Clomiphene Citrate in the Treatment of Luteal Phase Defects

Transcription

1 Clomiphene Citrate in the Treatment of Luteal Phase Defects CHARLES R. ECHT, M.D., FLOYD T. ROMBERGER, M.D., and JERRY A. GOODMAN, A.B. IT HAS BEEN STATED that the incidence of luteal phase defects as the cause of infertility is relatively high. 3 Gillam noted that the endometrial biopsy should lag at least 2 days behind the basal body temperature (BBT) rise before this diagnosis could be established. If the definite time of ovulation could be determined by the BBT, then, certainly, establishment of this diagnosis would be simplified. The BBT in ovulatory patients usually rises from 0.5 to 1.0 F. at the time of ovulation. 8 This ovulation period, as indicated by BBT, may actually extend over a 60-hr. period. 5 Three basic types of luteal phase defects in the endometrium have been described: 1 (1) late or "short" secretion, (2) weak secretion, and (3) irregular maturation. Human chorionic gonadotropin (HCG), estrogen, and progesterone have been used in an effort to improve the luteal phase Of particular interest is the reported improvement of the luteal phase with HCG. Theoretically, this treatment was thought to prolong the life of the corpus luteum. Since Clomid* (clomiphene citrate) has been shown to induce ovulation by the possible release of luteinizing hormone (LH) from the pituitary gland/2 and since HCG has been shown to be quite similar in many respects to LH,6 it was thought by the authors that an attempt to improve luteal phase defects with this medication may be in order. MATERIAL AND METHODS All patients were selected from our infertility clinic and the private practices of the authors. Those patients in whom a defect was demonstrated by BBT alone were not included. The time of ovulation as determined by the From the Infertility Clinic, Indiana University Medical Center, Indianapolis, Ind. The authors wish to express their thanks to Dr. A. H. Macgregor and The Wm. S. Merrell Co., for supplying clomiphene citrate, and to Dr. Frank Vellios for his cooperation in evaluating the endometrial biopsies. *The Wm. S. Merrell Co., Div. Richardson-Merrell Inc., Cincinnati, Ohio. 564

2 VoL. 20, No.4, 1969 CLOMIPHENE CITRATE 565 BBT was indicated by the lowest level of temperature at midcycle. Only patients who exhibited a luteal phase defect of 48 hr. or more, as demonstrated by endometrial biopsies, were included in this study. The endometrial specimens were evaluated by one pathologist using the criteria of Noyes et al. The first two treatment cycles were conducted in placebo double-blind fashion; distribution of drug and placebo was randomized, and each patient took the same medication during the second cycle as she took during the first. Treatment Cycles 3 and 4 were conducted without the use of placebo so that all patients received clomiphene citrate in the last two cycles. Endometrial biopsies were performed as closely as possible to 3 or 4 days after ovulation, and the biopsies were repeated in each successive cycle on the same day as the original biopsy. All other medication, except thyroid preparations, was discontinued at least 2 weeks prior to the introduction of treatment; however, if the patient had been stabilized on thyroid medication, it was continued in the pretreatment dosage. The patients received clomiphen~ citrate ( 100 mg.) or placebo daily for 3 days beginning on Day 5 of the menstrual cycle. BBT charts were maintained through all treatment cycles. RESULTS The responses during this clinical investigation were classified as follows: (1) no improvement, (2) improvement with no pregnancy, and (3) pregnancy. When pregnancy did not occur, improvement was established if there was no endometrial defect in the fourth treatment cycle. A total of 19 patients were studied. Complete BBT's and endometrial biopsies were compared in 20 pretreatment cycles and 62 treatment cycles (18 placebo and 44 drugs). No Innprovernent Eleven patients failed to show improvement by the above criteria. Of these, 7 were gravida 0 and 4 were gravida 1. The premenstrual patterns in these patients ranged from 21 to 35 days. Infertility ranged from 30 to 141 months. Prior to treatment, BBT charts indicated that all patients had a lower than normal temperature rise ( F.). In this group, 8 were treated with placebo for their first two cycles, followed by two treatment cycles with clomiphene citrate (Table 1). Within the first 24 hr. after ovulation during the placebo cycles, BBT shifts ranged from a 0.1 to a 0.7 F. increase, with an average rise of 0.3. At 24 hr. after ovulation during the next two cycles with patients taking

