William J. Garrett

Double-Blind Study of Effect of 17-Hydroxyprogesterone Caproate on Abortion Rate

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THE EFFECTS OF ADRENALINE AND NORADRENALINE ON THE INTACT HUMAN UTERUS IN LATE PREGNANCY AND LABOUR

THE response of the intact human uterus to adrenal medullary hormones has for years been the subject of differing opinions. This confusion has often arisen from the scanty evidence put forward, the inadequate methods of investigation employed and, in retrospect, the crude nature of the preparations used. Adrenaline B.P. (Epinephrine U.S.P.) when prepared from mammalian adrenal glands contains, according to the manufacturers, 15-20 per cent noradrenaline. As will be seen later the presence of this fraction may help to explain some, but not all, of the discrepancies of past work.

The effects of adrenaline and noradrenaline on the intact non-pregnant human uterus; with a note on the effects of these hormones in early pregnancy.

THE first direct studies of uterine contractions during the various stages of the menstrual cycle in the living patient were those of Knaus (1929, 1933). At first he obtained kymographic records by filling the uterine cavity with iodized oil through a cervical cannula which he left in place and connected to a mercury manometer. His later improved method employed a small, thinwalled, water-filled balloon of 3 to 4 ml. capacity distended to a pressure not exceeding 20 mm. mercury, which he placed within the lumen of the uterus. From these studies, Knaus propounded the theory that in the course of the normal menstrual cycle the human uterus exhibited its greatest rhythmic spontaneous motility before ovulation and in the few days preceding menstruation. Immediately after ovulation he found a period of almost complete quiescence. This theory met with wide acceptance at first as it appeared to agree closely with the then recent findings in the rabbit (Knaus, 1930a, b ; Corner, 1928 ; Allen and Corner, 1930; Reynolds and Allen, 1932), although some modifications were soon added to it. Wittenbeek (1930) thought that the period of quiescence occurred earlier in the cycle than Knaus had stated, and also that it was not invariably present. G a u l (1935) found that a constantly filled fingerstall balloon acted as a foreign body and incited steadily increasing contractions which frequently culminated in severe parturient activity. A second school of thought was opened when Moir (1934, 1944) described his studies on the intact non-pregnant human uterus. His balloon was 1 to 2 ml. in capacity and kymographic records were made with a delicate water tambour. With this apparatus, contrary to the teaching of Knaus, Moir recorded spontaneous rhythmic motility at all stages of the cycle. Before ovulation he found minute rapid waves of contraction which were gradually replaced in the second half of the cycle by much larger, much slower and more prolonged contractions ; these he named A waves and B waves, respectively. Since Moir’s original paper many other workers have published comparable tracings. Robertson (1937) repeated Knaus’s experiments and checked his recordings by endometrial biopsy. He confirmed Moir’s (1934) results, and later showed that emotional stress had no effect on the A waves although it caused an immediate increase in activity in the presence of B waves (Robertson, 1939). Similarly, in their description of a “functional myometrial cycle” in normal patients, Wilson and Kurzrok (1938, 1940) recorded small frequent waves of contraction before ovulation and large slow ones after it. Henry and Browne (1943) have added their support to these results and have gone farther by demonstrating that contractions similar to those in the post-ovulatory period (Moir’s B waves) can be reproduced in oestrogen-treated ovariectomized patients by the administration of progesterone (Henry, Browne and Venning, 1950). Finally, with recording methods differing in detail from those described above, Lackner, Krohn and Soskin (1937), Bickers and Main (1941) and, more recently, Karlson (1954) have all published tracings which seem to fit into the pattern of activity as described in Moir in the non-pregnant uterus.

