ABSTRACT
Doisynolic acids, a class of seco-steroid acids some of which exhibit greater uterotropic estrogenicity than estradiol-17 beta, are D-ring cleavage products of steroidal estrogens formed by fusion with KOH above 200 degrees C. We have found that electron-transfer reactions between estrone or estradiol and CCl4 or CBrCl3 in KOH-t-BuOH at 25 degrees C rapidly provide 16,16-dichloro- or -dibromodoisynolic acid, respectively, the former approaching estradiol in uterotropic potency. Simple esters from these highly hindered tertiary carboxylic acids, easily prepared via phase-transfer-catalyzed alkylations, also rival estradiol in uterotropic activity. Unlike natural steroidal estrogens or their commonly used artificial equivalents (DES, hexoestrol, ethynylestradiol, etc.) whose uterotropic activity is accompanied by substantial binding affinity for cytosolic estradiol receptors, these highly uterotropic doisynolic-type acids and esters exhibit binding affinities for this receptor of only about 1% that of estradiol-17 beta as determined by the usual competitive binding-inhibition studies with [3H]estradiol. Other highly uterotropic carboxylic acids may exhibit similar characteristics. These unusual results leave open the possibilities that uterotropic seco-steroid and related carboxylic acids undergo some unknown metabolic activation, are exceptionally persistent estrogens, bind to a cytosolic receptor site other than the conventional (type I) estradiol site, or bind directly to type I or type II nuclear receptor sites. At dosages of 1000 times those required for a uterotropic effect, the doisynolic-type acids (24 doses over an 8-week period) were neither toxic nor carcinogenic.
Subject(s)
Estradiol/metabolism , Estrenes/metabolism , Receptors, Estradiol/metabolism , Secosteroids/metabolism , Uterus/anatomy & histology , Animals , Binding, Competitive , Breast Neoplasms/pathology , Cytosol/metabolism , Estrenes/pharmacology , Estrenes/toxicity , Female , Humans , Mice , Mice, Inbred C3H , Molecular Structure , Organ Size/drug effects , Ovariectomy , Secosteroids/pharmacology , Secosteroids/toxicity , Structure-Activity Relationship , Tumor Cells, Cultured , Vagina/drug effectsABSTRACT
The relation of serum protein levels to age was investigated in the Swiss mouse. The present study demonstrates for the first time a dynamic age-dependent relationship between the various serum proteins. Total serum protein displayed a nonlinear change, decreasing from 10 to 136 days of age and thereafter increasing with advancing age with a peak at 465 days of age. Globulin concentration increased throughout the life span while albumin decreased for the first 136 days, after which it rose and peaked at 465 days of age. The relative percentage of each serum protein undergoes a significant non-constant, non-linear and non-quadratic change with increasing age. The patterns displayed by the various globulin fractions are strikingly similar to each other and tend to be inversely related to the pattern displayed by albumin. The relative percentage of each globulin fraction displayed a biphasic change with a peak at 200 days and a trough at 500 days of age.
Subject(s)
Aging , Serum Albumin/analysis , Serum Globulins/analysis , Age Factors , Alpha-Globulins/analysis , Animals , Beta-Globulins/analysis , Male , Mice , gamma-Globulins/analysisSubject(s)
Aging , Hemoglobins/analysis , Animals , Blood Protein Electrophoresis/methods , Male , MiceABSTRACT
Weight increases in the testes of pre-pubertal rodents when FSH was administered were revealed by histological observations to be a result of seminiferous tubule lengthening. LH administration effected a sex accessory gland weight increase (seminal vesicles) but there were no apparent testicular effects. The serum androgen level, in response to increased LH administration, showed a continuous decrease in concentration although there was a significant seminal vesicle weight increase. The evidence presented in this paper leads us to postulate that LH has a sensitizing effect on androgen dependent tissues in the pre-pubertal rodent.
Subject(s)
Follicle Stimulating Hormone/pharmacology , Luteinizing Hormone/pharmacology , Seminal Vesicles/drug effects , Testis/drug effects , Age Factors , Androgens/blood , Animals , Male , Organ Size/drug effects , RatsABSTRACT
Groups of male or female mice were pretreated for 2 wk and 1 wk, respectively, with flesh (liver or muscle) diets prepared from steers. In one experiment diethylstilbestrol (DES) was added to the diet at 0.5 or 5.0 ppb. In a second experiment diets prepared from DES-implanted steer flesh (liver or muscle) were fed. Tissues used in the control diet and DES-added diets were from DES-free steers. The animals were allowed to mate and diets continued until the first litter was delivered. Increasing DES levels in either liver or muscle diets or flesh from DES-implanted steers resulted in no significant differences either in litter size or in the number of fertile male or female mice between the control group and experimental groups. The offspring from each litter were mated and showed no significant difference in their reproductive performance. No abnormalities were noted in any offspring.
Subject(s)
Diethylstilbestrol/pharmacology , Reproduction/drug effects , Animals , Diet , Female , Fertility/drug effects , Liver , Male , Mice , Muscles , PregnancyABSTRACT
Diets containing powdered whole milk caused a dose dependent increase in seminal vesicle weights when fed to 21 day old intact male mice. Blood cholesterol levels increased as the lipids in the diet increased. Triglyceride levels were high and inversely related to lipid intake. Peripheral androgen concentrations decreased as the lipid intake and seminal vesicle weights increased, indicating a possible shift of the hormone to the target organ tissue.
Subject(s)
Androgens/blood , Dietary Fats , Lipids/blood , Milk , Seminal Vesicles/metabolism , Administration, Oral , Animals , Cholesterol/blood , Dietary Fats/administration & dosage , Dose-Response Relationship, Drug , Male , Mice , Organ Size , Triglycerides/bloodABSTRACT
New born Sprague Dawley rats were injected daily either with 50 (n=8), 100 (9) or 200 (10) mug FSH; with 50 (9), 100 (5), 200 (10) mug LH; with a combination of 50 mug FSH + 50 mug LH (10); or with the vehicle 0.9% saline (10). The animals were sacrificied at an age of 16 days. There was no influence of the hormones on the body weight. FSH caused a dose dependant stimulation of the testes growth (163, 186, 227 mg for the 50, 100 and 200 mug group; control 139 mg; diff. to control P less than or equal to 0.05, 0.01, and 0.01), whereas LH had no effect (123, 154 and 133 mg for the 50, 100 and 200 mug. LH group). The weight of the seminal vesicles was increased slightly by LH only (Diff. to control P less than 0l01). The serum androgen level was not changed by any of the treatments. The stage of the spermatogenesis was not altered by the hormones. There was no significant difference in the diameter of the seminiferous tubules. The higher testes weight after FSH administration was caused by an increase of length of the seminiferous tubules (25 m, 30 m and 35 m for 50 mug, 100 mug, and 200 mug FSH; control 23 m; diff.: P less than or equal to 0.05, less than or equal to 0.01, less than or equal to 0.01). The conclusion is that FSH has a specific effect on the longitudinal growth of the seminiferous tubules in prepubertal rats.
