Effect of Continuous Administration of Small Doses of Chlormadinone Acetate on the Cervical Mucus and Postcoital Test

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1 Effect of Continuous Administration of Small Doses of Chlormadinone Acetate on the Cervical Mucus and Postcoital Test YAIR GIBOR, M.D., MELVIN R. COHEN, M.D., and ANTONIO SCOMMEGNA, M.D. THE DEVELOPMENT of various hormonal contraceptives and their wide acceptance by women all over the world, while greatly contributing toward the solution of world overpopulation, has raised doubts in the minds of physicians and public health officials alike as to the long-range safety of these medications It is now apparent that oral ovulation-suppressants in the regimens currently used will alter many physiologic parameters besides affecting the hypothalamic-pituitary-ovarian axis It is therefore imperative that other forms or regimens be devised that would retain a high degree of effectiveness and acceptance, but would do away with the associated undesired effects on other physiologic systems. As far as hormonal contraception is concerned, it is now clear that ovulation suppression is not essential for prevention of pregnancy. Both Rudel and Martinez-Manautou 10 have recently reported that the continuous administration of a very low dose ( 0.5 mg.) of a potent progestogen, chlormadinone acetate (6-chloro-17-hydroxypregna-4,6-diene-acetate) can achieve adequate fertility control without consistent inhibition of ovulation. Alterations in the tubal, endometrial, or cervical physiology must be postulated to explain the remarkable effectiveness of such "minipills." Cervical mucus is one of the first barriers that spermatozoa have to cross in their journey within the female genital tract. Alteration in cervical mucus composition could affect the survival of the spermatozoa and effectively interfere with reproduction. It was the purpose of this study to investigate the physical properties of the cervical mucus and spermatozoa survival in patients taking 0.5 mg. of chlormadinone acetate daily, without interruption. From the Fertility Institute and the Section on Gynecic Endocrinology, Department of Obstetrics and Gynecology, Michael Reese Hospital and Medical Center, Chicago, Ill. 572

2 VoL. 20, No.4, 1969 PROGESTOGEN EFFECTS 573 MATERIAL AND METHODS In the present investigation, 10 patients complaining of infertility were utilized.* The effectiveness of the continuous daily administration of 0.5 mg. of chlormadinone acetate as a contraceptive technic was concurrently investigated in 100 fertile patients attending the ovulation control clinic for the past 18 months. This latter study will be the subject of a separate report. However, none of these women became pregnant while taking the drug. In the 10 infertility patients utilized for this study, repeated examinations of cervical mucus, as well as postcoital tests, were performed over a period of 2-8 cycles prior to treatment. The pertinent features investigated in these examinations were: the amount of mucus, the viscosity, the spinnbarkheit, the ferning reaction, and the presence of spermatozoa in the cervical mucus. The majority of the observations were concentrated in the period of maximal physiologic estrogenic activity (just prior to ovulation), and the remainder were performed during the po.stovulatory and early postmenstrual intervals. Data from these cycles were used as controls for the treatment cycles. A dry speculum was inserted to expose the cervix; then, by means of suction through a glass cannula with an attached Luer syringe, a quantity of mucus was obtained. When the mucus was too tenacious, a cotton swab was inserted into the endocervix. The mucus was then transferred onto a glass slide and the amount estimated and graded from 1 to 4. Then the mucus was stretched between the slide and a cover slip in order to estimate the viscosity according to 5 degrees: K, thick; MK, moderately thick; M, moderate; MT, moderately thin; and T, thin. The spinnbarkheit was measured in centimeters. The mucus was covered again with the cover slip and examined microscopically for the presence of spermatozoa. The cover slip was then removed to let the mucus dry for the ferning reaction. The same testing technics were employed during the treatment cycles. The treatment consisted of continuous administration of 0.5 mg. of chlormadinone acetate daily for about 45 days beginning on the first day after ovulation in one cycle until the first day of menstrual flow at the end of the next cycle. In 1 patient the treatment was continued in the following cycle also. RESULTS During 32 control cycles of the 10 patients, 238 samples were obtained and examined. During 11 treatment cycles in the same patients, 90 mucus *Patients with infertility received this treatment for a possible "rebound" effect on their fertility on discontinuation of the medication."'.. However, no such effect was noted.