Ergometrine with Hyaluronidase: Speed of Action

Intravenous ergometrine given at the crowning of the foetal head or with the delivery of the anterior shoulder is a most effective means of expediting delivery of the placenta and preventing post-partum haemorrhage. This procedure was first introduced by Davis, of Chicago, in 1940. Lister (1950), in Liverpool, and Martin and Dumoulin (1953), of University College Hospital, have demonstrated its efficacy in well-planned clinical trials, and the method is now firmly established in obstetric practice. Although the technique is widely used by obstetricians, it has one great drawback in that midwives, who in this country conduct the majority of public hospital and domiciliary deliveries, are denied its use because normally they are not trained to give intravenous injections. For this reason a simplified method is often used in which ergometrine is given by intramuscular injection instead of by the original intravenous route (Flew, 1947; Daley, 1951). Although some of the speed and reliability of the intravenous method is sacrificed in this modification the much greater general applicability of the intramuscular injection has led to its general acceptance. In an attempt to enhance the value of the intramuscular method still further, Kimbell (1954) has advised that hyaluronidase ( hyalase, rondase, wydase ) be added to the ergometrine injection. The rationale of this method is that hyaluronidase, acting as

A STUDY OF THE EFFECTS OF DIHYDROERGOTAMINE ON THE INTACT HUMAN UTERUS Part II–“Oxytocic” Properties

THE identification and isolation of the alkaloids of ergot and their mode of action have been matters of great interest to pharmacologists and clinicians alike since the turn of the century. Beginning with the discovery of ergotoxine in 1906, followed by ergotamine in 1918, and with the notable landmark for clinicians of the identification of ergometrine by Dudley and Moir in 1935, the story has recently continued with the elaboration of the semi-synthetic alkaloid dihydroergotamine by Stoll and Hoffman in 1943. This new drug was claimed to possess powerful sympatholytic properties; yet, despite its family relationship to the other ergot alkaloids, was alleged to have no direct oxytocic effect on the uterus. The first report of its use in clinical obstetrics was from Sauter (1948) who commented favourably on its use in 43 cases of uterine inertia. In 1951 Gill and Farrar further studied the new alkaloid. They compared its properties with those of ergotamine and ergometrine, and, in the belief that it was a sympatholytic drug devoid of oxytocic properties, used dihydroergotamine in 43 cases with uterine inertia. They reported favourably on its action and recommended its use particularly in cases of “ hypertonic inertia” but advised that the dose should not exceed 0.25 mg. intramuscularly. Reviewing the literature these authors quoted Orth and Ritchie’s observation (1947) that dihydroergotamine had no oxytocic action in animal experiments. In rats, it was found that daily injection of dihydroergotamine throughout pregnancy was without effect on the gestation, labour or lactation-but in fairness it might have been added that Orth and Ritchie obtained exactly similar results with ergotamine, the oxytocic properties of which are not doubted. Not all opinions expressed on the value of dihydroergotamine as an anti-spasmodic in incoordinate uterine action have been enthusiastic; and some workers have suggested that on occasion the drug may be oxytocic. In one case in this department the injection of 0.25 mg. of dihydroergotamine intravenously during labour was followed by violent uterine contractions, threatened tonic contraction and foetal distress; in another case 1 mg. by intramuscular injection produced like effects. Other evidence that dihydroergotamine has undesirable effects has been produced by Altman, Waltman, Lubin and Reynolds (1952) who gave the drug by slow intravenous infusion to 20 patients in labour, and by external tocography demonstrated oxytocic activity. Almost certainly the dose used (1 mg. in 2-4 hours) was excessive, and it is significant that in the 20 deliveries there were 11 cases of foetal distress, 5 foetal deaths and 1 additional sub-dural haematoma, besides 3 cases of maternal haematuria. More recently Bruns, Snow and Drose (1953) have also shown that dihydroergotamine by slow intravenous infusion has a motor effect on the parturient uterus. As a result of their experience, they recommended that the dose by this method should not exceed 0-1 mg. per Q-hour, lest untoward effects ensue.

