Perry Gliessman

Acute administration of estrogen suppresses LH secretion without altering GnRH release in ovariectomized rhesus macaques

The pattern of hypothalamic gonadotropin-releasing hormone (GnRH) release was examined during estrogen (E)-induced suppression of plasma luteinizing hormone (LH) in ovariectomized (OVX) rhesus macaques. In Expt. 1, 4 OVX macaques were fitted with a jugular catheter and a push-pull cannula (PPC) directed into the median eminence (ME). Push-pull perfusion (PPP) was initiated 10 h before and continued for 10 h after subcutaneous estradiol benzoate (EB) injection (42 micrograms/kg b.wt.). In Expt. 2, 4 additional monkeys were subjected to local intrahypothalamic perfusion with estradiol-17 beta (E2, 3 microM) for the last 10 h of a 20-h PPP. In Expt. 2, OVX animals were challenged with 5 micrograms exogenous GnRH 3 h before and 8 h after EB injection to test for changes in altered LH release. Integrated 10-min ME perfusate and intermittent 10- or 60-min peripheral plasma samples were assayed for GnRH and LH by radioimmunoassay and bioassay, respectively. In addition, 2 other OVX macaques that received similar ME-PPC placement were sacrificed 2 days after the completion of a PPP for immunocytochemical labeling of GnRH neurons at the perfusion site. The results show that after EB, hypothalamic GnRH (MBH-GnRH) release remained unaltered while LH levels declined rapidly (Expt. 1). Similarly, intrahypothalamic perfusion of E2 failed to change the pattern of MBH-GnRH release in any of 4 monkeys (Expt. 2). Conversely, plasma LH release in response to exogenous GnRH was greatly reduced after EB (Expt. 3).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of estrogen on hypothalamic gonadotropin-releasing hormone release in castrated male rhesus macaques

The evidence that hypothalamic gonadotropin-releasing hormone (GnRH) release increases during the estrogen-induced luteinizing hormone (LH) surge in castrated female macaques and that estrogen induces a similar LH surge in the male suggests that either sexual differentiation of GnRH secretion does not exist or that changes in brain GnRH are not critical for ovulation. We tested this hypothesis by using the push-pull perfusion (PPP) technique to monitor GnRH release in the mediobasal hypothalamus continuously from 10 h before to 50 h after estrogen injection in 9 castrated male rhesus macaques. Blood sampling and PPP were performed with monkeys freely moving in their own cage by using a specially designed swivel/tethering system. PPP samples were collected every 10 min and analyzed for GnRH concentration by radioimmunoassay. Blood samples were collected every hour and plasma LH was measured by bioassay. Estradiol benzoate (EB, 42 micrograms/kg, b. wt.) was subcutaneously injected after 10 h of initial PPP. The PPP was continued for 10 h after EB in 4 and 50 h after EB in 5 monkeys. Hypothalamic GnRH patterns were analyzed by the Pulsar algorithms. The results show that during the 10 h after EB, plasma LH declined rapidly, reaching low or non-detectable levels by 7-9 h, while hypothalamic GnRH releasing patterns did not change during this period (n = 9). In contrast, estrogen enhanced GnRH level and pulse amplitude, but not pulse frequency, several hours before mean peripheral plasma LH increased from suppressed values (n = 4).(ABSTRACT TRUNCATED AT 250 WORDS)

The Pharmacokinetics of L-DOPA in Plasma and CSF of the Monkey

L-DOPA is the single most effective therapeutic agent in the treatment of Parkinson’s disease (PD). After years of treatment, however, its efficacy is mitigated by the development of a fluctuating response (“on-off”) that may be as disabling as the disease. There are no changes in the peripheral pharmacokinetics of L-DOPA to explain the development of fluctuations1. Therefore, a change in the central pharmacokinetics or pharmacodynamics of L-DOPA and dopamine are postulated to underlie the appearance of fluctuations2–6. When a constant plasma concentration of L-DOPA is maintained by intravenous infusion in Parkinsonian patients, the motor fluctuations may be abolished for hours to days, indicating that the clinical response is dependant on the plasma level and that pharmacokinetic mechanisms contribute to the clinical fluctuations7. The short plasma half-life of L-DOPA and the regulation of its entry into brain by carrier-mediated transport may become critical factors when the decreased striatal storage of dopamine due to the loss of dopaminergic nerve terminals makes motor function dependant on the constant delivery of L-DOPA to striatum to support the continuous synthesis of dopamine8.