Metabolic clearance of progesterone in the menstrual cycle.

PIP: To study the metabolic clearance rate (MCR) of progesterone in the normal female menstrual cycle and to estimate progesterone production rates from reported plasma concentration values, 21 normally menstruating women, 19-36 years old, were tested during various stages of the menstrual cycle. The MCR of progesterone as measured by the continuous infusion method was found to be 2510/day or 1512 1/day per sq. m, which is greater than the MCR in males, ovariectomized females, and pregnant women. The conversion rate of 20 alpha-hydroxypregn-4-en-3-one/progesterone was 10.9%. No relation was found between the day of the cycle and either the MCR or the conversion ratio, as measured in 3 women at 3 stages of the same menstrual cycle and in 3 women 3 times every other day at midcycle. The MCR appears to be relatively constant throughout the cycle. This experiment confirms a calculated progesterone production rate based on known plasma concentrations of .75-2.5 mg/day in the follicular phase and 15-50 mg/day in the luteal phase.^ieng

Acute effects of progesterone and the antiprogestin RU 486 on gonadotropin secretion in the follicular phase of the menstrual cycle.

Considerable controversy still exists concerning the role of progesterone in the initiation of the midcycle gonadotropin surge in humans. We, therefore, carried out a prospective randomized study to determine the potential of progesterone to initiate a gonadotropin surge and the acute effects of a potent progesterone antagonist (RU 486) on follicular phase gonadotropin secretion in normal women. The women underwent frequent blood sampling for 4 in the midfollicular (day 6) or late follicular phase (day 10). They then received either progesterone (10 mg, im) or RU 486 (10 or 100 mg, orally), and blood sampling was continued for an additional 8 h. Four women received each of the drug regimens in the early follicular phase, and four received each regimen in the late follicular phase. Two additional women were studied as control subjects at each stage of the cycle. Progesterone administration in the mid- and late follicular phases resulted in an acute increase in plasma LH and FSH concentrations, and the increases correlated with the base line plasma estradiol concentrations (P less than 0.05). In contrast to progesterone, the women who received RU 486 in the mid- and late follicular phases had a reduction in plasma LH and FSH concentrations after drug administration. The response in the mid-follicular phase was considerably less than that in the late follicular phase, and the extent of the response correlated with the baseline plasma estradiol concentrations (P less than 0.005). The changes were similar in response to both RU 486 doses. We conclude that progesterone can initiate a gonadotropin surge in the late follicular phase of the menstrual cycle. The inhibitory effect of the progesterone antagonist RU 486 suggests that a positive feedback mechanism involving progesterone may be influential some time before the surge onset.

Effect of oestrogens and progesterone alone and in combination on the female rat plasma kininogen concentrations.

PIP: The effect of estrogens and progesterone alone and in combination on virgin, female rat plasma kininogen levels was studied. Doses of 5 and 10 mcg/kg/day beta-estradiol and 50 and 250 mcg 2,4dimethyl-5,5-diphenyl pent-4-enoic acid sodium salt for 5 days gave a dose response effect. Doses of .5, 2.5, and 5 mg/kg progesterone had no effect on kinin precursor concentration. However, when varying doses of progesterone were used in conjunction with estrogen, a marked increase in kininogen concentrations produced by the estrogens was reduced by, and in proportion to, the dose of progesterone. The effect was more pronounced with the lower doses of estrogen. It appeared that progesterone reduced the increase in kinin precursor produced by the estrogen alone, in proportion to the estrogen/progesterone ration.^ieng

Progestagen effects on elicitation of aggressive behaviour in male mice.

Effects of progesterone on production of androgen-dependent aggression-eliciting pheromones were investigated. Two groups of anosmic (non-fighting) castrated mice treated with testosterone or with testosterone and progesterone, respectively, were attacked to the same degree by intact, isolated (fighting) mice while control mice (castrated only) were attacked less. The findings support the ideas that progesterone may inhibit androgen-induced aggression via a neural and not via a somatic mechanism.

