Do Won Hahn

Smooth muscle contraction as a model to study the mediator role of endogenous lipoxygenase products of arachidonic acid

In the lung, the contraction of smooth muscle, or bronchospasm, is generally caused by an immunologic insult resulting in mast cell degranulation and the release of histamine, slow reacting substances, and other mediators of inflammation (1). Although the immediate response is bronchospasm, continued activation of this sequence of events results in a chronic inflammatory disease. In the uterus, numerous conditions can result in smooth muscle contraction. One major pathophysiological syndrome associated with increased uterine tone and severe rhythmic contraction is primary dysmenorrhea (2). In this disease state, prostaglandins have been shown to play a major role in these contractions (3,4), and inhibitors of cyclooxygenase have proven beneficial in clinical practice (5). Both dysmenorrhea and cervical ripening have been likened to inflammatory reactions due to varying degrees of vasodilation, invasion by inflammatory cells, proliferation of fibroblasts and smooth muscle contraction (6,7). Metabolism of arachidonic acid (AA) via cyclooxygenase to prostaglandins and thromboxanes and via lipoxygenase to hydroxyeicosatetraenoic acids (HETEs) and leukotrienes is an integral part of both the acute and chronic inflammatory reaction in the lung or uterus. The material reviewed here examines the effect of endogenous leukotrienes on both the lung and uterus and suggests that other smooth muscles and pathophysiological states may be more involved with the lipoxygenase pathway of AA metabolism than previously believed.

Effect of androgens and gonadotropins on progesterone secretion of chicken granulosa cells.

A culture system has been used to study the effect of PMSG in vivo pretreatment and androgens on the in vitro secretion of progesterone from avian granulosa cells. PMSG in vivo pretreated cells secreted greater amounts of progesterone than did cells obtained from untreated hens. Testosterone and 5-alpha-dihydrotestosterone significantly increased basal progesterone secretion in PMSG pretreated cells as well as in granulosa cells harvested from non-treated hens. Testosterone or 5 alpha-dihydrotestosterone in combination with FSH or LH were additive and never resulted in a synergistic stimulation of progesterone secretion.

Influence of ovarian steroids on prostaglandin- and leukotriene-induced uterine contractions

The mammalian uterus is capable of metabolizing arachidonic acid via the lipoxygenase pathway, and the uterus responds to lipoxygenase products. We postulated that progesterone influences the production of leukotrienes in the uterus in a way similar to that in which estradiol influences prostaglandin production. Uterine contractions were measured in actively sensitized guinea pigs throughout the estrous cycle and in ovariectomized, hormonally primed, sensitized guinea pigs. Antigen challenge stimulated uterine contractions (caused by prostaglandins) that increased throughout the estrous cycle to a maximum in day 15, when estradiol is at its peak. Pretreatment with indomethacin abolished uterine contractions except on day 9 of the cycle, when progesterone levels are at their highest. Day 9 contractions were blocked by FPL 55712, a selective receptor antagonist of leukotrienes. These findings were confirmed in ovariectomized/sensitized guinea pigs. Our data suggest that endogenous synthesis of leukotrienes in the uterus may be directly related to the rise of progesterone.

Anaphylactoid and anti-ovulatory activities of LHRH antagonists in rats

Studies were conducted with LHRH antagonists examining the relationship of structure to anaphylactoid-like activity and the relationship of anaphylactoid-like activity to anti-ovulatory activity in rats. Substitution of basic amino acids appeared to enhance the anaphylactoid-like activity of these peptides but other complex structural characteristics may also be involved. Anaphylactoid and anti-ovulatory activities were clearly independent and potent LHRH antagonists with minimal anaphylactoid-like activity were identified.

Comparative effect of estriol and equine conjugated estrogens on the uterus and the vagina

Estriol has been reported to act selectively on the vagina and cervix without causing endometrial proliferations. Studies comparing this effect of estriol to that of equine conjugated estrogens after intravaginal administration have not been reported. In this study, intravaginally administered Ortho- Gynest which contains estriol, and Premarin which contains equine conjugated estrogens, were evaluated for their ability to stimulate vaginal maturation and uterine growth in rats. Approximately 15 times more conjugated estrogens than estriol was needed to induce the same degree of vaginal cornification in castrated rats. In contrast, estriol was less potent than the conjugated estrogens in causing uterine growth in immature rats after subcutaneous administration in sesame oil and in mature rats after intravaginal administration in cream preparations. In studies evaluating the vaginal irritation potential of estriol vaginal cream, the irritation exhibited by treated rabbits was found to be comparable to that of sham-treated control rabbits. Estriol was well-tolerated in an oral acute safety study in rats.

Sensitivity differences in reproductive/endocrine organs to chronically administered LHRH agonists in female rats

The acute and chronic effects of two LHRH agonists on reproductive endocrine target organs were examined in female rats. Animals were injected twice daily with [(ImBzl)-D-His6,Pro9-NEt]LHRH (histrelin) or [D-Trp6,Pro9-NEt]LHRH for 1, 3, 5, 7, 11 or 28 days at 1, 10, 100 or 1000 micrograms/kg/day beginning in the luteal phase. The responses observed with the two agonists were similar. An initial stimulatory phase was observed on the first day of treatment with substantial increases in serum LH and progesterone levels. A significant diminution of hormone response was seen by day 3. Only 1000 micrograms/kg abolished the pituitary LH response at later treatment periods. Estrous cyclicity, ovarian and uterine weight, and progesterone and estradiol levels were inhibited in a time and dose dependent manner. The results demonstrate target organ sensitivity differences. In contrast to the relatively high doses needed to inhibit the pituitary response and decrease ovarian weight, doses as low as 1 microgram/kg were sufficient to decrease uterine weight. If these findings extrapolate to humans, it may be that conditions in which the desired therapeutic action is suppression of uterine tissue, may be treated with lower doses of LHRH agonists than conditions requiring complete gonadal suppression.