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Background: Some studies with inconclusive results have reported a link between sarcoidosis and an increased risk of pulmonary embolism (PE). This study aimed at assessing a possible correlation between potential risk factors and PE in sarcoidosis patients., Methods: A total of 256 sarcoidosis patients (84 males and 172 females; mean age at diagnosis 49 ± 13) were enrolled after giving written informed consent. Clinical evaluations, laboratory and radiology tests were performed to evaluate the presence of pulmonary embolism., Results: Fifteen sarcoidosis patients with PE (4 males and 11 females; mean age at diagnosis 50 ± 11), diagnosed by lung scintigraphy and 241 sarcoidosis patients without PE (80 males and 161 females; mean age at diagnosis 47 ± 13), were observed. There was a statistically significant increase of the presence of antiphospholipid antibodies in the sarcoidosis group with pulmonary embolism. There was no statistically significant difference between the two groups as to smoking habit, obesity or hereditary thrombophilia frequency ( p > 0.05, respectively)., Conclusions: This study demonstrates a significant correlation between the presence of antiphospholipid antibody positivity and the pulmonary embolism events in our sarcoidosis patients. Furthermore, we propose screening for these antibodies and monitoring, aimed at timely treatment.

In 17beta-estradiol (E)-treated ovariectomized (OVX) rabbits, the coitus-induced luteinizing hormone (LH) surge is only one fourth that in ovarian-intact rabbits. In this study, we determined the pattern of the coitus-induced gonadotropin release, i.e., LH and follicle-stimulating hormone (FSH), in OVX + E animals without or with continuous 3-wk treatment of 20-alphahydroxypregn-4-en-3-one (20alphaP). For positive and negative experimental controls, ovarian-intact rabbits were either mated or sham mated, respectively. The pituitary hormones prolactin (PRL) and growth hormone (GH) were measured to serve as collateral controls for gonadotropins. The addition of continuous 20alphaP in OVX + E does fail to stimulate a coitus-induced LH surge equal in magnitude and duration to the LH surge in ovarian-intact rabbits. Postcoital levels of FSH were greater in OVX + E + 20alphaP animals than those in OVX + E rabbits. Coitus induced a PRL surge in ovarian-intact and OVX + steroid-treated females, but not in mated males, thereby suggesting a gender difference in this neuroendocrine circuit. Neither coitus nor steroids altered plasma GH values in female or male animals. We conclude that chronic administration of neither E nor E + 20alphaP can restore full-scale gonadotropin surges in OVX rabbits, whereas replacement of one or both of these steroids is sufficient for a coitus-induced PRL surge. Moreover, the presented observation that activin stimulates hypothalamic gonadotropin-releasing hormone (GnRH) release suggests a possible involvement of ovarian proteins in the production of a full-scale coitus-induced GnRH/LH surge.

Concomitant fluctuations in median eminence perfusate GnRH and plasma LH occur in rhesus macaques during the periovulatory period and after ovariectomy. The association between GnRH and LH pulses during the follicular and luteal phases of the monkey menstrual cycle is less clearly defined. However, observed LH patterns suggest higher amplitude and slower pulses of GnRH in the luteal than in the follicular phase of the menstrual cycle. The present studies were planned to compare the GnRH/LH patterns in individual monkeys by simultaneous push-pull perfusion (PPP) and blood sampling during different ovarian steroid milieus. In the initial trial, placement of two push-pull cannulae (PPCs) in the median eminence and a jugular vein catheter caused immediate loss of regular menstrual cycles in 3 monkeys, although cycles resumed over 3-6 mo postoperatively. After the return of normal reproductive cycles, PPP was performed for 12 h on either Day 7, 8, or 9 of the luteal phase. The results showed an unexpected and profound decline in LH and progesterone (P4) concentrations during the initial 4 h. No pulses of LH or P4 were observed in the remaining 8 h. All 3 monkeys exhibited menstrual bleeding 2-3 days after PPP. In subsequent trials, we continuously infused the opioid receptor antagonist nalmefene (Nmf, 1 mg/h, i.v.), starting the fourth day after PPC implantation into 11 monkeys. Menstrual cycles with accompanying fluctuations of circulating estradiol-17 beta (E2) and P4 returned in less than 40 days in these macaques and continued without further Nmf treatment. Trials of 12-h PPP/blood sampling were performed during the follicular phase with (n = 4) or without (n = 4) Nmf, and during the luteal phase with (n = 6) or without (n = 3) Nmf. Endocrine data from the 3 animals without Nmf during the luteal phase were combined with the hormonal values that were obtained in the initial trial because all 6 animals exhibited similar GnRH, LH, and P4 profiles, i.e., low levels and infrequent or absent pulses. Treatment with Nmf during luteal sampling enhanced hypothalamic GnRH secretion (> 10-fold increase in mean GnRH levels over those without Nmf) and reinitiated distinctive serum LH and P4 pulses. In contrast, patterns of hypothalamic GnRH and serum LH during the follicular phase were similar with or without Nmf treatment. These GnRH/LH profiles consisted of low-amplitude hourly pulses. Collectively, the observations suggest that stress-induced activation of opiatergic neurons can inhibit the GnRH pulse generator and that these neuronal systems are more sensitive to such inhibition in the presence of elevated levels of circulating P4. However, our observation that Nmf accelerated the reinstatement of ovarian cycles after surgery, when circulating E2 and P4 were very low, suggests that GnRH secretions are influenced by activation of different opioid receptor subtypes in response to different stresses. Some of these GnRH/opioid interactions are independent of P4.

