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STUDIES ON THE OPTIMAL DOSAGE OF ESTROGENS: Title and subTitle BreakAN EXPERIMENTAL AND CLINICAL EVALUATION

HARLES MAZER, M.D.; S. LEON ISRAEL, M.D.
[+] Author Affiliations

Because of lack of space, this article is abbreviated in The Journal. The complete article appears in the author's reprints.

Read before the Section on Pharmacology and Therapeutics at the Eighty-Seventh Annual Session of the American Medical Association, Kansas City, Mo., May 13, 1936.

The international unit (weight unit) of estrogen is one-tenth microgram. The ratio between the rat unit and the international unit varies with the chemical composition of the product and its purity. In our laboratory various samples of estrone yielded from 500,000 to 1,000,000 rat units per gram; estriol, 150,000 rat units per gram; estradiol, 6,500,000 rat units per gram, and estradiol benzoate 5,500,000 rat units per gram. It is therefore evident that the use of the rat unit is preferable when dealing with the several estrogens.


PHILADELPHIA

From the Department of Gynecology, Mount Sinai Hospital.


JAMA. 1937;108(3):163-169. doi:10.1001/jama.1937.02780030001001
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With the recent availability of chemically pure and highly concentrated estrogenic products, the medical profession is confronted with the problems of the margin of safety, therapeutic indications and optimal dosage. In a previous study on the constitutional effects of relatively large doses of estrogens, we1 found that the administration of from 100,000 to 260,000 rat units of the principle, given in divided doses over a period of from two to three months, produces no appreciable changes in body weight, basal metabolism, blood pressure, blood count, coagulation and bleeding times, blood chemistry and urine. The present study was undertaken in an attempt to evaluate the indications for the clinical use of estrogens, their respective optimal dosage and the most effective modes of administration.

THE PHYSIOLOGIC EFFECTS OF ESTROGEN IN THE EXPERIMENTAL ANIMAL  Clinical studies in optimal dosage of a new therapeutic agent are by necessity based primarily on the varied

