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CLINICAL THERAPEUTICS/VOL. 3, NO. 3, 1980 Allylestrenol: Three Years of Experience with Gestanon in Threatened Abortion and Premature Labor Joaquín Cortes-Priéto, Alberto Oriol Bosch, and José Arendbia Rocha School of Medicine, Complutensis University, Madrid, Spain ABSTRACT Allylestrenol* was used to treat 375 women with threatened pregnancies. Results show that this drug is capable of maintaining pregnancy in a large series of ambulant patients and is safe for both mother and child. Allylestrenol does not maintain pregnancy if placental dysfunction is present, however. Newborns whose mothers are treated with allylestrenol have slightly higher birth weights than controls. The possible role of allylestrenol in this process is discussed. At high doses, allylestrenol effectively stops premature labor, suggesting a selective action on the myometrium. INTRODUCTION In normal fertile women the ovary performs a dual function: providing an ovum for fertilization and preparing the endometrium for the nidation of the fertilized ovum. Once pregnancy is initiated the ovary must supply the principal substances required to maintain it. *Trademark: Gestanon® (Organon International, Oss, Holland). 200 By the end of the first trimester ovarian function gradually subsides and its task is taken over by the placenta. Both ovary and placenta may be the source of many disturbances associated with failures to carry a pregnancy to term. Many women suffer from a deficiency in the pre gnancy-maintaining system. These deficiencies can either be fetal — e.g., in severe malformations — or maternal in origin. In the latter case progesterone is thought to play a major role. Hormonal deficiencies resulting from corpus luteum graviditatis insufficiency or an impaired trophoblastic function have been postulated as principal causes of threatened and habitual abortion. How progesterone protects pregnancy has not yet been fully elucidated. The protection of the myometrium against contractions is one of the most accepted possibilities. It has been known for a long time that progesterone reduces the sensitivity of the myometrium to oxytocin. 1 This progesterone blockade during pregnancy may be due to the fact that the placenta releases its progesterone directly into the adjacent tissue. This theory may explain many of the phenomena ob- J. CORTÉS-PRIETO ET AL. served.2 For this reason investigators have looked for methods and drugs to stimulate placental progesterone production. Allylestrenol is thought to be such a substance.3 Observations in this direction demonstrate that allylestre nol stimulates the enzymatic activity of the existing syncytiotrophoblast. 4 Earlier investigations indicated an increase in placental 3β-hydroxy-steroid dehydrogenase activity. 5 Judged from HPL levels in serum Spona et al. 6 suggested that the pregnancy-maintaining effect of allylestrenol is at least partly due to a stimulation of the placental function. The demonstration of alpha- and beta-receptors in the uterus has led to a better understanding of the uterine mechanism. 7 Moreover, it has been demonstrated that stimulation of the alpha-receptors increased uterine contractility. Conversely, stimulation of beta-receptors inhibited such effect. There is also a difference between the beta-receptors in the various tissues. Beta 2-receptors are present in the uterus 8 whereas the cardiac muscle appears to contain beta1-receptors. 9 Allylestrenol has a strong prevalence for predominance of beta-receptors. 10 In earlier studies on allylestrenol the relatively quick onset of its clinical effect was often questioned as it could not be explained on the basis of hormonal action. An alternative explanation is that allylestrenol has some form of neural-mediated action resulting in uterine relaxation by stimulating the myometrial beta2-receptors. A combination of actions of allylestrenol—improvement of the trophoblastic function, which promotes the production of progesterone, and the beta2-adrenergic action—could account for the results of this drug in the treatment of myometrial spasmodic conditions that may interrupt pregnancy. Other factors, such as the influence on AMP, may also play a role in allylestrenol's highly complex mechanism of action.3,11 MATERIALS AND METHODS Objectives of the Study Allylestrenol was evaluated for its efficacy in the management of threatened abortion and premature labor. For ethical reasons a