The dosage of the estrogens

Editorial The Dosage of the Estrogens increasing employment of sex hormones in the treatment of T HE gynecologic and other diseases calls for definite and accurate knowledge of the indications for their use and above all, of their dosage. While brilliant results are claimed for them as substitutes after operative or radiation treatment, much confusion has arisen from the many trade names under which estrogenic compounds are dispensed. Refinements in manufacture have made some of them available in crystalline form, synthetically produced, parti(,~ularly the estrogens which are commonly known as estrone (theelin, ketohydroxyestrin, etc.) or estradiol (theelol, dihydroxyestrin, etc.). Their satisfactory clinical application depends largely on proper and adequate dosage. The estrogens, one of the two female sex hormones, the other being progesterone, the nidatory corpus luteum hormone, are now available in pure crystalline form. The estrogens are used clinically mainly in the form of estrone (theelin, ketohydroxyestrin) or estradiol (theelol, dihydroxyestrin). Confusion arises from the many trade names under which estrogenic compounds are disguised, amniotin, theelin, progynonB and DH, ago and sistomensin, emmenin, menformon, to mention only a few. An international unit evaluating the potency of any given preparation of estrogens has been accepted. It is the effect produced by 0.1 gamma (~0,000 of a gram) of estrone (theelin). This roughly corresponds to a mouse unit or ~ to 1/~tof a rat unit. For uniformity 's sake all preparations should be standardized to the international unit (I.U.). Some of the preparations are dispensed in water soluble, other in ]ipoid soluble form. The rate of ab~rption, continuity of action and consequent physiologic effect produced is profoundly influenced both by the vehicle used and the site of injection. Water soluble preparations are both more rapidly absorbed and excreted. Consequently more frequent injections and larger dosage is required. Oily solutions are taken up more slowly. The rate of absorption is more rapid from muscle than subcutaneous tissues. The disadvantage arising from repeated oil injections are the possible formation of painful, long persisting indurations or granulomas. Several preparations can be given by mouth. This is preferable to the patient but does not permit of as accurate dosage as by the parenteral route, because the amount of absorption through the intestinal tract varies in different individuals and under different conditions of food intake and intestinal function. Absorption of estrogens through the vaginal mucosa and through the skin likewise occurs. This method should not be used over long periods of time because carcinogenic potentialities are increased by topical application. 525

526

AMERICAN

JOURNAL

Olt~ OBSTI!~TRICS A N D G Y N E C O L O G Y

There are many pitfalls and variables to be considered, therefore the question of dosage always demands thought and consideration. In the treatment of gonorrheal vaginitis of children as advised by Lewis ~ 1,000 I.U. by vaginal suppository are given daily until the discharge becomes acid and gonococci disappear (total dosage 30-50,000 I.U.). In the treatment of the menopause marked divergence of opinion exists. In a series of cases controlled by hormone assay and vaginal spreads 2 an average of 150,000 I.U. per month were required. The estrogens were found equally effective whether given by injection or by mouth, although larger dosage is required. Werner3 obtained relief of symptoms with as little as 5,000 I.U. total (500 I.U. every third day for ten doses) injected in oily medium. All agree that repeated courses of treatment are required at intervals as the symptoms recur. Uterine bleeding may follow when medication is stopped. This form of treatment relieves not only the flushes and sweats but also psychical, arthritic, digestive and local vaginitic symptoms temporarily. To produce bleeding in amenorrhea a much larger dosage is required. 4 Bleeding may result from one million I.U. ; frequently triple this amount is needed. The periodic return of menstruation by means of estrogens still remains a doubtful procedure, many careful observers having denied its success. Estrogens have been used empirically for the treatment of numerous other conditions among which are hirsutes, toxemia of pregnancy, frigidity, sterility, dysmenorrhea, ache, etc. Theoretically such application appears illogical; the published reports are uncritical; no attempt to standardize dosage can be made for these conditions. In prescribing and using estrogens the physician must select the preparation to be given according to the special requirements of the patient, keeping in mind the potency (I.U.), the vehicle, and the rate of absorption and excretion.

~ L ~ i s , R. M., a ~ Adler, E . L . : J. A. M. A. 106: 2054. 1936. ! ~ , R. T., Go~berg~r, M. A., a~td Salmon, U. J . : N. Y. S t a t e J . M e d . 86: t 3 6 3 . 1936.

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