Ovulation After Equine Gonadotropin Therapy

Ovulation After Equine Gonadotropin Therapy A Report of Four Cases Irving I. Kurland, M.D. IN 1930 COLE AND HART discovered a gonad-stimulating hormone in pregnant mare serum. It proved effective in producing ovulation not only in hypophysectomized laboratory animals but also in ewes, sows, and cows. Its effect in the human, however, has been the subject of much investigation and is definitely controversial in character. A decade ago Davis and Koff, and Siegler and Fein reported the successful production of ovulation in approximately half of their cases coming to operation for some pelvic pathology. Both groups of investigators used an average of 60 Cartland-Nelson units of Gonadogen given by the intravenous route. Ten years later Wolfe and Neigus attempted to repeat the experiment of the early workers. While they failed to produce ovulation in any of their 22 cases subjected to pelvic surgery, they arrived at the following pertinent conclusions: "Ovaries of young women would appear most desirable for examination, yet radical surgery and removal of organs can only be practiced upon older patients. The time of the cycle during which Gonadogen is given is of importance, for cyclic ovarian changes are occurring concurrently with those which may be induced by this hormone. In retrospect, studies with Gonadogen should have best been conducted immediately after the close of the menses, at a time when the normal inhibition to the pituitary by estrogen is in abeyance." Huber and Davis had their greatest success with pregnant mare serum in previously sterile patients in whom From the Department of Gynecology and Obstetrics and the Gynecological Endocrine Clinic, Beth-EI Hospital, New York. I wish to express my appreciation to Dr. Oscar Bloom for his valuable encouragement and guidance in the preparation of this paper. 61

62 KURLAND [Fertility & Sterility anovulatory menstrual cycles were demonstrated by endometrial biopsy. They felt that the correct mode of administration of this active substance held the key to successful clinical therapy. They concluded that the amount of hormone, the route by which it is administered, and the proper timing in the cycle may be of the greatest importance. The following report consists of 4 cases of young women brought successfully to term. They were selected from 12 private and clinic cases treated with pregnant mare serum during the past six years. All demonstrated anovulatory cycles as proven by endometrial biopsies and basal temperature readings. As pregnancy was attended along with therapy, repeated endometrial biopsies were not done in every case. However, since basal temperature readings have been proven to be a reliable index of the type of cycle present, we used the latter to evaluate therapy.6 The 4 successful cases are reported in detail. Out of the remaining 8, 6 are considered failures even though changes in the basal temperature readings and endometrial biopsies were obtained some time during therapy. These changes were not sustained, a reversal to the monophasic type of cycle occurring in the basal temperature charts. Two out of the 6 are still under treatment, 3 failed to continue, and 1 developed serum sickness after the first course of injections. Since it is necessary to have at least three to four months of temperature charts to obtain a true picture of the pattern, we have included only those cases where several months of temperature charts were available in order to evaluate our results properly. For this reason the seventh case is not included in detail even though carried successfully to term after receiving pregnant mare serum. A sufficient number of temperature charts showing persistent anovulatory cycles were not obtained before therapy was instituted. The eighth case is considered only a partial success. Anovulatory cycles ranging from forty-two to fifty-five days were proven by serial biopsies taken at weekly intervals, as well as by basal temperature readings. Three courses of pregnant mare serum were given before the cycle was changed to a biphasic type of thirty days. Conception occurred as proven by a positive frog test. However, the patient aborted spontaneously at the eighth week of gestation. All the criteria suggested by Wolfe and Neigus, and Huber and Davis are met in Our cases. All are young women without pelvic pathology. Pregnant mare serum therapy was instituted immediately upon cessation of menses in

Vol. 2, No.1, 19511 OVULATION 63 order to avoid the' inhibition to the pituitary by estrogen. The total dose used was 150 Cartland-Nelson units in the form of Gonadogen given intramuscularly in three equally divided doses on days one, three, and five following the close of the menses. Case I CASE REPORTS H. P., aged 24, complained of sterility of two years' duration. Her husband had previously been found to have a complete azoospermia. In view of this finding the couple requested artificial insemination. A complete examination of the patient was therefore made to determine her fertility. Her menses began at the age of 13 at intervals of six weeks, lasting for five days: for the past four years, intervals have become five to six weeks. Her weight was 138 Ibs. and her height 60". The B.M.R. was minus 11 per cent and blood cholesterol 223 mg. per cent. Uterotubal insufhation revealed patent tubes. An endometrial biopsy taken on the thirty-fourth day of a thirty-seven-day cycle showed a resting-phase, inactive endometrium. At first a 1200-calorie diet with desiccated thyroid extract gr. 1/10 three times daily was given and the patient lost 10 Ibs. gradually over a period of three months. Basal body temperature readings were started immediately following the biopsy and continued for the next fifteen months until pregnancy occurred. The progress of this case can best be followed by the changes in the temperature charts, which will give a more comprehensive picture of the progress made (Fig. 1). The first two periods on Figure 1 are monophasic. The patient received pregnant mare serum <> for a period of four months. During this period, the character of the basal temperature curves changed to a biphasic type. A second biopsy taken at the end of the four months showed the endometrium to be in the late lutein phase. In view of this report, no further injections were given, but artificial insemination with a donor was attempted at the ovulatory phase of the subsequent cycles. In February, 1947, an upper respiratory infection prevented the procedure. In March and April, 1947, insemination was attempted following the preovulatory dip without any result. As the May and June charts were not typical inseminations were deferred. The charts reverted to the monophasic type with a prolonged interval of forty-nine days in the June period. It appeared that the effect of the medication had not persisted. Gonadotropic therapy was reinstituted in August, 1947. An apparent biphasic curve followed with the cycle reduced to thirty-two days. Insemination was attempted on the fifteenth day but no conception occurred. In September, 1947, Gonadogen, 50 Cartland-Nelson units per dose.