double-blind study was considered not to be acceptable. Patients The study group comprised 415 pregnant women without anatomical anomalies of the genital tract. Of these, 40 women who did not use drugs during pregnancy serve as controls for hormonal determinations. The remaining 375 patients were treated with allylestrenol because of difficulties during current or previous pregnancies (Table I). Treatment In 297 patients treatment was instituted because of threatened abortion 201 CLINICAL THERAPEUTICS in the first trimester, in 37 women because of threatened abortion in the second trimester, and in 41 because of premature labor (Table II). Allylestrenol was the only drug given. This was combined with bedrest until vaginal bleeding subsided. The daily dosage of allylestrenol ranged from 10 to 40 mg per day. As prophylaxis in women who had aborted previously, treatment was started directly after pregnancy had been diagnosed. In patients with premature labor complete bedrest and 10 mg of allylestrenol orally every four hours was prescribed. When uterine contractility had ceased the dose was gradually lowered to 10 to 15 mg per day. This was continued until one to two weeks before term. Hormonal Assays For hormonal determinations we selected 77 women. Forty were normal pregnant women who served as controls, and 37 were from the allylestrenol group who had difficulties in the first trimester of their pregnancy. Assays were carried out for total estrogens and for pregnanediol. Urine was 202 collected every 24 hours whenever possible. Once the patient's condition remained stable there was less necessity for daily delivery of urine and subsequent analysis. In such cases determinations were made every fortnight. Hormonal determinations for total estrogens were performed according to Brown's method and expressed in micrograms per 24 hours. Pregnanediol was determined by gas chromatography using a semi-automated method. At all births the placenta was carefully inspected. For most of the patients subjected to hormonal assays a histologic examination of placental tissue was carried out as well. RESULTS Allylestrenol was administered in 375 pregnancies for the reasons mentioned. In total, each of 281 women gave birth to one baby, and one woman gave birth to twin girls (Table II). Each of the 40 normal women serving as controls gave birth to one baby. Figure 1 shows the excretion patterns J. CORTÉS-PRIETO ET AL. of total estrogens of the normal women and of the 37 patients treated with allylestrenol. In the latter group some initial low values are noteworthy. In the course of the treatment, however, all values were well within our normal limits. The pregnanediol excretion patterns are set out in Figure 2. The same pattern as described for estrogens is found here. We carefully determined the weight of the babies born to mo thers for whom hormonal levels were known. The difference in mean birth weights between the babies originating from 40 normal mothers and from 25 allylestrenol-treated patients is striking: 3,186 grams versus 3,455, respectively. Apart from one baby with tetralogy of Fallot, no other easily detectable malformation was evident in children from mothers treated with allylestrenol. The perinatal mortality was well within the limits of our experience. DISCUSSION Threatened Abortion The prognosis for the continuation of pregnancies in our patients was poor as nearly all patients had already had one or more abortions. The fact that in such patients allylestrenol normalized the excretion patterns of urinary hormones confirms earlier findings that the drug promotes placental hormonal production. A number of failures also oc- 203 CLINICAL THERAPEUTICS curred. According to the literature, however, in 50% of abortions the cause is unknown. In the other half trophoblastic changes are reported. 