Some Aspects of Human Infertility*

Glasgow Medical Journal 7th Series March, 1945 Vol. XXV. No. III.

SOME ASPECTS OF HUMAN INFERTILITY*

By ALBERT SHARMAN, B.Sc., M.D., Ph.D., M.R.C.O.G., Assistant Surgeon, Royal Samaritan Hospital for Women, Glasgow.

The title of our paper indicates both its scope and its limitations. Its limitations are determined by the time at our disposal, which makes it quite impossible to give an exhaustive account of the subject or to make any reference to the enormous literature which has now accumulated; we are compelled to confine our attention to certain major aspects of the problem. Although infertility is one of the oldest human problems, it is only within the present century that real progress has been made in its study. The social significance of the problem is illustrated by the fact that, according to various estimates by English and American investigators, the proportion of childless marriages is about ten per cent, of the total. As there are almost one million barren marriages (as far as can be estimated) in Britain, the seriousness of the position is obvious: the last precise figure was given in the census of 1931 as 1,092,399. Moreover, in the year 1890, 869,937 babies were born in England and Wales; in the year 1940 this figure fell to 590,120. In Scotland, the figures are comparable: in 1890, 121,526 babies were born, in 1940 the figure fell to 86,403. The successful treatment of sterility must therefore be one of the more important tasks of medical science.

* Based on a communication read to the Royal Medico-Chirurgical Society of Glasgow on 1st December, 1944.

VOL. CXLIII. NO. III. 77 E Albert Sharman

It is unnecessary to postulate a period of years of married life as a criterion of sterility, because in normal relations, in the large majority of cases, pregnancy follows within one year of marriage. Indeed, one authority states that 84 per- cent. of first children are born within 2 years of marriage and that after another year only 4*5 per cent, of marriages prove fertile. Moreover there is good cause for investigating the couple who complain of their barren marriage even if it is only of as little as one year's standing, for at this stage it is possible to treat with success a number of lesions which, if neglected, tend to become incurable. Thanks to modern research, notably of the American gynaecologist, Meaker, it is now recognized that while sterility is sometimes due to a single cause in one or other partner, " it is more often due to several infertility factors." A search for the causal factors involves a complete examination of both parties. "There is more to the problem of sterility than potent males and patent tubes." A minimal diagnostic survey should include the systematic investigation of the following 5 major factors: 1. Grossly recognizable pelvic conditions. 2. The condition of the Fallopian tubes. 3. The endocrine balance. 4. The cervical secretion. 5. The investigationo 0f the male.

