IT IS RECOGNIZED that the time during which the human egg is susceptible

Transcription

1 The Clinical Signs of Ovulation A Survey of Opinions* Somers H. Sturgis, M.D., and W. T. Pommerenke, M.D. IT IS RECOGNIZED that the time during which the human egg is susceptible to fertilization is short. The importance of ascertaining the most propitious time for fertilization based on the functional viability of the egg is obvious. Though obscured from view, ovulation is nevertheless closely related to other physiologic processes, some of which are susceptible to determination and experimental modification. The quality of these physiologic relationships has been subject to numerous interpretations with the result that different investigators assign varying weights to the various tests of ovulation. It was believed that members of our Society, by reason of their special interest and experience, could contribute information which might serve as the basis of more extended studies. Therefore the membership was polled to obtain an expression of opinion concerning: ( 1) the validity of methods they employ to determine ovulation; and ( 2), factors which are believed to be operative ii;t the process of ovulation., A variety of opinions was revealed by the 87 replies from 121 members receiving the questionnaire. This was expected. It is natural that an investigator should be conditioned by his experience, his successes, and his failures. His opinions may, likewise, be influenced by the prestige of his colleagues in allied fields. In appraising criteria which have no sharply defined end points, subjective evaluations must play an important part in the conclusions drawn. The authors feel that it is unwise to subject the replies A report of the Subcommittee on Ovulation, Research Correlating Committee, American Society for the Study of Sterility. 113

2 114 STURGIS & POMMERENKE [Fertility & Sterility to a detailed statistical breakdown. We have, moreover, occasionally taken the editorial liberty of paraphrasing some of the comments of various communicants, either singly or in groups. It is to be emphasized that this report only summarizes the current opinions of our members. The data in no way should be interpreted as a valid representation of an official stand of the American Society for the Study of Sterility on specific tests. This compilation of opinion is published for the information of members of the Society. The replies to specific questions analyzed in our tables will not always add up to the same sum. This results from the failure to obtain completely classifiable replies. Some of our members do not practice gynecology, others have contributed valuable information gained from long and painstaking observations on other mammals. This survey is divided into the following sections: 1. Analysis of replies concerning the use, interpretation, and validity of ovulation tests. 2. Summary of opinions on three questions: (a) the duration of fertility of the ovum; (b) the value of gonadotropins; (c) the effect of sexual stimulation on ovulation. 3. Composite summary and recommendations. 1. ANALYSIS OF REPLIES In Table 1, the "tests" are arranged in the order of their value indicated by the replies; thus, 92 per cent of the 71 reports on the endometrial biopsy stated it to be valuable while only 31 per cent of the 51 reporting on the vaginal smear felt this was a valuable test. Only a few of the members expressed an opinion on pregnanediol assay or the ovarian hyperemia test, yet a majority of those who did report ( 63 per cent and 56 per cent), regard these as valuable criteria of ovulation. On the other hand, although midinterval pain, changes in cervical secretions and in the smear are familiar indices to most members, less than 50 per cent of the replies stated that they were practical adjuncts. Endometrial Biopsy This test is used routinely by 68 per cent of those replying; 61 per cent interpret the biopsy themselves, and 92 per cent feel it is a good test. The

3 Vol. 1, No. 2, 1950] OVULATION 115 choice of time to take the biopsy is equally divided between "premenstrual" and "first day of menses"; 3 doctors only gave "postovulatory" as their preference. The Novak suction curette was mentioned eight times as the preferred instrument. Among those enthusiastic about the biopsy, it is stated that, "Secretory endometrium is presumptive evidence of ovulation, and the chances of error are small." Its limitations are conceded to be that it is a "post-hoc method valuable for confirmation only." Further, it is pointed out that "evidence of luteinization of the granulosa without ovulation does cast considerable doubt on the reliability of endometrial changes, except prede- TABLE 1. Rating of Tests Number of Used Interpreted Replies Valuable Routinely by Clinician Endometrial biopsy (92%) 48 (68%)" 43 (61%)" Basal temperatures (80%) 77 (96%) 77 (96%) Pregnanediol assay (63%) 3 (16%) 8 (50%) Ovarian hyperemia test 16 9 (56%) 2 (17%) 5 (42%) Cervical mucous study (48%) 32 (51%) 50 (91%) Mittelschmerz, etc (42%) 26 (43%) 40 (80%) Vaginal smear cytology (31%) 15 (29%) 33 (69%) Percentages refer to the number replying in full on each test. cidual changes, in certifying occurrence of ovulation... One is inclined to doubt that minor changes are always preceded by ovulation." Basal Temperature Charts Basal temperature records are used routinely by more of the members as a test for ovulation than any other procedure (Table 1). Fifteen replies stated that temperatures were taken rectally, while only 5 mentioned the oral, and 4 the vaginal route. We were surprised to receive so few comments on interpretation of the temperature charts. No doubt the limitations of the method are widely known and accepted. It is certainly the "simplest method" and has "limitation in respect to potential errors inherent in the actual technic" but 81 per cent of the replies agree that this is a "good" method of testing for ovulation, qualified in one report as "very helpful."

