Clinical and metabolic responses of menopausal women to sequential versus continuous estrogen and progestin replacement therapy.

To minimize the cyclic menstrual bleeding associated with the sequential administration of estrogen and progestin in menopausal women, medroxyprogesterone acetate at the daily dose of 10 mg orally was administered, either sequentially for ten days of each 25-day treatment cycle or continuously with conjugated equine estrogen for three months. Cyclic menstrual bleeding occurred in all ten patients on sequential therapy; their endometrial histology was secretory in six, proliferative in two, and adenomatous hyperplasia in one. Of the ten patients on continuous therapy, four were amenorrheic and six experienced acyclic bleeding, but the endometrial histology was atrophic or inactive in all ten. The continuous treatment group experienced a statistically significant decrease in the mean serum levels of total cholesterol, whereas the serum levels of both low- and high-density cholesterol fractions decreased slightly. However, the sequential group experienced no change in serum levels of total cholesterol, a slight rise in high-density lipoprotein, and a significant decrease in low-density lipoprotein cholesterol fractions. Our data suggest that the combined and continuous use of conjugated equine estrogen and medroxyprogesterone acetate effectively relieves menopausal symptoms, decreases the frequency of uterine bleeding, induces endometrial atrophy, and significantly decreases serum levels of total cholesterol.

Sebum production and plasma testosterone levels in man after high-dose medroxyprogesterone acetate treatment and androgen administration.

PIP: In 47 healthy male volunteers, the administration of 100 mg of oral (MPA) medroxyprogesterone acetate daily for 42 consecutive days caused a modest 16.7% decrease in sebum production from a baseline mean of 2.28 mg to a posttreatment mean of 1.90 mg. This represented a considerably smaller decrement than had been reported in the literature. Immediately following the period of MPA administration, the addition of daily oral doses of either 50 mg of fluoxymesterone, methyltestosterone, or calusterone to the 100 mg daily dose of MPA for 42 additional days resulted in the return of sebum production to essentially presuppression values. A statistically significant decrease in serum testosterone levels from a pretreatment mean of 862 ng/100 ml to a posttreatment mean of 251 ng/100 ml, was seen in all groups treated during the first 42 days with 100 mg of MPA daily (P0.05). The addition of 50 mg of fluoxymesterone, methyltestosterone, or calusterone to the 100 mg of MPA for another 42 day period caused a further decrease in serum testosterone levels (P0.001); the fluoxymesterone-MPA combination produced the greatest decrease of serum testosterone levels, from a pretreatment mean value of 932.8 ng/100 ml (Day 1), to a posttreatment mean value of 70.6 ng/100 ml (Day 85). The daily dose of 20 mg of MPA for 42 consecutive days caused less suppression of serum testosterone levels (from 831 ng/100 ml to a mean of 585 ng/100 ml) than 100 mg of MPA from 831 ng/100 ml to a more than that of placebo (pretreatment mean of 886 ng/100 ml to a posttreatment mean of 871 ng/100 ml). Except for changes in hemoglobin, hematocrit, and haptoglobin values, no other medically significant changes were seen in the routine screening chemistries and urine analyses for any of the drug groups. These changes were not unexpected, as they are known to occur with androgen therapy. Of potentially clinical importance was the absence of any effect of antithrombin-3 levels during the study period. No major side effects were reported other than in 1 patient who developed gynecomastia of his right breast on Day 42 of MPA therapy. After his being removed from the study, the gynecomastia disappeared rapidly.^ieng

Endogenous serum testosterone in males after different doses and routes of administration of medroxyprogesterone acetate.

The effects of different doses and routes of administration (oral and IM) of medroxyprogesterone acetate on endogenous testosterone secretion were studied in healthy male volunteers. There were three treatment groups. Serum testosterone levels, measured by radioimmunoassay before, during and after different doses of medroxyprogesterone acetate, were significantly lowered (p < 0.05) in these subjects. A tendency to return toward pretreatment values was noted within three to six weeks after the last dose of medroxyprogesterone acetate. The IM route of administration suppressed the testosterone levels for the longest period of time. No indication of drug-induced toxicity, as judged by vital signs, systemic side effects, standard laboratory evaluations and some special clinical evaluations, was found during treatment or in the period immediately following the course of therapy. No serious or untoward side effects were encountered.