PIP: The effects of progestagen on elicitation of aggressive behavior in male mice were tested. 48 mice were divided as follows: 1) 16 mice used as pheromone testers; 2) 24 mice bilaterally gonadectomized and subcutaneously implanted with either 20 mg testosterone (T), T + progesterone (P), or control beads; and 3) 8 mice sham-castrated and implanted with control beads. 4 days after the beginning of replacement therapy the treated mice were placed on an 18-hour food deprivation schedule in preparation for olfaction tests. A mouse was considered nonaggressive if response was absent (locating a food pellet) within 5 minutes. Zinc sulphate was administered intranasally to produce a peripheral olfactory dysfunction and produce anosmia. P failed to interfere with the actions of T in the production of aggression-eliciting pheromones and in the maintenance of the preputial and seminal vesicle-coagulating glands. Mice which were only castrated were attacked less than either T-treated or T + P-treated mice.

Effects of exogenous progesterone and oestradiol on prostaglandin F and 13,14-dihydro-15-oxo prostaglandin F2alpha concentrations in uteri and plasma of ovariectomized ewes.

PIP: The effects of progesterone and estradiol administration on plasma and uterine concentrations of prostaglandin F2alpha (PGF2a) and 13,14-dihydro-15-oxo PGF (PGFM) were studied in ovariectomized ewes. Treatment with 30 mcg/day estradiol for 9 days did not alter the concentration of PGF2a in uterine caruncles and intercaruncular tissue, the release of PGF2a or PGFM from these tissues in vitro, or the concentrations of PGF2a in the utero-ovarian vein or PGFM in the jugular vein. Nonetheless, there was an accumulation of estradiol in uterine tissue. Treatment with 20 mg/day progesterone for 9 days resulted in a significant (p less than .01) increase in PGF2a concentration in the uterine caruncles, a significant (p less than .01) increase in the release of PGF2a from caruncles incubated in the presence of arachidonic acid, and an increase in the concentration of PGFM in the jugular vein. The administration of estradiol to animals pretreated with progesterone further increased the PGF content of uterine caruncles, the release of PGF2a into the utero-ovarian vein, and the concentration of PGFM in the jugular vein. The amount of PGF2a in the caruncles was significantly (p less than .05) greater than that in the intercaruncular area, and the amount of PGF2a and PGFM released in vitro was also greater in the caruncles. Animals treated with progesterone plus estradiol showed a good correlation between PGF2a concentrations in blood samples obtained at the same time from the right and left utero-ovarian vains, and all animals showed a high correlation between utero-ovarian PGF2a and peripheral PGFM concentrations. Lipid droplets were also more predominant in the caruncular epithelium of progesterone-treated animals than in other groups. The results demonstrate the necessary presence of progesterone for the activation of prostaglandin synthetase activity and the promotion of PGF2a production.^ieng

In vitro and in vivo interactions of [3H]dimethylstilbestrol with the estrogen receptor.

PIP: The binding of an antiestrogen with the uterine estrogen receptor (R) has been studied directly in vitro using tritiated dimethylstilbestrol (DMS). The affinity of DMS for R as determined at equilibrium was similar to that of estradiol-17beta (E2) (K(D) approximately .3 nN) when taking into account the higher nonspecific binding of DMS. The number of DMS binding sites was constantly found to be inferior to that of E2. The fact that the DMS binding entity specifically bound estrogen and antiestrogen, was destroyed by pronase, displayed an 8S sedimentation constant, and interacted in vitro with DNA, strongly suggested that DMS interacted directly with R. The association of DMS to R was a simple 2nd-order reaction while its dissociation was a 1st-order reaction with 2 slopes. The association and dissociation rate constants of the R-DMS complex were, respectively, slower and higher than those of the R-E2 complex. The rapid dissociation rate of DMS could be responsible for its inability to protect the receptor binding sites against thermo-inactivation. Tritiated DMS was able in vivo to induce the nuclear translocation of the receptor. However, as with other short-acting antiestrogens and contrary to Nafoxidine, the time of nuclear retention of R was short. These results are in agreement with the assumption that the length of the nuclear retention of R is determinant in explaining the weak agonist activity of this compound.^ieng

Influence of progesterone on serotonin metabolism: a possible causal factor for mood changes.