3 566 ECHT ET AL. FERTILITY & STERILITY TABLE 1. Ovulation Dates for Patients with Responses Classified as No Improvement Treatment cycles Patient Pretreatment (placebo) (placebo) (drug) (drug) H.K /5* 0 + 5/ / /5 E.F / / / / / /10 D.E / / / / /7 N.O / / / /11 E.B / / ; /14 E.S /6 Prolif /6 R.T.t 0 + 3/ / / /8 Prolif. J.F / / /7 0+ 6/ /7 J.D.t 0 + 4/ /7 0 +4/ / /6 D.B.t / / / / /5 M.Z. 0 +4/ / / ; /6 *The time of ovulation (0) was the lowest temperature at midcycle, as determined by the BBT. The numerator is the number of days after the time of ovulation based on the endometrial biopsy, and the denominator is the number of days after the time of ovulation based on the BBT. t Clomiphene citrate taken for all four cycles. clomiphene citrate, the average temperature showed an increase of F., with an average rise of 0.3. The total temperature increase for the entire luteal phase during the first two placebo cycles ranged from 0.6 to 1.5 F. above the mean proliferative phase level. For the following two clomiphene citrate treatment cycles, the range was F. These patients did not demonstrate much change in temperature shifts while taking clomiphene citrate. The characteristic menses in all patients were scant to moderate in flow. Of the husbands in this group, 6 exhibited subfertile semen analyses as indicated by decreased motility and counts below 40 million per cubic centimeter. Improvement But No Pregnancy Improvement, diagnosed by endometrial biopsies and 24-hr. postovulatory BBT rise, was seen in 4 patients, who were years old (Table 2). None of these women had ever conceived. The pretreatment menstrual cycles in these patients ranged from 25 to 66 days. The length of infertility ranged from 9 to 48 months. Prior to treatment, gradual shift in temperature to levels lower than normal postovulatory levels were seen in these patients. All patients were treated with clomiphene citrate for all four of the treatment cycles, and it is interesting to note that these patients improved by

4 TABLE3. Ovulation Dates for Patients Who Became Pregnant Treatment cycles Pre Patient treatment Med. Ovul. Date Med. Ovul. Date Med. Ovul. Date C.R. 0+4/7* Drug 0+9/9 Drug 0+3/6 Drug 0+3/4 E.G. 0+3/7 Placebo 0+3/8 Placebo 0+4/7 Drug 0+3/3 B.E. 0+6/11 Placebo 0+12/13 Placebo 0+13/13 Drug /12 J.C.t 0+9/14 Drug * Refer to the first footnote in Table 1. t Pregnancy occurred during the first treatment cycle. Med. 4 Ovul. Date Drug 0+7/8 Drug 0+3/4