REFERENCES

Mazer, Charles; Meranze, D. R., and Israel, S. L.:  Evalution of the Constitutional Effects of Large Doses of Estrogenic Principle , J. A. M. A. 105:257 ( (July 27) ) 1935;.
Dorfman, R. I.; Gallagher, T. F., and Koch, F. C.:  Nature of Estrogenic Substance in Human Male Urine and Bull Testis , Endocrinology 1933 (Jan.) -Feb.) 1935;.
Mazer, Charles, and Israel, S. L.: Unpublished observations.
Leonard, S. L.; Meyer, R. K., and Hisaw, F. L.:  The Effect of Estrin on Development of the Ovary in Immature Female Rats , Endocrinology 15: 17 ( (Jan.) -Feb.) 1931;.
Moore, C. R., and Price, D.:  Gonad Hormone Functions, and Reciprocal Influence Between Gonads and Hypophysis with Its Bearing on Problem of Sex Hormone Antagonism , Am. J. Anat. 50: 13 ( (March) ) 1932;.
Bialet-Laprida, Z.:  Action de la folliculine sur l'hypertrophie compensatrice de l'ovaire , Compt. rend. Soc. de biol. 114: 383, 1933;.
Spencer, J.; D'Amour, F. E., and Gustavson, R. G.:  Further Studies on Estrin-Hypophyseal Antagonism in White Rat , Endocrinology 16:647 ( (Nov.) -Dec.) 1932;.
Katzman, P. A.:  Note on Effect of Theelin, Theelol and Luteinizing Substance on Reproduction , Proc. Soc. Exper. Biol. & Med. 29:700 ( (March) ) 1932;.
Barnes, B. O.; Regan, J. F., and Nelson, W. O.:  Improvement in Experimental Diabetes Following the Administration of Amniotin , J. A. M. A. 101:926 ( (Sept. 16) ) 1933;.
Zondek, Bernhard:  The Inhibitory Effect of Follicular Hormone on the Anterior Lobe of the Pituitary Gland , Lancet 1: 10 ( (Jan. 4) ) 1936;.
Hohlweg, W.:  Veränderungen des Hypophysenvorderlappens und des Ovariums nach Behandlung mit grossen Dosen von Follikelhormon , Klin. Wchnschr. 13:92 ( (Jan. 20) ) 1934;.
Mazer, Charles; Israel, S. L., and Alpers, B. J.:  The Time Element in the Pituitary-Ovarian Response to Large Doses of the Estrogenic Hormone , Endocrinology 20: 746 ( (Nov.) ) 1936;.
Hohlweg, W., and Dohrn, M.:  Beziehungen zwischen Hypophysenvorderlappen und Keimdrüsen , Wien. Arch. f. inn. Med. 21:337 ( (July 15) ) 1931;.
Clauberg, C., and Breipohl, W.:  Follikel- und Luteohormon in ihrer Rückwirkung auf den Hypophysenvorderlappen , Klin. Wchnschr. 14: 119 ( (Jan. 26) ) 1935;.
Evans, H. M.:  Clinical Manifestations of Dysfunction of the Anterior Pituitary ,J. A. M. A. 104: 464 ( (Feb. 9) ) 1935;.
Lacassagne, A.:  Sur la pathogénie de l'adéno-carcinome mammaire de la souris , Compt. rend. Soc. de biol. 115:937, 1934;.
Gardner, W. U.; Smith, G. M.; Allen, Edgar, and Strong, L. C.:  Cancer of the Mammary Glands Induced in Male Mice Receiving Estrogenic Hormone , Arch. Path. 21:265 ( (March) ) 1936;.
Frank, R. T., and Goldberger, M. A.:  VI. Demonstration of Female Sex Hormone in the Human Blood: Technic: Clinical Applicability , J. A. M. A. 87:1719 ( (Nov. 20) ) 1926;.
Kurzrok, Raphael, and Ratner, Sarah:  Relation of Amenorrhea Accompanied by Genital Hypoplasia to Follicular Hormone in Urine , Am. J. Obst. & Gynec. 23: 689 ( (May) ) 1932;.
We are indebted to Drs. Gregory Stragnell and Erwin Schwenk of the Schering Corporation for the generous supply of progynon-B and to Dr. E. A. Sharp of Parke, Davis & Co. for the supply of theelol.
Morrell, J. A.; Powers, H. H.; Varley, J. R., and DeFrates, J.:  The Results of Oral Administration of Amniotin to Monkeys , Endocrinology 14: 174 ( (May) -June) 1930;.
Schoeller, W.; Dohrn, M., and Hohlweg, W.:  The Peroral Effect of Follicular Hormones , M. J. & Rec. 132:487 ( (Nov. 19) ) 1930;.
Albright, Fuller:  Studies on Ovarian Dysfunction: III. The Menopause , Endocrinology 20:24 ( (Jan.) -Feb.) 1936;.