Grossly recognizable pelvic conditions. The first condition to be considered is that of tumour or neoplasm. It may involve any portion of the genital tract and, when it arises in the vulva or vagina, operates mainly in the direction of producing dyspareunia, i.e. as a mechanical or obstructing agent. Much more commonly, however, the tumour involves the uterus or ovaries. In the former case it is most frequently a fibroid (single or multiple) and in the ovaries one variety or another of cyst. The association of fibroids with sterility is well known ; their mode of action, however, has been the source of much discussion. The fibroid may act in a mechanical way, or its frequently associated cystic ovarian changes may be the main factor. The present tendency, 78 Some Aspects of Human Infertility however, is to regard both the fibroid and the infertility as being due to a common extragenital factor, probably pituitary dysfunction, which is responsible for both conditions. The mere presence of a fibroid or fibroids is not in itself a major infertility factor, since the association of fibroids and pregnancy is common. Cysts of the ovaries may act in two ways : (a) by pressure upon or blockage of a tube, or (b) by inter- ference with or complete inhibition of ovulation. Infections of the genital tract may act inimically to fertilisation wherever they may be, but particularly when they involve the tubes and ovaries. Cervical and vaginal infections are not in themselves, in normally fertile women, barriers to conception. Gross inflammatory infection of the tubes, however, is responsible for tubal blockage and is obviously a major infertility factor. Uterine hypoplasia has for long been blamed for infertility. Recent investigations have produced evidence which would seem to show that minor degrees of hypoplasia have but little relationship to it and are purely an incidental finding. " As Meaker expresses it: The infantile womb is a favourite diagnosis of many practitioners." It is quite different, however, with major degrees, which are uncommon, but which very definitely afford a poor fertility prognosis. Severe genital hypoplasia, involving the external genitalia in addition, and especially when associated with a narrow vaginal canal or introitus, is a serious infertility factor. The relative incidence of these conditions is seen in the following figures, obtained in a survey of 810 consecutive cases of sterility in the Royal Samaritan Hospital for Women: 388 (48 per cent.) showed a minor degree of uterine hypoplasia, 10 a major degree and 160 had a narrow vaginal introitus or canal or both. Any conditions which render normal coitus impossible or very infrequent are obviously definite factors in infertility. It is not uncommon to find that, even after a relatively long period of marriage, there is present a more or less unruptured hymen. The Fallopian tubes. ? The tubo-ovarian apparatus is not a static entity, but is subject to continuous changes in the interrelationship of its parts. In all animals (including the monkey) which have been 79 Albert Sharman investigated, it has been found that the muscular equipment of the adnexa effects periodic changes in the relative position of the fimbriae and the ovary. In some animals the ovary appears to be cupped by the tube at certain stages of the cycle, and this approximation, which seems to facilitate the reception of the ovum by the tube, coincides with the ovulatory phase. When, as in the monkey, the infundibulum reaches and embraces the ovary, the latter plays more than a purely passive part. There is evidence that a similar mechanism operates in woman. The tube itself is subject to cyclical changes, the fibres of the muscular coat of the tube increasing and decreasing in length with the phases of the cycle. Changes in the nature and function of the epithelial lining also occur; in the first phase of the cycle the epithelium is mainly ciliary in character, whereas after ovulation secretory activity becomes manifest. Since the functional condition of the tube and the associated muscular apparatus determines to a large extent the chances of fertilisation, it is obviously desirable to investigate this aspect of the reproductive mechanism. Although the available methods are relatively unphysiological, they have the advantage of being easy to apply and of yielding sufficiently accurate information for clinical purposes. They should be adopted as part of the routine examination of the wife, for impairment of tubal function cannot be excluded by the ordinary gynaecological examination, however carefully conducted. The methods in general use fall into two main groups? those designed to investigate the passage of a gas through the genital tract (Utero-tubal insufflation) and those in which the condition of the tubes is revealed by their radiographic appearances after the injection of a suitable opaque substance (Hysterosalpingography). Utero-tubal insufflation. In 1920 Rubin first described his methods of investigating tubal patency by means of intra-uterine inflation with oxygen.* *The following quotation from the Aphorisms of Hippocrates, vol. IX, is of interest: 4'If a woman does not conceive and you wish to know if she will, cover her head with wraps and burn perfume underneath. If the smell seems to pass through the body to the mouth and nostrils, be assured that the woman is not barren through her own physical fault." 80 Some Aspects of Human Infertility Since that date, the principle of Rubin's method has been universally adopted and variations and modifications of apparatus and technique have been developed. Oxygen was abandoned at an early stage and carbon dioxide substituted. It is now well established that the tubes may be occluded and the patient rendered sterile without physical signs or symptoms. It is 4not proposed to discuss the various types of apparatus for testing tubal patency, but merely to refer briefly to the one introduced by the writer in 1943 to the Royal Society of Medicine, London. This apparatus, the most recent in the kymograph class, is a modification of that of Bonnet of Paris and has given excellent results. It contains a regulating and measuring system whereby the pressure of gas is kept constant and its rate of flow is accurately regulated by moving a tap indicator on a dial till it faces the figure corresponding to the desired rate. A metal manometer measures the pressure of gas, whose variations are recorded on a revolving drum, oper- ated by an electric motor. [The apparatus was shown.] Whereas most methods serve only to distinguish between " " " " the blocked and the open tube, the use of the kymograph makes possible the registration of tubal contractions and thus takes into consideration the actual behaviour of the tubes during the test. Four types of record are obtained, corresponding to the following conditions: (1) Normal tubal patency, (2) Non-patency, (3) Tubal spasm, and (4) Tubal stenosis, i.e. stricture of the canals, either by an internal cause (e.g. mucosal lesion) or by an external one (e.g. peritubal adhesions or kinks). [Examples of kymographic tracings were shown.] A study of the behaviour of patent tubes as revealed by repeated insufflations shows that under similar conditions, e.g., the constancy of the rate of flow of the gas, there is a note- worthy constancy in the appearance of the tracings obtained. No great difference, either in the level at which patency is established, or in the appearance of tubal contraction waves, is usually seen in any given patient when insufflation is repeated, even after several months. Increase in the rate of flow of gas may be followed by a marked increase in the patency-pressure level and by more active, deeper peristaltic waves; but this is not invariable. Around ovulation-time (presumptive) more active or more frequent peristalsis may occur. This alto is 81 Albert Sharmari

