Vicente Cortés-Gallegos

Plasma gonadotropins and gonadal steroids in children treated with cyclophosphamide.

Twelve boys (4.7 to 15.4 years) and five girls (4.3 to 14.1 years) treated with cyclophosphamide, 50 to 100 mg/day for periods of two to 12 months were studied. Plasma follicle-stimulating hormone, luteinizing hormone, Δ 4 -androstenedione, testosterone, 17β-estradiol, 17-hydroxyprogesterone, and progesterone were determined by radioimmunoassay in four to six samples from each patient. At time of the study, cyclophosphamide had not been given for 1.0 to 5.3 years. Results were compared to age-matched healthy boys and girls. Four boys treated when prepubertal had a normal hormonal profile. Three out of seven boys treated during stage II of puberty had elevated FSH and LH levels, low Δ 4 -androstenedione levels, but normal plasma testosterone (0.9 to 2.7 years after therapy). Follow-up studies in two of these three boys (4.0 and 6.1 years, respectively, after therapy) disclosed azzospermia in one and severe oligospermia in the other; each had elevated plasma FSH concentrations. In the remaining four boys of this group with previously normal hormonal profiles, follow-up studies in three of them (4.0 to 7.9 years after cyclophosphamide therapy) disclosed normal sperm counts and plasma FSH in one boy and mild oligospermia with normal plasma concentration in two. No evidence of primary ovarian failure was detected in any of the girls. It is suggested that caution should be maintained not only in the total dose and duration of cyclophosphamide therapy, but also in the degree of pubertal development at time of initial therapy.

A Simultaneous Assay to Quantitate Plasma and Endometrial Hormone Concentrations

A method for radioimmunoassay determination of hormones in both plasma and endometrium is presented. Total estrogen (TE) and progesterone (P) concentrations were measured simultaneously in plasma and endometrium in 59 women throughout the menstrual cycle. TE values in endometrium showed an increase of 0.45 ng/gm wet tissue weight on days 7 to 9, reaching a peak of 4.89 ng/gm wet weight at midcycle; values of 2.2 ng/gm wet weight were constant during the secretory phase. The endometrial P concentrations were 5.31 and 44.93 ng/gm wet weight during the proliferative and luteal phases, respectively. Plasma P levels during the proliferative phase were below 1 ng/ml, in comparison with values above 5.71 ng/ml during the luteal phase. The quadratic coefficients of correlation between plasma and endometrial concentrations of TE and P were 0.8 and 0.9, respectively, indicating that under such conditions modifications in the amount of circulating hormones are reflected in the target tissue. These simultaneous studies may permit further investigation of the role of circulationg hormones in local biologic phenomena.

Accumulation of Ethinylestradiol in Blood and Endometrium of Women Taking Oral Contraceptives: The Sequential Therapy *

A radioimmunoassay to quantitate ethinylestradiol (EE-2) in both plasma and endometrium is described. In 29 women under sequential oral contraceptive therapy (chlormadinone acetate, 2 mg, plus mestranol, 80 microgram) for 6 to 84 months, a single blood sample and a single endometrial sample were simultaneously obtained on different days of the pseudomenstrual cycle. In 24 women under 40 years of age the mean plasma EE-2 concentrations were similar during the first (989 +/- 94 pg/ml) and the second half of the cycle (1053 +/- 186 pg/ml) (P greater than 0.05). A similar finding was observed with regard to mean endometrial EE-2 concentrations (3.55 +/- 2.1 and 5.89 +/- 1.7 microgram/gm of wet tissue, respectively). On the other hand, five women over 40 years of age had plasma EE-2 concentrations similar to those of the previous group, but the mean endometrial EE-2 concentrations was 0.9 +/- 0.6 microgram/gm of wet tissue (P less than 0.05). Although plasma follicle-stimulating hormone and luteinizing hormone did not show midcycle peak values, complete suppression of both gonadotropins was not observed. These results show that endometrium has a great ability to concentrate EE-2, and this ability seems to be greater in women below age 40 than above. Whether or not this observation might be related to the known higher incidence of endometrial cancer in women less than 40 years old who have been under chronic sequential oral contraceptive therapy cannot be disclosed from this limited number of determinations.