PIP: The influence of progesterone on gestagen upon stress reactions and the metabolism of the biogenic amines, noradrenaline (NA) and serotonin (5-HT), were evaluated. For the 1st experiments, the 54 subjects ranged in age from 18 to 30 years. Of these, 19 (35%) had reported premenstrual tension, depression, or somatic complaints. After a preliminary interview the Moss Menstrual Distress Questionnarie and the Eysenck Personality Inventory were completed. Each subject was subsequently seen at Day 8 before predicted menstruation and 1 day before menstruation. At each session, blood samples were taken for progesterone assay. The patients sat in a darkened room and were asked to memorize words heard from a tape recording while being given a mild electric shock. The morning after the session, subjects completed the Scale of Well-Being. Psychic difficulty shortly before menstruation was higher in 49 subjects; in 16.3% of these it was severe. Only 10.2% had a negative effect. There was a correlation between the different tests. Only in the medroxyprogesterone-treated group was there a significantly higher reaction to stress on Day 1 before menstruation than a week earlier. There were large individual variations. For studies of the effects of progesterone on NA metabolism, Sprague-Dawley rats which had been ovariectomized 3 weeks earlier, were given progesterone 20 mg/kg sc on 2 consecutive days. These animals were injected with tritiated NA intracisternally and underwent a stress procedure. 3 hours after the intracisternal injection, rats were killed and tritiated-NA and its metabolites estimated. Progesterone injections did not influence NA turnover or percentage distribution of tritiated-NA and its metabolites in unstressed rats but did increase 5-HT turnover. In stress-altered 5-HT metabolism an effect of progesterone was shown. Footshock also raised endogenous progesterone levels.^ieng

Effects of oestrogen and androgen on the sexual behaviour responses of the ovariectomized ewe.

PIP: The secretion of gonadal steroid hormones that stimulate sexual behavior differs between males and females in 2 respects: the hormones are chemically different, estrogen and progesterone on 1 hand and androgen on the other, and their pattern of release into the blood stream differs according to the sex of the animal. Those produced by the female are released during a limited period whereas testosterone exhibits little day-to-day variation. 12 ovariectomized Ile-de-France ewes were injected either with 50 mg of estradiol benzoate of 10 mg or testosterone propionate 48 hours after the last of 5 daily injections of 25 mg of progesterone. In both cases the experimental females exhibited normal female sexual behavior. In a 2nd experiment, the ewes were injected daily for 4 weeks either with 50 mg of estradiol benzoate or with 10 mg of testosterone propionate. In both cases male patterns of sexual behavior appeared, but more intensely with androgen than with estrogen, and simultaneously, the ewes became receptive. However, receptivity declined rapidly after a few days of estrogen treatment. This decline did not occur with androgen.^ieng

Cardiopulmonary effects of progestational agents in emphysematous rats.

PIP: Experiments were designed to investigate whether induced emphysema would lead to pulmonary hypertension and cor pulmonale. Also additional proof was sought on the effect of progestational hormones in preventing the occurrence of emphysema in rats. Measurements of mechanical properties of the lung, of pulmonary circulation and cardiac function of the emphysematous rats were made. To some a solution of .5 ml/100 gm body weight of phytohemagglutinin was injected intratrocheally during the first week and 1 mg/100 gm body weight during the second week. Subcutaneous injections were given daily for 6 weeks. 1 group received .1 ml of .5% methocel. Another group received 5 mg/kg progesterone and a third group, .1 mg/kg medroxyprogesterone. Only about 50% of the rats survived all of these procedures. After 6 weeks the special measurements were made. The functional residual capacity of the group receiving phytohemagglutinin was increased to 4.3 ml compared with 3 ml for control rats with saline injections only and 2.8 ml for the rats with tracheal constriciton only. Also histologic examination of the lungs showed a greater percentage of air spaces in rats having had the combined procedure. This histological change was interpreted as pulmonary emphysema. The protective action of progesterone was based on normal values for functional capactiy (3 ml) and normal values for percentage of air spaces in histologic section of the lung. Both the progesterone and medroxyprogesterone prevented the development of the abnormal functional changes of emphysema. Blood changes determined by catheterization of the carotid artery support the occurrence of lesions which were interpreted as emphysema after the tracheal procedures. Tracheal obstruction was considered responsible for the abnormal values of gas tension in the arterial blood. The emphysematous rats showed higher blood pressures than those without emphysema but values for those with only tracheal obstruction were also higher than controls. The high levels of pulmonary arterial pressure were associated with hypoxia and relieved by inhalation of high oxygen. Cardiac output was diminished in those with as well as those without emphysema. This reduction may be an early functional manisfestation prior to cardiac enlargement and cor pulmonale. Rats with tracheal constriction had elevated pulmonary vascular resistance. The only electrocardiographic changes in emphysematous rats were increased height of P waves. Results indicate that the antiemphysematous effect of progesterone is not exerted on the cardiopulmonary system. The reactivity of the bronchial musculature is not affected. The administration of sympathomimetic bronchodilators does not prevent the appearance of emphysema.^ieng