Variable, and there is no indication that there is any constant close correspondence between the type of tracing obtained and the stage of endometrial cycle. On the other hand, repeated insufflations have shed some interesting light on the criteria of non-patency. The first point is that a single finding of non-patency is not reliable. This has been proved by the subsequent occurrence of pregnancy, or by the occurrence of a characteristic kymographic tracing of patency (corroborated by the occurrence of shoulder pain or by the demonstration of pneumoperitoneum), or by hysterosalpingography Complete tubal occlusion may be the result of gross tubal damage, readily recognizable, or suspected by the finding of palpable pelvic lesions, inflammatory or neoplastic; but much, more often no physical signs can be elicited. The etiology of blockage in these cases which appear normal on bimanual examination is somewhat of a problem. In the past, it has been widely accepted that in most instances the occlusion of the lumen results from gonococcal salpingitis, or from tubal infection from a nearby pelvic lesion (particularly appendicitis) or from congenital hypoplasia. Recent work, however, on endometrial tuberculosis has shown that this condition is unexpectedly common in sterile women (4.7 per cent, in 1,150 cases), and has suggested the probability that tubal tuberculosis of a degree insufficient to be grossly recognizable, except on laparotomy, is responsible for a much greater number of cases of tubal non-patency than is generally recognized. More- over, there is evidence to show that, although the gonococcus may occasionally be the cause of gross tubal damage, it is seldom responsible for the occlusion of tubes which are not palpably thickened.

Hystervsaljringography. The earliest attempts to visualize the uterine and tubal cavities, and thereby to test tubal patency, were made in 1914. In that year Rubin experimented with collargol, but abandoned its use owing to the irritant reaction on the peritoneum. Other solutions, such as sodium bromide and sodium iodide, were tried but gave similar disagreeable reactions or poor shadows. In 1925, Forsdike obtained satisfactory hysterograms by the use of lipiodol, an iodised oil introduced into surgery by 82 Some Aspects of Huftian Infertility Sichard. Lipiodol has been found to have three outstanding advantages: (a) it is relatively non-irritating, (b) it gives shadows which have proved to be of considerable value in the investigation of tubal patency, and (c) according to many investigators it is therapeutically effective in a fair proportion of cases.

Hysterosalpingography may be used as a diagnostic aid in several gynaecological disorders, but in cases of sterility its chief value is in the information which it yields about tubal blockage. The chief contraindications to its use, as to the use of insufflation, are as follows: (1) inflammations of the genital tract, e.g., vaginitis, endocervicitis or salpingitis; (2) tenderness or swelling of pelvic organs; (3) cardiovascular, pulmonary or other serious systemic disease ; (4) menstruation. The procedure, even after due observance of the contra^ indications, is not wholly devoid of risk. Pelvic pain, pyrexia and sepsis in occasional cases have been recorded by many observers.

In concluding this brief account of the tubal factor, it may be stated that it is the commonest single factor in the female : in my series of 1,188 cases of primary sterility, 25 0 per cent, showed complete tubal blockage. It must be emphasized, however, that a definite diagnosis of tubal occlusion must not be made unless two insufflations (one, at least, without anaesthesia) plus a salpingogram show non-patency.

