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The Antiovulatory Dose of Ethinyl Estradiol
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The Antiovulatory Dose of Ethinyl Estradiol A Titration Study J. L. JACKSON III, M.D., W. T. SPAIN, M.D., and H. PAYNE, B.S.
have reported on the oral use of estrogenic agents alone to inhibit ovulation. 3 - 5 Greenblatt first described the use of such agents followed by the addition of a progestin. 2 Such a dosage program, utilizing the orally effective progestins for conception control, was proposed in 1961. 1 This has come to be known as the sequential regimen. Despite the general acceptance of the sequential regimen, the minimum effective dose of the estrogens employed in such regimens has not been established by target-organ response. The purposes of this clinical study were to determine, by titration, the optimum dose of ethinyl estradiol which would inhibit ovulation consistently when used in a sequential regimen, and to learn if the standard dose of 0.08 mg. ethinyl estradiol-3-methyl ether (mestranol) would inhibit ovulation.
SEVERAL INVESTIGATORS
METHOD
A total of 14 women of proven fertility were the clinical subjects. They had had tubal ligations or their husbands had had vasectomies, with proven operative success. A physical examination established the subject's general good health. A normal cytologic smear was necessary before inclusion in the program. Finally, an endometrial biopsy on Cycle Day 1 was obtained to establish normal ovarian function. Each woman received a successive dose of ethinyl estradiol in a sequential regimen. The dose used was 0.05 mg., beginning on Cycle Day 5 for 16 days, followed by 5 days of 0.05 mg. of ethinyl estradiol with 25 mg. (limethisterone. On Cycle Day 21 an endometrial biopsy was obtained. It was felt that an endometrial biopsy would be most specific in ascertaining fhe presence or absence of ovulation and would eliminate errors often 649
650
JACKSON ET AL.
FERTILITY
& STERILITY
Fig. 1-3. (Patient C.H.) Endometrial biopsies on Cycle Day 21, after 16 days of treatment. Fig. 1 (top). Secretory, after treatment with 0.065 mg. ethinyl estradiol. Fig. 2 (center). Proliferative, after treatment with 0.08 mg. ethinyl estradiol. Fig. 3 (bottom). Secretory, after treatment with mestranol.
VOL.
19, No.4, 1968
ESTROGEN DOSAGE
651
associated with basal body temperature readings and urinary hormone analyses. The subsequent doses of ethinyl estradiol used in the same sequence were 0.065, 0.08, and 0.1 mg. Following this, each patient had a non therapy or spontaneous cycle. Again, on Cycle Day 1 an endometrial
Fig. 4 and 5. (Patient J.W.) Endometrial biopsies on Cycle Day 21 after 16 days of treatment. Fig. 4 (top). Proliferative, after treatment with 0.08 mg. ethinyl estradiol. Fig. 5 (bottom). Proliferative, after treatment with 0.1 mg. ethinyl estradiol.
f
biopsy was obtained and examined for evidence of ovulation, indicative of return to endogenous ovarian function. Finally, a few patients received 0.08 mg. mestranol in the same sequential fashion as described above. On Cycle Day 21 an endometrial biopsy was obtained and compared with the individual's previous response to a similar dose of ethinyl estradiol.
652
FERTILITY
JACKSON ET AL.
& STERILITY
RESULTS
Of the 14 patients, 10 completed the study. Three patients discontinued because they lost interest. One patient, a post-poliomyelitis victim, discontinued because of leg edema which interfered with her leg brace. Eight patients received 0.08 mg. mestranol in a sequential regimen. Figures 1-3 show the endometrial biopsies of Patient C.H. Evidence of ovulation occurred at doses of 0.05 and 0.065 mg. ethinyl estradiol and 0.08 mg. mestranol. No evidence of ovulation was seen at 0.08 and 0.1 mg. ethinyl estradiol. Figures 4 and 5 show the endometrial biopsies of Patient J.W. Evidence of ovulation inhibition occurred at all dose levels of estrogens used. Table 1 summarizes the response of all patients to the various levels of estrogens used. At all levels employed, except 0.1 mg. ethinyl estradiol, some patients ovulated. We do not know why one patient ovulated with a given dose of ethinyl estradiol and another patient did not ovulate with the same dose. In this clinical series there was no correlation between weight and height of patient and the antiovulatory dose of estrogen. Likewise, on reviewing their past responses to suppression of lactation with estrogens, no relationships could be established between the patient's physical size and the effective dose of estrogen. Most patients showed evidence of ovulation inhibition at the lowest level of ethinyl estradiol; TABLE 1. Ovulation Response to Different Dosages of Ethinyl Estradiol Dosage (mg.) Patient
Pre Rx
N.A. S. B. B. C. C.H. E. Me. B.N. A. R. N.S. V.S. J. T. O.W. G.W. M.W. J.W.
