N orethindrone-mestranol as a Therapeutic Agent WILLIAM J. CAMERON, M.D., and JAMES C. WARREN, M.D., Ph.D. OVER THE LAST SEVERAL YEARS, intensive research has resulted in the availability of potent synthetic progestational agents which are effective when taken orally. One of these is norethindrone (17tx-ethinyl-19- nortestosterone). The ability of an appropriate combination of norethindrone and mestranol (ethinyl estradiol-3-methyl ether) to inhibit ovulation has been well demonstrated,3 giving rise to its primary use as an anovulatory agent. The drug is supplied in 2 forms; a mixture of 10 mg. of norethindrone with 60 JLg. of mestranol and a newer preparation of 2 mg. of norethindrone with 100 JLg. of mestranol. I'> For the purposes of this report, these will be referred to as N/M 10/60 and 2/100. Because the literature contains no reference to the use of this medication as a therapeutic agent, evaluation of the drug in this role has been carried out. This communication reports on the ability of the drug to: stop estrogen breakthrough bleeding in women with persistent anovulation, promote adequate progestational withdrawal bleeding, provide estrogen in deficiency syndromes, and treat other conditions associated with abnormal hormone production. MATERIALS AND METHODS The clinical material consisted of patients seen in the gynecologicendocrine clinic at the University of Kansas Medical Center. These subjects were divided into 3 general groups. The first was composed of those patients who are anovulatory, presumably on a hypothalamic or central nervous system basis, and whose chief complaint was related to amenorrhea or abnormal uterine bleeding. A patient whose interval between menses was long enough to cause her to From the Department of Obstetrics and Gynecology, University of Kansas School of Medicine, Kansas City, Kan. *Supplied by Ortho Pharmaceutical Corporation, Raritan, N. J., as Ortho-Novum, 10 mg. and 2 mg. 85
86 CAMERON & WARREN FERTILITY & STERILITY seek medical advice is assessed as having a chief complaint of amenorrhea. The patient with functional uterine bleeding (FUB) has irregular, patternless vaginal bleeding frequently consisting of alternate Hooding and spotting. The drug was used in the first group to stop estrogen-type bleeding during the drug's administration and to effect a progestational withdrawal episode after its discontinuance. The second group of patients had a chief complaint of primary or secondary amenorrhea due to some underlying pathology. The drug in these patients was used to elicit withdrawal bleeding and to provide an exogenous source of estrogen. The third group of patients had miscellaneous conditions which defied precise classification. The N 1M was given in variable doses in an attempt to detect any decided advantage of one over the other. The dosage schedule was varied-some patients receiving all of their tablets at once, others daily over short periods of time, and others being cycled in the classic 20-day manner. Careful records of bleeding were kept on all patients. Anovulation Group RESULTS Forty-nine patients with complaints related to anovulation were treated (Table 1). In all but 3 the response was classified as excellent, e.g., functional uterine bleeding was halted while the subject was on the agent and cessation of therapy resulted in normal, limited withdrawal bleeding. In 1 patient the result was equivocal; although uterine bleeding ceased while she was on the drug, the withdrawal bleeding episode was unsatisfactory in that it lasted 2 weeks. Two patients had pooi' results, one having unsatisfactory withdrawal periods with severe nausea. The other, whose primary complaint was regular, heavy menstrual periods, failed to note a decrease in How after a single premenstrual administration of the drug. It is problematical whether this patient was really anovulatory. In summary, the drug produced excellent results in 94% of the patients treated. Uniformly excellent results, i.e., withdrawal bleeding, were noted in those with anovulatory amenorrhea. The experience gained by the authors during this study also dictated a general theorem as to the selection of which tablet to use in this group of patients (see Discussion). Amenorrhea Group Twenty-six patients with amenorrhea secondary to factors other than anovulation alone were classified in this group (Table 2). Eighteen showed