Ethynyl-estradiol (EE-2) content in blood and endometrium caused by oral contraceptives☆

Abstract A comparison of EE-2 concentrations in blood and endometrium of women under sequential therapy (Group I: chlormadinone acetate + mestranol; 2 mg + 80μg, n = 24) and under combined therapy (Group II: norgestrel + EE-2: 0.5 mg + 30μg, n = 23), was performed. By means of reliable radioimmunoassay techniques, simultaneous determinations were made of the synthetic estrogen in both plasma and endometrium covering several days of the pseudomenstrual cycle. The mean ± SD plasma EE-2 concentrations observed for Group I was 1021 ± 140 pg/ml and that for Group II was 83 ± 16pg/ml. while endometrial concentrations (wet tissue) were: 4.7 ± 1.9 μg/g and 89 ± 13 ng/g respectively. The results show: (1) Greater EE-2 concentrations in the endometrium than in plasma, in both groups. (2) The EE-2 concentrates 10 times more in blood and in the order of μg in endometrium of Group I than in Group II. Together with data presented in other papers of this series, these simultaneous studies may permit understanding the role of circulating hormones in local biologic phenomena.

Effect of Paramethasone Acetate on Women with Secondary Amenorrhea: A Preliminary Report

Twelve women of normal weight (ages 17 to 36 years) with scanty menstrual bleeding were studied. They had no signs of virilization, gynecologic or endocrine pathology, or past history of hormonal treatment. Five women (group 1) experienced withdrawal bleeding after a 3-day course of chlormadinone acetate (2 mg/day) and the other seven did not (group 2). Daily venous blood samples were obtained 10 to 15 days afterward for 5 consecutive days of no treatment (control period) and during the next 5 days while the women received paramethasone acetate (PA), 2 mg/day (treatment period). In each plasma sample the concentrations of 17beta-estradiol (E2) and luteinizing hormone (LH; LER-907) were determined. The mean plasma E2 levels in group 1 were 35 +/- 8 and 86 +/- 10 pg/ml during the control and treatment periods, respectively (P less than 0.001), and the mean plasma LH levels were 28 +/- 6 and 94 +/- 34 ng/ml, respectively (P less than 0.001). No significant changes in plasma E2 and LH levels were observed in group 2 in either period. During the control period, the plasma E2 level in group 2 (14 +/- 2 pg/ml) was lower than that in group 1 (P less than 0.01); however, plasma LH levels were similar in both groups. The administration of PA for 5 months induced monthly ovulation in group 1 but not in group 2. These data suggest that the best results are obtained in women with optimal pretreatment levels of plasma E2.

Effect of paramethasone acetate upon estrogen action

To test the antiestrogenic action of paramethasone acetate (PA), a group of five postmenopausal women were treated in two ways. For phase I, PA + mestranol, 6 mg + 80 micrograms per day for 10 days, was administered. Ten days were allowed for withdrawal of medication. For phase II, mestranol, 80 micrograms per day for 10 days, free of the glucocorticoid was administered. Daily samples of cervical mucus, vaginal cells, and peripheral blood were obtained to analyze fernlike crystallization (%), cornified pyknotic nuclei cells (%), and concentrations of ethynyl-estradiol (EE-2, pg/ml) during both phases. The fernlike crystallization pattern had a mean value of 8 +/- 0.9% for phase I, while for phase II it was 85 +/- 8% (P less than 0.05). The percentage mean value of cornified pyknotic nuclei cells of phase I was 28 +/- 5% in comparison with 53 +/- 7% observed in phase II (P less than 0.05). EE-2 mean value concentrations for phase I were 85 +/- 90 pg/ml, while for phase II they were 724 +/- 418 pg/ml (P less than 0.05). These results demonstrate that 6 mg of PA is able to compete against the estrogenic action in the parameters of the study selected.

Paramethasone Acetate (PA): Corticosteroid potency vs hypothalamic pituitary-gonadal axis☆

Because paramethasone acetate (PA) suppresses basal and midcycle LH surge and blocks estrogen synthesis in the female, its possible effect upon testicular physiology was evaluated in 13 healthy men by measuring the circulating levels of FSH, LH, prolactin (PRL), testosterone (T), dihydrotestosterone (DHT), androstenedione (A), estradiol (E2) and cortisol (C) every 4 h throughout the day, before (control) and after PA (6 mg/d/7 d). The total concentrations of each hormone, as well as the PA-induced suppressibility (measured as percent decrease in the mean 24 h plasma level) were analyzed. PA suppressed neither the basal nor circadian rhythm of T and had no effect on LH, FSH or PRL output. DHT, A, E2 were significantly reduced and the basal concentrations and circadian variations of C were abolished. PA showed a dual control on the pituitary gonadal axis and while causing a maximal suppressed adrenocortical activity it had no interference in testosterone synthesis.