Oral substitution therapy with ethinyl estradiol and alpha–estradiol

ORAL SUBSTITUTION THERAPY WITH ETHINYL ESTRADIOL AND ALPHA-ESTRADIOL FLOYD

E.

HARDING,

(From the Department of

M.D., Los

~Endocrinology,

A~GELES, CALIF.

Ross·Loos l'[l'dical Group)

THI~

1 recent years a new phase in ovarian substitution therapyW the oml phase-has heen developed. With injection therapy previously favored by the availability of potent hypodermic preparations, a return to thc oral method of treatment has been initiated by the discovery and manufacture of active, orally effective estrogenic substances sueh as diethylstilbestr'ol, ethinyl estradiol and conjugated estrogens equine. The Endocrine Department of this elinic was founded in 1930, and since that time several thousand women have been treated with estrogens for ovarian deficiency. Pollowing this baekground of unpublished material, data have been kept and published 011 502 patients treated orally and hypodermi('ally with estrone, estradiol benzoate and diethylstilbestrol dipropionate.' An additional report has been made on 138 patients treated orally with eon juga ted estrol!ens equme. 2 In the present study, the clinical rc.'!ponse of 47 patients to ethinyl estradiol has been tabulatcd along with previously unpublished observations on 80 patients treated with oral alpha-estradiol (dihydroxyestrin). It has thus been possible to eompare the relative elin ical effectiveness of six estrogenie suhstanres whieh have been emplo~reJ in the treatment of 767 patients. Ethinyl Estradi-ol Reports appearing in the literatur(~ on ethinyl estradiol appear to he quite favorable. s, 9, 12-16 This estrogen was prepared in 1938 by Inhoffen and Hohlweg 17 , 'S by replacement of the hydrogen of the seventeenth carbon atom in estradiol with an ethinyl group. In our studies, enterie eoated ethinyl estradiol tablets· of 0.01 mg., 0.02 mg., 0.05 mg., and 0.1 mg. were used. rncoated tablets of 0.05 mg. were also employed. A total of 47 patients ranging in age from 24 to 60 years were treated with ethinyl estradiol. Included in this series were 17 cases of natural menopause, ]5 cases of artificial menopause and 15 other cases, part of which were associated with hypoestrinism. Results in this series are summarized in Table I. Analysis of Results With Ethinyl Estradiol When ethinyl estradiol was given, it was possible to duplicate any therapeutic effect obtained with diethylstilbestrol dipropionatc. Furthermore, equally effective results were obtained with smaller amounts of material. Indeed, it was observed ttHlt a dose as low as 0.02 mg. of ethinyl estradiol prodlwed a definite therapeutic response. While .The ethinyl estradiol tablets (Estinyl) used in this investigation were supplied through the courtesy of Dr. Max Gilbert and Dr. William R. Bond of the Schering Corporation, Bloomfield, N. J.

181

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184

AMERICA~ JOGRXAI. OJ<' OBSTETRICS AND GYNECOI,QGY

s?me patients requ~red as much as 0.2 mg., optimal dosage for most patIents averaged 0.0;) mg. to 0.1 mg. The average per cent of improvement on ethinyl estradiol at various dosage levels is tabulated helow: DOSE IN MG.

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Improvement Improvement Improvement

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0.02

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M% 71% :17%

86% 83% ill %

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------

1'lental depression ill the menopause proved most refractory to therapy. However, ethinyl estradiol was much more beneficial than an,V of the other natural estrogens used. J n this respect, its action was similar to that afforded by diethylstilbestrol dipropionate. Vaginal smears were normal in 6 of 27 patients examined before trea1ment, while the remaining 21 patients Hhowed varying degrees of eHtrogen deficiency. Ten of these patients had vaginal smears taken after treatment and improvement was noted in eight eases.f
(a) A-Asthenia; C--Difficulty thinking and concentrating; DM-Dsymcnorrhea; I;'-:r'rigidity; G-Globus; H-Headache; IX--Insomnia; M-,Mental depres~ion; P--Palpitation; S-Sterility; RA- Secondary amenorrhea. (h) I-Irregular; O-No longer menstruating; R-Regular. (e) O-Ovaries removed; u-Uterus removed; X-X-ray menopause. (d) D-Dizziness; N-Xausf'a; T-"Nervous tension;" V-Vomiting. (e) B-Some type of uterine bleeding or menstruation caused hy the tahIf)t.~; I.-Tablets ('aused menstruation to he late. ( f) 1-1'\ormal; 2-Slight defieie>ney of estrogen; :l--Moderate c1nficien<'y; 4-St'vere deficiency. (g) Pituitary tumo~; Hirsuitislll; HornHJUP assay of urine: HI C. Co of androgens per 24 honrs.

