Factors influencing the positive feedback action of estrogen, especially those related to dose and the time of day of injection, were investigated in the ovariectomized female guinea pig Adult guinea pigs were housed in a light-controlled room (12 h light, 0600–1800 h) and ovariectomized 2 weeks before estradiol benzoate (EB) injections. EB doses of 1.5, 10, or 50 μg were administered sc at 1000 or 2200 h. Blood samples were obtained through a chronic indwelling venous catheter. Plasma LH was estimated by RIA. The mean latency from the time of EB injection to the occurrence of the LH surge was not influenced by the time of day of injection but was clearly related to the dose of estrogen administered. The mean latency to the LH surge from the time of injection decreased with increasing doses of estrogen but the mean dose-dependent latency was comparable in the same dose groups regardless of the time of day of injection. However, at each dose of estrogen, the temporal distributions of the individual LH surges were clearly different between morning and evening groups. Overall, a greater percentage of animals showed the LH surge during the dark phase than light phase. At all doses tested, 100% of the responders showed LH surges in the dark phase when the estrogen injection was timed so that the dosetypical latency was coincident with the midpoint of the dark phase of the cycle. When the dose-typical latency was coincident with the midpoint of the light phase, episodes of the LH surge were widely distributed and occurred in the dark as well as in the light phases of the cycle. This tendency for episodes of the LH surge to be shifted out of the light phase into the preceding and subsequent dark phases was inversely related to the dose of estrogen administered. Thus, the effect was most clearly observed in animals given 1.5 μg EB. These data indicate that the timing of the estrogen-induced LH surge in the ovariectomized guinea pig is regulated by two major factors: 1) the dose of estrogen given and 2) the lighting conditions (environmental light-dark cycle).
The synergistic effects of progesterone (P) and estrogen on LH release were examined in nine monkeys with regular menstrual cycles. During six menstrual cycles, animals were subjected, in alternate cycles, to each of the following treatments in random order beginning at 0830 on the third day of the cycle: 1) 30
Antiserum to ovine luteinizing hormone was prepared in rabbits by the multiple intradermal technique. Ouchterlony double immunodiffusion tests and biological neutralization experiments in rats as well as in a cyclic rhesus monkey revealed that this LH antiserum (LH-A/S) contained specific antibodies for rhesus LH. No cross reactivity was observed with monkey chorionic gonadotropin (mCG). Similar observations were made in a modified radioimmunoassay, which produced parallel inhibition curves with a purified rhesus monkey LH reference preparation and a serum pool obtained from spayed monkeys. Three ml of this LH specific antiserum or normal rabbit serum (NRS) were administered i.m. twice daily to pregnant rhesus monkeys on Days 15–19 of gestation. Daily blood samples were drawn by femoral venipuncture and the sera assayed by RIA from mCG, progesterone and circulating levels of LH antibodies. All monkeys treated with LH-A/S, as well as NRS, maintained pregnancies as evidenced by normal circulating levels of mCG and pregnancy positive rectal palpation on Day 30 or 35 of gestation. Serum progesterone levels were not significantly different in these groups of animals. Circulating LH antibodies were present even after discontinuation of LH-A/S treatment. These observations suggest that LH is not a luteotropic hormone during the period following CL rescue and until Day 21 of gestation in the rhesus monkey. The normal levels of mCG and progesterone in LH-A/S treated animals strongly support the concept that mCG is the luteotropic principle during this portion of gestation in this species.