In rodents and rabbits, neuropeptide Y (NPY) has a bimodal effect on gonadotropin-releasing hormone (GnRH) secretion. Intracerebroventricular (icv) administration or direct infusion of NPY into the median eminence (ime) suppresses GnRH release in ovariectomized (OVX) animals, but stimulates GnRH release in intact or OVX animals treated with ovarian steroids. Specific ovarian steroid-dependent NPY effects are, however, not obvious in non-human primates. In OVX rhesus monkeys, icv administration of NPY has been shown to suppress luteinizing hormone (LH) secretion whereas ime infusion of NPY stimulates GnRH pulses. In such animals, estrogen replacement does not reverse the inhibitory NPY effect on LH release, although estrogen enhances the stimulatory NPY effect on GnRH secretion. These observations led us to speculate that the bimodal NPY effects in non-human primates may depend on either the site of NPY action or the nature of the steroid milieu. This study utilized the push-pull perfusion (PPP) technique to examine the effects of either ime or icv infusion of NPY on GnRH release in OVX monkeys treated with or without both ovarian steroids. Without exception, ime infusion of NPY increased GnRH concentrations in push-pull perfusates regardless of the steroid status of the animals. In contrast, GnRH levels were reduced during icv infusion of NPY in both untreated and estrogen/progesterone-treated, OVX monkeys. These results indicate that, unlike other mammalian species, in the rhesus monkey the stimulatory and inhibitory effects of NPY on GnRH release depend on the site of NPY infusion within the brain rather than the ovarian steroidal environment.

The occurrence and profile of the preovulatory hypothalamic GnRH surge in relation to plasma profiles of LH and ovarian steroids, i.e. 17 beta-estradiol (E2) and progesterone (P4), were examined in ovarian intact, freely moving rhesus macaques. Nine monkeys with active ovarian cycles were each fitted with a jugular venous catheter and two push-pull cannulae directed to separate sites within the median eminence (ME). Each female was connected continuously to a tether/swivel device through which daily blood samples or frequent blood samples and ME perfusates (simultaneously at 10- to 20-min intervals for 18-24 h) were obtained without disturbing the animals. An increment in the plasma E2 level (> 150 pg/ml) during the follicular phase (FP) was selected as the preovulatory ovarian signal and served as the index for initiating the ME push-pull perfusion (PPP). Daily increased P4 concentrations of more than 1 ng P4/ml plasma for several consecutive days were consistent with the assumption of ovulation and subsequent formation of a corpus luteum after PPP. A total of 18 PPP trials were completed; each in a fresh ME site. Five of these PPPs were performed during the mid- and late FP (3 were between 6-8 days before and 2 were 4 days before the E2 peak). The remaining 13 PPPs, each of 18- to 24-h duration, were performed between 24 h before and 48 h after the highest daily plasma E2 level, i.e. time zero. Of these 13 PPPs, 2 started within 12 h before (-12 to 0 h), 8 began within 12 h after (0-12 h), and 3 started between 12-24 h after this peak E2 value. During the FP, mean levels of GnRH and LH were less than 2 pg/ml and 20 ng/ml, respectively. During the periovulatory interval (-24 to 48 h around time zero), the release of hypothalamic GnRH (expressed in picograms per ml) increased to 6.63 +/- 2.35 between -12 to 0 h (n = 2), peaked at 20.70 +/- 6.09 between 0-12 h (n = 10), declined to 3.25 +/- 1.39 between 12-24 h (n = 11), and further declined to 0.89 +/- 0.18 between 24-36 h (n = 3). The mean GnRH value from 0-12 h was higher (P < 0.05) than other means (including those during the FP), except for the value between -12 to 0 h. Changes in mean plasma LH values during the same periods paralleled those in GnRH.(ABSTRACT TRUNCATED AT 400 WORDS)