+ + + + +
RATIO*
+ + + +
0.05
+
+
0.08
0.1
+
+ + + 3/13
3/12
2/11
Post Rx
Mestranol (0.08 mg.)
+ + + + + + + +
+
+
+ + + 12/14
0.065
0/10
+ + + +
+
+
+ + +
+
12/12
6/8
Plus signs indicate ovulation; minus signs, no ovulation. * Numerator, number of patients ovulating; denominator, number of patients studied.
VOL. 19, No.4, 1968
ESTROGEN DOSAGE
653
however, evidence of ovulation by any patient suggests that this dose of the estrogen would not be acceptable for a sequential regimen if it is to be used for family-planning purposes.
SUMMARY A clinical study based on the results obtained by endometrial biopsy demonstrates that the consistently effective dose of ethinyl estradiol to inhibit ovulation in a sequential regimen is 0.1 mg. Failure to inhibit ovulation with 0.08 mg. mestranol was noted in 6 of the 8 patients subjected to this study. 1617 Tenth St. Wichita Falls, Tex.
REFERENCES 1. GREENBLATT, R. B. Antiovulatory drugs and indications for their use. Med Glin N Arner 45:973, 1961. 2. GREENBLATT, R. B., HAMMOND, D.O., and CLARK, S. L. Membranous dysmenorrhea: Studies in etiology and treatment. Arner J Obstet Cynec 68:835, 1954. . 3. HAMBLEN, E. C., CUYLER, W. K., HIRST, D. V., and HORNER, V. O. Effects of contraphysiologically administered diethylstilbestrol on the menstrual cycle. J Glin Endocr 2:369, 1942. 4. LYON, R. A. Relief of essential dysmenorrhea with ethinyl estradiol. Surg Cynec Obstet 77:657, 1943. 5. STURGIS, S. H., and ALBRIGHT, F. The mechanism of estrin therapy in the relief of dysmenorrhea. Endocrinology 26:68, 1940.
n il r-
rs
n
The Antiovulatory Dose of Ethinyl Estradiol A Titration Study J. L. JACKSON III, M.D., W. T. SPAIN, M.D., and H. PAYNE, B.S.
have reported on the oral use of estrogenic agents alone to inhibit ovulation. 3 - 5 Greenblatt first described the use of such agents followed by the addition of a progestin. 2 Such a dosage program, utilizing the orally effective progestins for conception control, was proposed in 1961. 1 This has come to be known as the sequential regimen. Despite the general acceptance of the sequential regimen, the minimum effective dose of the estrogens employed in such regimens has not been established by target-organ response. The purposes of this clinical study were to determine, by titration, the optimum dose of ethinyl estradiol which would inhibit ovulation consistently when used in a sequential regimen, and to learn if the standard dose of 0.08 mg. ethinyl estradiol-3-methyl ether (mestranol) would inhibit ovulation.
SEVERAL INVESTIGATORS
METHOD
A total of 14 women of proven fertility were the clinical subjects. They had had tubal ligations or their husbands had had vasectomies, with proven operative success. A physical examination established the subject's general good health. A normal cytologic smear was necessary before inclusion in the program. Finally, an endometrial biopsy on Cycle Day 1 was obtained to establish normal ovarian function. Each woman received a successive dose of ethinyl estradiol in a sequential regimen. The dose used was 0.05 mg., beginning on Cycle Day 5 for 16 days, followed by 5 days of 0.05 mg. of ethinyl estradiol with 25 mg. (limethisterone. On Cycle Day 21 an endometrial biopsy was obtained. It was felt that an endometrial biopsy would be most specific in ascertaining fhe presence or absence of ovulation and would eliminate errors often 649
650
JACKSON ET AL.
FERTILITY
& STERILITY
Fig. 1-3. (Patient C.H.) Endometrial biopsies on Cycle Day 21, after 16 days of treatment. Fig. 1 (top). Secretory, after treatment with 0.065 mg. ethinyl estradiol. Fig. 2 (center). Proliferative, after treatment with 0.08 mg. ethinyl estradiol. Fig. 3 (bottom). Secretory, after treatment with mestranol.
VOL.