PIP: The effects of different doses and routes of administration (both oral and intramuscular) of medroxyprogesterone acetate on endogenous testosterone secretions were studied in healthy male volunteers. There were 3 treatment groups. Serum testosterone levels, measured by radioimmunoassay before, during, and after different doses of medroxyprogesterone acetate, were significantly lowered (P0.05) in these subjects. A tendency to return toward pretreatment values was noted within 3-6 weeks after the last dose of medroxyprogesterone acetate. Testosterone levels were suppressed for the longest period of time through intramuscular administration. No indication of drug-induced toxicity, as judged by vital signs, systemic side effects, standard laboratory evaluations and some special clinical evaluations, was found during treatment or in the period immediately following therapy. No serious or untoward side effects were encountered.

The use of medroxyprogesterone acetate for relief of climacteric symptoms.

Climacteric symptoms in the menopausal woman are perplexing to the physician. Recent literature concerning the relationship of estrogen to carcinogenesis has caused many women to discontinue this medication; thus, there is a need for an alternative therapy for the relief of these symptoms. The drug medroxyprogesterone acetate (Depo-Provera) was assessed in a double-blind, randomized, placebo-controlled study involving 48 subjects. Only one of the placebo-treated patients claimed any relief from climacteric symptoms while only two of the patients who received the study drug noted little or no relief (P < 0.0001). Relief from climacteric symptoms began at 4 to 7 days after entry into the study and extended for 8 to 20 weeks. The only side effects were withdrawal bleeding and a slight, transient weight gain. Depo-Provera appears to be a reliable substitute for estrogen in the treatment of climacteric symptoms. Further investigations with this medication seem indicated.

Ceramide aminoethylphosphonate in the fungus Pythium prolatum.

Ceramide aminoethylphosphonate was characterized from the lower fungus Pythium prolatum. The compound was purified by silicic acid column chromatography, DEAE-cellulose column chromatography, the action of phospholipase D, and two-dimensional thin-layer chromatography. Infrared spectra lacked ester bands and suggested the presence of a bonded NH group. The compound was hydrolyzed by strong acid. Sphingosine comprised 98% of the long chain bases. The predominant fatty acids were palmitate, oleate, linoleate, and an unidentified long chain acid. The aqueous portion of the hydrolysis products gave an elemental analysis consistent with 2-aminoethylphosphonate. On paper and thin layer chromatograms, the ammonium salt of the aqueous hydrolysis product chromatographed with 2-aminoethylphosphoate but not 1-aminoethylphosphonate, 2-aminoethanol, serine or alanine. This appears to be the first report of a phosphonolipid from fungi.

Differential uptake and metabolism of sitosterol and cholesterol by Achlya, Pythium, and Phytophthora species.

The relative ability of isolates of Achlya bisexualis and A. ambisexualis and isolates of Pythium and Phytophthora to take up and metabolize sitosterol and cholesterol was studied. Species of Pythium and Phytophthora took up cholesterol and sitosterol efficiently, whereas Achlya species took up booth sterols inefficiently. Species of Pythium and Phytophthora produced a polar metabolite and esters from sitosterol as they did from cholesterol. Achlya species did not produce the polar metabolite from either sterol. In these experiments Achlya species produced esters only from cholesterol; however, their failure to produce esters from sitosterol may have been due to the higher sitosterol than cholesterol concentration.

Annulment of sterol-induced sexual reproduction by estradiol in Pythium periplocum.

Estradiol prevented cholesterol-induced sexual reproduction by the fungus Pythium periplocum. Inhibition by estradiol was partial at 10-(6)M and complete at 10-(5)M, the same concentrations at which cholesterol and beta-sitosterol were initially and maximally active. Higher concentrations of estradiol were required for growth inhibition than for inhibition of reproduction.