Mazer, Charles:  The Endocrine Glands in Relation to Abnormal Breast Hyperplasias , M. Rec. 140:417 ( (Oct. 17) ) 1934;.
Riley, H. A.; Brickner, R. M., and Kurzrok, Raphael:  Abnormal Excretion of Theelin and Prolan in Patients Suffering from Migraine: Preliminary Report , Bull. Neurol. Inst., New York. 3:53 ( (June) ) 1933;.
Kirklin, O. L., and Wilder, R. M.:  Follicular Hormone Administered in Acromegaly , Proc. Staff Meet., Mayo Clin. 11:121 ( (Feb. 19) ) 1936;.
Patton, P. B., and Beardwood, J. T., Jr.: The Effects of Estrogenic Substances upon Certain Cases of Diabetes Mellitus, to be published.
Pratt, J. P.:  Ovarian Therapy , Endocrinology 16:45 ( (Jan.) -Feb.) 1932;.
Collens, W. S.; Slo-Bodkin, S. G.; Rosenbliett, Samuel, and Boas, L. C.:  The Effect of Estrogenic Substance on Human Diabetes , J. A. M. A. 106:678 ( (Feb. 29) ) 1936;.
Lewis, R. M.:  Study of Effects of Theelin on Gonorrheal Vaginitis in Children , Am. J. Obst. & Gynec. 26:593 ( (Oct.) ) 1933;.
Davis, M. E.:  The Treatment of Senile Vaginitis with Ovarian Follicular Hormone , Surg., Gynec. & Obst. 61:680 ( (Nov.) ) 1935;.
TeLinde, R. W., and Brawner, J. N., Jr.:  Experiences with Amniotin in the Treatment of Gonococcal Vaginitis in Children , Am. J. Obst. & Gynec. 30: 512 ( (Oct.) ) 1935;.
Drips, Della G.:  Treatment of Functional Menstrual Irregularities of Young Women , J. Iowa M. Soc. 24: 1 ( (Jan.) ) 1934;.
Mazer, Charles, and Spitz, Louis, Jr.:  The Therapeutic Value of Low-Dosage Irradiation of the Pituitary Gland and Ovaries in Functional Menstrual Disorders , Am. J. Obst. & Gynec. 30:214 ( (Aug.) ) 1935;.
Zondek, Bernhard:  Folliculin , Klin. Wchnschr. 8:2229 ( (Nov. 26) ) 1929;.
Kaufmann, C.:  Die Behandlung des Amenorrhöe mit hohen Dosen der Ovarialhormone , Klin. Wchnschr. 12:1557 ( (Oct. 7) ) 1933;.
Clauberg, C.:  Studien an infantilen und insuffizienten menschlichen Uteri (zum Problem der Ovarialinsuffizienz) , Ztschr. f. Geburtsh. u. Gynäk. 107: 331, 1934;.
Werner, A. A., and Collier, W. D.:  The Effect of Theelin Injections on the Castrated Woman, with Histologic Report , J. A. M. A. 100: 633 ( (March 4) ) 1933;.
Israel, S. L.:  Evaluation of Endocrine Therapy in Primary Dysmenorrhea , J. A. M. A. 106: 1698 ( (May 16) ) 1936;.
Mazer, Charles, and Israel, S. L.:  The Symptoms and Treatment of the Menopause , M. Clin. North America 19:205 ( (July) ) 1935;.
Frank, R. T., and Salmon, U. J.:  Effect of Administration of Estrogenic Factor upon Hypophyseal Hyperactivity in the Menopause , Proc. Soc. Exper. Biol. & Med. 33:311 ( (Nov.) ) 1935;.
Leriche, R., and Oppel, W. A.:  Essais de traitement de la mammite scléro-kystique de reclus par la folliculine , Lyon chir. 30: 54 ( (Jan.) -Feb.) 1933;.
Whitehouse, H. B.:  Mastopathia and Chronic Mastitis , Surg., Gynec. & Obst. 58:278 ( (Feb. 2A) ) 1934;.
Lewis, Dean, and Geschickter, C. F.:  Ovarian Hormones in Relation to Chronic Cystic Mastitis , Am. J. Surg. 24:280 ( (May) ) 1934;.
Bloodgood, J. C.:  The Changing Clinical Picture of Lesions of the Breast , Am. J. M. Sc. 179:27 ( (Jan.) ) 1930;.
Deaver, J. B., and McFarland, Joseph: The Breast: Its Anomalies, Its Diseases, and Their Treatment , Philadelphia, P. Blakiston's Son & Co., 1917;.
Witherspoon, J. T.:  The Treatment of Gonorrheal Vulvovaginitis of Childhood with the Ovarian Follicular Hormone , Am. J. Obst. & Gynec. 29:906 ( (June) ) 1935;.
Berger, M.: Klin. Wchnschr. 14:1601 ( (Nov. 9) ) 1935;
abstr. J. A. M. A. 105:2191 ( (Dec. 28) ) 1935;.