Effect of progestins on glucose and lipid metabolism.

Gestamimetic amounts of progesterone enhance basal and glucose-stimulated insulin production. Contraceptive doses of synthetic progestins cause a moderate increase or no change in glucose-stimulated insulin production, depending on route of administration and species tested. Estrogens potentiate the insulinotropic effects of progesterone and the synthetic progestins. Basal serum triglyceride concentrations are generally unaffected by progesterone or 17 alpha-acetoxyprogesterone treatment but may decrease during 19-nortestosterone administration. Glucose tolerance does not change during treatment with gestamimetic doses of progesterone alone but may improve in rats and monkeys during concurrent estrogen administration. By contrast, deterioration of glucose tolerance is observed in women treated concurrently with synthetic estrogen plus 19-nortestosterone derivatives and, occasionally, with 19-nortestosterone derivatives alone. No consistent changes in glucose metabolism have been observed after treatment with 17 alpha-acetoxyprogesterone derivatives alone. The cause of the species-related differences in glucose metabolism during 19-nortestosterone treatment is obscure.

PIP: Literature on the effect of progestins on glucose and lipid metabolism is reviewed. Progesterone, in doses mimicking pregnancy, enhances basal and glucose-stimulated insulin production. Synthetic progestins, in contraceptive doses, have no effect, or produce a moderate increase in glucose-stimulated production, depending on the route of administration and the species studied. The insulinotropic effects of progesterone and synthetic progestins are potentiated by estrogens. Generally, basal serum triglyceride concentrations are unaltered by progesterone or 17alpha-acetoxy-progesterone, though they may be decreased by 19-nortestosterone. Progesterone, in doses mimicking pregnancy, does not affect glucose tolerance. However, the concurrent administration of estrogen may improve glucose tolerance in rats and monkeys. Conversely, the administration of synthetic estrogen in combination with 19-nortestosterone derivatives impairs glucose tolerance in women; in some cases, 19-nortestosterone derivatives alone also have this effect. No consistent alterations in glucose metabolism have been observed with 17alpha-acetoxyprogesterone derivatives alone. The reasons for the species-related differences in glucose metabolism during treatment with 19-nortestosterone remains to be elucidated.

Episodic secretion of LH and FSH after ovariectomy. Secretory patterns in response to estrogen and progesterone.