TABLE 1. Results of Treatment of 49 Patients with Probable Hypothalamic Anovulation Results Chief NQ.of Contributing No. of Dose of No. of Borderline complaint pts. factor pts. N/M* Schedule pts. Successt Failure::: success Functional 20 Obesity 4 10/60 5 as single monthly dose 5 uterine Menarchal 6 10/60 As daily dose, 2-5 days 8 18 1 (With- 1 (FUB bleeding II monthly drawal stopped, period, 12 withdrawal Other or 10/60 Cycles 1 1 days severe bleeding 14 unknown 10 2/100 Cycles 6 nausea days duration) Amenorrhea" " 28 Menarchal 3 10/60 5 as single monthly dose 14 28 Postpartum 10/60 As daily dose, 2-5 days 11 (2-6 mo.) 10 monthly 10/60 Cycles 1 Obesity 3 2/100 Cycles 1 Other or unknown 12 2/100 Daily X 14 days 1 Hypermenorrhea How) 1 Unknown 1 10/60 5 single dose, 1 1 (No depremenstrually crease in *Norethindrone (mg.) per mestranol (/Lg.). tcessation of bleeding while on medication; "normal period after withdrawal. :::Complete failure to stop abnormal bleeding, or inability to produce normal withdrawal bleeding or desired results. Specified in table. IIUsually estrogen withdrawal or breakthrough. 'ltdaily medication, days 5-24. **Defined as any interval between menstruation significantly longer than normal, and of at least 2 mo. duration.
TABLE 2. Results of Treatment of Patients with Amenorrhea Secondary to Other FactorsO Results Contributing No. of Dose No. of factor pts. N/Mt Schedule pts. Success Borderline success Failure Pregnancy suspected 7 10/60 5 as single dose 5 7 10/60 2 daily X 3 days 2 Confirmed, no withdrawal bleeding End-organ failure or 4 10/60 5 as single dose 1 1 (2 days spot- 3 (Severe nausea Asherman's syndrome ting after 1 dose) forced discontinuance of Rx) 10/60 Cyclest 1 2/100 Cycles 3 Stein-Leventhal 2 10/60 Cycles 1 1 1 2/100 Cycles 1 Libido increased Scanty menses Turner's syndrome 3 2/100 Cycles 3 3 Breast development Anorexia nervosa 2 10/60.5 as single dose 1 1 1 2/100 Cycles 1 Primary FSH 2 deficiency 2 2/100 Cycles 2 Breast development
Exogenous estrogen bleeding with each dosage) 1 10/60 5, 4, 3, 2, each given 1 1 as single monthly dose (Withdrawal Pseudocyesis 1 10/60 5 single dose 1 1 1 2/100 1 daily X 6 wk. 1 Colostrum regressed Ovarian failure 1 10/60 1 daily X 2 days 1 1 Spotted only Unknown: possible 1 daily X 40 days then 1 Chiari-Frommel 1 2/100 1 daily X 20 days 1 (Spotted after first cycle, good flow after second. colostrum increased) TOTAL 26 28t 17 4 6 *Number of patients under schedule and results total more than 26 because some were tried on more than 1 schedule. tnorethindrone (mg.) per mestranol (}Lg.). :l:daily medication on days 5-24. Other: 1 Severe metabolic disease 1 10/60 5 as single dose 1 Adrenal hyperplasia 1 10/60 Cycles 1 1 Breast development
90 CAMERON & WARREN FERTILITY & STERILITY satisfactory results. In 7 of these, pregnancy was suspected, and the drug failed to produce withdrawal bleeding. The pregnancies were all subsequently confirmed. Because of the reports! 2 of masculinization of the female fetus after administration of synthetic progestational agents, the drug was not given in extended periods or in high dosages to pregnant women. Nevertheless, in these cases, the newborn infants were examined and none of the females demonstrated masculinization. The result with the patient having pseudocyesis was judged satisfactory although 5 tablets of the 10/60 did fail to produce withdrawal bleeding when given as a single dose. When the 2/100 tablet was given daily for 6 weeks, there was satisfactory withdrawal bleeding and colostrum definitely decreased during the period of administration. Administration in 20 day cycles to patients with Turner's syndrome caused the development of a responsive endometrium, satisfactory menstrual periods, and adequate breast development. Three patients had equivocal results. One, with the Stein-Leventhal syndrome, had very scanty menses regardless of the agent or the dosage