To determine the sites of positive feedback action of estrogen and progesterone (P), pituitary responsiveness to LHRH under estradiol benzoate (EB) and P influence was examined in the ovariectomized guinea pig. Two to 3 days before the experiment, animals received an implantation of an indwelling venous catheter for blood sampling (drawn every 15 min) and for LHRH administration. Plasma LH was measured by RIA. In the fust experiment, a single dose of LHRH (1.0μg) was given to five groups of animals: non-EB-treated; 12 h, 30 h, and 36 h after 1.5 μg EB; and 30 h after 1.5 μg EB plus 2 h after 0.5 μg P. Plasma LH levels were significantly elevated 15 min after LHRH injection in all treatments. In the subsequent 60-90 min, LH levels decreased exponentially. The peak value was highest in the group of non-EB-treated animals and diminished as time elapsed after EB treatment. P plus EB priming did not facilitate an LH response significantly greater than priming with EB alone. In the second experiment, LHRH was given in a pulsatile fashion at a frequency of one bolus per h for 3 h (0.5 μg/bolus)to five groups of animals: non-EB treated; 12 h, 36 h, and 48 h after 1.5 μg EB; and 36 h after 1.5 μg EB plus 2 h after 0.5 mg P. The response to the first bolus of 0.5 μg LHRH was half of the response to 1.0 μg LHRH observed in the first experiment. Without EB treatment, all three boluses induced LH responses of equal magnitude. On the other hand, LH responses to the second and third boluses of LHRH were highly augmented under estrogen influences, especially 36 and 48 h after EB, indicating the priming effect of LHRH. P plus EB priming did not enhance pituitary responsiveness to the second and third boluses of LHRH more than did EB priming alone after 36 or 48 h. In light of our previous finding that an injection of P is effective in inducing an LH surge within 6-12 h in animals treated with 1.5 μg EB and that barbiturates block the P-induced LH surge, the present experiment suggests that the positive feedback action of P requires activation of the brain rather than the pituitary in order to facilitate the release of LH. In contrast, EB may act on the anterior pituitary as well as on the brain; the priming effect with pulsatile LHRH at the pituitary appears to contribute greatly to the positive feedback action of estrogen. (Endocrinology106: 425, 1980)
In female rats, pentobarbital anesthesia blocks estrogen- or progesterone-induced LH release. This experiment was designed to test the effects of barbiturates on the steroidinduced LH surge in the female guinea pig. Animals were housed in a light-controlled room (lights on from 0600–1800 h) and ovariectomized 2 weeks before the experiment. Blood samples were obtained through a chronic indwelling catheter. Plasma LH was estimated by RIA. Estradiol benzoate alone (EB; 10 fig injected sc at 1000 h) or EB (1.5 μg injected sc at 1000 h) folowed by progesterone (P4; 1.0 mg sc) 30 h later consistently induced an LH suige between 33–42 h after EB (10 μg) or between 6–12 h after P4. Multiple injections of pentobarbital (30 mg/kg), starting at 30 h after EB, or a single injection of phenobarbital (100 mg/kg), starting at 27 h after EB, were given before the expected LH surge in both EB alone and EB plus P4-treated animals. Animals slept for about 15 h under multiple injections of pentobarbital and for about 35 h under a single injection of phenobarbital. In all animals (n = 11), pentobarbital was effective in blocking the P4-induced LH surge completely. On the other hand, both pentobarbital and phenobarbital anesthesia failed to block the estrogen-induced LH surge; 7 of 14 and 6 of 9 animals, respectively, had LH surges during the expected period and 4 of 14 and 3 of 9 animals, respectively, had LH surges 24 h after the expected period. Thus, it is suggested that the mechanism of action by which P4 facilitates LH release differs from that of estrogen. P4 may act primarily on higher brain structures and for a limited period of time. However, estrogen (10 μg) may act primarily on the medial basal hypothalamus as well as on the pituitary and for a longer period so that LH release can occur during the time of anesthesia or 24 h after the expected period.
ABSTRACT Quinupristin-dalfopristin may be useful for treatment of organisms causing peritoneal dialysis-related peritonitis, including methicillin-resistant coagulase-negative staphylococci, methicillin-resistant Staphylococcus aureus , and vancomycin-resistant enterococci. The pharmacokinetic profiles of single intravenous doses of this combination streptogramin antibiotic of 7.5 mg/kg of body weight were characterized for eight noninfected patients receiving continuous ambulatory peritoneal dialysis. Comparison was made to pharmacokinetic profiles determined for eight healthy volunteers matched by age, sex, and race. Drug was measured in dialysate up to 6 h following the dose. Plasma and dialysate were assayed for parent compounds and metabolites. Mean pharmacokinetic parameters were compared between groups. No statistically significant differences were observed between groups for maximal concentrations in plasma, times to maximal concentration, areas under the curve, distribution volumes, rates of total body clearance, or half-lives in plasma for quinupristin and dalfopristin. No statistically significant differences were observed in maximal concentrations in plasma, times to maximal concentration, areas under the curve, or half-lives for cysteine, the glutathione conjugates of quinupristin, or the pristinamycin IIA metabolite of dalfopristin. The measurements in dialysate of the parent and most metabolites were below the expected MICs. Dialysis clearance was insignificant. Quinupristin-dalfopristin was well tolerated in both groups, causing only mild adverse events that resolved prior to discharge from the study. The disposition of quinupristin, dalfopristin, or their primary metabolites following a single dose was unaltered in patients receiving peritoneal dialysis. Intravenous dosing of this antibiotic combination is unlikely to be adequate for the treatment of peritonitis associated with peritoneal dialysis.