PIP: Patterns of LH and FSH secretion were studied in menopausal and ovariectomized subjects by frequent sampling and the influence of ovarian steroids upon these patterns was observed. Subjects were 5 women who had been subjected to bilateral oophorectomy. At 8:00 AM of Study Day 1 (control day), after fasting since midnight, 5 ml of venous blood was drawn and samples were taken at 20 minute intervals thereafter for a period of 8 hours. Patency of the needle was maintained by a slow infusion of normal saline. Blood serum was stored at - 20 degrees C. The next day blood samples were similarly collected for 2 hours. Then, in 2 patients, at 10:00 AM estradiol benzoate 1 mg was administered in a single dose, after which blood samples were collected at 20 minute intervals for an additional 6 hours. On Day 3 the same procedure was followed, except that at 10:00 AM progesterone 100 mg was given in a single intravenous dose. In 3 other patients the order of steroid administration was reversed so that progesterone was given on Study day 2 and estradiol on Day 3. Serum LH and FSH concentrations were determined by double antibody radioimmunoassays. Serum LH and FSH concentrations were increased in all patients. During control periods serum LH levels fluctuated periodically in all subjects. Serum FSH concentration varied episodically in 2 patients. No synchronous pattern was noted either before or after the administration of the drugs. After estradiol was administered on Day 2 to 2 patients, serum LH concentrations declined 39-55% from pretreatment levels and serum FSH levels decreased 15-20%. In these patients episodic increases in both LH and FSH values were observed even after estradiol injection. When progesterone was given on Day 2 and estradiol on Day 3, serum LH concentrations declined promptly. Fluctuation of LH levels were apparent in 2 of the 3 patients. FSH levels declined in only 1. Progesterone alone had no effect on FSH levels. Steroids seem to modify release of gonadotrophin rather than exert sole control over gonadotrophin release.^ieng

Uptake of (6,7-3H)estradiol-17beta in ovariectomized rats, guinea pigs, and hamsters: correlation with species differences in behavioral responsiveness to estradiol.

PIP: The amount of estradiol benzoate with progesterone required to induce lordosis in ovariectomized hamsters was determined to compare the responsiveness of hamsters to estradiol benzoate with that of rats and guinea pigs. In addition, the uptake and metabolism of tritiated estradiol in ovariectomized rats, guinea pigs, and hamsters was examined in an attempt to correlate species differences in behavioral sensitivity to estradiol with possible differences in neural affinity for the steroid. A dose of nearly 90 mg/kg was required to induce lordosis in 100% of the hamsters compared with the 2-5 mcg/kg which is effective in rats and guinea pigs. In all 3 species, highest uptake of estradiol was in the uterus and anterior pituitary gland. In the rat and guinea pig brains, the hypothalamus took up more estradiol than either the cortex or midbrain. In the hamster, there were no consistent differences in brain uptake. The affinity of the uterus, anterior pituitary, and hypothalamus of rats and guinea pigs for estradiol was greater than that of hamsters. In all 3 species, estrone was the principal metabolite of estradiol found in the tissues. The authors suggest that the higher the endogenous levels of a steroid, the less sensitive the animal is to that steroid.^ieng

Progesterone administration by nasal spray.

The bioavailability and the clinical usefulness of the P administered by nasal spray were investigated. Ten healthy menopausal women received an IN spray administration (4 doses of an oleic P solution 20 mg/mL, corresponding to nearly 11.2 mg of P) and the circulating P levels were calculated. Sixty minutes after administration, the maximum concentration (CMax, 3.75 +/- 0.214 ng/mL) was reached. High P levels (greater than 2 ng/mL) lasted until 360 minutes, and the AUC 0 to 720 was 1,481.6 +/- 343 ng.h/mL. Progesterone administration by spray formulation has proven to be effective in reaching therapeutic levels and to be acceptable to patients and, probably, clinically safe.

PIP: The bioavailability of progesterone administered by a nasal dose was investigated in 10 healthy menopausal women (average age. 56.4 years). Each woman received 2 spray doses per nostril, for a total progesterone dosage of 11.2 mg. Physiological circulating progesterone levels (greater than 2 ng/mL) were achieved within 2 minutes after intranasal spray administration, lasted an average of 6 hours, and returned to baseline values after 12 hours. The highest mean circulating level of progesterone was achieved at 60 minutes (3.750 + or - 0.214 ng/mL) and a secondary peak was recorded at 240 minutes (2.700 + or - 0.244 ng/mL). Variability in circulating levels of progesterone after spray administration did not exceed 34% in any patient until the final measurement point (720 minutes). There was no evidence of nasal irritation, but all subjects complained of the unpleasant taste of the spray. The effectiveness of intranasally administered progesterone appears due to progesterone's high solubility in the oleic carrier and the wide surface of the nasal mucosa covered by the nebulized solution. Considering the liver first-pass metabolic effect when progesterone is administered orally and the insufficient bioavailability of progesterone produced by rectal or vaginal administration, further investigation of the nasal spray approach is urged.

