Progesterone action in preparation for decidualization.

An attempt has been made to describe several actions of progesterone related to the preparation of the uterus for decidualization. These actions result from classical ligand-receptor interactions as well as from nonreceptor-mediated changes, that is, those imposed by metabolic inactivation of the steroid. By opposing some of the effects of estrogen, the progestogen alters the utilization of NAD in the endometrium to induce an increase in NADP+ production, elevation of the NADP+/NADPH ratio, and inhibition of the rate of degradation of NAD to NAM and ADP-ribose. These changes are correlated with an inhibition or delay in endometrial DNA synthesis and mitosis, an increased potential for differentiation, and the development of uterine sensitivity to decidual induction. A decidual-inducing stimulus can reverse these progestogen-dependent effects rapidly by limiting the rate of synthesis of NADP+ from NAD. Though one possible mechanism for this reversal may include the inhibition of NAD-kinase by cAMP, there is evidence to suggest that such a direct cause-effect relationship is at present tenuous.

Modulation of uterine sensitivity to decidual induction in the rat by nicotinamide; challenge and extension of a model of progestational differentiation.

A recently constructed model describes pyridine nucleotide metabolism as a key target of progesterone action during early progestational differentiation of the uterus ( progestation ). The present study was designed to challenge this model. Using uterine sensitivity to decidual induction as a "whole animal" index of preimplantational differentiation, nicotinamide (NAM) was administered as a probe, to test the model's validity. Pseudopregnant rats received NAM in two injections (100 mg each, i.p.) during a 3-h interval at selected times between 1200 h on Day 2 and 1200 h on Day 4. Deciduomata were induced by intrauterine instillation of phosphate buffer between 1800 h on Day 3 and 1200 h on Day 5. Uterine sensitivity was measured indirectly as uterine weight, 5 days after induction. The effect of NAM was dependent upon the time of its administration. Maximal sensitivity (1200 h on Day 4) was not altered by injection of NAM at 1200 h on Day 2, but was inhibited by 60% following injection at 1200 h on Day 3. After this period, the inhibitory effect of NAM was diminished. When NAM was injected at 1200 h on Day 4, a slight, but significant, augmentation of sensitivity was measured. These responses were predicted by the model. A comparison of the effects of NAM with those of progesterone suggested a mechanism of action for the hormone during early progestation .

Evidence for a photoperiod-sensitive pacemaker for estrous cycle of the rat.

To define how the periodicity of light regulates reproductive cyclicity in the rat, animals were exposed to slightly altered photoperiods in which the light/dark ratio was maintained as in the control (14L + 10D) environment. Exposure to a 22.5-h photoperiod (13.125L + 9.375D) for 10-80 days induced a significant prolongation of the first and all subsequent vaginal cycles by about 30 h. Ovulation in these animals was normal. By contrast, exposure to a 26-h photoperiod (15.167L + 10.833D) had no significant effect on vaginal cyclicity. A comparison of the data with theoreticaly generated results revealed that a significant prolongation of the estrous cycle under conditions of a shortened photoperiod cannot be accounted for by a simple entrainment of the estrous cycle to the timing of the new circadian rhythm. Rather, the evidence suggested that a photoperiod-entrained rhythm may interact with a second rhythm of different periodicity to alter the duration of the reproductive cycle as measured in this study.

Core temperature in the female rat: effect of ovariectomy and induction of pseudopregnancy.

Nocturnal peaks in core body temperature of rats during the estrous cycle were highest during the night of ovulation (2300-0200 h, proestrus-estrus) and lowest during the night before (diestrus 2-proestrus). Less dramatic diurnal secondary peaks, absent only during estrus, occurred 3-4 h after the onset of daylight. After induction of pseudopregnancy, mean temperature declined, but both daily peaks persisted until the first postluteal estrus, when the secondary peak was again absent transiently. Ovariectomy reduced mean core temperature and abolished all secondary peaks. In contrast, castration during pseudopregnancy did not abolish the secondary peaks. When cyclic rats were gonadectomized (abolishing the secondary rhythm) it was possible to re-establish this rhythm by stimulating the uterine cervix (as if to induce pseudopregnancy). However, in animals exposed to darkness (which also abolishes the secondary rhythm) reinduction by cervical stimulation was ineffective. These results indicated that the integrity of the secondary peak, though dependent on photoperiod, nevertheless was influenced by a neuroendocrine reflex arc.

Differentiation of the uterus in preparation for gestation: a model for the action of progesterone.

During the preimplantation stages of pregnancy, rising titers of progesterone alter the metabolism of the uterine endometrium to permit implantation of the blastocyst. In this model of progestational differentiation, it is proposed that endometrial pyridine nucleotide metabolism is a key target of progestogen action. The hormone may modulate NAD metabolism to promote NADP synthesis while inhibiting NAD breakdown to ADP ribose and nicotinamide. The result of such an action would impair uterine DNA synthesis and cell division, but provide increased NADP for coenzyme-limited synthetic processes and cytodifferentiation. As a result, the endometrium differentiates and becomes sensitive to decidual-inducing stimuli (the blastocyst). The decidual stimulus reverses the process by rapidly inhibiting NADP production, and by dramatically increasing poly ADP ribosylation of nuclear protein, thus facilitating DNA synthesis and the wave of cell division associated with the initiation of decidualization. The background information and evidence in support of this model are presented.

Core temperature in the female rat: effect of pinealectomy or altered lighting.

Radiotelemetry of core temperature in unrestrained, mature female rats revealed the existence of a 24-h rhythm that was bimodal. The principal peak occurred during the night under control conditions of 14 h light and 10 h darkness, and a less pronounced, secondary peak occurred 3-4 h after the onset of the light phase. Shifts in the phase of the photoperiod or alteration of the proportion of light per day revealed that the temperature rhythm was entrained by light, but that the two component peaks were governed by different aspects of the lighting regimen. Exposure of rats to continuous darkness, continuous light, or to a 20-h photoperiod revealed that the primary rhythm was endogenous, entrained by circadian photoperiods only, whereas the secondary rhythm was exogenous, requiring a circadian light/dark rhythm. A relationship between mean core temperature and ttion pressure, end-systolic L was constant, despite variations in filling and therefore independent of initial L and delta L; moreover, the L to which the ventricle shortened was determined by the course of the systolic force L-relation. Thus, irrespective of loading, delta L occurs within the confines of the contractile state-depdendent isovolumic force-L relation and where the latter is equivalent to the end-systolic force-length relation.