Peter Eggena

Biologic effects of transdermal estradiol.

Abstract We conducted a dose–response study in 23 postmenopausal women to compare the physiologic effects of transdermal estradiol and oral conjugated equine estrogens. The doses studied were 25, 50, 100, and 200 μg of transdermal estradiol per 24 hours, and 0.625 and 1.25 μg of oral conjugated estrogens. Transdermal estradiol increased circulating concentrations of estradiol and estrone. Oral conjugated estrogens also raised the levels of estrogen, particularly estrone. Both preparations lowered gonadotropin levels, decreased the percentages of vaginal parabasal cells, increased the percentage of superficial cells, and lowered urinary calcium excretion. The effects of 0.625 and 1.25 mg of oral estrogens were similar to those of 50 and 100 μg of transdermal estradiol per 24 hours, respectively. Oral estrogens significantly increased circulating levels of renin substrate, sex-hormone–binding globulin, thyroxine-binding globulin, and cortisol-binding globulin; transdermal estradiol had no effect. The higher...

Comparison of pharmacodynamic properties of various estrogen formulations.

A group of 23 healthy postmenopausal women received one or more 2-week courses of daily administration of the following estrogen preparations: piperazine estrone sulfate (Ogen), 0.3, 0.625, 1.25, 2.5, and 5.0 mg; micronized estradiol (Estrace), 1, 2, and 10 mg; conjugated estrogens (Premarin), 0.3, 0.625, 1.25, and 2.5 mg; ethinyl estradiol (Estinyl), 10 and 20 micrograms; and diethylstilbestrol, 0.1 and 0.5 mg. Each dosage of each formulation was ingested by three women. In those women who received more than one dosage, each course was separated by a drug-free interval of at least 4 weeks. Pretreatment and posttreatment levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), corticosteroid-binding globulin-binding capacity, sex hormone-binding globulin-binding capacity, angiotensinogen, estrone, and estradiol were determined. The relative potency of these five estrogen formulations was determined by parallel line analysis for each of these responses, except LH. On a weight basis, piperazine estrone sulfate and micronized estradiol were equipotent for all responses. Conjugated estrogens suppressed FSH in a fashion equipotent to that of the other nonsynthetic estrogens; however, for all three hepatic parameters, the response was exaggerated twofold to threefold. The synthetic estrogens, diethylstilbestrol and ethinyl estradiol, were relatively more potent on a weight basis for every response and produced the most marked response (fourfold to eighteenfold in excess of their FSH suppression) for the hepatic parameters.

Ovarian renin production in vitro and in vivo: characterization and clinical correlation.

The purpose of this study was to examine the in vitro production of prorenin and active renin by human theca cells and to examine the clinical significance of this production by correlating prorenin and active renin levels with oocyte maturity in follicular fluid samples. Human theca cell cultures were established and were found to produce both prorenin as well as active renin. Androstenedione levels (126 +/- 28 pg/500,000 cells/24-hr incubation) correlated with prorenin levels (8.5 +/- 1.1 ng angiotensin I per milliliter per hour (AI/ml/hr) in culture supernatant (r = 0.61, P less than 0.05). Active renin levels in follicular fluid were higher in stimulated versus spontaneous cycles (359 +/- 67 versus 126 +/- 37 ng AI/ml/hr, P less than 0.05). Renin substrate levels were similar in follicular fluid and in the peripheral serum (1,610 +/- 216 versus 2,160 +/- 490 ng/ml) in spontaneous cycles. Follicular fluid prorenin and active renin did not correlate with oocyte maturity or with steroid levels. The authors conclude that ovarian theca cells produce renin in vitro. However, renin production does not correlate with oocyte maturity or follicular fluid steroids in vivo.

Biologic effects of equilin sulfate in postmenopausal women.

In order to determine the relative potency of equilin sulfate (EqS), a major constituent of conjugated equine estrogens, 15 women received oral doses of EqS (0.15, 0.31, and 0.625 mg) for 25 days. Doses of 0.31 and 0.625 mg significantly stimulated hepatic globulins. This stimulatory effect ranged from being 1.5 to 8 times greater than the effects of comparable doses of estrone sulfate and conjugated equine estrogens. A significant stimulation in high-density lipoprotein-cholesterol occurred with as little as 0.15 mg of EqS. Elevations in the high-density lipoprotein/low-density lipoprotein-cholesterol ratio occurred with EqS, which resulted in an approximately 4-fold greater response than that achieved with comparable doses of conjugated equine estrogens. The fasting urinary calcium/creatinine ratio was only significantly lowered with 0.625 mg of EqS and was less potent than conjugated equine estrogens in this regard. It is concluded that EqS is a potent estrogen that contributes significantly to the hepatic stimulatory effects of conjugated equine estrogens. These data also provide support for the suggestion that there may be a dissociation in potency between estrogenic effects on liver and bone.

A contraceptive vaginal ring releasing norethindrone acetate and ethinyl estradiol.