schedule used. The result in another, with Asherman's syndrome, was judged equivocal because she had 2 days of vaginal spotting after a single dose of B~ tablets of the 2/100 mixture. This response was probably circumstantial. Severe nausea forced discontinuation after 1 dose. The patient with amenorrhea of 12 months' duration (associated with release of colostrum and low urinary gonadotropins) was classified as a Chiari-Frommel syndrome. She was judged to have an equivocal response. After the first cycle she only spotted, but had good flow after the second cycle. She did, however, note an increase in colostrum while she was on the medication. Five patients had unsatisfactory responses. One had a primary end-organ failure which did not respond to any of the progestational agents given and, while it is thought that she too had Asherman's syndrome, she has refused other therapy and a definitive diagnosis can not be made. Another, with anorexia nervosa, failed to respond to 5 tablets in a single dose. While this is listed as a failure, it is certainly what one would expect in a patient with an atrophic endometrium because the amount of estrogen in the dosage given is not sufficient to "prime" the endometrium. Two others, with endorgan failure or Asherman's syndrome, responded only with spotting after administration of the drug. In one case the dosage may have been inadequate, but the other failed to respond with bleeding despite a high and prolonged dosage. The patient with ovarian failure, presumed secondary to pelvic inflammatory disease, probably received inadequate dosage. In summary, one can say that in this groulj withdrawal bleeding usually occurred when it could be anticipated. Side effects included breast development in 4 patients with estrogenic or gonadotropin deficiencies which,
VOL. 16, No.1, 1965 NORETHINDRONE-MESTRANOL THERAPY 91 of course, was welcomed by all. One patient noticed increased libido and another, nausea too severe to tolerate continuing the drug, while 1 patient complained of slight nausea but was able to continue the regimen. Ruling out the patients with suspected pregnancy and Asherman's syndrome, one is left primarily with a group of patients with amenorrhea secondary to deficient estrogen production. In these instances, the effects were generally satisfactory with increasing breast development and appearance of menses. Group with Varied Symptoms In the third group of 20 patients with varied symptomatology and pathology (Table 3), one might expect to obtain equivocal results in a high percentage of cases. In those patients whose symptoms were thought to be associated with ovulation, inhibition of same produced fairly satisfactory results (see Cases 3, 5, 9, 10, 17, and 19). Most of these patients had 50-75% subjective relief from primary dysmenorrhea. On the other hand, Case 8, who was diagnosed as having bleeding at ovulation, failed to cease this midcycle event with the dosage schedule recorded. While it is possible that cycling this patient over a 20-day period might have halted her bleeding at time of ovulation, we did not wish to inhibit ovulation because of her desire for pregnancy. Case 13 had pain and tenderness of the left ovary and failed to achieve relief from dysmenorrhea despite complete inhibition of ovulation for 2 months. The same result occurred in Case 15 who had a surgically proven corpus luteum cyst of the left ovary. Her dysmenorrhea vanished after surgery. The 2 patients with endometriosis, Cases 1 and 19, received 50-75% relief on cyclic medication without creating pseudopregnancy. The 2 patients with menopausal symptoms, Cases 6 and 16, experienced partial abatement of their symptoms, but the drug was not as effective as diethylstilbestrol for this condition. It is interesting to note that the urinary gonadotropin level in Case 16 decreased from greater than 96 to less than 6 M.U.j24 hr. after medication was started. Despite this fact, only partial relief from her symptoms was obtained. These data would suggest that the symptomatology was not all secondary to estrogen deficiency. Case 4, with "implantation bleeding," stopped spotting after 10 days on the medication, but no definite credit for this can be given to the drug as the result could have been circumstantial. The patient with psoriasis, who had noticed improvement of her disease during pregnancy, failed to improve with therapeutic pseudopregnancy. Case 18 with untreated, incomplete adrenal hyperplasia had a very light episode of withdrawal bleeding following 5 tablets given as a single dose. She is currently on corticoids and has resumed normal periods. Case 20,