3 574 GIBOR ET AL. FERTILITY & STERILITY samples were examined. The results of these examinations are shown in Table 1. In the treated cycles, only 6% of the ferning reactions were definitely positive, and no thin mucus was observed. Similarly, in only 1 sample ( 1% of the examinations) could the mucus be stretched up to 4 em., and there was no sample that could be stretched more than that. The postcoital tests were positive in only 9% of the examinations. The posttreatment results were statistically compared with the ones obtained prior to treatment and were found to be significantly different in all parameters (Table 1). In order to evaluate further the degree of hostility of the cervical mucus toward the spermatozoa, the following criteria were investigated: 1. The number of spermatozoa per high power field ( HPF) 2. The percentage of motile spermatozoa 3. The grade of motility, divided into 3 degrees as follows: minimal motility; slow to moderate movement without a straight, forward direction; and fast movement in a straight, forward direction 4. The time of survival of the spermatozoa in the cervical mucus since intercourse The results are shown in Table 2. In 11 examinations performed in control cycles, spermatozoa were found more than 34 hr. after intercourse and exhibited motility in 9 cases. In the treated cycles, examinations performed at the same time interval showed nonmotile spermatozoa in only 1 case. However, when these results were statistically analyzed, the differences in the parameters studied were not significant (Table 3). DISCUSSION Cervical mucus mirrors the physiologic hormonal changes occurring during the normal menstrual cycle. 3 la The pattern of these changes varies in different individuals and in different cycles of the same individual. These factors must be taken into account in evaluating the significance of the results of the present study. However, by comparing the cycles of the same patients before and after treatment, these variations can be minimized. Approximately the same percentage of examinations was performed in the control cycles and in the treated cycles ( 62% and 53% of the total examinations, respectively) during the period between Day 10 and Day 16. This is the time when maximal estrogenic activity can be detected by cervical mucus changes favoring spermatozoa survival. For better comparison of the before-treatment and treatment groups, the findings were divided according to the days of the cycles in which the examinations were performed, and were expressed in percentages of the

4 TABLE I. Mucus Studies in 10 Patients Treated with 0.5 mg. of Chlormadinone Acetate Daily Ferning Amount Viscosity Spinnbarkheit (em.) Post coitus Cycles ± K MK M MT T ± + Before treatment (32) No % During treatment (11) No % p < < < < < x2* d.f * Calculated from a 2 X n contingency table.

5 TABLE 2. Number and Motility of Spermatozoa in Postcoital Examinations Before and During Treatment Motility No. per HPF % Grade Hours ojter interrourse < >25 Total <20 > Total BEFORE TREATMENT ToTAL 41 (55%) 22 (30%) 11 (15%) (29%) 44 (71%) 14 (23%) 34 (55%) 14 (22%) 62 DURING TREATMENT ToTAL 4 (29%) 6 (42%) 4 (29%) 14 1 (13%) 7 (87%) 3 (37%) 1 (13%) 4 (50%) 8

6 VoL. 20, No.4, 1969 PROGESTOGEN EFFECTS 577 TABLE 3. Statistical Comparison of Results of Postcoital Tests and Cervical Mucus Studies in 10 Patients Before and During Administration of Chlormadinone Acetate Finding x2* d. f. p Positive postcoital tests <0.010 No. of spermatozoa/hpf N.S. Percent motility N.S. Grade of motility N.S. Longevity N.S. Ferning <0.001 Amount <0.001 Viscosity <0.001 Spinnbarkheit <0.001 * Calculated from a 2 X n contingency table. number of examinations in that day showing an estrogenic type of mucus (amount, 3-4+; viscosity, moderately thin to thin; spinnbarkheit, more than 3 em.; and positive fern reaction). These data (Fig. 1-4) demonstrate the most significant result of the treatment, a marked overall decrease in the estrogenic type of mucus according to all the criteria used. The decrease in the amount of mucus during the treated cycles was less prominent than other criteria that seemed to be more affected by the treatment. Many factors may affect the results of the postcoital examinations, 9 and these factors must be taken into account when evaluating the data obtained from such a study. However, the use of the.same marital pair before and during the treatment, together with proper instruction of the couple as to optimal technic and frequency of intercourse, tend to minimize the bias introduced by these factors. Of the 10 patients studied, 7 showed positive postcoital tests during the control cycles. Of these, only 4 showed the presence of spermatozoa in the cervical mucus during the treatment cycles. Eight of the 12 positive examinations from the treatment cycles were in the same patient. In 6 of these examinations the spermatozoa were highly concentrated, highly motile, and with a good drive. Two of these examinations were performed as long as 34 hr. after coitus. In one examination a patient showed occasional Grade 1 moving.spermatozoa after 10 hr. Another patient showed 50 spermatozoa per HPF with 50% Grade 1 motility after 34 hr. In a fourth patient, nonmotile spermatozoa were observed in 2 examinations, 10 and 58 hr., respectively, after intercourse. The maximal survival time of the spermatozoa in the control cycles was 92 hr., but only 34 hr. in the treatment cycles. Only 3 patients had actively

7 before treatment day of cycle l i 1. "0. :. -:;; i 25 ~ ~ ~ 50 durin& tnbtment 7 Fig. 1 (left). Amount of cervical mucus (3+ or more) before and during treatment: percentage of examinations each day of menstrual cycle. Fig. 2 (right). Feming reaction of cervical mucus (positive) before and during treatment: percentage of examinations each day of menstrual cycle. 100 before treatment day or cycle.. g i.. 'E = '; Fig. 3 (left). Viscosity of cervical mucus (moderately thin or thin) before and during treatment: percentage of examinations each day of menstrual cycle. Fig. 4 (right). Spinnbarkheit of cervical mucus ( 3 em. or more) before and during treatment: percentage of examinations each day of menstrual cycle.