5 568 EcHT ET AL. FERTILITY & STERILITY TABLE 2. Ovulation Dates for Patients with Responses Classified as Improvement But No Pregnancy Treatment cycles of drug Patient Pretreatment M.D j12* / / / /3 E.G / / /7 0 +4/4 J.O / / / / /3 N.K / / / /3 * Refer to the first footnote in Table 1. their last treatment cycle as demonstrated by endometrial biopsies. During the first 24 hr. after ovulation ( 0 + 1), BBT shifts ranged from 0.1 o to 0.6 F., and the patients exhibited a total shift between 0.8 and 1.6 at peak. The average temperature increase was 1.0 F. during the first two treatment cycles with clomiphene citrate. This average increased to a 1.1 o shift for the third and fourth cycles. Menses were moderate in flow and 1 of the 4 husbands had a subfertile semen analysis. Pregnancy Of the 19 patients, 4 ( 21%) became pregnant with clomiphene citrate treatment after periods of infertility ranging from 30 to 131 months. Of the patients, 3 were gravida 0 and 1 was para 1, gravida 3, abortus 2. The pretreatment menstrual cycles in these patients were about 28 days, and the posttreatment menses were moderate in flow. The ages of the patients ranged from 26 to 29 years. Semen analyses for 3 of the husbands were in the fertile range, while 1 husband was subfertile. At pretreatment physical examination, 1 of these patients had mild external endometriosis as diagnosed by coarse, tender nodulations high on the cervix. Another patient was found to have slight tender nodularity along sacro-uterine ligaments, also suggestive of endometriosis. BBT shifts within the first 24 hr. of the rise ranged from 0.2 to 0.7 F., with an average total rise of 1.0. Of the patients, 2 took the placebo for their first two cycles; however, conception occurred in all patients only after treatment with clomiphene citrate. Medication and ovulation dates are shown in Table 3. Patient C.R. became pregnant during Cycle 4. She had an uneventful pregnancy and gave birth to a normal, healthy 2780-gm. female, 2~ weeks before the estimated date of confinement ( EDC). Conception in Patient E.G. occurred in the fourth treatment cycle in which the endometrial biopsy taken on Day 5 after the onset of the BBT

6 VoL. 20, No.4, 1969 CLOMIPHENE CITRATE 569 TABLE 4. Frequency of Adverse Reactions Adverse reaction Vaginal spotting Ovarian enlargement Pelvic pain Uterine enlargement Premenstrual mastalgia Hot flashes Spots before eyes Nausea Dizziness Patients (No.) shift showed Note is made of the fact that this biopsy specimen actually was taken before implantation was likely to have occurred. The pregnancy progressed uneventfully until midmorning on the sixty-second day after the onset of the last period. A sudden, sharp pain was experienced in the lower left quadrant of the abdomen. The patient was seen in the office, on an emergency basis, and a ruptured tubal pregnancy was suspected. She was admitted to our hospital and an exploratory laparotomy revealed cc. of fresh blood in the abdominal cavity. There was an impending tubal abortion from the distal and of the left tube. It is believed that clomiphene citrate exerted a beneficial effect on the luteal phase defect in this instance. This patient conceived again without additional therapy of any kind. The EDC was Sept. 11, Unfortunately, however, intrapartum death resulted from complications of term breech delivery of a 6 lb. 13 oz., female infant. Patient B.E., who became pregnant in the third cycle, had an antenatal course that was complicated by an episode of bleeding during the sixth to eighth week of pregnancy. This threatened abortion was treated only with Vitamin K, 5 mg. t.i.d.; Cevalin,* 500 mg. b.i.d., and sedation with phenobarbital and belladonna. The pregnancy progressed uneventfully until the membranes ruptured spontaneously in the thirty-sixth week of gestation. Labor began and lasted for 8 hr. 49 min. The infant was a female weighing 1875 gm. with multiple congenital anomalies involving the right ear and mandible. The placenta was one of circumvallate type with an area of premature separation along one margin. The parents and child were of normal chromosomal type. Conception occurred during the first clomiphene citrate treatment cycle of Patient J.C. Pregnancy was normal and uneventful. A healthy 3000-gm. female was delivered after 40 weeks of gestation. *Eli Lilly and Co., Indianapolis, Ind.