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Mazer, Charles; Meranze, D. R., and Israel, S. L.:  Evalution of the Constitutional Effects of Large Doses of Estrogenic Principle , J. A. M. A. 105:257 ( (July 27) ) 1935;.
Dorfman, R. I.; Gallagher, T. F., and Koch, F. C.:  Nature of Estrogenic Substance in Human Male Urine and Bull Testis , Endocrinology 1933 (Jan.) -Feb.) 1935;.
Mazer, Charles, and Israel, S. L.: Unpublished observations.
Leonard, S. L.; Meyer, R. K., and Hisaw, F. L.:  The Effect of Estrin on Development of the Ovary in Immature Female Rats , Endocrinology 15: 17 ( (Jan.) -Feb.) 1931;.
Moore, C. R., and Price, D.:  Gonad Hormone Functions, and Reciprocal Influence Between Gonads and Hypophysis with Its Bearing on Problem of Sex Hormone Antagonism , Am. J. Anat. 50: 13 ( (March) ) 1932;.
Bialet-Laprida, Z.:  Action de la folliculine sur l'hypertrophie compensatrice de l'ovaire , Compt. rend. Soc. de biol. 114: 383, 1933;.
Spencer, J.; D'Amour, F. E., and Gustavson, R. G.:  Further Studies on Estrin-Hypophyseal Antagonism in White Rat , Endocrinology 16:647 ( (Nov.) -Dec.) 1932;.
Katzman, P. A.:  Note on Effect of Theelin, Theelol and Luteinizing Substance on Reproduction , Proc. Soc. Exper. Biol. & Med. 29:700 ( (March) ) 1932;.
Barnes, B. O.; Regan, J. F., and Nelson, W. O.:  Improvement in Experimental Diabetes Following the Administration of Amniotin , J. A. M. A. 101:926 ( (Sept. 16) ) 1933;.
Zondek, Bernhard:  The Inhibitory Effect of Follicular Hormone on the Anterior Lobe of the Pituitary Gland , Lancet 1: 10 ( (Jan. 4) ) 1936;.
Hohlweg, W.:  Veränderungen des Hypophysenvorderlappens und des Ovariums nach Behandlung mit grossen Dosen von Follikelhormon , Klin. Wchnschr. 13:92 ( (Jan. 20) ) 1934;.
Mazer, Charles; Israel, S. L., and Alpers, B. J.:  The Time Element in the Pituitary-Ovarian Response to Large Doses of the Estrogenic Hormone , Endocrinology 20: 746 ( (Nov.) ) 1936;.
Hohlweg, W., and Dohrn, M.:  Beziehungen zwischen Hypophysenvorderlappen und Keimdrüsen , Wien. Arch. f. inn. Med. 21:337 ( (July 15) ) 1931;.
Clauberg, C., and Breipohl, W.:  Follikel- und Luteohormon in ihrer Rückwirkung auf den Hypophysenvorderlappen , Klin. Wchnschr. 14: 119 ( (Jan. 26) ) 1935;.
Evans, H. M.:  Clinical Manifestations of Dysfunction of the Anterior Pituitary ,J. A. M. A. 104: 464 ( (Feb. 9) ) 1935;.
Lacassagne, A.:  Sur la pathogénie de l'adéno-carcinome mammaire de la souris , Compt. rend. Soc. de biol. 115:937, 1934;.
Gardner, W. U.; Smith, G. M.; Allen, Edgar, and Strong, L. C.:  Cancer of the Mammary Glands Induced in Male Mice Receiving Estrogenic Hormone , Arch. Path. 21:265 ( (March) ) 1936;.
Frank, R. T., and Goldberger, M. A.:  VI. Demonstration of Female Sex Hormone in the Human Blood: Technic: Clinical Applicability , J. A. M. A. 87:1719 ( (Nov. 20) ) 1926;.
Kurzrok, Raphael, and Ratner, Sarah:  Relation of Amenorrhea Accompanied by Genital Hypoplasia to Follicular Hormone in Urine , Am. J. Obst. & Gynec. 23: 689 ( (May) ) 1932;.
We are indebted to Drs. Gregory Stragnell and Erwin Schwenk of the Schering Corporation for the generous supply of progynon-B and to Dr. E. A. Sharp of Parke, Davis & Co. for the supply of theelol.
Morrell, J. A.; Powers, H. H.; Varley, J. R., and DeFrates, J.:  The Results of Oral Administration of Amniotin to Monkeys , Endocrinology 14: 174 ( (May) -June) 1930;.
Schoeller, W.; Dohrn, M., and Hohlweg, W.:  The Peroral Effect of Follicular Hormones , M. J. & Rec. 132:487 ( (Nov. 19) ) 1930;.
Albright, Fuller:  Studies on Ovarian Dysfunction: III. The Menopause , Endocrinology 20:24 ( (Jan.) -Feb.) 1936;.