"'Remarks after treatment: Patient l;j had a constant pain at the end of the urethra which was not relieved; Patient W had had a nervou~ breakdown from which she did not recover; Patient 25 had improvement in hot. flashes and breast soreness only; Patient 29 had migraine headaches from which she obtained no relief; Patient :15 had a marked increase in the size of her breasts; Patient 36 had an increase in her libido associated with a lessening in asthenia and nervousness; Patient 37 had an increase in libido and in the size of her breasts; Patient 39 had less asthenia and nervousness, but she was not otherwise benefited; Patient 4l had relief of the hot flashes, but the menstruation, which was scanty before treatment, became more profuse and painful; Patient 4:~ had fifty per c.ent improvement of symptoms, but the effed was at least partly pharmacodynamie j Patient 44 had an increase in the' i sweats" on 0.1 mg., proving that they were not. hot flashes. Breast soreness developed showing effectiveness of material; Patient 4(; had abnormal vaginal smears because of marked vaginitis.

HARDI~G

:

1R5

ETHINYL AXD ALPHA-ESTRADIOL

reduced. While no attempt was made to use smaller dosage with the other cases, it was evident that the above three patients improved when the dose was decreased and it is believed that most patients would toler~te small amounts of the drug. Toxicity for the entire group, covering all dosage levels, was 14 per cent, but the incidence was very much less with doses under 0.05 mg. dailv. There were five questionable reactions on ethinyl estradiol. With patient 16 insomnia developed while 0.02 mg. was being taken but later disappeared although the tablets were continued. Dizziness began in patient 21 with 0.1 mg. but cleared up when 0.3 mg. was taken. Patient 25 developed a "gnawing in the stomach" on 0.1 mg. but this symptom was noticed occasionally before taking the tablets. Patient 44 began to , 'sweat" more with 0.1 mg. but not with smaller doses. Patient 47 had a poor appetite on 0.1 mg. but tolerated 0.03 mg. There was all increase in 1'ullness and tenderness in the breasts in many cases treated with ethinyl estradiol, and three patients complained of severe soreness. Several mentioned that the nipples and areola darkened in color; while others, in whom breast soreness was present before treatment reported improvement while taking the tablets. Several patients noted an increase in vaginal moisture or leucorrhea during treatment. This has also been observed when other potent estrogens are employed, either orally or parenterally. Eleven of the patients who had no reactions with enteric coated tablets of ethinyl estradiol werc given 0.05 mg. uncoated tablets. Kone of these patients had a reaction, and symptoms were relieved as effectively with the uncoated tablcts as with the enteric couted tablets.

Alpha-Estradiol The Ulwoated tablets of alpha-estradiol· (dihydroxyestrin) a natural estrogenic substance found in the ovary and blood of human beings, were standardized by weight to contain 0.1 mg., 0.2 mg. and 0.5 mg. They were taken from one to three times daily depending on the dose prescrihed. Alpha-estradiol was also obtained as a stable, chemically pure, crystalline substance. It was highly insoluble in water, but some of it. was dis.'!olved in sesame seed oil with the use of a solvent. This oil, containing various amounl'! of alpha-estradiol, was taken by patients in 20 drop doses, three times daily. The following doses represent the largest amount of alpha-estradiol given to each patient. pCI' day. DAILY DOSE OF ALPHA-ESTRADIOl.

0.2 0.3 0.4 0.5 0.6

mg. mg. mg. mg. mg.

NUMBER OF PATIENTS

DAILY DOSE m' AI,PHA -ESTRADIOL

5 2 17 27 Ii

0.8 mg. 1.0 mg. 1.5 mg. 2.0 mg. :\.0 mg.

NUMBER OF PATIENTS

2

10 9

1 1

Results With Alpha-Estradiol While a favorable response was obtained with alpha-estradiol administered orally as tablets, improvement was definitely less in degree. Only patients with milder symptoms who did not wish to take injections were given alpha-estradiol. Sedatives were not used in any Of the cases. "These tablets, called Progynon-DH, were obtaineil from the Schering Corporation . Bloomfield, N. J.

