ALL PRACTITIONERS studying the ~auses

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1 Oral Terramycin Therapy of Chronic Endocervicitis in Infertile Women Herbert W. Horne, Jr., M.D.,* and John Rock, M.D. t ALL PRACTITIONERS studying the ~auses of infertility encounter many cases where no evident pathology exists in either husband or wife, except that sperm penetration into the cervical mucus at ovulation time is either unaccountably poor or absent, as shown by Huhner's test. Clinically, no obvious cause for this may be encountered grossly, yet many times the endocervix, even at ovulation time, contains semipurulent or truly purulent mucus. Deep cauterization or careful conization has been the time-honored method of treatment. Matthews and Buxton studied the bacteriologic components of these endocervices in an effort to determine any spermicidal effect of the bacteria or their toxins. Their treatment consisted in injection of the cervix with dilute solutions of an antibiotic chosen on the basis of in vitro sensitivity of the flora. Varying degrees of success followed. Seeking the same objective by a different method we administered high oral doses of terramycin in an attempt to establish an intracervical concentration of an antibiotic sufficient to clear the endocervical glands and canal of bacteria which might be lethal to sperm. Due to the numerous side effects, the later patients in the study also received gentian violet tablets orally in order to minimize fungus growth in the intestinal tract. From the Fertility and Endocrine Clinic, Free Hospital for Women, Brookline, Massachusetts. The authors are deeply indebted to Charles Pfizer & Company, Inc. for making this clinical study possible by financial assistance and generous supplies of terramycin. *Assistant in Gynecology, Harvard Medical School; Research Fellow, Free Hospital for Women. t Clinical Professor of Gynecology, Harvard Medical School; Visiting Surgeon, Free Hospital for Women. 321

2 322 HORNE & ROCK [Fertility & Sterility MATERIAL AND METHODS Fifty-six patients of long-standing infertility, whose husbands' semen was normal except as noted in the tables to follow, were treated in the Fertility and Endocrine Clinic With 250 mg. capsules of terramycin by mouth. Medication was given at six-hour intervals on the sixth, fifth, and fourth days before expected ovulation time, as suggested by prior temperature charts. Dosage varied from 3 Gm. daily ( 3 capsules every 6 hr.) to 6 Gm. daily ( 6 capsules every 6 hr.) taken with milk, and, as previously mentioned, in the later cases with 30 mg. of gentian violet by mouth. Usually, medication was given in one menstrual cycle only. Eleven patients received 3 Gm. daily in a given cycle, followed one or more cycles later by the 6-Gm. dosage. Two patients received the 6-Gm. dosage in two widely separated cycles. We evaluated the therapy mainly by counting the number of conceptions though an attempt was made to compare Huhner tests before and after treatment. No pregnancy was regarded as influenced by therapy if conception occurred more than three months after the last course of treatment. RESULTS Thirteen patients received 3 Gm. of terramycin daily for the specified three days (Table 1). No pregnancies ensued that could be attributed to therapy. However, 4 patients became pregnant, 2 of them following intervening tubal lavage with penicillin-locke solution. In 1 of the latter, the Huhner test was markedly improved after terramycin treatment. Complications during and after therapy were mild, consisting mainly of brief moderate diarrhea, nausea, or both. Eleven patients received 3 Gm. daily during one cycle followed after an interval of one or more cycles by treatment with 6 Gm. daily. Thirtytwo other patients received only the 6 Gm. dose daily in a single cycle and 2 of these had the therapeutic regimen repeated some months later (Table 2, Nos. 2 and 22). Among these patients (Table 2) who received the 6 Gm. dosage routine, 10 became pregnant within three months after treatment. One of these (No.7) had a diodrast tubogram performed during the same cycle in which terramycin was used; another (No. 1) had tubal lavage during the cycle after treatment. Three of these 10 patients showed moderate to marked improvement in the Huhner test (Nos. 1, 2, and 5).

3 Vol. 3, No. 4, 1952] TERRAMYCIN FOR ENDOCERVICITIS 323 TABLE 1. Data on 13 Infertile Women Treated with 3 Gm. of Terramycin by Mouth Daily for 3 Days 8 years p years s 0 42 years old. 3 6 years p 4 3 years p years p years s year p years s years s 9 months 0 Lavage Culdoscopy neg. HS greatly improved after treatment months s 2 months 2+ Repeated abortion. Preg. not due to treatment years p 9 months 0 Lavage 12 1 year s years p 4 months 1+ Number of patients treated 13 Pregnancies attributable to treatment 0 HS = Huhner-Sims test. Three others volunteered that their constant longstanding leukorrhea had disappeared (Nos. 6, 7, and 9). Complications were moderately severe to severe in 14 patients, consisting of diarrhea, nausea and vomiting, and vulvitis. Some symptoms lasted as long as two to three weeks, but finally subsided completely. Patients taking gentian violet with each dose of terramycin seem to have had fewer complications.