7 570 ECHT ET AL. FERTILITY & STERILITY Adverse Reactions The frequency of major adverse reactions is shown in Table 4. These effects of medication were relatively insignificant, however, and did not affect the outcome of the study. DISCUSSION In this study the BBT charts alone proved to be a poor method of predicting luteal phase defect when a total rise of at least 0.5 F. in 24 hr. at ovulation was used as a criterion for ovulation. When a total rise of less than 0.5 F. during the latter half of the cycle was used, no defects were detected by BBT. In no patient who took the placebo for the first two cycles was there any improvement by the fourth cycle. Of the patients who exhibited improvement in the luteal phase defect, all were taking clomiphene citrate for all four cycles. One might postulate that clomiphene citrate may have had a lingering or additive effect in this group of patients. Only in 1 patient who took clomiphene citrate in all four cycles was there no improvement. Improvement was seen in some isolated cycles in which the placebo was given. No patient became pregnant while taking the placebo. Four pregnancies were associated with clomiphene citrate treatment: two were uncomplicated, one resulted in a tubal pregnancy, and one resulted in a first branchial arch anomaly. It is doubtful whether these abnormalities were a result of clomiphene treatment. Improvement and pregnancy were seen only in those patients who had regular menstrual cycles prior to treatment. Further study and clinical trial with clomiphene citrate in an effort to improve luteal phase defects may prove to be worthwhile. Certainly the use of BBT charts alone in diagnosing the defect or evaluating the results of therapy have proved, in our hands, to be disappointing. Changes in the endometrium may indicate improvement, but a pregnancy is the only valid evidence of drug efficacy. SUMMARY 1. A double-blind study was undertaken to evaluate the use of clomiphene citrate in the treatment of luteal phase defects. 2. Only patients who received clomiphene citrate showed improvement in the correlation between basal body temperature and endometrial biopsies, and only 4 patients became pregnant. 3. The basal body temperature alone was unsatisfactory as a means of establishing a diagnosis of luteal phase defect or in evaluating therapy.

8 VoL.20,No.4,1969 CLOMIPHENE CITRATE The results of this study suggest that therapy with clomiphene citrate for one or two cycles has little benefit in luteal phase defect. However, therapy for multiple cycles (four or more) may have significant benefit. Indiana University Medical Center 1100 W. Michigan St. Indianapolis, Ind REFERENCES I. BoTELLA-LLUSIA, J. Endometrial biopsy in 2000 infertile women. Int ] Fertil 4: 300, BROWN, W. E., and BRADBURY, J. T. A study of the physiologic action of human chorionic hormone: The production of pseudopregnancy in women by chorionic hormone. Amer] Obstet Gynec 53:149, Foss, B. A., HoRNE, H. W., JR., and HERTIG, A. T. The endometrium and sterility. Fertil Steril 9:193, FRIED, P. H., and RAKOFF, A. E. The effects of chorionic gonadotropin and prolactin on the maintenance of corpus luteum function. ] Clin Endocr 12:321, GILLAM, J. S. Study of the inadequate secretion phase endometrium. Fertil Steril6:18, 1954., 6. Goss, D. A., and TAYMOR, M. L. Measurement of LH activity by latex-hcg agglutination inhibition. Endocrinology 74:321, HAMBLEN, E. C., and DAvis, C. D. Treatment of hypoovarianism by the sequential and cyclic administration of equine and chorionic gonadotropins-so-called one-two cyclic gonadotropic therapy: Summary of five-years' results. Amer ] Obstet Gynec 50:131, NovAK, E. R., and JONES, G. S. Novak's Textbook of Gynecology. Williams & Wilkins, Baltimore, 1965, p NoYES, R. W., HERTIG, A. T., and RocK, J. Dating the endometrial biopsy. Fertil Sterill:3, PALMER, A. Chorionic gonadotropin; its place in the treatment of infertility. Fertil Steril 8:220, ll. PALMER, R. La sterilite par insuffisance luteale et son traitement par la gonadotropin chorionique. Ann Ostet Ginec 75:951, RoY, S., GREENBLATT, R. B., MAHEsH, V. B., and JUNGCK, E. C. Clomiphene citrate: Further observations on its use in induction of ovulation in the human and on its mode of action. Fertil Steril14:515, SEGALOFF, A., STERNBERG, W. H., and GASKILL, C. J. Effects of luteotropic doses of chorionic gonadotropin in women. ] Clin Endocr 11:936, 1951.