4 116 STURGIS & POMMERENKE [Fertility & Sterility Pregnanediol The assay of the pregnanediol complex by the Venning method as well as the Gutterman color reaction are each mentioned 4 times, and the gravimetric determination of free pregnanediol introduced by Astwood is reported twice. However, one observer has "found pregnanediol in seemingly anovulatory cycles, and its absence in seemingly ovulatory cycles" and another points out that "in lower forms and at times in women, luteinization of unruptured follicles can be demonstrated." Ovarian Hyperemia Test The theoretical value of testing the urine for an increase of gonadotropins preceding ovulation, as developed by Farris, is remarked on by some, who do not, however, state that they have had personal experience with the Farris technic. This is seen in such statements as, "This probably will prove good, but such proof is not yet positive" and it is "very good if you have an immense rat colony and plenty of time." Actual experience with the Farris technic appears to be extremely limited. It is stated that, "If a sharper end point for reading the color reaction can be developed, this should be a most valuable tool." Yet the opinion of the originator of the test that he finds "other ovulation tests contributory and only the hyperemia test accurate" is confirmed by a worker in the same city who states that the method "correlates nicely with temperature charts, but where the chart is not characteristic, the Farris test is of great help." Cervical Mucus Observation of the cervical mucus is commonly used as an indication of ovulation timing; its reliability is questioned by many. Twelve reports indicate that aspiration is used to test amount and viscosity and one clinician observes the "fern pattern" of a dried smear. As a test for the occurrence of ovulation, it is stated to be "too variable, as is sperm penetration." The wording of the query on "sperm penetration in cervical mucus," was equivocal, and led many to interpret the question as applying to the use of the Huhner test. Since the Hubner test involves the husband's sperm, which may or may not be normal in sterility couples, it is always open to criticism as an ovulation test. Because of this misunderstanding, we can only

5 Vol. 1, No. 2, 1950] OVULATION 117 conclude from the replies that at least 51 per cent of members use a Huhner test routinely in their sterility work-up. Mittelschmerz or Bleeding Although the occurrence of these clinical signs is stated to be "very accurate" and their value is termed "excellent when properly interpreted" by some observers, there are several expressions of doubt concerning such criteria. "Pregnancies have occurred where Mittelschmerz preceded the rise in temperature and isolated coitus by more than 24 hours... and midinterval bleeding has occurred as long as 55 hours before the rise." These signs are "too inconstant" and "of no accurate value" to be of much clinical help in the opinion of some. It is pointed out that they depend on "subjective appraisal" by the patient, and this gives added significance to the opinion based on studies of monkeys that "intermenstrual bleeding only loosely correlates with the menses." Vaginal Smear Taking of a series of vaginal smears daily "has given information in a number of cases. But the whole cycle must be studied and ovulation time ascertained at the end of the cycle." In experienced hands it is "quite dependable in most instances" and "combines well with basal temperatures." The test is not widely used as a routine practice, however, since only "in a few exceptional cases" can ovulation be ascertained without reviewing a whole series of smears. General Comments and Suggestions The variability of opinions expressed in the replies appears to reinforce the comment that "any of these tests by itself can be misleading and puzzling, though as studies on an individual patient progress, it frequently develops that one method should be enough." The difficulty in estimating the exact occurrence of ovulation by biopsy, temperature charts, or pregnanediol assay is summed up by the statement that "no one has demonstrated the time relationship between rupture of the follicle, luteinization of the granulosa, and changes resulting from the elaboration of progesterone. This takes a period of time, the duration of which is not yet determined." Isolated planned coitus or insemination offers a method of checking the clinical value of anv of the ovulation tests under discussion. Thus, one in- '