186

AMERICAN JOURNAL 01;' OBSTETRIC8 A)';D GYNECOLOGY

Alpha-estradiol, orally, did not relieve hot flashes very well in doses less than 0.5 mg. daily, and a better response was obtained with 1.5 mg. daily. This natural estrogen had a good tonic effect and increased the sense of well-being in patients. Results regarding migraine, dysmenorrhea, premenstrual tension, etc., arc not included since these conditions were frequently not associated with hypoestrinism, and improvement in each case was prerlieated on the response to estrogens of patients with hypoestrinism. However, where these conditions were associated with the syndrome, they were frequently relieved by estrogen therapy. In some instances it was felt that the pharmacodynamic or drug action of the estrogen was responsible for relief. This has been noted frequently in previons ohservations with diethylstilbestrol dipropionate. Toxicity With Alpha-Estradiol (Oral) In general, untoward l'eaetiollS t.o alpha-estradiol were negligible. While taking alpha-estradiol, 1 mg. daily, one patient began to flow early, one late and one had severe dysmenorrhea. Only one patient developed nausea and vomiting, It reaction caused by many other types of medication. Thcre was no true toxicity. One patient felt nervous and more tense. Hyperestrinemia might have existed previously in thiH patient since the breasts had been sore and firm for two vears. Cnfortunately, a hormone assay of the urine was not made iiI this (,Hse. Two other patients receiving alpha-estradiol complained of breast soroness. Hormone assays of some of the other patients treated in thi~ series have been reported previously:! Comparison With Other Oral Estrogens After this study, it is possible to evaluate the strength of six estrog·enic substances used at the clinic. The data on estrone, estradiol benzoate, diethylstilbestrol dipropionate t and conjugated estrogensequine 2 were obtained from previous observations. Their relative Htrengths, judged on a weight basis milligram per milligram, are listed in Table II. Other desirable and undesirable results are also estimaterl as to degree of importance. It was impossible to obtain a strong estrogenic effect with estrone, estradiol benzoate or alpha-estradiol with the amount of material given, such as was produced by conjugated estrogens, diethylstilbestrol dipropionate or ethinyl estradiol. Of course, the hypodermic administration of estrone and estradiol benzoate gave a strong estrogenic response, the latter being stronger than the former, but the comparison in Table II was limited to material absorbed from the gastrointestinal tract.. One milligram of conjugated estrogens-equine was roughly equivalent to 0.3 mg. to 0.5 mg. of diethylstilbestrol dipropionatc or 0.05 mg. to 0.1 mg. of cthinyl estradiol. Since the strong effect of 0.05 mg. to 0.1 mg. of ethinyl estradiol was not produced by alpha-estradio1 6 - 11 in the doses used, 1 mg. to 1.5 mg., it was known that ethinyl estradiol was at least 15 to 30 times more effective than alpha-estradiol. While Hohlweg and Inhoffen 17 reported that ethinyl estradiol was 15 to 20 times as effective as alpha-estradiol, Soules, 9 stated that it was 50 to 70 times as effective. Thus, in adding the ethinyl radical to alpha-estradiol, a potent estrogen effect has been obtained with greater economy.

ETHINYL

HARDI~6:

TABLE

]

~G.

(W EACH

Quantitative

II.

ESTRONE

Very little Good 0 0

Qualitative Uterine bleeding Development of breasts Relief of mental 0 depression Relief of hot flashes Very little Toxicity per opt-i0 mum effective dose

EFFECT

A~D

m'

187

ALPBA-ES'l'RADIOL

ESTROGENS GIVEN

ESTRADIOL BE..."'ZOATE

ALPHAESTRADIOL

CONJUGATED ESTROGENS

DIETHYLSTILBESTROL DIPROPIONATE

ETHINYL ESTRADIOL

Some

More

Strong

Stronger

Strongest

Good

Good

Good

Not as good Good

~

+

Good

++ Rtronger

+++

+

++t

i !+t

\-+i--I-I-

Some

More

Strong

Stronger

Strongest

0

0

0

+

+

f

Slight

. T

Slight

Strongest

Discussion The oral method has several obvious advantages over the hypodermic. It is chcaper, timesaving and more convenient to the patients and doctor. It avoids local reactions frequently obtained with hypodermic inJections. 5 It allows frequent administration of material which has provcd to be advantageous, as pellet implantation of hormone 3 is more effective than intermittent doses by injection. The oral method also has some disadvantages. Patients are inclined to treat themselves, while the hypodermic method permits constant management by the physician. The stronger preparations have a toxic effect on some patients. This toxicity is of a very mild nature and diminishes when the dosage is cut. In some patients a small dose was well tolerated whereas a larger amount caused symptoms of toxicity. Gastrointestinal symptoms are believed to be central, possibly medullary, rather than local in origin. Enteric coating of the tablets did not prevent the symptoms. Patients who tolerated enteric coated tablets also tolerated noncoated tablets. Prior to thb study, patients who had had a toxic reaction to diethylstilbestrol dipropionate administered orally were given injections, but the nausea and vomiting still persisted. The toxic manifestations cleared up rapidly when medication was discontinued, leaving no permanent effect that was discernible. The symptoms were similar to those of early pregnaney,and although the patients generally asked to be permitted to stop taking the tablets, they did not feel that they had been harmed by the medicine. With ethinyl estradiol, seven of the patients in this study (14 per cent) had a true toxic reaction. During the treatment or 109 patients reported in five papers,9. 12-14, 16 there were 13 reactions (11 per cent toxicity). Kurzrok, Birnberg and Livingston'5 gave ethinyl estradiol to 59 patients after delivery to prevent lactation. In their series there was no evidence of toxicity. Of course, it is a well-known fact that patients who have recently been pregnant tolerate large doses of estrogenic substances.