Prolactin (PRL) is the primary pituitary hormone responsible for initiating increased function of the corpus luteum and blastocyst implantation in the western spotted skunk. Therefore, we have designed experiments to validate a PRL RIA, characterize the preimplantation profile in PRL secretion, and determine the effects of exogenous melatonin and lesions to the anterior hypothalamic area (AHA) on PRL secretion in the skunk. These objectives were investigated with a heterologous RIA using canine PRL standards and antiserum. Displacement curves of skunk pituitary extract and serum were parallel to the canine PRL standard curve. Growth hormone-releasing hormone injection did not cause a significant change in plasma PRL levels as detected by the assay (p = 0.74). Injection of pimozide increased and bromocriptine decreased plasma PRL levels (p less than 0.05). A seasonal trend in plasma PRL levels was observed during the preimplantation period, with mean concentrations ranging from 5 ng/ml during the period of short day length in January to 17.1 ng/ml during the long day photoperiod in early May. The average date of blastocyst implantation in this study was 2 May (n = 16). Silastic capsules containing melatonin (n = 5) significantly delayed both the seasonal rise in plasma PRL levels and the time of implantation (p less than 0.05) compared to controls with empty capsules (n = 4). Lesions to the AHA (AHAx, n = 5) eliminated these effects of melatonin on both the rise in PRL and time of implantation. PRL levels were highly correlated with progesterone levels (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Both neuropeptide Y (NPY) and norepinephrine stimulate gonadotropin-releasing hormone (GnRH) secretion in intact or ovariectomized (OVx) estradiol-treated rabbits. The mechanism by which NPY stimulates GnRH is currently unknown. We have tested the hypothesis that NPY increases GnRH release via an alpha-adrenergic pathway. Adult female rabbits were OVx and had Silastic capsules containing 17 beta-estradiol inserted subcutaneously that maintained plasma estradiol levels similar to those in ovarian intact rabbits. One week later, push-pull (PP) perfusion cannulae, with tips positioned in the mediobasal hypothalamus (MBH), and jugular vein catheters were placed in all does. Blood and PP perfusate samples were obtained every 20 min during 7 h perfusion of the MBH with Krebs-Ringer phosphate buffer (KRP). Intrahypothalamic treatment with NPY (n = 5), prazosin (alpha 1-adrenergic antagonist; n = 7), yohimbine (alpha 2-adrenergic antagonist; n = 7), NPY plus prazosin (n = 7) or NPY plus yohimbine (n = 6) dissolved in KRP occurred during hours 4 through 6. GnRH in hypothalamic perfusate and luteinizing hormone (LH) and prolactin (PRL) in peripheral plasma were measured by specific radioimmunoassays. As anticipated, NPY alone significantly increased MBH-GnRH secretion (0.93 +/- 0.24 vs. 2.46 +/- 0.37 pg/ml; p less than 0.05). In contrast, NPY infused concomitantly with prazosin did not increase MBH-GnRH release (1.26 +/- 0.50 vs. 0.78 +/- 0.19 pg/ml; p greater than 0.05) whereas NPY plus yohimbine did stimulate GnRH secretion (1.15 +/- 0.13 vs. 2.65 +/- 0.89 pg/ml; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Testes of the Western spotted skunk enlarge and regress seasonally. The pineal hormone, melatonin, may be important in timing this seasonal reproductive activity. Likewise, the suprachiasmatic nuclei (SCN) have been implicated as possible neural regulators of pineal and reproductive events. These experiments were conducted to determine whether ablation of the SCN or constant administration of melatonin alters timing of the seasonal pattern of testicular regression and recrudescence. Male skunks (n = 24) were treated as follows: six received two empty Silastic capsules, six received two melatonin-filled Silastic capsules, six received sham lesions to the SCN, and six received lesions to the SCN (SCNx). All skunks were exposed to a natural photoperiod and had regressed testes at the onset of the experiment. Four of six males from the SCNx group had an average of 94 +/- 11.3% of these nuclei destroyed. Sham SCNx, animals with less than 40% of the SCN ablated, and males with empty capsules did not have fully enlarged testes until October. SCNx and melatonin-treated skunks exhibited a hastening of testicular recrudescence with maximal testis size being reached in June. Skunks with lesions to the SCN maintained enlarged testes for 5 months while all other groups exhibited rapid regression after attaining maximal testis size. Testicular regression occurred from July through October in animals receiving continuous melatonin, while controls exhibited recrudescence during this same period. Our data suggest that the SCN, melatonin, and thus the pineal gland, play a role in regulating the seasonal testicular cycle of the spotted skunk.

