Dynamics of Progesterone Metabolism in the Pseudopregnant Rat

Abstract

The characteristics of the disappearance of progesterone and 20 alpha-dihydroprogesterone from blood were examined in rats made pseudopregnant by administration of gonadotrophins. Measurement of the disappearance of [3H]progesterone from blood indicated that progesterone metabolism can be represented by a two-compartment model in this animal preparation. The disappearance of [3H]progesterone from blood was described by two half-lives of 0.5 and 11.7 min. The metabolic clearance rate for this steroid was 2.9 litre/day, equivalent to a production rate of 3.9 mumol/day. The initial volume of distribution of the injected [3H]progesterone was 5.0 ml, a volume similar in size to the expected plasma volume. The total volume of distribution of [3H]progesterone (i.e. 'inner' and 'outer' pools) was in the range 24.8-35.4 ml. The disappearance of endogenous progesterone from the blood of pseudopregnant rats after vascular isolation of the ovaries showed two half-lives of 1.1 and 11.4 min respectively. The disappearance of a product of reductive metabolism of progesterone, 20 alpha-dihydroprogesterone, was apparently uniphasic, with a half-life of 41.3 min.

Withdrawal from 3α-OH-5α-Pregnan-20-One Using a Pseudopregnancy Model Alters the Kinetics of Hippocampal GABAA-Gated Current and Increases the GABAAReceptor α4 Subunit in Association with Increased Anxiety

“…The use of a pseudopregnancy model here provided several advantages over use of single or multiple injection or chronic implant, as reported earlier: (1) it is a more physiological paradigm than the other procedures, because progesterone is produced by an endogenous, ovarian source; (2) the time course of progesterone exposure, with progesterone elevated from day 4 to 12, is similar to progesterone exposure during the luteal phase of the menstrual cycle (Dennerstein et al, 1985;Rapkin et al, 1997), thus making this a usef ul model for PMS and postpartum conditions; (3) not only are progesterone and 3␣,5␣-THP released, but a number of other steroids are also naturally released by the ovary and corpus luteum, also making this a better in vivo model (Robinson et al, 1981;K im and Greenwald, 1986); (4) release of progesterone under physiological states, such as estrus, pregnancy, and pseudopregnancy is somewhat episodic (Robinson et al, 1981;K im and Greenwald, 1986), a phenomenon that could not easily be replicated by artificial means of administration. The fact that hormone release is episodic in this model may explain why a single withdrawal cycle was effective in the present study in triggering withdrawal properties, whereas in earlier studies, multiple withdrawal cycles were required (Costa et al, 1995;Smith et al, 1998).…”

“…The advantage of the pseudopregnant model is that endogenous progesterone production by the ovaries is both within physiological levels and is episodic (Kim and Greenwald, 1986;Robinson et al, 1981), a condition that may alter the potency of tolerance development and withdrawal properties, as has been shown for the BDZ s (Gallagher et al, 1986). Withdrawal from 3␣,5␣-THP can be induced either by ovariectomy or by injection of a 5␣-reductase blocker.…”

“…Pregnant mare serum gonadotropin (Sigma, St. L ouis, MO) dissolved in saline was injected intraperitoneally (20 I U/0.2 ml) on postnatal day 27 (Robinson et al, 1981;K im and Greenwald, 1986). Human chorionic gonadotropin (Sigma) was injected (10 I U/0.2 ml) on postnatal day 29, which was also considered day 0 of pseudopregnancy.…”

Gender and the injured brain

“…The pharmacokinetics of progesterone indicates that the half-life of this neurosteroid in serum is approximately 15 min, and it is fully metabolized by 24 h. [96][97][98] This results in a spiking effect that is attenuated by subcutaneous delivery, as the bolus of drug seeps into tissues at a slower rate. [99][100][101] al.…”

Production rate, metabolic clearance rate and blood concentration of progesterone in conscious and anaesthetized pregnant rats

“…Since blood concentration depends on the production rate and metabolic clearance rate (MCR) of progesterone, both factors could play a role. Estimates have been made of production rate and MCR in rats in different reproductive states (Pepe & Rothchild, 1973;Robinson, Merry, Lightfoot & Hall, 1981) but these are limited to single observations made on anaesthetized animals. The possibility that shortterm changes in production rate and MCR are related and so tend to stabilize blood concentration of progesterone during pregnancy has not been examined.…”