In vivo effects of delta 1-testololactone on peripheral aromatization.

To evaluate the in vivo effect of delta 1-testololactone on peripheral aromatization, studies were performed on seven postmenopausal women with metastatic breast cancer. Analysis of variance indicated that there were significant increases of circulating androstenedione (p less than 0.05) and estradiol (p less than 0.001) during administration of different doses of testololactone. Androstenedione levels were increased with all doses of testololactone tested (50, 100, 250, and 500 mg every 6 hr for 14 days each), while estradiol rose with only the 250- and 500-mg dosages. With administration, there was a significant decrease of estrone (p less than 0.001) with the mean level falling from 26 +/- 3 (S.E.) to 11 +/- 2 pg/ml. The addition of adrenal suppression (dexamethasone, 1 mg nightly at 11 p.m.) significantly lowered androstenedione (p less than 0.05) but had no effect on estrone or estradiol levels. Long-term therapy (up to 6 months) with the 250-mg dosage showed continual suppression of estrone with no escape being observed. Studies to determine the reason for the increase of estradiol with testololactone suggested cross-reactivity of the antibody with in vivo metabolites of the drug. However, these possible metabolites did not bind to uterine cytosol estrogen receptors. The decrease in estrone with testololactone administration presumably explains its antitumor properties.

The effect of membrane permeability and binding by human serum proteins on sex steroid influx into the uterus.

To determine the effect of such factors as capillary membrane permeability, plasma protein binding, and capillary transit time on the availability of sex steroids to the uterus, the unidirectional influxes of 3H-labeled steroids from the circulation into the uterus were measured in vivo in anesthetized rats using a tissue-sampling, single injection technique. When dihydrotestosterone (DHT), estradiol (E2), and progesterone (P) were injected with Ringer's solution, the tissue extraction was in excess of 80%; hence, membrane permeability did not play a limiting role. With the more polar steroids, corticosterone and cortisol, uterine extraction was less than 40%. Significant inhibition of tissue extraction of DHT and E2, but not P, occurred with the addition of 4% albumin to the injection solution. Human sera containing increasing concentrations of sex hormone-binding globulin demonstrated inhibition of extraction of DHT and E2. Human sera also inhibited P extraction, presumably secondary to the presence of cortisol-binding globulin and orosomucoid. Large concentrations of unlabeled DHT, E2, and P in the injection solutions did not result in competitive inhibition of labeled steroid extraction. Thus, there is no evidence for a carrier mechanism mediating steroid transport into the uterus. When tissue extraction of E2 from Ringer's solution was compared in liver, brain, and uterus, no difference of tissue permeability could be found. Liver consistently had higher tissue E2 extraction than brain or uterus in the presence of human sera. The results are compatible with the influx of albumin-bound E2 into all three tissues and the influx of sex hormone-binding globulin-bound E2 into the liver.

Steroid secretion in polycystic ovarian disease after ovarian suppression by a long-acting gonadotropin-releasing hormone agonist.

The principal glandular source of increased serum androgens in polycystic ovarian disease (PCO) is controversial), since complete separation of ovarian from adrenal function has not been achieved. The purpose of this study was to determine whether a long-acting GnRH agonist could be used to selectively inhibit ovarian steroid secretion in PCO and ovulatory women. Each of five typical PCO patients and six ovulatory subjects on day 2 of their menstrual cycles received D-Trp6-Pro9-NEt-LHRH (GnRH-a; 100 micrograms) for 28 consecutive days. Their results were compared to basal serum hormone values in eight oophorectomized women. In response to GnRH-a, PCO and normal subjects exhibited sharp and sustained rises of LH and gradual decreases in FSH. These levels were clearly less than basal levels seen in oophorectomized women. Episodic LH release was significantly attenuated in both groups at the end of GnRH-a treatment. After the administration of agonist, serum estradiol (E2), estrone (E1), androstenedione (A), and testosterone (T) were suppressed to castrate levels in both groups. The decrements of E2 and E1 in PCO were gradual and continuous compared to initial dramatic rises, which reached peaks at 14 days, and subsequent abrupt falls in the ovulatory controls. Serum A and T declined steadily in both groups. Basal serum dehydroepiandrosterone and dehydroepiandrosterone sulfate, but not cortisol, levels were elevated in PCO subjects. The 24-h secretion patterns and responses to ACTH of these hormones in PCO and ovulatory subjects were unaltered by GnRH-a administration. These data demonstrate that 1) in PCO subjects, GnRH-a induced complete suppression of ovarian steroid secretion, as circulating levels at the end of treatment were comparable to those seen in our oophorectomy subjects; 2) elevated A and T levels in PCO patients were derived primarily from the ovary; and 3) adrenal steroid secretion was unaltered by GnRH-a in both PCO and normal women.