188

Al:n;RICAX ,JOlJRXA), OF OBRTETRICS AX» GYNI';COLOGY

It was interesting to note that the optimum daily dose of cthinyl estradiol in this series was low (0.05 mg. to 0.1 mg.). According to the literature, most of the treatment was with doses of 0.3 mg. to 0.45 mg. The puerperal rases were given up to 2.4 mg. Howewl'. in two of the papers, the effective dose was ('onsidcl'ed to range from O.O!) mg. to O.l!) mg.

The 1hre(' estrogens that produced a greater respolise in the patient were believed to he less affected by the liver. The other estrogens going through the portal circulation did not reach 1he general eil'eulation in sufficient concentration to be vel'~' henefit'ial. However, sublingual administration was shown to he very much more effective.!!) 1t is helieved that this method of administration, like tIl(> hypodl'l'mie injcetioll, puts the hormone into the general circulation without its first having to pass through the liver, where it is padly ilHwtivated.

Summary Bthinyl estradiol was the most potent oral estrogen used up to the present time. Satisfactory relief of hypo-ovarian symptoms was usually obtained with 0.05 mg. to 0.1 mg. daily although larger doses were occasionally ne('e&'lary. Its effect was compared to that of alphaestradiol and to estrone, estradiol benzoate, diethylstilbestrol dipropionate and conjugated estrogens-equine previollsly studied. Of this group, ethinyl estradiol and diethylstilbestrol dipropionate ('aused mild toxic reactions in an occasional patient without apparent permanent harm. Keeping the dose down to the minimum needed for maximum effeetivl'ness reduced the toxic symptoms. The addition of the ethinyl l'adic'al greatly increased the effectiveJH'ss of alpha-estradiol, thus redll('ing' the cost of treatment. Tlw oral nwthod of treatmellt had man~' afJvantages.

References

1. 2. 3. 4-. 5. 6. 7. 8. 9. ]0. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Harding, P. E.: West .• r. Surg. 50: 207, 1!l42. Harding, P. E.: West. J. Surg. 52: in, 1944. Harding, P. E., and Praser, A. V.: Uro). & eutan. Rev. 46: G7G, 1!l42. Harding, P. K: 1.:"ro1. & eutan. Rev. 47: 603, ]!J.i3. Harding, P. E.: M. Ree. 152: 448, ]940. Neustaedter, T.: AM. J. OBST. & GYXEC. 42: 86, 1!l41. Berlind, M.: M. Ree. 153: 54, 1941. Soule, S. D.: AM. J. OBST. & GYNEC. 44: 684, 1942. Soule, S. D.: AM. J. OBST. & GYNEC. 45: 315, 1943. Herrnberger, K.: Zentralbl. f. Gyniik. 65: 1B, 1941. Giesen, W.: Deutsche med. Wchn8chr. 67: 547, 194-1. Groper, M . •T., and Biskind, G. R.: .J. Olin. Endocrinol. 2: 703, 1942. Watson, B. A.: .T. Clin. FJndocrinol. 2: 4+7, 1942. Salnwn, U. ,T., Geist. S. H., Walter, R. r.. and ).fintz, ::'{.: .T. Clin. Endocrinol. 1: 556, 1941. Kurzrok, L., Birnberg, C. H., and Livingston, s.: .J. Olin. Endocrinol. 2: 471, 1942. Clauberg, C., and Cnstun, Z.: ZentralbI. f. Gynak. 62: ]745, 1938. Hohlweg, H., and Inhoffen, H. H.: Klin. Wchnschr. 18: 77, 1939. Hohlweg, R., and Inhoffen, H. H.: Naturwissenschaften 6: 1I6, 1938. Hall, G. J.: J. Clin. Endocrinol. 2: 26, 1942.

947

WES~'

EIGHTH

STRE~;T