TABLE 3. Results in Patients with Other Conditions Treated with Ortho-Novum Dose schedule Dose of No. tablets Chief complaint Diagnosis of contributing factor N/M per day Duration Results 1. trol) sued after therapy stopped) Dysmenorrhea Endometriosis 2/100 1 2mo. About 50% relief 2. Premenstrual pelvic Corpus luteum hemorrhage (?) 2/100 1 2 mo. No relief pain 3. Midcycle pain Ovulatory pain 10/60 P 4 mo. Complete relief 4. First trimester spotting "Implantation bleeding" 10/60 1 10 days Spotting ceased 5. Dysmenorrhea 2/100 P 2 mo. About 90% relief 6. Menopausal symptoms Surgical castration 2/100 1 2wk. Partial relief (not as 2 1 wk. effective as stilbestrol) 7. Irregular bleeding Threatened abortion 10/60 5 single dose Aborted 8. Mid-cycle spotting Ovulatory bleeding 10/60 1 7 dayst Spotting persisted 9. Premenstrual tension Ovulatory periods 2/100 1 3 mo. Partial relief 10. Primary dysmenorrhea Precocious puberty with menses 2/100 P 3 mo. About 75% relief since age 4 (6 yr.) (lactation occurred) 11. Infertility Stein-Leventhal syndrome 10/60 P 3 mo. Menses were regular (no pregnancy ensued
12. level decreased from >96 to <6 M.U./24 hr.) Dysmenorrhea Anovulation produced by 10/60 5 single dose Good withdrawal stilbestrol 3 single dose bleeding (dysmenorrhea 13. Dysmenorrhea Pain and tenderness, 1. ovary 10/60 I" 2 mo. improved) No relief 14. Psoriasis Improvement noted during 2/100 Pseudo- 2mo. No improvement in pregnancy pregnancy psoriasis 15. Dysmenorrhea Corpus luteum cyst, 1. ovary 2/100 1 2 mo. No relief 16. Menopausal symptoms Surgical 2/100 1 1 mo. Partial abatement of 2 2mo. symptoms (FSH 17. Pelvic pain Ovulatory pain 10/60 5 single doset Relief of pain 18. Irregular periods Adrenal hyperplasia 10/60 5 single dose Very light period 19. Dysmenorrhea Possible endometriosis 10/60 I" 1 mo. About 75% relief 20. Acne vulgaris Exacerbation during luteal 2/100 1 3mo. Marked improvephase of cycle ment of acne *In 20-day cycles. tat midcycle. :j:preovulatory.
94 CAMERON & WARREN FERTILITY & STERILITY who in the past had noted exacerbation of severe acne vulgaris during the luteal phase of her cycles, experienced marked improvement of acne while ovulation was inhibited. DISCUSSION The compound used, essentially a mixture of a progestational and an estrogenic agent, would be expected to be efficacious in certain syndromes where either of the compounds might be singly indicated. Indications for the uses of sex hormones have been previously listed by one of us. 4 In that paper, it was stated that the most important single use of the progestational agents is in the control of anovulatory menorrhagia. This is the genera] category comprised by the patients in Group 1. In the anovulatory female, regardless of what the primary etiology of anovulation may be, and provided that sufficient estrogen is present, the administration of 5 of the 10/60 tablets as a single dose should produce withdrawal bleeding. This regimen will control menstrual bleeding without necessarily inducing ovulation. Nevertheless, it does allow one to control abnormal bleeding until the primary situation is corrected. It is our experience that the premenopausal females solve their own problem as the production of estrogen stops, and the postpartum patients usually improve spontaneously if allowed the time to do so. The obese will frequently return to ovulatory cycles if they lose weight. The problems occurring at menarche usually improve with advancing age. In all these situations, Ortho-Novum has been, in our hands, a satisfactory way to control menstrual periods. We think one should administer 5 10-mg. tablets rather than cycling the patient, particularly