David L. Healy

Induction of menstruation by an antiprogesterone steroid (RU 486) in primates: site of action, dose-response relationships, and hormonal effects

The antiprogesterone compound RU 486 (17 beta-hydroxy-11 beta-[4-dimethylaminophenyl]-17 alpha-[ 1-propynyl]estra-4,9-dien-3-one; Roussel-Uclaf, Paris, France) was used to induce menstruation in a randomized controlled trial. Castrated adult female cynomolgus monkeys (n = 17) received sequential subcutaneous Silastic capsules of estradiol or progesterone over a 49-day regimen which stimulated the steroidal milieu of the fertile ovarian/menstrual cycle. RU 486 was injected at 10.0, 1.0 to 3.0, or 0.1 mg/kg from days 31 to 34 of this protocol. At all concentrations tested, menstruation followed RU 486 injection within 48 hours and persisted through 72 hours. No bleeding followed placebo injections. All monkeys that menstruated after RU 486 administration also manifested vaginal bleeding after removal of exogenous steroid treatments. No changes in daily serum follicle-stimulating hormone, luteinizing hormone, prolactin, or serum and urinary free cortisol accompanied RU 486 treatment. We conclude that (1) RU 486 promptly induces menstruation by a local action upon the endometrium; (2) familiar endometrial proliferation and withdrawal bleeding can redevelop after exposure to this compound; (3) no effects of RU 486 on serum cortisol or pituitary gonadotropins were noted; and (4) extensive combination therapy with estrogen and progesterone causes mild hyperprolactinemia.

The progesterone antagonist RU 486. A potential new contraceptive agent.

Abstract Since progesterone supports endometrial nidation of the fertilized ovum, a progesterone antagonist would theoretically block this process and thus have contraceptive potential. We have explored the ability of RU 486, a newly developed competitive progesterone antagonist, to function as a contraceptive agent. A single oral dose of 10 mg per kilogram of body weight given in the midluteal phase consistently induced menses within 72 hours in women with normal cycles and no risk of pregnancy. Bleeding was not prevented by administration of human chorionic gonadotropin in the midluteal phase. This suggested that giving a single dose of RU 486 late in the menstrual cycle might be an effective contraceptive strategy. This concept was tested in monkeys. When given to rhesus females on day 25 of the cycle, a single intramuscular dose of RU 486 (5 mg per kilogram) prevented pregnancy. The vehicle-treated control animals had a 28 percent pregnancy rate (P<0.05 by chi-square analysis). No side effects were no...

Pulsatile progesterone secretion: its relevance to clinical evaluation of corpus luteum function

Pulsatile progesterone (P) secretory patterns were characterized in rhesus macaques (nxa0=xa013) during the midluteal phase (cycle days 18 to 20) of the normal ovarian/menstrual cycle. Sixty high-amplitude (>xa01xa0ng/ml) P pulses were observed during a total of 169 hours of sampling. Typically, P pulses had an ultradian periodicity of 2 hours and were independent of detectable luteinizing hormone (LH) and prolactin (PRL) pulses in 70% of instances. LH pulses were associated with a concomitant P and PRL pulse in 100% to 80% of occasions, respectively. Pulsatile P release was augmented by exogenous cynomolgus monkey LH and suppressed by administration of a gonadotropin-releasing hormone antagonist. Two individuals with apparently normal ovulation and once daily plasma P concentrations within the normal range demonstrated a nonpulsatile P profile. These findings encourage clinical investigations to characterize pulsatile P secretion in normal women and patients in whom corpus luteum dysfunction is suspected.

The Clinical Significance of Endometrial Prolactin

Summary: Prolactin (PRL) is produced not only by the anterior pituitary gland but also by human endometrium. That decidual stromal cells secrete PRL from day 22 of the menstrual cycle is demonstrated by: 1) nett accumulation of PRL during in vitro culture; 2) PRL accumulation is prevented by inhibitors of protein synthesis; and 3) identification of PRL mRNA within endometrial decidua. Endometrial PRL is biologically and immunologically equipotent with pituitary PRL and its amino acid sequence is very similar. In human pregnancy, decidual PRL binds to receptors on the fetal chorion and amnion and thereby passes into amniotic fluid in high concentration. Three putative functions of uterine PRL are suggested from current studies: a) a PRL receptor defect is present in the chorion laeve of patients with pregnancies complicated by chronic polyhydramnios and this deficiency in chorionic receptors for endometrial PRL may result in the development of excessive amniotic fluid; b) decidual PRL may modulate prostag‐landin synthesis not only within the endometrium prior to menstruation, but also within the chorion and amnion to allow labour to proceed in a timely manner; and c) amniotic fluid PRL may pass into the fetal tracheo‐bronchial system to promote surfactant production. Unlike pituitary PRL with distant target organs, decidual PRL appears to have paracrine or cybernetic functions in the human uterus, placental membranes and the fetus.

Use of Single Doses of the Antiprogesterone Steroid RU 486 for Induction of Menstruation in Normal Women

Progesterone supports secretory endometrium during the luteal phase of the menstrual cycle. We tested the hypothesis that a single mid-luteal dose of a progesterone antagonist, RU 486, could cause menstruation and thus potentially function as a single dose contraceptive agent. RU 486 was given in increasing doses to 11 regularly cycling women on day 21. Menses was induced in all subjects with an established luteal phase at doses of RU 486 > 5 mg/kg. Thus, RU 486 may be an effective menstrual cycle regulator and contraceptive agent.

Pituitary Responses to Acute Administration of Thymosin and to Thymectomy in Prepubertal Primates

There is firm clinical and laboratory evidence that adrenal glucocorticoids induce thymic involution, reduce mitotic activity in thymus-dependent (T) lymphocytes, and inhibit phagocytic activity of human leukocytes (Ishidate and Metcalf, 1963; Monjan, 1981). By contrast, low concentrations of glucocorticoids enhance thymocyte differentiation and stimulate antibody formation in vitro (Ambrose, 1964; Ritter, 1977). How this interaction between the hypophyseal-adrenal axis and the immune system is controlled is unclear.

Immune Regulation of the Hypothalamic-Hypophysial-Adrenal Axis: A Role for Thymosins and Lymphokines

Considerable evidence suggests that the central nervous system is able to modulate the course of immunogenesis. It is also apparent that certain products of the immune system are able to influence the hypothalamic-hypophysial-adrenal axis. Evidence is discussed to support the concept that the thymosins and lymphokines constitute part of a bidirectional circuit through which the immune system regulates itself via a neuroendocrine axis. The possibility that there exists a micro-environmental circuit consisting of a releasing factor and ACTH within the immunologic compartment is also considered.