64 [Fertility & Sterility KURLAND insemination was attempted without therapy, a monophasic curve of forty-two days following. A new plan was therefore adopted: to institute a course of injections before attempting any insemination. In October, 1947, this plan was followed; insemination was attempted on the seventeenth day and while the cycle CYCLE AUG._ 19% SED'pnl-_ = = FIGURE 1. Basal temperature chart, patient H. P. _ 98 F. at base. G Gonadogen, 50 Cartland-Nelson units per dose. I = artificial insemination. B = biopsy. reverted to a twenty-nine-day interval, no conception took place. In November, 1947, the same plan was followed but insemination was done on the twelfth day as a sharper rise and fall occurred, giving us a better index of ovulation and thereby showing distinctly the optimum time for insemination. The rest of the November curve indicates pregnancy. The patient was delivered of a healthy baby at term on September 7,1948.

Vol. 2, No.1, 1951] OVULATION 65 Case II H. K., aged 22, complained of involuntary sterility for two years. Her periods were regular until one year before presentation, when she developed menorrhagia for two successive periods. This condition was corrected by three doses of A.P.L., 500 I.U. per dose. Her periods were regular for the next ten months, occurring every twenty-eight days and lasting three to four days, but no conception took place. On June 24, 1948 (see Fig. 2), she had a regular menses lasting three days. Vaginal staining recurred on the eighth to the nineteenth day of the cycle. Gen- OYCLE "., 61. AU&_ OCT. FIGURE 2. Basal temperature chart, patient H. K. _ = 98 F. at base. S = vaginal staining. A = A.P.L., 500 LV. per dose. B = biopsy.,j, = coitus. G = Gonadogen, 50 Cartland-Nelson units per dose. eral physical examination revealed no abnormality or endocrine stigmata. Pelvic examination revealed no pathology. The staining ceased after four doses of A.P.L., 500 I.U. per dose. The cycle was monophasic in type and lasted for forty-one days. The August, 1948, period lasted for two days. Staining recurred on the sixth day of the cycle, but no bleeding occurred after two doses of A.P.L. Basal temperature graphs revealed a monophasic type of cycle of twenty-six days. The September, 1948, period was normal except for slight staining on the fifth day. A monophasic type of cycle of thirty-one days occurred. An endometrial biopsy taken on the twenty-eighth day of the cycle revealed the endometrium to be in the proliferative phase. Pregnant mare serum was given on days 1, 3, and 5, following the cessation of the October menses. A biphasic curve appeared and the temperature remained at a uniform level for sixteen days beyond the time of expected menses. No

66 KURLAND [Fertility & Sterility further periods occurred. The patient was delivered of a living baby on June 6, 1949. Case III S. B., aged 26, complained of sterility for eighteen months or more. Her menstrual periods occurred between twenty-eight to forty-one days. The uterus was of the hypoplastic type and markedly antihexed. The cavity measured two and one-half inches in depth. Uterotubal insuillation revealed patency of tubes. Endometrial biopsy taken on the twenty-sixth day of a twenty-eight-day cycle revealed fragments of rather inactive appearing endometrium. CYCLe..., "AY, itunele ;nily'._ AUG. FIGURE.J, 3. Basal temperature chart, patient S. B. _ = 98 F. at base. = coitus. G = Gonadogen, 50 Cartland-Nelson units per dose. The May and June periods (Fig. 3) were monophasic in type, the latter being forty-one days long. In July, 1948, pregnant mare serum was given for three doses following the close of the menses. Although the cycle was twenty-nine days, the temperature curve was still anovulatory in type. The treatment was repeated at the cessation of the August, 1948, period, and a biphasic curve appeared. Conception occurred and the patient was delivered of a normal healthy baby on May 20, 1949. Case IV S. S., aged 31 years, presented herself in September, 1944, complaining of amenorrhea of seven months' duration. The history revealed a thyroidectomy in 1931, a miscarriage in 1939, and a normal delivery in 1943. FollOwing the thyroidectomy the intervals were prolonged to five or six weeks. She had one