A core design contraceptive vaginal ring (CVR) releasing 650 mcg of norethindrone acetate (NA) and 10, 20, 30 or 65 mcg of ethinyl estradiol (EE) daily was developed and tested in 99 women. The CVR inhibited ovulation well with 30 or 65 mcg EE. Vaginal bleeding was better controlled than in 23 control women using NA/EE oral contraceptives. Side effects were comparable to controls for the 20 and 30 mcg EE CVR. The 65 mcg EE CVR resulted in an unacceptably high level of nausea. The 20 and 30 mcg EE CVR caused an increase in serum HDL cholesterol and triglycerides. Total cholesterol was unchanged. Angiotensinogen and sex hormone binding globulin-binding capacity were increased in a subgroup of the 20 and 30 mcg EE CVR subjects, similar to that of 20 controls using EE/gestodene oral contraceptives. This new CVR offers an excellent contraceptive alternative with the best performance provided by the 30 mcg EE dose.

Dose-finding study of a contraceptive ring releasing norethindrone acetate/ethinyl estradiol

A core design contraceptive vaginal ring (CVR) with average daily release of 650 mcg of norethindrone acetate (NA) and 30 mcg of ethinyl estradiol (EE) inhibited ovulation and controlled vaginal bleeding well, but caused some nausea. This study was designed to minimally alter the dose of steroid to see if nausea could be reduced without loss of contraceptive efficacy. This 30/650 CVR was compared to a CVR releasing 20 mcg of EE and 1000 mcg of NA (20/1000) and another releasing 25 mcg of EE and 650 mcg of NA (25/650) in 69 subjects. Twenty-three subjects using an oral contraceptive containing NA/EE served as controls. Ovulation inhibition was excellent and comparable to the OC for all formulations. The CVR provided better control of vaginal bleeding than did the OC. Side effects were equivalent to the OC with the exception of a slight increase in nausea in CVR users. Lipid changes and globulin increases were comparable to oral contraceptive users. The 20/1000 CVR increased sex hormone binding globulin-binding capacity less than the other two CVRs. The performance of the three CVRs was not significantly different, but the 25/650 showed a trend of reduced performance relative to the other two formulations.

Isoelectric heterogeneity of human serum high-density of lipoproteins

Abstract Human serum high-density lipoproteins isolated in the density range 1.063–1.125 gm/ml (HDL2) has normally been considered to be homogeneous, though immunochemical heterogeneity of HDL2 was indicated by Aladjem et al. (1) on the basis of simple immunochemical analysis. Immunochemical heterogeneity has also been reported by Scanu (2) and Levy and Frederickson (3). Heterogeneity of HDL has recently been confirmed by two different approaches. We have observed that subpopulations of HDL2 exist which contain both the polypeptides R-Thr and R-Gln (classified by their C-terminal amino acid 2 and others which contain only R-Thr (4, 5). Kostner et al. (6) have observed that upon analytical isoelectric focusing of HDL2 four distinct bands occur. In the present report we show that HDL2 is composed of at least seven different isoelectric subpopulations and that each differs with respect to polypeptide composition.

The human serum high density lipoprotein peptides of very low density lipoproteins and chylomicrons—an appendix

Abstract Very low density lipoproteins (VLDL) are shown to contain to high density lipoprotein (HDL) peptides R-thr, R-gln, and R-x and that chylomicrons contain the HDL peptides R-thr and R-gln but not R-x. The R-thr peptide is found in at least two distinct molecular species in VLDL but apparently in only one species in chylomicrons. The R-x peptide is similarly found in at least two distinct molecular species in VLDL. The R-gln peptide seems to be associated with only one species in both VLDL and chylomicrons.

Biologic Effects of Transdermal Estradiol

We conducted a dose-response study in 23 postmenopausal women to compare the physiologic effects of transdermal estradiol and oral conjugated equine estrogens. The doses studied were 25, 50, 100, and 200 micrograms of transdermal estradiol per 24 hours, and 0.625 and 1.25 mg of oral conjugated estrogens. Transdermal estradiol increased circulating concentrations of estradiol and estrone. Oral conjugated estrogens also raised the levels of estrogen, particularly estrone. Both preparations lowered gonadotropin levels, decreased the percentages of vaginal parabasal cells, increased the percentage of superficial cells, and lowered urinary calcium excretion. The effects of 0.625 and 1.25 mg of oral estrogens were similar to those of 50 and 100 micrograms of transdermal estradiol per 24 hours, respectively. Oral estrogens significantly increased circulating levels of renin substrate, sex-hormone-binding globulin, thyroxine-binding globulin, and cortisol-binding globulin; transdermal estradiol had no effect. The higher dose of oral estrogens had favorable effects on concentrations of low-density and high-density lipoproteins, but transdermal estradiol did not. Neither preparation affected any of the four clotting factors studied. These data indicate that transdermal estradiol can elicit many of the desirable actions of estrogen while avoiding the pharmacologic effects of oral estrogens on hepatic proteins.