The Endocrine Factor. There is no doubt that endocrinopathies are responsible for many cases of female infertility and it is for this reason that in many clinics, especially in America, a fairly complete endocrinological investigation has become a routine procedure in every case under diagnosis. But severe endocrine distur- bances? e.g., thyroid deficiency, diabetes mellitus, or even more complex syndromes are not always associated with sterility. Nevertheless, the proper functional activity of all the major endocrine organs is necessary if fertility is to be normal, the ones most directly concerned being the ovaries and the anterior pituitary gland. The endocrine deficiencies may be due either to failure of response to the hormone stimulus or to an inadequate stimulus. Thus, the reproductive 83 Albert Sharman tract may have acquired an increased resistance to the sex hormones produced by the ovary, or the ovary may fail to respond to normal or even excessive gonadotrophs secretion by the pituitary. On the other hand, the defect may be primarily in the secreting cells of the glands themselves, leading to deficient output of gonadal or gonadotrophs hormones (Bishop). Clinically, there may be little or nothing to indicate endocrine dysfunction, but a number of cases show distur- bances of menstrual rhythm such as spells of amenorrhoea, metrorrhagia or epimenorrhoea; these are often indicative of hormonal imbalance. Apparently normal and regular menstruation, however, does not preclude failure of ovulation, since pseudo-menstruation may occur from a proliferative endometrium instead of from the normal secretory type, the presence of which is presumptive evidence of ovulation. In my series of 358 -consecutive cases of primary sterility in which endometrium was removed (without anaesthesia) by a biopsy curette in the premenstrual phase of the cycle, 335 showed the normal, characteristic, secretory features of this phase. The remainder (23), however, showed anovulatory cycles, 11 of them on one or more occasions but not on all, and 12 on all occasions on which biopsy was performed. These may be described as follows: (a) those exhibiting both anovulatory and secretory cycles in the same patient? "periodically anovular"; and (b) "constantly anovular It must be appreciated that these titles are being used descrip- tively and as a matter of convenience, and cannot be expected to refer to more than the relatively small period ol time during which the patients were studied. The two groups therefore are not mutually exclusive, since the patients in group (a) might at any future date show the features of group (b), and, alternatively, cases in group (b) might later show secretory endometrium. Moreover, many of the series of 335 patients who showed normal secretory characters might have shown apparently anovular cycles at one time or another if the duration of their study had been prolonged. It must be emphasized that an erroneous diagnosis of anovular cycles may be made if reliance is wholly placed on the date of the preceding menstruation and biopsy is 84 Some Aspects of Human Infertility performed only in the presumptive premenstrual phase. The date of menstruation after biopsy must be ascertained. Two further observations must be made. (1) Although it is a simple matter to distinguish an early proliferative from a late differentiative endometrium, it is very difficult in some cases to decide whether an endometrium is in the late proliferative or early secretory phase, since the one merges into the other; and (2) a second potential source of error is that the observer is dependent very frequently on the patient correctly noting or accurately remembering the date of menstruation.

It may be observed at this point that none of these 23 patients became pregnant during the period of study, but that- 2 did so under treatment by gonadotrophins. This high rate of infertility is not surprising in view of the serious nature of the dysfunction. Anovular menstruation is therefore a major infertility factor when it occurs, although its actual incidence is low.

The Cervical Factor. From the purely clinical approach to the study of a barren union, it is logical to include under the term "cervical factor" (a) hostility of the cervical secretions, and (b) failure of insemination of the cervix, though the latter is rarely caused by abnormalities of the cervix or its position in the pelvis (Mazer). It is necessary to determine whether sperms reach and enter the cervical canal and whether they remain active there for a reasonable period of time. The post-coital test generally used in the investigation of the cervical passage follows essentially the procedure described by Marion Sims in 1868; the test is, however, more usually associated with the name of Huhner. It should be carried out in every case in which there is reason to doubt the normality or adequacy of spermatozoal ingress in the cervical canal. It is best performed at the presumptive ovulatory phase, since it is almost certain that the conditions of cervical passage are particularly favourable at this period. The .method is as follows: The patient is placed in the usual gynecological position, a vaginal speculum is introduced without any lubricant or anti- septic and a drop of the vaginal pool is aspirated by means 85 Albert SHarman of a dry sterile pipette and placed under a cover-glass, to be " examined without delay as a hanging drop" preparation. The cervical canal is then aspirated by means of another dry sterile pipette (or appropriate cannula). The interpretation of results, to be correlated with the findings of ordinary semen analysis, is briefly as follows:

(1) A considerable number of spermatozoa (motile or non- motile) in the vaginal pool, per high-power field, indicates that the semen has been properly deposited; their repeated absence, in association with normal semen, found on ordinary analysis, implies failure of insemination, which is most commonly due to premature ejaculation, faulty coital technique or vaginismus.

(2) The presence of motile spermatozoa (preferably 'migrating') in the cervical canal?these should be present one hour after coitus?indicates a normal cervico-sperm relationship.

(3) The repeated presence in the cervical secretion of non- motile spermatozoa (in a case of normal semen) is indicative " of cervical hostility." (4) The repeated absence of spermatozoa from the cervical canal and their simultaneous presence in the vaginal pool implies their inability to enter the canal; this may be due to the state of the semen, e.g., asthenozoospeimia, or it may be due to cervical factors, e.g., infection or viscosity or opacity of the cervical plug. Errors of interpretation are possible, but these will be greatly minimised if the following points are borne in mind:

(1) A single test giving negative results must be repeated, as the finding, for various reasons, might be exceptional. (2) The precise time of coitus should not be ordered. (3) The optimum time of examination is 6-8 hours after coitus. (4) The test should be preceded by a few days' rest from coitus.

The Male Factor. This is discussed by Mr. Mack. 86