Juan Zanartu

Antifertility effect of continuous low-dosage oral progestogen therapy.

Chlormadinone acetate .5 mg was given daily as a continuous nonstop oral contraceptive from 1965 to March 1967 to 390 fertile healthy young women from 2 different socioeconomic and educational groups. 45 were educated and came from families with an above-average income and 345 were from low-income groups. 24 undesired pregnancies occurred. In 11 of the women the method was incorrectly used; and 13 subjects claimed they used the method correctly. Advantages of the method are that it is easy to carry out it is effective it is tolerated well it does not interfere with lactation it does not disturb the hypothalamic-pituitary axis recovery of fertility after its discontinuance is almost immediate it rarely causes severe side effects it is inexpensive and it does not appear to affect liver function.

Effect of oral continuous progestogen therapy in microdosage on human ovary and sperm transport.

This study attempted to determine the antifertility mechanism of continuous oral therapy with microdoses of oral progestogens. 12 women aged 32 to 39 years who were scheduled for surgical operation received oral chlormadinone acetate .5 mg daily continuously for 4-19 months. Macroscopic findings of the uterus fallopian tubes and ovaries were normal. Wedge biopsies from an ovary of each patient and studies of cervical mucus tolerance to sperm endometrial histology and urinary pregnanediol excretion were compared with those from nontreated women. An antiestrogenic effect was demonstrated. Ovulation was preserved in some subjects. Cervical mucus changes and hostility to spermatozoa were shown: no spermatozoa were found on flushing the oviduct 12-20 hours after coitus. The antifertility effect of the progestogen therapy was evident at the endometrial level. No significant abnormalities of uterus Fallopian tubes or ovaries were found and the incidence of follicular cysts was not higher than that found in untreated women. Chlormadinone acetate in doses given is thought to inhibit fertility by interfering at the levels of the cervical glands and endometrium. Occasionally ovulation is inhibited. The gonadotrophic effects of FSH and LH hormones are not fully blocked. However the therapy interfered with the control of ovarian function in some women.

Induction of Ovulation with Synthetic Gonadotrophin-Releasing Hormone in Women with Constant Anovulation Induced by Contraceptive Steroids

The ovarian response to stimulation with follicle-stimulating hormone/luteinizing hormone-releasing hormone (FSH/LH-RH) was studied in young, healthy, and fertile women with constant iatrogenic anovulation caused by depot medroxyprogesterone acetate or depot chlormadinone acetate injected for contraceptive purposes. Results were compared with those in unstimulated controls. The response was observed directly on the ovaries at laparotomy performed after treatment with FSH/LH-RH. A wedge biopsy provided ovarian tissue for histological and histochemical studies of steroid dehydrogenase activity. Treatment with FSH/LH-RH caused a trophic effect on the ovaries, with evidence of follicular development; ovulation occurred in two out of 16 treated women. Preovulatory mature follicles were found in three others. Clearly the FSH/LH-RH-induced release of FSH and LH caused follicular growth up to Graafian follicles, mature preovulatory follicles, and ovulation. Mitosis in granulosa and theca cells was also observed. A wide individual variation in gonadal response to hypothalamic FSH/LH-RH was evident, however. Nonetheless, our data support the possibility that treatment with FSH/LH-RH may prove valuable in patients with anovulatory sterility of hypothalamic origin.

CONCENTRATION OF UNCONJUGATED ESTROGENS, ANDROGENS AND GESTAGENS IN OVARIAN AND PERIPHERAL VENOUS PLASMA OF WOMEN: THE NORMAL MENSTRUAL CYCLE