if one awaits a sign of improvement. With the cyclic administration of the 2/100 tablet, gonadotropin release would be almost contin\lously suppressed. The advantage of the use of the lo-mg. tablet, given as 5 tablets in a single dose taken on the first day of each month or at some other convenient date, is that the pituitary functions on its own most of the time. Should ovulation occur, it can be detected by a normal, limited menstrual period which occurs at a time other than that expected following the administration of the drug. In that rare group of patients who have episodes of estrogen breakthrough or withdrawal bleeding before the time for the administration of the single dose, cyclic therapy can be used. The use of any progestational agent in a dosage adequate to produce withdrawal bleeding is satisfactory as a diagnostic test for pregnancy. Administration of the lo-mg. tablet was undertaken several times in this study and in all instances, the pregnancies were confirmed. We can surmise that it is efficacious as a pregnancy test since, from the experiences
VOL. 16, No.1, 1965 NORETHINDRONE-MESTRANOL THERAPY 95 delineated in Table 1, progesterone withdrawal bleeding should have occurred at this dosage. The infants of the mothers treated in this manner were not ~bnormal at time of birth. There are two primary indications for the administration of estrogen. The first of these is an estrogen deficiency and the second is to inhibit ovulation. The patients in our Group 2 were women to whom the drug was given primarily as an estrogen source, either to differentiate between endorgan failure and pituitary or hypothalamic amenorrhea, or to provide estrogen to patients who had a clearcut deficiency. In these deficiency states, only replacement therapy can be utilized. These patients were given the 2-mg. tablet because it contains an extra 40 /Lg. of estrogen. The results have been generally good with the satisfactory development of secondary sexual characteristics, particularly breast size. The other primary indication for estrogen administration has been to inhibit ovulation. We have used the drug in several cases of primary dysmenorrhea with variable relief, although the majority of the patients reported subjectively evaluated improvement of 50-75%. The third group of patients consists of a heterogeneous group and it is difficult to draw any firm conclusions. SUMMARY 1. The combination of norethindrone and mestranol is an effective, useful, safe, well-tolerated therapeutic agent. 2. It is most effective in the treatment of hypothalamic anovulation, achieving satisfactory results in 94% of those with this condition. Optimum dosage is 5 of the 10-mg. tablets given as a single dose. 3. It is also effective in producing a menstrual period in a patient with primary or secondary amenorrhea due to other pathology. In all cases save one where withdrawal bleeding could be expected on the basis of a responsive uterus, withdrawal bleeding did occur. 4. If symptoms are due to ovulation, they are often relieved by inhibition which routinely occurred when the drug is used in cyclic fashion on days 5-24 of each cycle. 5. Satisfactory results were obtained in patients with estrogen-deficiency states and good development of secondary sex characteristics was observed. 6. The drug deserves consideration as a therapeutic agent. Department of Obstetrics and Gynecology University of Kansas Medical Center Rainbow Blvd. at 39th St. Kansas City 3, Kans.
915 CAMERON & WARREN FERTILITY & STERILITY REFERENCES 1. GRUMBACH, M. M., and DUCHARME, J. R. The effects of androgens on fetal sexual development. Fertil. and Steril. 11:157, 1960. 2. JONES, H. W., and WILKINS, L. The genital anomaly associated with prenatal exposure to progestogens. Fertil. and Steril. 11:148, 1960. 3. TYLER, E. T., OLSON, H. J., WOLF, L., FINKELSTEIN, S., THAYER, J., KAPLAN, N., LEVIN, M., and WEINTRAUB, J. An oral contraceptive. Obst. and Gynec. 18:363, 1961. 4. WARREN, J. c., and CHEATUM, S. G. "Endocrine Therapy." In Gynecology Obstetrics Guide, Ed. by Holly, R. G., and Woolf, R. B. Commerce Clearing House, Inc., Chicago, 1963, pp. 1701-1721.