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This article was published in 1953
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INSTITUTE OF INSPECTORS OF STOCK OF N.S.W. YEAR BOOK.
Practical Application of the Use of Oestrogens
C.W. EMMENS, D.Sc., Ph.D., Professor of Veterinary Physiology, the University of Sydney
1. Types of Oestrogen Available
There ia a large range of oestrogenic preparations on the market. Of these, the synthetics are now the most commonly used, although, particularly in the U.S.A. certain sections of the community may exhibit a strong preference for the natural product. In fact, no difference in action has been firmly established between the two, and the use of synthetic oestrogens for all purposes seems quite in order.
Natural oestrogens are rarely commercially available in pure form. Most preparations contain a mixture of oestrogens in extracts from urine of pregnancy. These are typically dissolved in an oily solution for injection, but also may be prepared in some of the forms discussed below. Synthetic oestrogens, on the other hand, practically always are dispensed in pure form; again frequently dissolved in oil for parenteral injection.
On injection, the esters of both the natural and synthetic oestrogens are more prolonged in action than are the parent compounds. These, therefore, frequently are employed when it is desirable to have an action lasting for several days or even longer following a single administration.
The only oestrogen produced by the ovary in most mammalian species appears to be oestradiol. It is the most active of all oestrogens, although under conditions of optimal utilisation the activity of other natural oestrogens such os oestrone and oestriol and of the more potent synthetics such as diethylstilboestrol, hexoestrol and dienoestriol, closely approach it.
2. Methods of Administration
Injection. The majority of oestrogens are injected in oily solution not only because they are more soluble in oil but because some of the hormone remains in the tissue for an appreciable period and gradually passes into the blood stream. However, unless esters are used the effects of a single injection are relatively transient, and treatment must be repeated at least once daily. Injection in aqueous solution is absorbed even more rapidly, but there has been developed recently a method of administering crystalline mushes consisting of small crystals suspended in saline, which may take several weeks to become completely absorbed.
By Mouth. The natural oestrogens are much less effective by mouth than by injection, mainly because they pass through the liver before entering the general circulation and are inactivated partially therein. The synthetic oestrogens, however, are not destroyed in the liver to an appreciable extent and therefore exhibit about the same potency whichever route is used. A degree of protection is conferred upon oestradiol by converting it to aethinyl oestradiol, which does exert considerable oral activity. It should be noted that esterification does not affect the potency of oestrogens when they are taken by mouth nor does it prolong their actions.
Oral administration to the ruminants is not successful since the oestrogens are largely destroyed before absorption.
By Inunction. Oestrogens rubbed on to the skin are absorbed readily, particularly from organic solvents such as ether or chloroform. They pass into the blood stream and exert their characteristic effect almost as if they had been injected. If administered in an oily medium or an ointment the effect is more localised so that it is possible to exert the effect on a particular surface organ without much influence on the rest of the body. In the human, for instance, one breast may be inuncted with restrogenic ointment and the effects will be confined to that breast.
Sub-lingual Administration, which is a form of inunction, also is used at times.
By implantation. The most prolonged action by esters such as oestriol benzoate may be insufficient following a single injection, so that for the continuous and usually relatively low dosage with oestrogens required over a prolonged period a technique of implantation has been developed. Sterile compressed tablets of the hormone are slipped beneath the skin with a trochar or by making a small slit and inserting with a pair of forceps. Such tablets slowly release the hormone over the course of several months. There is no foreign body reaction but the tablet usually is surrounded by a fibrous capsule through which adequate absorption remains possible.
3. General Effects
By definition, an oestrogen is a substance which causes the onset of heat in females. In practice an oestrogen virtually has become a compound which causes the vagina of the ovariectomized rat or mouse to become cornified. This, in effect the Allen-Doisy test, is used so widely for testing oestrogenic activity that one practically can state that an oestrogen is really a compound which causes that reaction.
The natural function of oestradiol is to maintain the female secondary sexual characteristics, the development of the genital tract, of the breasts, of such subcutaneous fat or other characteristics of femininity in the particular species under discussion. In addition to this general maintenance function, the cyclic production of relatively larger amounts of oestrogen in the course of the normal sexual cycle of mammals results in the periodic onset of the symptoms of heat or sexual receptivity. The great majority of mammalian females will only accept the male during this period.
In addition to these more obvious effects, some other important actions of oestrogens are the stimulation of the release of luteinising hormone from the anterior pituitary gland when relatively small amounts of oestrogen are released into the blood stream, but the depression of pituitary activity when relatively large amounts of oestrogen are in the circulation. This depression of pituitary activity may spread from an effect on the gonadotrophic hormone alone, to a depression of the release of growth hormone and perhaps of other pituitary hormones such as thyroid stimulating hormone. Another action which oestrogens also have, in antagonising male hormone, is of considerable clinical importance in that oestrogens may be used tor the abolition of maleness.