12 Macroscopic and microscopic inspection of the placentas from the allylestrenoi group revealed no deviations from normal. In 12 of 90 women who aborted despite treatment in the first trimester, placental changes could be demonstrated microscopically. Inspection revealed such placental deficiencies that significant aberrations of the fetus had to be feared if they had been carried to term. To our knowledge, however, none of the changes found are attributable to the influence of allyiestrenol. Our findings suggest that allyiestrenol is not capable of maintaining pregnancy 204 in the presence of serious placental aberrations. It is this selective capacity that makes the product safe in the treatment of habitual abortion. All newborns were examined systematically for the presence of any obvious anomalies. As the mothers were treated with hormones during pregnancy we were particularly alert for signs of masculinization. None such signs could be found in any of the babies whose mothers had been treated. We also weighed all children directly after birth. When comparing the children's weight of the control group with the weight of the babies of the allyiestrenol group, the difference was striking. Andelkovic 13 also reported a higher birthweight of ne wborns from J. CORTÉS-PRIETO ET AL. patients treated with allylestrenol than of newborns from normal mothers. In this investigation the difference ranged from 250 to 400 grams per child. There is no adequate explanation for this weight difference. Possibly the betaadrenergic action of allylestrenol is at the basis of this difference. This betaadrenergic action reduces the activity of the uterus (myometrium activity) and subsequently the permanent hypertonic state. It is logical to conclude that this relaxation induces a better blood supply thus enhancing the action of the fetoplacental unit. Consequently a better fetal metabolic exchange can exist and intrauterine hypoxia would be far less likely to occur. The relaxed atmosphere in which the fetus lives might also ensure better fetal development (Figure 3). The extent to which these slightly higher birth weights are an advantage and will be followed by future better academic results, as described elsewhere,14 is beyond the scope of the present trial. The real beta-adrenergic drugs used to maintain pregnancy in patients with imminent abortion, such as ritodrine, isoxsuprine, and orciprenaline are known to cause such high birth weights that the partus itself becomes more risky or at least gives rise to heavy labor. In our opinion this limits the use of such products. Moreover, we consider the side effects observed with, for example, ritodrine (tachycardia and other cardiovascular complaints, dizziness, vomiting)15 hardly acceptable for pregnant women. We prefer the smoother, perhaps even more physiologic and selective beta-adrenergic action of allylestrenol. This latter effect together with the placentotrophic effect described by others 3-6 and the complete absence of side effects for both mother 205 CLINICAL THERAPEUTICS and child, make allylestrenol a safe drug in the management of situations that endanger a pregnancy at an early stage. Premature Delivery Birth before term but after week 28 of pregnancy is usually designated as premature. Uncomplicated spontaneous premature labor occurs frequently. Prevention seems to be difficult because patients at risk can only occasionally be identified. The problem of prematurity is to find an effective treatment to stop premature labor. Proposed treatments have to be substantially better than the conservative treatment. There are many known ways to block the process, one of which is interference with the release of oxytocin by means of intravenous ethanol. 16 The initially good results reported17 were not confirmed by later data.18 Widely used nowadays are betaadrenergic drugs such as isoxsuprine and ritodrine. The quantity to be given is adjusted individually. Treatment is usually started by intravenous drip infusion. The side effects of these drugs are, as mentioned, very important in pregnant women. The difference between the beta-receptors in the uterus and the cardiac muscle and the less selective action of these substances may well be at the basis of these side effects. Moreover, a true myometrial action of these drugs is questionable, as it has been stated that the efficacy of drugs such as ritodrine for the treatment of high-risk pregnancies after week 30 does not differ significantly from that of other infusion therapies using substances such as Hartmann's solution, aminofusin, or a 206 solution containing 10% dextrose.19 These investigators consider the effects of the various therapeutic regimens on metabolic acidosis to be one of the main factors in this respect. Our report deals with 37 patients with threatened abortion in the second trimester and 41 pregnancies with premature labor. In the latter group the membranes were not yet ruptured. In the first group in all but one case the baby was born during week 39 to 41; in one case labor could be delayed only until week 36. Of the 41 patients with premature labor only three could not be brought to term. Two were cases of immature unidentical twins (abortion in week 31 and 34). In one case a cesarian section was performed. The fact that despite massive doses of the drug no subjective or clinical effects on smooth muscle organs containing beta-receptors, including the heart, were reported strongly suggests that allylestrenol has a highly selective influence. Our data support our earlier theory that allylestrenol has some form of beta-adrenergic action on the betareceptors of the myometrium. 