4 324 HORNE & ROCK [Fertility & Sterility TABLE 2. Data on 43 Infertile Women Who Received 6 Gm. of Terramycin by Mouth Daily for 3 Days 1 3 years p 3 months 4+ Lavage Marked improvementinhs.aborted at 9 wk. Preg. again years p 3 months 4+ Mod. improvement in HS. Only 46 capsules in 2 days second series. 3 4 years p Same month 4+ Eclampsia. Pregnant again. 4 2 years p Same month years p Same month 0 Moderately improvedhs.aborted. Pregnant again. 6 2 years s Same month 4+ 0 Discharge disappeared. Delivered Sept. ' years p Same month 3+ Vulvitis after Tubo- Discharge disaptreatment. gram peared. Delivered same Sept. '51. month. 8* 372 years p Same month 2+ Delivered January * 5 years p 1 month 2+ Discharge disappeared. 10* 3 years s 2 months 2+ Had had ovarian resection years p years p years s years p years p 2+

5 Vol. 3, No. 4, 1952] TERRAMYCIN FOR ENDOCERVICITIS 325 TABLE 2. (Continued) years s years p years p years p years p years s years s years p years p 0 Culdoscopy years p years p years s years p years s years s 2+ 31* 872 years p 0 32* 5 years s 4+ 33* 72 year s 2+ 34* 13 years p 0 35* 3 years p 0 Had had deep cauterization of cervix years p 4+ Had small Ca ovary years p 0 Husband away. Army years s 0 Oligospermia years s 2+ Clumping of sperm.

6 326 HORNE & ROC.K [Fertility & Sterility TABLE 2. (Continued) 40 5 years p 0 Mter Stein-Leventhai operation. 41* 4 years p 0 Had tuboplasty. Tubes closed after. 42* 5 years p 0 Has had tuboplasty 43* 2 years s 0 Had had ectopic. Ca of cervix in situ with hysterectomy. *Received, in a previous cycle, 3 Gm./day. HS = Huhner-Sims postcoital examination of cervical mucus. DISCUSSION It is acknowledged that the Huhner test is a fallible method of evaluating the degree of spermigration, for variations may be great in a single individual, even during her supposed ovulation phases. However, inlproved Huhner tests after treatment in some cases and the ensuing pregnancies, to say nothing of the objective absence of a longstanding leukorrhea in some patients, suggests that spermigration was improved. Since all patients had been under study in the clinic for several months (many for years) because of infertility averaging 4.5 years, the number of pregnancies within three months of therapy is greater than would be expected among such a group. No pregnancies that could be attributed to therapy followed the course of 3 Gm. daily. Ten pregnancies followed the 6 Gm. routine. It would seem, therefore, that further clinical studies should be in this dosage range. Although evaluation of a possible metabolic stimulating factor, known to be a characteristic of terramycin in small doses in animals, has not been considered in this study, the brief duration of treatment tends to minimize this factor. Qur results suggest that the value of terramycin is due to its wide antibacterial properties. If 8 cases, in which there were known abnormal factors other than suspected endocervicitis ( Nos ), are eliminated from the group of 43

7 Vol. 3, No.4, 1952] TABLE 3. TERRAMYCIN FOR ENDOCERVICITIS Summary of Results of Treatment with 6 Gm. of Terramycin by Mouth Daily for 3 Days 327 Number of patients treated Primary sterility 29 Secondary sterility (1+ Number of complications J l4+ Total 0 patients ( 0%) 6 patients (12%) 2 patients ( 4%) 7 patients (14%) 15 patients (34%) Number of patients with no known abnormal factor except endocervicitis of some degree Primary sterility 24 Secondary sterility Average yrs. infertility in these 35 cases Primary sterility 4.5 Secondary sterility yrs. Number of pregnancies attributed to therapy Primary sterility 8 Secondary sterility 2 10 Average yrs. infertility in these 10 cases Primary sterility 3.5 Secondary sterility yrs. Pregnancies attributed to therapy 28% patients, the percentage of pregnancies rises to 28% ( 10 pregnancies among 35 patients), a figure higher than the expectation of chance. SUMMARY It seems reasonable to consider that terramycin, given orally in 6-Gm. dosage for three days just before ovulation, improves the chance of conception when the only recognized abnormality is poor or absent spermigration in women whose husbands' semen is normal. REFERENCE I. Matthews, C. S., and Buxton, C. L.: Fertil. & Steril. 2:45, 1951.