Comparative bioavailability of orally and vaginally administered progesterone.

OBJECTIVE: To study the pharmacokinetics of progesterone (P) in healthy premenopausal female volunteers to compare the bioavailability of orally or vaginally administered hormone. DESIGN: Subjects were randomly allocated to receive either oral P or a vaginal pessary then crossed over to the alternate preparation 1 month later. SETTING: The study was conducted in outpatient setting. SUBJECTS: All subjects were healthy, normal female volunteers who underwent a physical and gynecological examination before the study. None were using oral contraceptives. Ten subjects (mean age 32.6 +/- 7.3 years) entered the study and all completed it. INTERVENTIONS: Progesterone was administered as 200 mg of micronized hormone or as a pessary containing 400 mg. MAIN OUTCOME MEASURE: Plasma levels of P were measured by radioimmunoassay to test the apriori hypothesis of similar bioavailability. RESULTS: Peak plasma P concentrations attained within 4 hours after oral administration ranged from 8.5 to 70.6 ng/mL, whereas after vaginal administration the peak levels were attained within 8 hours and ranged from 4.4 to 181.1 ng/mL. Considerable interindividual variation was noted. Area under the plasma concentration-time curve for the two formulations was not significantly different (F = 1.09; P greater than 0.1; ANOVA). CONCLUSIONS: The two formulations had similar bioavailability.

PIP: This study examined the pharmacokinetics of progesterone (P) in healthy, premenopausal female volunteers in order to compare the bioavailability of orally or vaginally administered hormone. Subjects were randomly allocated to receive either oral P or a vaginal pessary and were then crossed over to the alternate preparation 1 month later. All subjects were healthy, normal female volunteers who underwent a physical and gynecological examination prior to this outpatient study. None used oral contraceptives. There were 10 subjects (mean age 32.6 +or- 7.3 years) who entered the study and all completed it. P was administered as 200 mg of micronized hormone or as a pessary containing 400 mg. Plasma levels of P were measured by radioimmunoassay in order to test the apriori hypothesis of similar bioavailability. Peak plasma P concentrations attained within 4 hours after oral administration ranged from 8.5 to 70.6 ng/mL, whereas after vaginal administration, the peak levels were attained within 8 hours and ranged from 4.4-181.1 ng/mL. Considerable interindividual variation was evident. Area under the plasma concentration-time curve for the 2 formulations was not significantly different (f=1.09; p0.1; ANOVA). The conclusion is that the 2 formulations had similar bioavailability.

A new long-acting injectable microcapsule system for the administration of progesterone.

A long-acting injectable microcapsule system for the controlled-release systemic administration of progesterone (P4) is described. The system consists of microcapsules made of the biodegradable polymer, d,l-polylactic acid, which contain crystalline P4. Following injection, P4 is released from the microcapsules by diffusion and biodegradation of the polymer matrix. The rate of P4 release from the prototype microcapsule system in vivo is 1.3 microgram of P4/day/mg of microcapsules, and the duration of release is 30 days. Vaginal estrous cycles in rats and cyclic ovarian function in baboons were inhibited for 1 month following a single injection of P4 microcapsules. The effects of continuous progesterone therapy on reproductive function in both rats and baboons are dose-dependent. The utility of the system as a once-a-month injectable contraceptive is established in the baboon model.

PIP: A longacting injectable microcapsule system for the controlled-release systemic administration of progesterone is described and photographed. The microcapsules are made of biodegradable polymer which contain crystalline progesterone. After injection, the progesterone is released over time from the microcapsules by diffusion and biodegradation of the polymer matrix. Rats and baboons were used to evaluate the in vivo rates of progesterone release from different capsule preparations. Results are graphed and tabulated. Tests showed that 50% of the progesterone is available for quick release while the other 50% remains to be released at a slower rate. Smaller microcapsules released the progesterone at a greater rate and a shorter duration. By using larger microcapules, it should be possible to extend the useful duration of the microcapsule system. Vaginal estrus cycles in rats and cyclic ovarian function in baboons were inhibited for 1 month following injection of the progesterone microcapsules. This method of delivery has the advantages that it obviates cyclic overdosing and underdosing and it can be delivered both locally and systemically.