THE EFFECT OF RELAXIN ON THE CONTRACTILITY OF THE HUMAN PREGNANT UTERUS

RELAXIN THE existence of Relaxin was first postulated by Hisaw in 1926 when he found that an extract of swine corpora lutea produced pelvic relaxation in oestrogen-treated guinea-pigs. Relaxation of pelvic ligaments and joints has since been demonstrated in other mammals, but the response has been shown to be the subject of species difference (Hall and Newton, 1947; Kliman et al., 1953). The hormone has been shown to have other effects too. In oestrogentreated spayed sows and heifers Relaxin is said to bring about marked cervical dilatation (Zarrow, Sikes and Nehen, 1954), while there is evidence that uterine contractility as a whole is inhibited in the guinea-pig (Felton, Frieden and Bryant, 1953), rat and mouse (Sawyer, Frieden and Martin, 1953). Relaxin has been identified as a water-soluble polypeptide and purified preparations obtained from the ovaries of pregnant sows are now available for clinical assessment. The hormone has been found in the bloodstream of pregnant women and recent evidence suggests that its concentration increases to term and rapidly falls after parturition (Zarrow, Holstrom and Salhanick, 1955). The results of animal experimentation with Relaxin have only been partially substantiated in the human subject and much work remains to be done before the functions of the hormone are clearly defined. Relaxation of pelvic joints is an accepted phenomenon of normal human pregnancy but it has yet to be shown that it is relaxin-induced. A number of observers have commented on the softness of the cervix in patients after relaxin therapy, but such an effect is difficult to assess accurately. Chief attention, so far as the human subject is concerned, has been focussed on the supposed effect of relaxin in inhibiting contractility of the human myometrium. There have, indeed, been several favourable reports on the ability of relaxin to suppress uterine contractions in premature labour (Abramson and Reid, 1955; Eichner et al., 1956; Folsome et al., 1956), but these studies have been based on clinical impression only. There appears to have been only one investigation, so far, in which the uterine contractions were recorded objectively (Kelly and Posse, 1956); in this the results seemed less impressive and no actual record of the uterine response was reproduced. We therefore determined to conduct an objective study of the effect of relaxin on the contractility of the intact pregnant human uterus by tocographic means. This study was not designed to examine directly the effect of relaxin on premature labour because of the difficulty in selection of suitable cases and in accumulating a sufficient number in a relatively short space of time. Instead, the purpose of the investigation was simply to assess the effect, if any, of relaxin on the spontaneous contractions of late pregnancy and early labour at term.

A STUDY OF THE EFFECTS OF DIHYDROERGOTAMINE ON THE INTACT HUMAN UTERUS

THE aetiology of incoordinate uterine action remains obscure. Excess endogenous adrenaline and over-action of the uterine sympathetic nerves may be contributing factors, so in recent years the use of an adrenaline blocking drug has been suggested as the logical therapeutic measure to be applied in such cases. With this theory in mind, dihydroergotamine has held favour with some workers as it is said to possess powerful adrenaline-blocking properties yet to be devoid of the oxytocic activity characteristic of the ergot series as a whole-an activity which is potentially dangerous in labour because of the unpredictable spasm which it may produce. Crude ergot extracts were first shown to antagonize the effects of adrenaline by Dale in 1906. In cats, dogs and ferrets he showed that, after the administration of ergot, adrenaline failed to produce the customary rise in blood pressure, and in many instances caused an actual fall from the resting level. With the uterus of those species in which adrenaline normally produced stimulation (rabbit, monkey and pregnant cat), he found that adrenaline caused relaxation after the administration of ergot. In the non-pregnant cat, however, adrenaline caused relaxation of the uterus both before and after the administration of ergot. In succeeding years the active alkaloids were isolated one by one from crude ergot. These were shown to possess in varying degrees both the oxytocic and adrenaline-blocking characteristics of the crude preparation; the latter property was strongest in the case of ergotoxine and ergotamine and weakest in the case of ergometrine. After the semi-synthetic dihydroergotamine was elaborated by Stoll and Hoffman (1943) it also was found to have powerful adrenalineblocking properties (Rothlin, 1947). At that time dihydroergotamine was supposed to lack the direct oxytocic properties of the other ergot alkaloids, and so was used by Sauter (1948) in incoordinate human labour for its adrenalineblocking properties, to counter the alleged overaction of the sympathetic nervous system. Reist (1949) and Gill and Farrer (1951) reported favourably on further cases. In each of these series the clinical response observed was attributed to the “sympatholytic” properties of the drug-an assumption based on animal experiment alone. Recently, Garrett (1955) showed in vitro that both adrenaline and noradrenaline stimulated excised human myometrium to contract, and that this stimulation could be blocked by dihydroergotamine-an observation in keeping with previous experimental work in other excised mammalian uteri. Despite this evidence with excised human tissue, it does not follow that dihydroergotamine will exert similar adrenaline-blocking and noradrenaline-blocking properties in the parturient patient, because