Two experiments were designed to determine which tissues accumulate [3H]-melatonin and the metabolic fate of this hormone in the spotted skunk. Tritiated melatonin was injected into the jugular vein of 10 anesthetized skunks 1-3 h before the onset of darkness and allowed to circulate for 22 min before the vasculature was flushed with saline to clear radioactivity from the blood. Selected tissues were removed from five skunks and oxidized in a Packard Biological Oxidizer which yielded 95 +/- 5% recovery of radioactivity. Relatively high amounts of radioactivity were found in the pineal (367 +/- 304 dpm/mg tissue), ovary (69 +/- 38 dpm/mg), pituitary (89 +/- 56 dpm/mg), liver (107 +/- 29 dpm/mg), and kidney (63 +/- 15 dpm/mg). Relatively small amounts of [3H] were found in different brain regions (approximately 6-7 dpm/mg). The uterus, pancreas, and temporalis muscle also accumulated radioactivity (approximately 13 dpm/mg). The lung retained the least amount of radioactivity (4 +/- 1.3 dpm/mg). In the second experiment, hypothalami, pituitaries, and ovaries were removed from the remaining five females. Radioactivity from these tissues was extracted and subjected to thin-layer chromatography. Melatonin accounted for approximately 70% of the radioactivity recovered while 6-hydroxymelatonin and unidentified more polar compounds made up the majority of the melatonin metabolites. These data indicate that tissues other than the hypothalamus are able to accumulate [3H]-melatonin.

The suprachiasmatic nuclei (SCN) have been implicated as neural timers of reproductive events and as possible sites of action for melatonin. We tested the hypothesis that ablation of the SCN (SCNx) would counteract the inhibitory effect of exogenous melatonin in blastocyst implantation in the spotted skunk by removing a possible site of action. Thirty-eight pregnant females with unimplanted blastocysts were treated as follows: 4 served as untreated controls, 6 received empty Silastic capsules, 5 received Silastic capsules containing melatonin, 10 received sham lesions in the SCN, 7 received lesions in the SCN and Silastic capsules containing melatonin, and 6 received lesions in the SCN and empty Silastic capsules. All surgical treatments were completed by February 15. The skunks were subjected to a natural photoperiod, and the duration of preimplantation was measured. The lesions destroyed an average of 87 +/- 10% of the SCN and a small amount of the surrounding hypothalamus. SCNx had no significant effect on duration of preimplantation (200 +/- 25.6 days) when compared to sham SCNx (205 +/- 21.5 days). Melatonin significantly (p less than 0.05) lengthened the duration of preimplantation in both intact (277 +/- 59 days) and SCNx (265 +/- 64.7 days) skunks when compared to all other groups. These data are not consistent with the hypothesis that the SCN are required for melatonin to exert its influence on timing of implantation in the spotted skunk.

This study was designed to test the hypothesis that ferret corpora lutea (CL) secrete a compound that acts in conjunction with progesterone to induce blastocyst implantation and to identify the chemical nature of this compound. CL and the residual ovarian tissue, obtained predominantly on the ninth day of pseudopregnancy, were extracted with 0.05 M phosphate-buffered saline. The extracts were injected into pregnant ferrets that had been ovariectomized on Day 6 of pregnancy and had received Silastic implants containing progesterone. Aqueous luteal extracts, but not those of the residual ovarian tissue, induced implantation in test animals. Fractionation of the luteal extracts by passage through a series of filters with molecular weight (MW) cutoffs ranging from 500 to 50,000 consistently revealed that the biologically active fraction was retained on the filter with the highest MW cutoff employed. Moreover, blastocyst implantation failed to occur in ovariectomized, progesterone-treated ferrets after one-half of a luteal preparation (MW greater than 50,000) was incubated with a broad-spectrum protease. These data are consistent with the hypothesis that CL of the ferret secrete a protein during the preimplantation period that is essential for blastocyst implantation.