Effect of clonidine on hot flashes in postmenopausal women.

The effectiveness of clonidine in suppressing the occurrence of postmenopausal hot flashes was examined using a dose-response study design and objective recordings of hot flashes. Patients with frequent flashes were studied before and after oral administration of placebo and 0.1, 0.2, and 0.4 mg of clonidine daily for 2 weeks at each dose level. Finger temperature and skin resistance were recorded as indices of hot flash episodes. Four of 10 subjects beginning the study withdrew because of drug-related side effects. Clonidine was found to reduce significantly the frequency of hot flashes as compared with baseline (P less than .005) and with effects of the placebo (P less than .05). At the maximum dosage the mean rate of hot flash occurrence decreased 46%. It was concluded that clonidine does reduce the frequency of postmenopausal flashes.

Impermeability of the rat blood-brain barrier to exogenously administered gonadotropin-releasing hormone.

To assess the permeability of the blood-brain barrier (BBB) to exogenously administered gondatrophin-releasing hormone (GnRH), a study was performed in male-rats using the double isotope, intracarotid, single injection technique of Oldendorf. The mean (+/- SEM) brain uptake indices (BUI) of 3H-GnRH in comparison to a freely diffusible reference compound, 14C-butanol, were 1.1 +/- 0.2, 3.5 +/- 0.7 and 3.0 +/- 0.6 when the injection vehicles were Ringer's lactate, rat serum and human serum, respectively. The BUI of 3H-GnRH was similar to that of 3H-inulin, a nondiffusible compound. With different concentrations, the BUI of 3H-GnRH did not change significantly. These data indicate that the BBB of the male rat is impermeable to exogenously administered GnRH.

Physical characteristics and sex hormone levels in patients with osteoporotic hip fractures or endometrial cancer.

Comparisons were made of the physical characteristics and the sex hormone levels of 50 postmenopausal women, half of whom had sustained an osteoporotic hip fracture while the remainder had developed endometrial carcinoma. None of the patients had received estrogen replacement therapy for longer than 3 months during their lifetime. At the time of injury hip fracture patients were found to be lighter (121 +/- 5 versus 167 +/- 9 pounds) and older (73.4 +/- 1.0 versus 62.6 +/- 1.7 years) than the cancer patients at the time of diagnosis. Estrone, estradiol, percentage of free estradiol, and free estradiol levels were significantly lower in the hip fracture patients than in subjects with endometrial cancer, while sex hormone-binding globulin levels were significantly higher in the former group. Androstenedione and testosterone levels were similar. Previous studies have shown that the incidence of both lesions is influenced by body size. These data suggest that body size may exert this influence through alteration of endogenous estrogen metabolism with hip fracture patients having lower concentrations and endometrial cancer patients having higher concentrations of endogenous estrogens.

Estrogen replacement therapy by transdermal estradiol administration.

To determine whether the nonoral administration of estradiol (E2) might provide physiologic replacement without alteration of hepatic function, 20 postmenopausal women were studied before and after 3 weeks of treatment with either E2-containing transdermal therapeutic systems or placebo. Twenty premenopausal women were also studied. With E2-containing systems, serum E2 and estrone levels were restored to the premenopausal range. Variable responses of the different biochemical and biologic markers of the actions of E2 were observed. The most sensitive marker was vaginal cytology, with the E2 dosage reverting the maturation index to premenopausal values. Hot flashes, measured objectively, were reduced in frequency but not abolished. Serum levels of follicle-stimulating hormone and luteinizing hormone were lowered but remained higher than the premenopausal range. No significant changes were noted in urinary calcium/creatinine and hydroxyproline/creatinine ratios, which were used as markers of bone resorption. With active systems, no significant changes were noted in the concentrations of the hepatic proteins renin substrate and thyroxine-binding globulin or in the binding capacities of cortisol-binding globulin and sex hormone-binding globulin. These results indicate that transdermal E2 administration may be used to provide estrogen replacement while exerting limited effects on hepatic function.