Bioavailability of nasally administered progesterone.

PIP: 8 healthy women volunteers between the ages of 22-38 participated in a study designed to explore the relationship between endogenous estradiol (E2) levels and progesterone (P) absorption. Physical and pelvic examinations and laboratory screening tests revealed no abnormalities. All women had regular menstrual cycles, at 24-32-day intervals, and all were free of a significant menstrual cycle symptoms. 2 studies were performed at least 72 hours apart in the follicular phase of the menstrual cycle. The following medications were administered in random order: nasal P (Pronasone), 20 mg and nasal P (Pronasone), 30 mg. Serum P levels were drawn at the following times: 0, 3, 6, 10, 20, 30, 60, 120, 180, 240, 360, and 480 minutes. Serum for E2 assay was taken from the 0 time sample. The women were examined with a nasal speculum after each nasal absorption study. Serum was separated and frozen for subsequent assay. The data were analyzed using the CLINFO system from the National Institutes of Health. All of the women complained of a mildly unpleasant taste within several minutes following Pronasone administration. No evidence of nasal irritation was observed in any woman. The similar absorption curves obtained with Pronasone 20 mg and 30 mg doses and the aberrantly high values and delayed peaks ob tained in 2 subjects with the 30 mg dose imply that further work on dosage range, ointment formulation, and the method of application may be necessary before dependable clinical utility can be demonstrated. The peak levels of P that were reached compare favorably with results using similar doses (25 mg) in cocoa butter rectal or vaginal suppositories but are somewhat lower than those seen with polyethylene glycol base suppositories. The apparent inverse relationship between serum E2 levels and P levels obtained with Pronasone in the 20-mg dose was not expected. Alterations of nasal vascularity, interstitial hydration, and mucous blanket production all might influence absorption. The study demonstrates that the intranasal route is a potentially useful approach for the administration of unmodified sex steroid medications and is likely to be clinically safe and acceptable to patients.^ieng

Studies on the effects of pharmacologic doses of cortisone acetate and several nonsteroidal anti-inflammatory compounds on ovo-implantation, early pregnancy, and the deciduomal response in the rat.

Cortisone acetate (10 mg/day), alone or in combination with progesterone (4 mg/day); progesterone (4 mg/day); progesterone (4 mg/day) plus estrone (1 microng/day); indomethacin (0.75 mg/day); phenylbutazone (20 mg/day); flufenamic acid (10 mg/day); and Compound 83161 (tetrazolo less than 1,5-alpha greater than s-triazolo less than 3,4-c greater than quinoxoline) (8 mg/day and 12 mg/day) were each given to intact rats during early pregnancy (days 1 and/or 2 through day 8). Only cortisone acetate treatment caused a true delay in ovo-implantation. Both progesterone treatment beginning on day 1 and cortisone acetate treatment beginning on day 1 or 2 caused an increased postimplantation fetal death rate. Compound 83161, at doses causing signs of general toxicity (12 mg/day), caused a marginal inhibition of implantation. Treatment with indomethacin, phenylbutazone, or flufenamic acid caused some inhibition of the traumatic deciduomal response in spayed rats treated with progesterone, while treatment with cortisone acetate and Compound 83161 did not.

PIP: The effects of pharmacologic doses of cortisone acetate and various nonsteroidal antiinflammatory compounds on ovo-implantation, early pregnancy, and the deciduomal response in rats were investigated. The animals received either 10 mg/day cortisone acetate, alone or in combination with 4 mg/day progesterone, 4 mg/day progesterone plus 1 mcg/day estrone, .75 mg/day indomethacin, 20 mg/day phenylbutazone, 10 mg/day flufenamic acid, or 8 or 12 mg/day Compound 83161 (tetrazolo-(1,5)-s-triazolo(3,4-c)quinoxoline) on Days 1 or 2 through 8 of pregnancy. Treatment with progesterone, beginning on Day 1, and with cortisone acetate, beginning on Day 1 or 2, increased the postimplantation fetal death rate, though only cortisone acetate produced a true delay in ovo-implantation. The highest dose of Compound 83161 had a marginal effect on implantation. Spayed rats treated with progesterone plus either indomethacin, phenylbutazone, or flufenamic acid exhibited some inhibition of the traumatic deciduomal response, though this effect was not observed with cortisone acetate and Compound 83161.