The western spotted skunk exhibits an obligate delay of implantation lasting 200-220 days. The pituitary is essential for luteal activation. The corpora lutea, in turn, secrete the hormones necessary for blastocyst implantation. Two experiments were designed to determine which pituitary hormones are responsible for increasing luteal activity and induction of implantation. Forty-two pregnant skunks with delayed implanting blastocysts were treated as follows: 13 served as untreated controls, 6 received 0.5 mg prolactin (PRL) daily, and 5 received diluent beginning in January. Four received 1.5 mg bromocriptine (CB-154) daily, 3 received both CB-154 and PRL, 3 received diluent, 5 received a gonadotropin-releasing hormone agonist (GnRHa) dispensed from osmotic minipumps, and 3 received diluent dispensed from osmotic minipumps starting in April. The skunks were subjected to a natural photoperiod. Duration of preimplantation and blood levels of progesterone and luteinizing hormone were measured. PRL significantly (p less than 0.05) shortened and CB-154 significantly (p less than 0.05) prolonged the duration of preimplantation when compared to controls (148 +/- 33.6 vs. 251 +/- 3.2 vs. 199 +/- 5.1 days, respectively). PRL was able to reverse the inhibitory effect of CB-154 when both were administered simultaneously (195 +/- 4.0 vs. 251 +/- 3.2 days). GnRHa had no significant (p greater than 0.05) effect on duration of preimplantation (199 +/- 5.1 days) when compared to controls (203 +/- 3.2 days). These results indicate that PRL is the primary pituitary hormone responsible for increased luteal activity and subsequent blastocyst implantation in the spotted skunk.

The anterior hypothalamic area (AHA) has been postulated as a site of action for melatonin. We tested the hypothesis that lesions to the AHA (AHAx) would counteract the inhibitory effect of exogenous melatonin on blastocyst implantation in the spotted skunk by removing a possible site of action. Forty-seven females were treated as follows during delayed implantation. In Exp 1, five received empty Silastic capsules, five received Silastic capsules containing melatonin, six received sham AHAx plus empty capsules, none received AHAx plus empty capsules, and eight received AHAx plus capsules containing melatonin. In Exp 2, four skunks each received two empty capsules, five skunks each received two capsules containing melatonin, and five skunks received AHAx plus capsules containing melatonin. All capsules were inserted sc in the interscapular region 14-35 days after surgery in Exp 1 and 2 weeks before surgery in Exp 2. Surgery was performed between January 22 and February 12, 1988, in Exp 1 and on March 2-3, 1989, in Exp 2. The skunks were subjected to a natural photoperiod, and the duration of preimplantation was measured. In Exp 1, AHAx plus empty capsules significantly (P less than 0.05) shortened the duration of preimplantation (163 +/- 14.7 days) compared to that in sham AHAx or intact controls (193 +/- 26.1 and 188 +/- 10.6 days, respectively). Melatonin significantly (P less than 0.05) prolonged the duration of preimplantation (289 +/- 2.9 days) in intact skunks, but failed to do so in skunks with AHAx, as the preimplantation period was significantly shortened (159 +/- 6.1 days). In Exp 2, AHAx reversed the inhibitory effect of melatonin on the duration of preimplantation (191 +/- 21.5 days), as intact melatonin-treated skunks had a significantly longer preimplantation period (260 +/- 2.5 days) than skunks receiving empty capsules (191 +/- 16.4 days). The inhibitory effect of melatonin was reversible in all intact skunks, as blastocysts implanted 23 days, on the average, after cessation of treatment with melatonin. These data are consistent with the hypothesis that a portion of the AHA and/or adjacent regions play an essential role in timing blastocyst implantation in the spotted skunk. The lesions may have given this result by ablating a neural pathway controlling PRL secretion and may or may not have involved a site of action for melatonin.