4. Uses of Oestrogens.
The Production of Heat. As would be expected, the administration of oestrogen to the typical mammalian female is followed by the onset of a period of heat. With the right level of dosage this heat period may be characteristic of that seen in the normal oestrous cycle, but if an overdose is administered or if administration is continued for a relatively prolonged period a condition of nymphomania may be produced. In normal or physiological doses, the tendency for oestrogens to stimulate release of luteinising hormone from the pituitary gland may result in the heat period being accompanied by ovulation, although such evidence as we have does not suggest that this occurs in a majority of cases. Instead, the heat period is more likely to be a sterile period, since it would be purely coincidental if the ova were ripe for shedding at the time that any pituitary stimulation may have taken effect. Thus, the uses of oestrogens currently advocated for the induction of heat in domestic animals when it is desired to breed them cannot be recommended unreservedly. It so happens that in some species, outstandingly the sheep, the first induced heat period often is followed by one or two more during which a relatively normal heat accompanied by ovulation occurs; and advantage may be taken of these subsequent fertile heats for mating the ewe.
5. Relief of Menopausal Symptoms.
Although not of veterinary interest, it should be noted that one of the main uses of oestrogens in human clinical medicine is for the relief of symptoms which often accompany the menopause. In the majority of cases the hormone treatment is followed by both prompt and striking relief of symptoms.
6. Mammary Growth.
The development of the mammary glands appears normally to be initiated by oestrogenic hormones, although the extent to which it is possible to complete their development without the addition of other hormones varies with the species. In the cow, as an example, the mammary glands may be brought to substantially normal development by the implantation of tablets of oestrogen and in the case of the virgin heifer these glands may proceed to lactate. In other species, the addition of progesterone and perhaps in all species the co-operation of pituitary factors, which, however, may be supplied by the animal's own gland, is necessary. In such, oestrogens may initiate only the early phases of mammary development, as in the rat or mouse.
7. Lactation.
In addition to the effect on mammary growth, and whether or not lactation may have been initiated by using oestrogenic hormones, the administration of oestrogen in existing lactation may increase its magnitude. The most important use of the hormone would seem to be in the possibility of inducing lactation in virgin heifers as remarked above, a phenomenon which oddly enough is nowhere near so regularly or fully realised in parous animals. The composition of the milk so formed is substantially normal.
8. Termination of Pregnancy.
The administration of oestrogenic hormones at almost any stage shortly after coitus results in sterility. Before conception occurs as such, excessive oestrogen may cause tubal locking of tho eggs or, according to species, lethal acceleration of the ova down the Fallopian tube. Subsequently, it may inhibit implantation and will cause rejection of the implanted egg if given at a still later stage. Subsequent to that, however, the response varies with species. In some rodents and in sheep a high sensitivity continues so that abortion may be induced quite late in pregnancy by the administration of oestrogen. In others such as the human, this earlier sensitivity is rapidly lost and after the first few weeks the human female will tolerate surprisingly high doses of oestrogen with no effect whatever.
9. Retained Placental Membranes.
In those species where the placental membranes are shed some time after the birth of the foetus there seems now to be little doubt that oestrogens are useful in aiding the elimination of retained membranes. This seems especially the case in the mare. In other species, particularly the human, oestrogen administration appears ineffective in causing the after-birth to be extruded.
10. Anti-masculine Effects.
Dosage of the male with oestrogens causes a phenomenon of de-masculinisation. Oestrogens have a dual effect of both antagonising the actions of male hormone and of inducing feminising responses where possible. These effects are utilised in calming the belligerent bull or other males and have been used in humans in the attempted abolition of sexual perversion,etc.
Widespread commercial use of the phenomenon has arisen recently in the field of poultry and turkey husbandry. In chickens, the early implantation of a small tablet of a synthetic such as stilboestrol into the neck of the bird causes a type of chemical "caponisation" and renders the flesh more palatable for the market. There is little effect on body weight. In the turkey, in addition to this effect there is also a considerable calming of the rather fierce gobbler. Some earlier qualms about the possible effect on the consumer appear to have arisen because of the ingestion of tablets which were not removed from poultry before their consumption.
Some recent developments in the use of oestrogens for the suppression of certain types of prostatic carcinoma seem promising. Outstanding features of the report so far are that although the carcinoma is not cured, the life of the patient may be considerably prolonged; with relief of much of the pain. The rather frequent prostatic carcinoma seen in dogs appears amenable to the same type of treatment.
11. Contra-indications.
With any continuous administration of oestrogens care must be taken over possible pituitary effects. Even low dosages administered over a long period are liable to cause suppression of the type of hormones, discussed earlier, from the pituitary, and worse still, the development of pituitary enlargement and even tumour formation. Thus, in the laboratory mouse or rat, the administration of oestrogens for periods of more than a few months is liable to be followed by gross pituitary enlargement, blindness and death. When given intermittently, with stimulation more resembling the peaks and troughs of oestrogen production by the ovary, the effects of quite prolonged highish doses are apparently much less. In particular, the intermittent alternated dosage of oestrogen and progesterone, even more closely resembling the natural course of events in the oestrous cycle. seems to be without harmful consequences.
The dog is particularly susceptible to an effect of oestrogens which has not been mentioned above; namely, suppression of the blood-forming elements. Whilst this is seen on prolonged dosage in all species it is particularly liable to cause trouble in canines.