulatory LH surge was greater ( P < .05), and progesterone production was greater (P < .05) from 108 h until 256 h after the LH surge than in the Fat-fed sows. Results indicate that feeding Starch-rich diets to multiparous sows compared with Fat-rich diets, on an isocaloric basis, increases LH pulsatility during early lactation, the preovulatory LH surge, and progesterone production after the LH surge.

Chronic stress and pituitary-adrenocortical responses to corticotropin-releasing hormone and vasopressin in female pigs.

Effects of long-term tethered housing (a condition of chronic stress) on pituitary-adrenocortical responsiveness to exogenous corticotropin-releasing hormone (CRH) and lysine8-vasopressin (LVP) were investigated in female pigs. Intravenous administration of CRH (dose range 10-440 pmol/kg body wt) or LVP (10-880 pmol/kg body wt) elicited transient and dose-related increases in plasma concentrations of adrenocorticotropic hormone (ACTH) and cortisol. Comparison of the responses induced by the peptides indicated that CRH is a more potent ACTH secretagogue than LVP. Treatment with LVP produced a fivefold greater plasma cortisol/ACTH ratio than treatment with CRH, suggesting that in addition to stimulating pituitary ACTH release it enhanced the ability of the adrenal cortex to secrete cortisol in response to ACTH. Whereas concomitant administration of 10 pmol CRH/kg body wt and 20 pmol LVP/kg body wt revealed an additive effect on ACTH release, synergism between both peptides was found with respect to their cortisol-releasing effect. Ten to thirteen weeks of chronic stress did not alter significantly the absolute ACTH and cortisol responses to the two peptides. In tethered pigs, the cortisol/ACTH ratio after CRH treatment, calculated from the area under the curve, was twofold that in loose-housed pigs. From these observations we conclude that after chronic stress the sensitivity of the adrenocortex to circulating ACTH was increased, whereas the sensitivity of the pituitary to CRH and/or LVP remained unaltered.

Chronic stress increases the opioid-mediated inhibition of the pituitary-adrenocortical response to acute stress in pigs.

The role of endogenous opioid mechanisms in the pituitary-adrenocortical response to acute stress was investigated in a longitudinal study in cyclic female pigs before and after exposure to chronic stress (long term tethered housing). Challenge of loose-housed pigs with acute nose-sling stress for 15 min induced an activation of the hypothalamic-pituitary-adrenocortical axis, evidenced by a transient increase in plasma ACTH (peak height above basal, 98 +/- 12 pg/ml; mean +/- SEM) and cortisol (54 +/- 3 ng/ml) concentrations. Pretreatment with the opioid receptor antagonist naloxone (0.5 mg/kg BW, iv bolus) increased the challenge-induced ACTH and cortisol responses to 244 +/- 36 pg/ml and 65 +/- 5 ng/ml, respectively. This indicates that during acute nose-sling stress, endogenous opioid systems are activated that inhibit the pituitary-adrenocortical response. After exposure of the pigs to chronic stress (10-11 weeks of tethered housing), the challenge-induced ACTH response was attenuated, whereas the cortisol response remained unchanged, suggesting an increased adrenocortical sensitivity to circulating ACTH. In addition, pretreatment with naloxone induced a greater increment in the ACTH and cortisol responses in tethered pigs than in loose-housed pigs. As no such changes were found in control animals housed loose during the entire experimental period, this indicates that the impact of opioid systems had increased due to chronic stress. The increased impact of opioid systems during chronic stress may prevent excessive hypothalamic-pituitary-adrenocortical responses to acute stressors and, thus, may be of adaptive value.

The effect of chronic stress on plasma cortisol concentrations in cyclic female pigs depends on the time of day.

The influence of tethered housing (a condition of chronic stress) on morning and evening basal plasma cortisol levels was investigated in a longitudinal study in cyclic female nulliparous pigs (gilts). After a period of loose housing in individual pens ("nonstress" estrous cycles), six cannulated gilts were tethered by a neck chain and housed for a period of 20 wk (chronic stress estrous cycles). Blood was sampled twice daily (1000 and 1800 hr) for cortisol determination. Plasma cortisol levels showed a diurnal rhythm with significantly higher levels at 1000 hr than at 1800 hr. Tethered housing induced a significant increase in the 1800-hr plasma cortisol concentrations during the first three estrous cycles after tethering, whereas the 1000-hr plasma cortisol concentrations did not change throughout the experimental period. During the period of increased 1800-hr levels, cortisol was still released in a circadian fashion, albeit, the rhythm was flattened. In control gilts, housed loose during the entire experimental period, plasma cortisol concentrations at 1000 hr and at 1800 hr remained unaltered and 1000-hr cortisol concentrations were significantly higher than the 1800-hr concentrations during the experimental period. Therefore, possible effects of the experimental procedure or age-related effects could be excluded. These data indicate that, in tethered gilts, the chronic stress-induced hypercortisolemia is of transient nature, suggesting adaptive changes in the regulation of the hypothalamic-pituitary-adrenocortical axis. In addition, the data reveal circadian differences in the effect of chronic stress on hypothalamic-pituitary- adrenocortical function.

Periovulatory profiles of oestradiol, LH and progesterone in relation to oestrus and embryo mortality in multiparous sows using transrectal ultrasonography to detect ovulation.