Vol. 2, No. I, 1951] OVULATION 67 period shortly after the delivery and was amenorrheic up to the time of examination. Her weight was 124 lbs. and height 63", B.M.R. was minus 26 per cent and blood cholesterol was 435 mg. per cent. Thyroid therapy (gr. 1~ t.i.d.) was instituted along with vitamins and improved diet. Her first period in ten months occurred on June 19, 1945, and in the ensuing year only four periods occurred. In 1946, however, eight periods occurred, starting at eight-week intervals and diminishing to six-week intervals. An endometrial biopsy taken five days before the January, 1947, period showed a follicular pattern. During 1947 the periods occurred at five- to six-week intervals. The B.M.R. was minus 5 per cent and cholesterol was 272 mg. per cent. During the latter half of the year the patient CYCLE SEPT._,...7 NO\/. _ J"IIII.,M-8 FEa 4. Basal temperature chart, patient S. S. _ = 98 F. at base. = coitus. G = Gonadogen, 50 Cartland-Nelson units per dose. FIGURE.J, attempted to conceive without success. Basal temperature readings were started in September, 1947 (see Fig. 4). They revealed anovulatory type of cycles with prolonged intervals ranging from forty to fifty days. On December 31, 1947, she began to menstruate after the first seven-week interval in over a year. An endometrial biopsy taken at this time again showed a follicular pattern. Pregnant mare serum therapy was instituted following the close of the January, 1948, period. An apparent biphasic curve of thirty-nine days resulted. A second course was given following the close of the February, 1948, period. No subsequent menstrual periods occurred, and the temperature remained at a uniform high level. The Friedman test was positive on May 3, 1948, and she was delivered at term of a healthy baby on November 19, 1948. DISCUSSION The administration of gonadotropic hormone from pregnant mare serum has been followed by pregnancy in previously sterile patients in whom anovulatory

68 KURLAND [Fertility & Sterility cycles have been demonstrated. Each case presented other abnormalities in addition to the anovulatory cycles common to all. While other forms of therapy corrected irregularities in menstruation, they did not overcome the problem of infertility. This was demonstrated by the persistence of monophasic cycles which were not changed until pregnant mare serum was administered. Case I presented the added task of artificial insemination. After the first four months of Gonadogen therapy biphasic curves, indicating ovulation, were obtained. This was confirmed by the second endometrial biopsy taken at the end of the fourth month (January, 1947). The failure of conception was probably due to faulty interpretation of basal temperature curves. Artificial insemination was attempted at first at the peak of the thermal shift. Since the shift is probably a physiologic response to ovarian activity it would tend to lag behind the stimulating factor. 4 Therefore, we advised coitus, or performed the inseminations, just prior to the thermal shift. In Case I the artificial insemination which was successful was done on the twelfth day of the November, 1947, cycle. The previous unsuccessful inseminations were attempted between the fourteenth and sixteenth days of the cycles. This failure to obtain conception soon after producing ovulation afforded us an opportunity to study another important aspect of pregnant mare serum therapy. Early workers deemed it inadvisable to use gonadotropic hormone over a long period of time for fear of interfering with the normal pituitary-ovarian relationship. This patient received seven courses of injections, totaling over 1000 Cartland Nelson units, during fifteen months without any ill effects. On the contrary, we regard the repeated biphasic curves from June to November as indicative of the efficacy of the hormone. Case II had anovulatory cycles associated with metrorrhagia. While administration of chorionic gonadotropic hormone from pregnant urine in the form of A.P.L. was followed by more nearly normal menses, "anovulatory" curves persisted (June, August, and September cycles). After pregnant mare serum therapy was instituted, a biphasic curve appeared (October cycle). Case III demonstrated anovulatory cycles associated with oligomenorrhea. The uterus was hypoplastic, the cavity being only 2~f inches in depth. Hypoplasia of the uterus, irregular cycles, and infertility has always been a triad which has resisted correction. Pregnant mare serum seemed to be of value in this case. Since her delivery the patient has been menstruating regularly about every twentyeight days. Case IV demonstrates anovulatory cycles, associated with amenorrhea and hypothyroidism. Thyroid therapy was followed by cyclic bleeding after a tenmonth period of amenorrhea, but these cycles proved to be of the monophasic type. After the administration of pregnant mare serum a biphasic curve and conception occurred. SUMMARY From a group of 12 women with anovulatory cycles treated with gonadotropic hormone from pregnant mare serum, 4 eventually ovulated, con-

Vol. 2, No.1, 1951] OVULATION 69 ceived, and delivered at term. Endometrial biopsies and basal temperature graphs had demonstrated ovulatory failure. Therapy consisted of 50 Cartland-Nelson units of Gonadogen given intramuscularly on the first, third, and fifth day after the end of menstrual bleeding. REFERENCES 1. Cole, N. H., and Hart, G. H.: Am. J. Physiol. 93:57, 1930. 2. Davis, M. E., and Koff, A. K.: Am. J. Obst. & Gynec. 36:183, 1938. 3. Huber, C. P., and Davis, M. E.: Surg., Gynec. & Obst. 70:996, 1940. 4. Israel, L. S.: M. Clinics North America, Phila. Number, 1948. 5. Siegler, S. L., and Fein, M. J.: Am. J. Obst. & Gynec. 38:1021, 1939. 6. Tompkins, P.: J. Obst. & Gynec. Brit. Emp. 52:241, 1945. 7. Wolfe, S. A., and Neigus, 1.: Am. J. Obst. & Gynec. 55:979, 1948.