6 118 STURGIS & POMMERENKE [Fertility & Sterility vestigator states that, "Artificial insemination has given 90 per cent takes at the low point in basal temperature charts in 30 or 40 cases." Another report states that, "Insemination or coitus on the rise in temperature resulted in impregnation in 50 women-while no pregnancies resulted from insemination on the second day following the initial rise." The suggestion that, "If a group of some 50 normal women could have insemination on the day after the rise, then the second day after, we might estimate the life of ova under normal conditions" presupposes a known temporal correlation between liberation of the ovum and the rise in temperature. Perhaps factual information can only be obtained by "recovery of ova" or histologic appraisal of the age of the corpus luteum, correlated with one or several of the routine methods. 2. SUMMARY OF OPINIONS ON THREE QUESTIONS RELATED TO OVULATION The questionnaire was intended to gather opinion concerning: (a) The functional life of the human egg before fertilization; (b) The value of gonadotropin therapy in inducing ovulation; (c) The relation of sexual stimulation to ovulation. The question: "In your opinion, how long after ovulation, is the human egg susceptible to fertilization?" brought forth answers ranging from a few minutes to 72 hours in different patients. Five members estimated the time limit at less than 6 hours. Twenty-four replies gave 12 to 24 hours as the period of functional viability of the ovum. Twenty-seven members believed that the limit could be extended beyond 24 hours. Eight persons believed that under certain conditions the egg could successfully await the sperm for 72 hours. If spermatozoa were as short-lived as the ova, and if one accepts the low figure ( 2 to 4 hours) during which the latter remains reactive, then the successful meeting of egg and sperm would indeed be a matter for fortunate coincidence. Determination of the length of time spermatozoa can retain their potency in the female genital tract, while anticipating the liberation of the egg, is a collateral problem deserving study. The second question sought an appraisal of the value of gonadotropins for inducing ovulation in women and elicited a wide variety of answers. Thirty-two persons expressed belief that they possessed no value; 13, that they had little value; 9 doubted the efficiency of present preparations; 14

7 Vol. 1, No. 2, 1950] OVULATION 119 deemed that gonadotropins were possibly useful; and 8 suggested their administration under proper circumstances. Several communicants, while questioning the value of present commercial preparations, believed that newer and purer preparations might prove effective. The matter of dosage and spacing of the administration was also mentioned in several replies. Certainly, final appraisal must take into consideration the quality and quantity of the material given. Because of possible adverse effects upon the ovary, one author cautioned against the use of large doses. In a number of replies, the conditions requisite to the action of gonadotropins were stressed. Thus several members expressed the belief that present preparations were of no use in women who do not ovulate spontaneously, and that their value was limited chiefly to cases in which the level of follicular growth is already fairly high at the time of administration. Thus almost mature follicles or otherwise receptive ovaries might be induced to ovulate a few hours or days TABLE 2. Relation of Sexual Stimulation and Ovulation Don't know 10 No value 24 No proof of value 3 Seriously doubt value 12 Questionable value 3 Occasional or possible value 16 Valuable 12 TOTAL REPLIES 80 earlier by the use of gonadotropins. One author expressed the opinion that the cases most refractory to their use are those with cystic ovaries and endometria! hyperplasia. In one reply to the questionnaire, the preference was expressed for fractional small doses of X-ray to the pituitary gland and ovaries for induction of ovulation in selected cases. It is apparent that evidence concerning the value of gonadotropins is equivocal. Their use in most cases of sterility does not seem justified. However, some optimistic reports indicate that they may be useful to the ovulation process in some cases, which otherwise might be abortive. It is generally hoped that better preparations will become available. A third question was: "In your opinion can ovulation be induced in women by sexual stimulation, and if so within what limits?" Almost all communicants regarded the question as relating to coital stimulation. The distribution of opinions is summarized in Table 2.