THE EFFECT OF THE HYDROGENATED ERGOTOXINE‐GROUP ALKALOIDS ON THE INTACT HUMAN UTERUS

IN attempts to overcome the dysrhythmia of contractility in cases of incoordinate uterine action in labour, sympatholytic drugs have had some vogue in recent years. The first drug used for this purpose was dihydroergotamine. This was claimed to be devoid of direct oxytocic properties, and was believed to shorten labour by hastening cervical dilatation through an adrenaline-blocking or sympatholytic mechanism (Sauter, 1948; Gill and Farrar, 1951 ; Baskin and Crealock, 1950, 1951). A few clinicians have, however, warned that the administration of dihydroergotamine is not without considerable risk, and the prodigious foetal mortality of 25 per cent has even been reported following its use (Altman et al., 1952). Recently, one of us showed that dihydroergotamine failed to impede the action of circulating adrenaline on the intact human uterus in labour (Garrett, 1955). As this finding invalidated the theories previously advanced regarding the mode of action of dihydroergotamine, further studies were undertaken in which we were able to demonstrate that, in reality, the drug exhibited simple, direct oxytocic properties. Qualitatively dihydroergotamine resembled the parent alkaloid ergotamine in every respect, although quantitatively it was somewhat weaker in action (Embrey and Garrett, 1955). With this evidence before us it seemed appropriate that the newer semi-synthetic hydrogenated alkaloids related to ergotoxine should be investigated along similar lines to our earlier work. “HYDERGINE” * A mixture of dihydroergotoxine, dihydroergocristine and dihydroergokryptine, available under the trade-name “Hydergine” contains 0.3 mg. of the mixed methanesulphonates (0.1 mg. of each) per ml. of solution.

ERGOT AND THE NON‐PREGNANT UTERUS

THE efficacy of ergot in arresting haemorrhage after delivery is undoubted and, by analogy, ergot has been thought to hold a place in the treatment of haemorrhage in gynaecological disease. For years Martindale’s Extra Pharmacopoeia supported two conflicting views when it described ergometrine as a palliative measure in menorrhagia, and crude ergot as an emmenagogue (Martindale, 1941). Thirty years ago Howard Kelly was in no doubt when he wrote of the treatment of menorrhagia, “Ergot, ingested in the past by thousands of tons, is useless” (Kelly, 1928). Today the British Obstetric and Gynaecological Practice recommends ergot in acute episodes of serious haemorrhage from metropathia but adds that this use is traditional rather than efficacious (Jeffcoate, 1955). The present paper reports a study of the effects of a crude ergot preparation and two ergot alkaloids on the contractility of the intact non-pregnant uterus. This is not straightforward like similar studies on the pregnant and puerperal uterus as the type of spontaneous activity in non-pregnant uteri varies with the phase of the menstrual cycle. In the first half of the cycle the characteristic pattern is one of rapid, feeble contractions or A waves, whereas later in the cycle (or during menstruation after ovulation) slower and many times more powerful contractions, or B waves, are the dominant feature (Moir, 1944). The several ergot preparations have been tried at all stages of the menstrual cycle and in a few anovulatory cycles. METHOD Records of uterine activity were obtained from 33 volunteer patients by the intra-uterine balloon method (Moir, 1934). Only cases giving a normal menstrual history were included in the series. Where curettage was indicated on medical grounds, endometrial biopsy was obtained to give more objective information concerning the endocrine conditions prevailing at the time of the study. With the usual antiseptic precautions the cervix was exposed and a small, collapsed, sterile balloon mounted on a hollow uterine sound was passed into the cavity of the uterus under direct vision and without anaesthesia. When in place the balloon was filled with water to 15 mm. of mercury initial distending pressure. As the maximum capacity of the balloon was designed not to exceed 2 ml., this initial distending pressure was “balanced” by the elasticity of the balloon walls. The balloon was then connected by water-filled pressure-tubing to a very fine tambour or, in appropriate cases, to a mercury manometer recording on smoked paper. After a suitable control period of recording, the ergot preparation was given and the effect noted.