Endometrial histology during intermittent intranasal luteinizing hormone-releasing hormone (LH-RH) agonist sequentially combined with an oral progestogen as an antiovulatory contraceptive approach.

Endometrial biopsies were performed in four groups of six or seven women treated for periods of 14 or 21 days with 200 micrograms twice daily or 400 micrograms once daily of intranasal Buserelin acetate. Five milligrams of medroxyprogesterone acetate (MPA) was taken orally twice daily on days 15 to 21. A medication-free week followed each treatment period. Between days 12 and 15 of the first treatment cycle, a proliferative endometrium was described in 16 out of 24 biopsies (66%). In 8 specimens (33%), early secretory changes were related to an early and/or short-lived rise in serum progesterone (P). At the end of the fourth treatment cycle, advanced maturation (days 23 to 28) was observed mainly in the 14-day schedules where serum estradiol (E2) was stimulated in or above the normal range of control cycles. Early to midluteal phase dating (days 16 to 22) was described mainly in the 21-day schedules. There was no P elevation in these groups. Five biopsies showing only proliferative tissue were associated with low levels of E2 mainly in the 400 micrograms/day group. The regimen capable of maintaining E2 in the low physiologic range (200 micrograms/12 hours X 21 days) was associated with incomplete secretory changes of the endometrium. A longer period of progestogen administration should produce a more complete maturation of the endometrium.

Diffusion of progestogens through Silastic rubber implants.

PIP: Silastic rubber capsules in 2 thicknesses (.42 mm and .80 mm) and 3 lengths (9, 14, and 19 mm) were filled with progesterone, Provera, Norgestrel, or chlormadinone acetate and implanted under the skin of rats, and the amount of steroid released was measured after 1, 2, 4, and 8 weeks. The amount of steroid released was also measured from progesterone-filled capsules .42 mm thick and varying from 19-32 mm long inserted in the uterus of 16 women volunteers for 1-7 days. The rate of release of each steroid in the rats was found to be proportionate to the length of the capsule and related, but not proportional to the thickness of the capsule. The release rate of progesterone was 3-20 times greater than that of the other steroids, while Norgestrel diffused at the lowest rate. The influence of thickness of capsule was greater for the steroids with the highest diffusion rate, progesterone and chlormadinone acetate. The release rates of all except chlormadinone acetate were higher in the 1st week. The release rates of the synthetic progestins, unlike that of progesterone, were relatively constant after the 1st week. The release rate of progesterone tended to be related to the amount remaining in the capsule when the amount became small. The measured amount of progesterone released each day from each intrauterine capsule was also proportional to its length. It appears that Norgestrel, Provera, and chlormadinone acetate are all released slowly enough and have enough biologic activity at low concentrations to have a contraceptive effect for well over 1 year when administered in a 30 mm intrauterine capsule.^ieng

Nidation in weanling rats treated with PMS and gonadal steroids.

PIP: Implantation was studied in 22-day-old female rats to determine the precise amounts of ovarian hormones needed for implantation of blastocysts. 3 mg of medroxyprogesterone was given to increase the percentage of animals with delayed implantation. .1 mcg estradiol-17beta given on Day 4 produced about 50% blastocyst implantation. 105 or .025 mcg estradiol-17beta given on Day 5 of pregnancy induced nidation in 8 out of 17 and 6 out of 8 rats, respectively. There was no significant difference between control and treated groups with regard to the number of animals with delayed blastocyst implantation and the average number of blastocysts recovered. Daily injection of progesterone helped to cause nidation. High doses of progesterone provide the ratio of progesterone to estrogen needed for implantation and also support the idea that nidation may be triggered by the rise in progesterone level in the presence of a constant amount of estrogen.^ieng