8 120 STURGIS & POMMERENKE [Fertility & Sterility Of necessity, remarks relating to the possibly stimulating effect of coitus on ovulation are based on impressions and theoretical considerations. The familiar observation that sexual frigidity is no hindrance to fertility was repeatedly mentioned. Several expressed the belief that sexual stimulation can precipitate ovulation in normally ovulating women. The time limit in which this effect might possibly be operative was estimated by three members to be within 24 hours. In three replies, reference was made to accidents in the "rhythm technic" and to the fact that single sexual contacts, any number of days after menstruation, have on occasion resulted in pregnancy, as evidenced by the fact that wives who were exposed during very brief and unselected leaves by the soldier husbands frequently became pregnant. 3. COMPOSITE SUMMARY AND RECOMMENDATIONS The wide range of opinion expressed in answer to the questionnaire bears evidence that there is no reliable, practical test widely accepted as a true criterion of ovulation. The apparent contradiction of beliefs calls for caution in forming a concise summary of the answers. It is hazardous to place reliance on majority opinions. Nevertheless, this survey does reflect the current thoughts of most of the membership of the Society as they apply to the process of ovulation. The following summary is offered, then, in an attempt to consolidate the various individual responses into a trend of thought that, we hope, will not lie far outside the beliefs of most of the members. The most satisfactory "proof" of ovulation is the presence of a secretory endometrium late in the cycle. This effect, with certain reservations, is acceptable only as it applies to the cycle in question. Basal temperatures, used routinely by 96 per cent of those reporting, demand skeptical and critical interpretation before acceptance as sole proof of ovulation. The value of temperature charts may properly lie in their correlation with other confirmatory tests or signs. Daily vaginal smears, pregnanediol determinations, and ovarian hyperemia tests may have considerable value in the hands of their proponents but demand laboratory facilities that probably will never be universally available. Clinical signs-mid-interval pain or bleeding-are open to question since they are subjective and not objective, and since we have no knowledge of the time interval between ovulation and their first appearance. The functional life of the unfertilized human ovum is measur-

9 Vol. 1, No. 2, 1950] OVULATION 121 able in hours rather than days, and probably less than even one day. Sexual stimulation may precipitate impending ovulation but such a response would appear to be limited to those follicles already so mature that rupture would occur spontaneously in any event in a matter of hours. While the value of commercial gonadotropins appears very limited, one should not minimize the possibility that new and better preparations may become available. The committee thanks the members of the Society for participating in this survey. From their experience and opinions may come suggestions in the use of new tests, and no doubt the technics of the veterinarian, the zoologist, and the chemist will supplement the routines of the clinician in the solution of problems suggested by this study. It is suggested that a central registry and repository be established in which members of the Society may contribute laboratory data and anatomic and histologic specimens, supplemented by carefully documented case histories. The critical study of the increasing mass of data which might be expected to gravitate to this repository should help solve some of the questions which still confront students of the reproduction process and the clinician concerned with sterility problems. In conclusion, we recommend two further lines of investigation to the Research Correlating Committee of the American Society for the Study of Sterility. 1. Since conception after isolated exposure is undeniable evidence of ovulation within narrow time limits, it would be desirable to collect all records of such cases that included basal temperatures, pregnanediol assays, or ovarian hyperemia tests preceding the exposure. No one observer is likely to collect the many hundreds of such cases necessary to make it possible to handle the data statistically. The Research Correlating Committee might profitably undertake to assemble all records of successful isolated insemination in which accurate cycle dates, basal temperatures, and reliable proof of pregnancy are simultaneously available. 2. The accurate estimation of the age of corpora lutea in the Macacus Rhesus by histologic study has proved reliable in the hands of G. W. Corner. Equally reliable criteria for the human corpus have been suggested by the work of Hertig and Rock in a relatively limited series of cases using the salvaged fertile egg as a guide to conception date. Very few members of the Society would be able to contribute fertile human eggs, but many members doing elective gynecologic surgery could make a contribution by

10 122 STURGIS & POMMERENKE [Fertility & Sterility scheduling their operations in the latter half of the cycle and sending a slide of the corpus luteum, with basal temperatures, dates, and other important data to the Research Correlating Committee. A review of the histologic sections by a single competent investigator correlated with the other material might provide more factual evidence upon which to base our judgment of the value of the common ovulation tests. Ovulation itself must be recognized as an event poorly defined. To some, ovulation may mean the moment of the break in the wall of the mature follicle. Others may consider ovulation to mean the passage of the egg into the peritoneal cavity. Still others may conceive it as the elastic period of time embracing both of these events. The first pin-point rupture of the ovarian capsule perhaps may precede extrusion of the ovum by minutes or hours. At times the egg may never escape. Occasionally rupture may be rather explosive; it is probably more apt to be a gradual exudative process. In some follicles, there may be a degree of luteinization with hormone production before rupture. In others, progesterone may not be produced for days after the follicle has burst. It would seem a futile search to look for a single, simple, reliable all-purpose test to tell precisely when "ovulation" occurs. There is no unanimous agreement even on the exact meaning of the term. Nevertheless, we must continue to seek for patterns in clinical observations. A few cases may have little value; many cases, however, may give us probabilities that are statistically important. The American Society for the Study of Sterility is particularly well organized to make the collection of significant data worth while. Massachusetts General Hospital, Boston 14, Mass. (S.H.S.)