Mazer, Charles:  The Endocrine Glands in Relation to Abnormal Breast Hyperplasias , M. Rec. 140:417 ( (Oct. 17) ) 1934;.
Riley, H. A.; Brickner, R. M., and Kurzrok, Raphael:  Abnormal Excretion of Theelin and Prolan in Patients Suffering from Migraine: Preliminary Report , Bull. Neurol. Inst., New York. 3:53 ( (June) ) 1933;.
Kirklin, O. L., and Wilder, R. M.:  Follicular Hormone Administered in Acromegaly , Proc. Staff Meet., Mayo Clin. 11:121 ( (Feb. 19) ) 1936;.
Patton, P. B., and Beardwood, J. T., Jr.: The Effects of Estrogenic Substances upon Certain Cases of Diabetes Mellitus, to be published.
Pratt, J. P.:  Ovarian Therapy , Endocrinology 16:45 ( (Jan.) -Feb.) 1932;.
Collens, W. S.; Slo-Bodkin, S. G.; Rosenbliett, Samuel, and Boas, L. C.:  The Effect of Estrogenic Substance on Human Diabetes , J. A. M. A. 106:678 ( (Feb. 29) ) 1936;.
Lewis, R. M.:  Study of Effects of Theelin on Gonorrheal Vaginitis in Children , Am. J. Obst. & Gynec. 26:593 ( (Oct.) ) 1933;.
Davis, M. E.:  The Treatment of Senile Vaginitis with Ovarian Follicular Hormone , Surg., Gynec. & Obst. 61:680 ( (Nov.) ) 1935;.
TeLinde, R. W., and Brawner, J. N., Jr.:  Experiences with Amniotin in the Treatment of Gonococcal Vaginitis in Children , Am. J. Obst. & Gynec. 30: 512 ( (Oct.) ) 1935;.
Drips, Della G.:  Treatment of Functional Menstrual Irregularities of Young Women , J. Iowa M. Soc. 24: 1 ( (Jan.) ) 1934;.
Mazer, Charles, and Spitz, Louis, Jr.:  The Therapeutic Value of Low-Dosage Irradiation of the Pituitary Gland and Ovaries in Functional Menstrual Disorders , Am. J. Obst. & Gynec. 30:214 ( (Aug.) ) 1935;.
Zondek, Bernhard:  Folliculin , Klin. Wchnschr. 8:2229 ( (Nov. 26) ) 1929;.
Kaufmann, C.:  Die Behandlung des Amenorrhöe mit hohen Dosen der Ovarialhormone , Klin. Wchnschr. 12:1557 ( (Oct. 7) ) 1933;.
Clauberg, C.:  Studien an infantilen und insuffizienten menschlichen Uteri (zum Problem der Ovarialinsuffizienz) , Ztschr. f. Geburtsh. u. Gynäk. 107: 331, 1934;.
Werner, A. A., and Collier, W. D.:  The Effect of Theelin Injections on the Castrated Woman, with Histologic Report , J. A. M. A. 100: 633 ( (March 4) ) 1933;.
Israel, S. L.:  Evaluation of Endocrine Therapy in Primary Dysmenorrhea , J. A. M. A. 106: 1698 ( (May 16) ) 1936;.
Mazer, Charles, and Israel, S. L.:  The Symptoms and Treatment of the Menopause , M. Clin. North America 19:205 ( (July) ) 1935;.
Frank, R. T., and Salmon, U. J.:  Effect of Administration of Estrogenic Factor upon Hypophyseal Hyperactivity in the Menopause , Proc. Soc. Exper. Biol. & Med. 33:311 ( (Nov.) ) 1935;.
Leriche, R., and Oppel, W. A.:  Essais de traitement de la mammite scléro-kystique de reclus par la folliculine , Lyon chir. 30: 54 ( (Jan.) -Feb.) 1933;.
Whitehouse, H. B.:  Mastopathia and Chronic Mastitis , Surg., Gynec. & Obst. 58:278 ( (Feb. 2A) ) 1934;.
Lewis, Dean, and Geschickter, C. F.:  Ovarian Hormones in Relation to Chronic Cystic Mastitis , Am. J. Surg. 24:280 ( (May) ) 1934;.
Bloodgood, J. C.:  The Changing Clinical Picture of Lesions of the Breast , Am. J. M. Sc. 179:27 ( (Jan.) ) 1930;.
Deaver, J. B., and McFarland, Joseph: The Breast: Its Anomalies, Its Diseases, and Their Treatment , Philadelphia, P. Blakiston's Son & Co., 1917;.
Witherspoon, J. T.:  The Treatment of Gonorrheal Vulvovaginitis of Childhood with the Ovarian Follicular Hormone , Am. J. Obst. & Gynec. 29:906 ( (June) ) 1935;.
Berger, M.: Klin. Wchnschr. 14:1601 ( (Nov. 9) ) 1935;
abstr. J. A. M. A. 105:2191 ( (Dec. 28) ) 1935;.
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