8 VoL. 20, No. 4, 1969 PROGESTOGEN EFFECTS 579 motile spermatozoa during the treatment cycles, and only 1 had more than 20 spermatozoajhpf with more than 50% good motility. The present observations on the effect of chlormadinone acetate, 0.5 mg., on the cervical mucus and postcoital tests are in agreement with the results of other investigators who used other progestogens in similar studies Although the results of this study show a significant deterioration in the quality of the postcoital tests and an increased hostility of the cervical mucus to sperm penetration during the period of treatment, the remarkable effectiveness of the drug as a contraceptive cannot be explained by the cervical mucus changes alone. The concept that the antifertility mechanism of the continuous low-dosage progestogens technic is principally related to the changes in the cervical mucus is not supported by the findings of active spermatozoa in the cervical mucus of 3 of 10 patients treated. Whether these spermatozoa are indeed capable of fertilization is a moot point which could not be elucidated by the experimental design of this study. It seems plausible, however, to assume that while the cervical mucus changes observed could contribute to the contraceptive effectiveness of this regimen, the principal antifertility effect must lie elsewhere. SUMMARY Ten women of reproductive age who complained of infertility were treated with 0.5 mg. of chlormadinone acetate daily without interruption for 1 or 2 months. Cervical mucus and postcoital tests were performed over a period of 2-8 cycles prior to treatment and compared with similar tests performed during the administration of the drug. A marked decrease in the estrogenic pattern of the cervical mucus was seen during the treatment cycle. Similarly, a decreased number of positive postcoital tests was observed. However, active spermatozoa were present in 3 of the 10 patients studied. Moreover, when spermatozoa were present, their number, motility, or longevity did not differ significantly from the same parameters studied before the administration of the drug. These findings are interpreted to signify that while chlormadinone acetate administration might cause an increased hostility of the cervical mucus to sperm penetration and survival, the contraceptive effect of this drug cannot be explained by cervical mucus changes alone. Medical Research Institute Michael Reese Hospital Chicago, Ill REFERENCES 1. CoHEN, M. R. Cervical mucorrhea and spinnbarkeit in patients taking norethindrone plus mestranol (Norinyl 1 mg.). Fertil Sterill9:405, 1968.

9 580 GIBOR ET AL. FERTILITY & STERILITY 2. COHEN, M. R., and PEREZ-PELAEZ, M. The effect of norethindrone acetate-ethinyl estradiol, clomiphene citrate, and dydrogesterone on spinnbarkeit. Fertil Steril16: 141, CoHEN, M. R., STEIN, I. F., and KAYE, B. Spinnbarkeit: A characteristic of cervical mucus: Significance at ovulation time. Fertil Steril 3:201, Editorial. Oral contraceptives and thromboembolism. Brit Med ] 2:187, EISALO, A. Liver function tests during intake of contraceptive tablets in premenopausal women. Brit Med] 1:1416, GARCIA, C. R., and PINcus, G. Ovulation inhibition by progestin-estrogen combination. Int] Fertil 9:95, GoLD, J. J., SMITH, L., ScoMMEGNA, A., and BoRUSHEK, S. The efficacy of Provest in inhibiting ovulation. Int] Fertil 8:723, INMAN, W. H. W., and VESSEY, M. P. Investigation of deaths from pulmonary, coronary and cerebral thrombosis and embolism in women of child-bearing age. Brit Med] 2:193, MAcLEOD, J., and SoBRERO, A. "L'examen de Ia Claire Cervicale Post-coitale et Ia Qualite du Sperme." In Les Fonctions du Col Uterin. Masson, Paris, 1964, p MARTINEZ-MANAUTOU, J. "Hormonal Fertility Control Without Ovulation Suppression." In Fertility and Sterility, Proceedings of the Fifth World Congress. Westin, B., and Wigvist, N., Eds. Excerpta Medica, Amsterdam, 1967, p MARTINEZ-MANAUTOU, J., GINER-VELASQUEZ, J., CORTEZ-GALLEGUS, v., AzNAR, R., RoJAS, B., GuriTEREZ-NAJAR, A., and RuDEL, H. W. Daily progestogen for contraception evaluation in nursing mothers. Brit Med] 2:130, METCALF, M., and BEAVER, D. W. Plasma corticoid levels in women receiving oral contraceptive tablets. Lancet 2:1095, A. MEARS, E. "Clinical Application of Oral Contraceptives." In Agents Affecting Fertility, Austin, C. R., and Peny, J. S., Eds. Churchill, London, 1965, pp RAuscHER, H. "Repercussions du Cycle Ovarien sur le Col Uterin et Ia Secretion Cervicale." In Les Fonctions du Col Uterin. Masson, Paris, 1964, p RUDEL, H. W. "Hormonal Fertility Control-Newer Biological Consideration." In Fertility and Sterility, Proceedings of the Fifth World Congress. Westin, B., and Wiqvist, N., Eds. Excerpta Medica, Amsterdam, 1967, p SHEARMAN, R. P. Investigation and treatment of amenoithea developing after treatment with oral contraceptives. Lancet 1:325, VESSEY, M. P., and DoLL, R. Investigation of relation between use of oral contraceptives and thromboembolic disease. Brit Med J 2:199, 1968.