The concentrations of unconjugated estrone (Ei), estradiol (E2), testosterone (T), androstenedione (A) and progesterone (P) were measured in peripheral and ovarian venous plasma collected from 18 healthy women on days 7-30 of the menstrual cycle at the time of elective tubal ligation. An additional 4 steroids, pregnenolone, 17a-hydroxyprogesterone (17-OHP), 20«-dihydroxyprogesterone (20-OHP) and dehydroepiandrosterone (DHEA), were measured in ovarian venous plasma. In 2 subjects, one in the follicular phase and one in the luteal phase, blood was obtained from both ovaries. There was evidence of secretion by the ovary of all the steroids measured. Of the Cis and Cio steroids, E2 and A, respectively, were secreted by the ovary in largest amounts. There was a wide range of concentration of each steroid in ovarian venous plasma collected at the same time of the cycle from different subjects. High concentrations of E2 were associated with high levels of Ei, T and A. DHEA appeared to be higher in plasma from the less actively secreting ovary. Equally high values of all these steroids were found in specimens from both phases of the cycle. There clearly was secretion of progesterone in the luteal phase from the ovary containing the corpus luteum. In the subject where bilateral sampling was performed, the ovary that did not contain the corpus luteum secreted lesser, though still significant, amounts of P than the one containing the corpus luteum. In the follicular phase, there was a suggestion of secretion of P in 2 cases. In 3 of 4 subjects in the follicular phase in which 17-OHP was measured, it was increased; in one of these, 17-OHP was higher in blood from the ovary secreting the smaller amount of e3trogen. In the luteal phase, high levels of 17-OHP were found in some subjects. The relationship between 17-OHP and P or E2 was not consistent. The range of concentrations of all the steroids in the peripheral plasma was much less than in the ovarian plasma. The ratios of A/T and E2/Ei in ovarian vein plasma were 4-6 times higher than in peripheral vein plasma. (J Clin Endocr 32: 155, 1971) M of the concepts concerning the endocrine events in the menstrual cycle have been deiived from observations Received April 28, 1970. Supported in part by Grant AM-08184 from the NIH, Grant GB-6231 X (J. McCracken), NSF, Division of Biological and Medical Sciences, by a grant from the Ford Foundation through its Training Program in the Physiology of Reproduction, and by grants from Ortho, Searle, Syntex, Upjohn and Warner-Lambert Companies, and by a grant from the Ford Foundation to the Department of Obstetrics, The University of Chile. 1 Presented in part before the Sixth World Congress of Fertility, Tel-Aviv, Israel, May 1968, and the Third Meeting of ALIHR, Bahia, Brazil, October 1968. 2 Present address: Department of Obstetrics and Gynaecology, University of Edinburgh, 39 Chalmers St., Edinburgh, Scotland. 3 Deceased May 12, 1968. of changes in the endometrium or from the pattern of excretion of various hormones in the urine. Only recently have sufficiently sensitive methods-become available to permit direct measurement of the content of steroid hormones and gonadotrophins in the blood of individual subjects. A number of investigators have measured the levels of unconjugated testosterone, androstenedione, estrone and estradiol in ovarian venous plasma of the human (1-15). However, a study of these steroids in both ovarian and peripheral blood throughout the menstrual cycle has not previously been made. In this study we measured unconjugated testosterone (T), androstenedione (A), estrone (Ei), 17/3-

Long Term Effect of Medroxyprogesterone Acetate in Human Ovarian Morphophysiology and Sperm Transport**This work was supported in part by a grant from the Ford Foundation to the University Maternity Hospital (University of Chile Medical School) for the University Program for Research and Training in Reproductive Biology and Human Fertility Control.

To assess the effect of Depo-medroxyprogesterone acetate (DMPA) an injectable contraceptive therapy administered every 6 months upon the human ovarian morphology 27 fertile women ages ranging from 25 to 46 years were explored by surgical laparotomy after 6-37 months of treatment. Ovaries uterus and oviducts were examined by direct inspection and by histologic and histochemical study of a wedge excision of 1 ovary. Initial dosages of DMPA varied from 100 to 200 mg. Thereafter 250-300 mg doses were administered at 6-month intervals. The laparotomy was performed from 2 to 6 months after the last injection on 13 women and from 7 to 14 months after the final dosage on the other 14 women. For all patients examined the histology of the germinal epithelium tunica albuginea ovarian cortex stroma hilum cells egg cells and follicles were normal. No albuginea thickening or stroma fibrosis was observed. Follicular growth and development were not impaired. Carbohydrate metabolism enzyme activity for lactic succinic and glucose-6-phosphate dehydrogenases was demonstrated in the same ovarian units as those of a normal nontreated preovulatory ovary. It appeared that DMPA did not block completely the FSH-gonadotropin required for follicular growth nor LH gonadotropin activity. Apparently the compound inhibited the preovulatory LH surge which conditions full follicle maturation and its rupture. Sperm penetration in cervical mucus was positive in all of the postcoital tests.(AUTHORS MODIFIED)