The timing of oestrus, the concentrations of oestradiol, LH and progesterone, and embryo survival on day 35 of pregnancy in 16 weaned multiparous sows were studied in relation to the moment of ovulation. Ovulation was detected using transrectal ultrasonography. The interval between weaning and ovulation varied between 126 and 214 h (156 +/- 29). The peak oestradiol concentration was 27 +/- 17 pg ml-7; sows with a shorter interval between weaning and ovulation had higher peaks of oestradiol (r = -0.54, P = 0.02). The interval between the peak oestradiol concentration and peak LH concentration was 11 +/- 4 h. The shape, width and height of the LH surge were variable, but did not influence the interval between the peak LH concentration and ovulation, which varied between 26 and 34 h (30 +/- 3). The interval between ovulation and the time when the progesterone concentration rose to more than 1.0 ng ml-1 above basal progesterone concentrations varied from 6 to 19 h (13 +/- 4). Ovulation took place at a more or less constant relative time of the oestrous period (after 72 +/- 8% of the duration of oestrus), irrespective of the duration of oestrus. The timing of the peak concentrations of oestradiol and LH and the rise in progesterone concentrations were closely related to the occurrence of ovulation but not to the onset of oestrus. Embryo survival on day 35 of pregnancy was related to the interval between the peak concentrations of oestradiol and LH (r = -0.68, P = 0.02); shorter intervals resulted in higher embryo survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased cortisol response to exogenous adrenocorticotropic hormone in chronically stressed pigs: influence of housing conditions.

In a longitudinal experiment, the influence of tethered housing (a condition of chronic stress) on the reactivity of the adrenal cortex to exogenous ACTH was investigated in gilts. To that end, the plasma cortisol response to synthetic ACTH (1-24; 10 micrograms/kg of BW; i.v. bolus injection via a permanent catheter) was determined before and after prolonged tethered housing. Two systems for tethered housing were used, one more restrictive than the other with regard to possibilities for visual and tactile contacts with conspecifics and visual control over the environment. The ACTH treatment induced a marked, transient plasma cortisol response in all gilts studied, irrespective of their housing conditions. Long-term tethered housing increased the ACTH-induced cortisol response. Possible effects of the experimental procedure or age-related effects could be excluded, because in control gilts, which were housed loose during the entire experimental period, the cortisol response to ACTH remained unaltered. The chronic stress-induced increase in the ACTH-induced cortisol response was considerably more pronounced and persistent in gilts that were deprived of possibilities for social contacts with conspecifics and visual control over the environment than in gilts with such possibilities. These data indicate that in tethered gilts adaptational changes occur at the level of the adrenal cortex that affect the ACTH-induced adrenocortical response. In addition, not only physical restraint but also restriction of social contact and visual control play an important role in the development of these changes.

Effect of flushing of blastocysts on days 10-13 on the life-span of the corpora lutea in the pig.

Blastocysts were flushed out of both uterine horns of gilts on Days 10, 11, 12 or 13. In mated non-pregnant gilts flushing had no effect on progesterone profile or cycle length (20.8 +/- 0.4 versus 20.6 +/- 0.6 days in the preflush cycle, N = 6, mean +/- s.e.m.). Flushing the blastocysts out of the uterine horns on Day 10 resulted in a cycle with a normal progesterone profile and a normal length (21.2 +/- 0.4 days, N = 5). Flushing on Days 11, 12 or 13 resulted in a normal cycle or in maintenance of the CL for 3-13 days as indicated by elevated progesterone concentrations and an increased interoestrous interval of, respectively, 22.0 +/- 1.2 versus 19.8 +/- 0.6 days (Day 11; N = 6), 24.8 +/- 1.4 versus 21.0 +/- 0.6 days (Day 12; N = 5; P less than 0.05) and 26.3 +/- 2.3 versus 20.5 +/- 0.4 days (Day 13; N = 6; P less than 0.05). There was a positive relationship between the change in interoestrous interval and the interval between the first observed standing oestrus and flushing of the blastocysts (rs = 0.350; n = 22; P less than 0.1). There was a large variation in the diameter of the blastocysts flushed on the same day. Only in those gilts in which the blastocysts were greater than or equal to 8 mm or filamentous were the CL maintained for 3 or more days. These results indicate that a first signal for maternal recognition of pregnancy is generated on Day 12 and that blastocysts greater than or equal to 8 mm are required for prolongation of CL function for 3 or more days. Since CL function is only extended for a maximum of 13 days (mean 7.4 +/- 1.0), a second signal seems necessary to maintain the CL for the whole period of pregnancy.

Strength and duration characteristics of the facilitory and inhibitory effects of progesterone on the estrogen-induced gonadotropin surge in the female rhesus monkey.

The dose-dependent effects of progesterone (P) on estradiol (E2)-induced gonadotropin release were investigated in the early follicular phase of female rhesus monkeys by sc implanting Silastic capsules containing either crystalline E2 or P. In group 1, E2 alone (250 pg/ml) and E2 in combination with P (1.5, 3, and 5 ng/ml) were administered in four consecutive experiments. The lowest P dosage (1.5 ng/ml) advanced the time of the maximal gonadotropin release, but the magnitude seemed to be decreased compared to that in the experiment with E2 alone. The higher P dosages (3 and 5 ng/ml) blocked the previously observed E2-induced gonadotropin surges. In group 2, E2 alone (250 pg/ml) and E2 in combination with P (1.5, 5, and 20 ng/ml), added 46 h after E2, were administered in four consecutive experiments. In all experiments, P advanced and increased the gonadotropin peaks. The FSH surges could be increased even further in the experiments with the two highest P dosages (5 and 20 ng/ml). After this period of facilitated gonadotropin secretion, we observed lower gonadotropin levels than those in the control experiment with E2 alone. This effect became more apparent by increasing by P dosage. These results point to a biphasic effect of P across time and dosage on the release of gonadotropins.