Upsala J Med Sci 78: 189-190, 1973 Effect of Norhydroxyprogesterone Caproate on Cervical Sperm penetration and Secretion of Ovarian Steroids in the Human Female LARS CARLBORG From the Department of Obstetrics and Gynecology (Head: Prof. Carl Gernzell), University Hospital, Uppsala, Sweden ABSTRACT Compound SH 8.0582 (19-norhydroxyprogesterone 1701- caproate) is a dep8t gestagen which in experiments o n laboratory animals seemed to have a slightly higher inhibi- tory affinity for peripheral reproductive organs than for gonadotropin. In this study it was injected on day 5 of the menstrual cycle in healthy young subjects. The action was recorded by daily quantitative determination of sperm Penetration in the cervical mncus. The influence on ovarian function was estimated by determination of uri- nary total oestrogens and urinary pregnanediol or plasma progesterone. Doses of 5 mg or more tended to prolong the cycle length, prevented cervical sperm penelration and decreased ovarian steroid secretion. Lower doses did not consistently influence any of these parameters. There was no certain specificity for the cervix. INTRODUCTION Compound SH 8.0582 (19-norhydroxyprogesterone 17a caproate) was synthesized by Schering AG, Berlin. In routine bioassays on laboratory animals it was found to possess a strong gestagenic action on perip!ieral reproductive organs and a mild sup- pressive action on pituitary gonadotropins. I t was also found that the compound, when given intra- muscularly in oil, had a more prolonged action than had progesterone or most synthetic deri- vatives of progesterone. The effect was estimated to last for about 14 days (unpublished data, Scher- ing AG, Berlin). I n the human, a single dose of 200 to 500 mg caused no changes in liver function or carbohydrate metabolism. To elicit a signifi- cant biological response in the endometrium, doses below 50 mg were sufficient ( 5 ) . In post-meno- pausal women 40 to 200 mg reduced the gonado- tropin output. Therefore it was of interest to determine whether the compound would have a high af- finity for the peripheral reproductive organs (inter- ference with cervical sperm penetration) without disturbing the ovarian function (estimated by de- termination of oestrogens and progesterone in the human female). If this were the case the drug could possibly be used as a novel contraceptive injected early in the menstrual cycle. MATERIALS AND METHODS Regularly menstruating women between 20 and 30 years of age were chosen as test subjects. They had not used any hormonal contraceptives for at least 3 cycles before the experiments. The compound was given in oil in a single intramuscular injection on day 5 of the cycle at doses ranging from 2.5 to 20 mg. Daily samples of cervical mucus were taken and tested for quantitative sperm penetration in vitro (2). T h e daily basal body temperature was recorded in all cycles. The total urinary oestrogen excretion was measured on days 12 to 18 (1). The occurrence of ovulation was esti- mated either by determination of urinary pregnanediol ex- cretion ( 3 ) o n days 10 and 22, o r by the determination of plasma progesterone concentration on days 9, 13, 17 and 23 (4). RESULTS 20 rng ( 2 subjects): Bleeding was delayed by 17 days and an immediate thermogenic effect lasted for about 2 weeks. All hormone determinations were low. Sperm penetration tests were negative or became positive after 19 days. 10 mg ( 2 subjects): Bleeding was postponed by 5 days. With regard to temperature, sperm pene- tration, and hormone determinations, the data were similar to those obtained after the 20 mg dose. 5 rng (5 subjects): In one cycle, bleeding was delayed by 20 days but otherwise the cycle length was unaffected. Ovulation probably occurred in the remaining 4 cycles. No sperm penetration was found in 3 subjects and the last subject with unim- paired cervical function conceived and delivered a healty infant in due course. Upsala J M e d Sci 78 190 L. Carlborg 3 mg ( 4 subjects): In this group all subjects had an untreated control cycle before the test period, and the determination of sperm penetration, uri- nary oestrogens, and plasma progesterone were within the normal range. Administration of the compound did not affect the length of the cycle and no major hormonal changes were detected. Only in 2 subjects was there a marked inter- ference with sperm penetration. One subject with a positive sperm penetration conceived and deliv- ered a healthy infant in due course, 2.5 mg ( 4 subjects): There was no interferance with cycle length and all cycles appeared to be ovulatory. However, in 3 cycles there was no sperm penetration. DISCUSSION Gestagens injected early in the menstrual cycle have been tried as a means of contraception (6, 7). The treatment generally resulted in amenor- roea for 3 to 5 months. I t is possible that the postponed bleeding could have been preceded by an ovulation-a situation which would reduce the reliability of the contraceptive method. The pres- ent study was undertaken to determine whether a long-acting gestagen (SH S.OSS2) given early in the cycle would act as a contraceptive without impairing menstruation. The limited data show that doses as low as 5 mg did postpone the ex- pected bleeding. After an interval of up to 2 weeks when a thermogenic action of the compound was manifest a positive cervical sperm penetration could bz demonstrated. Ovulation might possibly have occurred after the schedded investigational intervals. The inter- est was thus focused on doses less than 5 mg. The data revealed that there was no consistent influ- ence on cycle length, ovarian estrogen and pro- gesterone production or inhibition of sperm pcne- t r a t i x iil the cervical mucus. The inability to act as a contraceptive a t these doses was evidenced by two conceptions. To prevent sperm penetration, higher doses were needed but with thc increased risk of disturbance of a menstrual rhythm. It was shown that the lowest doses needed to interfere with cervical sperm penetration were also liable to postpone uterine bleeding and to interfere with ovarian steroid production. The mechanism for the latter phenomenon was beyond the scope of the study. Upsala J M e d Sci 78 ACKNOWLEDGEMENTS The author is indebted to Schering AG, Berlin, Germany from which company generous financial support was received, to Professor Carl Gemzell for reviewing the manuscript, to Docent E. D. B. Johansson for determina- tion of plasma progesterone and to Miss Ulla Geifalk for skilled technical assistance. REFERENCES 1. Brown, J. B., Macleod, S. S . , Macnaughtan, C., Smith, M. A. & Smyth, B.: A rapid method for estimating oestrogens in urine using a semiautomatic extractor. J Endocr 42: 5, 1968. 2. Carlborg, L.: Determination of sperm migration rate in small samples of cervical mucus. Acta Endocr (Kbh) 62: 132, 1969. 3. Cox, R. I.: Gas chromatography in the analysis of urinary pregnanediol. J Chromatogr 12: 242, 1963. 4. Johansson, E. D. B.: Progesterone lev& in peripheral plasma during the luteal phase of the normal human menstrual cycle mzasured by a rapid competitive protein binding technique. Acta Endocr (Kbh) 61: 592, 1969. 5. Nevinny-Stickel, J.: Die unterschiedliche morphologische Wirkung verschiedener synthetischer Gestagenz auf das Endometrium. Neuntes Symp. d. Dtsch. Ges. f . Endo- krin. Wiesbaden u. Mainz 3.-5.5. 1962, 177. 6. Tyler, T. E., Levin, M., Elliot, J . & Dolman, H.: Present status of injectable contraceptives: Result of seven years study, Fertil Steril 21: 469, 1970. 7. Zanartu, J., Pupkin, M., Rosenberg, D., Davansens, A , , Guerrero, R., Rodriquez-Bravo, R . & Garcia- Huidobro, M.: Long term effects of medroxy pro- gesterone acetate in human ovarian morphophysiology and sperm transport. Fertil Steril 21: 525, 1970. Received March 2, 1973 Address for reprints: Lars Carlborg, M.D. Kliniken for gynekologisk radioterapi Akademiska sjukhuset S-750 14 Uppsala 14 Sweden