20 The rapid arrest of uterine contractions (usually within the first 24 hours) cannot be explained by bedrest or by a higher production of progesterone only. In our opinion the beta-adrenergic action of allylestrenol is the main factor responsible for this rapid onset of action on the myometrium. Possibly this latter action combines with the placentotrophic action mentioned by other investigators, but this dual action or perhaps synergism has not been fully elucidated. Further studies, including the effect on other factors that figure in the initiation of labor, will be necessary J. CORT ÉS-PRIETO ET AL. to pinpoint the exact mechanism of allylestrenol. The difficulty, however, will be that no model other than woman can be found to test this. Indeed, apart from the hormonal and obstetrical, psychological processes may also play a major role in initiating uterine contractions leading to labor. Moreover, once this process has started it seems to be regulated by some autonomous process. This investigation provides grounds for assuming that allylestrenol selectively interferes with this process. ACKNOWLEDGMENT We want to thank Dr. F. Nogales-Ortiz for the inspection of the placentas. REFERENCES 1. 2. 3. 4. 5. 6. 7. Knaus, H. (1975): In: Pharmacology of Hormones. By M. Tausk. Georg Thieme Publishers, Stuttgart. Csapo, A.I. (1961): In: Progesterone and the Defence Mechanism of Pregnancy. Editors: G.E. Wolstenholme and M.P. Cameron, London. Fanard, A., and Picazo, J.J. (1976): How to stimulate the placental function. Reproduccion 3, 15-25. Stavric, V. (1974): Statistical evaluation of hormones and enzymes modifications during treatment of threatened abortion with allylestrenol. Lecture held at 25th Congress of the Federation of the Gynaecological Societies, Montreal, September 25-28. Toth, F., and Treit, S. (1964): The development of HCG and pregnanediol excretion in abortions treated with gestagens and tranquillizers. Z. Geburtshilfe u. Gynaek. 162, 140-152. Spona, J., Mütiller-Tyl, E., and Leodolter, S. (1976): Influence of allylestrenol on the serum level of human placentotropic lactogen in high risk pregnancies. Z. Geburtshilfe Perinatal. 180, 356-362. Willems, J.L., and de Schaepdryver, A.F. (1966): Adrenergic receptors in the oestradiol and allylestrenol domi - nated rabbit uterus. Arch. Int. Pharmacodyn. Ther. 161, 269-274. 8. Lands, A.M., Arnold, A., McAuliff, J.P., et al. (1967): Differentiation of receptor systems activated by sympathomimetic amines. Nature 214, 597-598. 9. Editorial (1977): Postponing premature labour. Br. Med. J. /, 1118-1119. 10. Willems, J.L. (1965): Gestanon and beta-receptors. Personal communication. 11. De La Fuente, P. (1972): J. Gynecol. Obstet. Biol. Reprod. 1, 497-507. 12. Botella-Llusia, J. (1973): Endocrinology of Women. W.B. Saunders Company, Philadelphia. 13. Andelkovic, S. (1978): Effect of gestanon on birth weight. Srp. Arh. Celok. Lek. 106, 53-55. 14. Dalton, K. ( 1 9 7 6 ) : Prenatal progesterone and educational attainments. Br. J. Psychiatry 129, 438-442. 15. Editorial (1974): Delaying premature labour. Lancet 2, 875-876. 16. Gibbens, G.L.D., and Chard, T. (1976): Observations of maternal oxytocin release during human labor and the effect of intravenous alcohol administration. Am. J. Obstet. Gynecol. 126, 243. 207 CLINICAL THERAPEUTICS 17. Zlatnik, F.J., and Fuchs, F. (1972): A controlled study of ethanol in threatened premature labor. Am. J. Obstet. Gynecol. 112, 610. al. (1977): Trial of intravenous therapy in women with low urinary estriol excretion. Am. J. Obstet. Gynecol 127, 793-797. 18. Castrén, O., Gummerus, M., and Saarikoski, S. (1975): Treatment of imminent premature labour. Acta Obstet. Gynecol. Scan. 54, 95-100. 19. Chang, A., Abell, D., Beischer, N., et 20. Cortes-Prieto, J. (1973): Beta-stimulant action of allylestrenol. Lecture held at the VII World Congress of Obstetrics and Gynecology, Moscow August 12-18. 208