19, No.4, 1968
ESTROGEN DOSAGE
651
associated with basal body temperature readings and urinary hormone analyses. The subsequent doses of ethinyl estradiol used in the same sequence were 0.065, 0.08, and 0.1 mg. Following this, each patient had a non therapy or spontaneous cycle. Again, on Cycle Day 1 an endometrial
Fig. 4 and 5. (Patient J.W.) Endometrial biopsies on Cycle Day 21 after 16 days of treatment. Fig. 4 (top). Proliferative, after treatment with 0.08 mg. ethinyl estradiol. Fig. 5 (bottom). Proliferative, after treatment with 0.1 mg. ethinyl estradiol.
f
biopsy was obtained and examined for evidence of ovulation, indicative of return to endogenous ovarian function. Finally, a few patients received 0.08 mg. mestranol in the same sequential fashion as described above. On Cycle Day 21 an endometrial biopsy was obtained and compared with the individual's previous response to a similar dose of ethinyl estradiol.
652
FERTILITY
JACKSON ET AL.
& STERILITY
RESULTS
Of the 14 patients, 10 completed the study. Three patients discontinued because they lost interest. One patient, a post-poliomyelitis victim, discontinued because of leg edema which interfered with her leg brace. Eight patients received 0.08 mg. mestranol in a sequential regimen. Figures 1-3 show the endometrial biopsies of Patient C.H. Evidence of ovulation occurred at doses of 0.05 and 0.065 mg. ethinyl estradiol and 0.08 mg. mestranol. No evidence of ovulation was seen at 0.08 and 0.1 mg. ethinyl estradiol. Figures 4 and 5 show the endometrial biopsies of Patient J.W. Evidence of ovulation inhibition occurred at all dose levels of estrogens used. Table 1 summarizes the response of all patients to the various levels of estrogens used. At all levels employed, except 0.1 mg. ethinyl estradiol, some patients ovulated. We do not know why one patient ovulated with a given dose of ethinyl estradiol and another patient did not ovulate with the same dose. In this clinical series there was no correlation between weight and height of patient and the antiovulatory dose of estrogen. Likewise, on reviewing their past responses to suppression of lactation with estrogens, no relationships could be established between the patient's physical size and the effective dose of estrogen. Most patients showed evidence of ovulation inhibition at the lowest level of ethinyl estradiol; TABLE 1. Ovulation Response to Different Dosages of Ethinyl Estradiol Dosage (mg.) Patient
Pre Rx
N.A. S. B. B. C. C.H. E. Me. B.N. A. R. N.S. V.S. J. T. O.W. G.W. M.W. J.W.
+ + + + +
RATIO*
+ + + +
0.05
+
+
0.08
0.1
+
+ + + 3/13
3/12
2/11
Post Rx
Mestranol (0.08 mg.)
+ + + + + + + +
+
+
+ + + 12/14
0.065
0/10
+ + + +
+
+
+ + +
+
12/12
6/8
Plus signs indicate ovulation; minus signs, no ovulation. * Numerator, number of patients ovulating; denominator, number of patients studied.
VOL. 19, No.4, 1968
ESTROGEN DOSAGE
653
however, evidence of ovulation by any patient suggests that this dose of the estrogen would not be acceptable for a sequential regimen if it is to be used for family-planning purposes.
SUMMARY A clinical study based on the results obtained by endometrial biopsy demonstrates that the consistently effective dose of ethinyl estradiol to inhibit ovulation in a sequential regimen is 0.1 mg. Failure to inhibit ovulation with 0.08 mg. mestranol was noted in 6 of the 8 patients subjected to this study. 1617 Tenth St. Wichita Falls, Tex.
REFERENCES 1. GREENBLATT, R. B. Antiovulatory drugs and indications for their use. Med Glin N Arner 45:973, 1961. 2. GREENBLATT, R. B., HAMMOND, D.O., and CLARK, S. L. Membranous dysmenorrhea: Studies in etiology and treatment. Arner J Obstet Cynec 68:835, 1954. . 3. HAMBLEN, E. C., CUYLER, W. K., HIRST, D. V., and HORNER, V. O. Effects of contraphysiologically administered diethylstilbestrol on the menstrual cycle. J Glin Endocr 2:369, 1942. 4. LYON, R. A. Relief of essential dysmenorrhea with ethinyl estradiol. Surg Cynec Obstet 77:657, 1943. 5. STURGIS, S. H., and ALBRIGHT, F. The mechanism of estrin therapy in the relief of dysmenorrhea. Endocrinology 26:68, 1940.