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Treatment of the menopause with estradiol dipropionate
TREATMENT
OF THE MENOPAUSE DIPROPIONATE”
WITH
ESTRADIOL
EDWARD M. DORR, M.D., AND R. R. GREENE, MS., CHICAGO, ILL. (Prom the Departments of Gynecology and Obstetrics, Pharmacology of Northwestern University Me&cd School Service of St. Luks Hospital)
and
M.D., Physiology
a%d
and the Gynecology
N ESTROGENIC substance is any substance which has activities similar to those exhibited by the hormone of the ovarian follicle. In the human being, 3 chemically dist,inct and biologically active estroEstradiol has been genie substances have thus far been isolated. separated from follicular fluid in crystalline form and presumably is the true follicular horm0ne.l Estrone (theelin) and estriol (theelol) are found in pregnancy urine,* placenta” and presumably in nonpregnant urine. They probably represent excretion forms of the metabolized estradioL4e6 Various observers do not agree as to the exact potency of these 3 compounds, but do agree that estradiol is more potent than estrone and that estriol is the least potent of the 3 substances. It has been demonstrated by various workers that esterification of estradiol or estrone leads to a more prolonged physiologic effect on parenteral administration. This enhanced effect is due, presumably, to slower absorption of the compound.
A
In 1937 Miescher and Scholz; synthesized &radio1 dipropionate, which is the In this compound the 2 hydroxyl groups on the doubly esterified form of eatradiol. molecule have been replaced by propionic acid radicles. Miescher, Tsehopp and Scholzs have investigated the relative potency of this substance, with other esterified forms and with free estrone and estradiol. According to these workers the minimal rffertive dose or rat unit of estrone, estradiol benzoate, and estradiol dipropionate is the same, 0.00075 mg. Other workers agree fairly well on this rat unit for estrone but believe the rat unit for e&radio1 benzoate to be lower. Miescher and his coworkers found a marked difference in physiologic effect between these compounds. If 0.05 mg. of estrone, estradiol benzoate, or e&radio1 dipropionate were injected into castrate rats, the animals would go into e&us. In the estrone injected animals this estrus would persist for four or five days. In the animals injected with estradiol benzoate, estrus would persist for fourteen days. In animals injected with estradiol dipropionate, estrus would persist for forty-two days. Similar differences were noted when growth of the rat uterus was used as the criterion of estrogenic effectiveness. With the same dosage (0.05 mg.) the effect of estrone persisted eight days, with estradiol benzoate twenty-four day s, and with estradiol dipropionate, sixty days.
The value of estrogenic substances in the treatment of menopausal symptoms is quite well established. However there is little a,greement of opinion as to which substance should be used, or the method or freWe are well aware of the fact that desiccated quency of administration. thyroid or sedatives may be of value in some menopausal patients. Some individuals may even be improved by suggestion therapy. However, it *PrcsentPcl
at
:I
nlrrting
of
thP
ChiCRfi.o Gynecological Rooiety. March 17, lg$$l, 453
DORR
AND
GREENE:
ESTRADIOL
DIPROPIONATE
459
is very doubtful whether true menopausal symptoms such as the hot flush can be relieved in all patients by such means. Estrogens, if given The one in adequate dosage, will relieve these symptoms in all patients. qualification that must be added to this statement is that the symptoms the estrogens are expected to relieve must truly be menopausal symptoms and not entirely independent or even unrelated symptoms present in the woman of menopausal age. Estrogens are effective by a variety of routes: the oral, the percutaneous or the parenteral. With the exception of estriol glucuronide (emmenin) g which is of low potency, natural estrogens are many times more effective by parenteral administration than when given orally. Estrogens are at the present time quite costly. Their price per effective mout,h unit is such that treatment of the ordinary patient with dosages adequate to control menopausal symptoms is financially prohibitive. Several workers have shown that estrogens are absorbed through the skin and have systemic effects after percutaneous administration.l”-l” According to Zondek’O estrone in solution in alcohol, benzene, or ethel is as effective percutaneously in the experimental animal as it is snhcutaneously in oil. In oil or ointment solution it is only one-seventh as potent percutaneously as it is subcutaneously. Whether this relativcl cffect.iveness by percutaneous administration is equally as true in the human being has yet to be shown. A report by Salmon’” and experime& in progress by one of us (R. R. G.) would indicate that this is dollht~ful.
At, the present time the majority of patients are given estrogenic therapy by the intramuscular route. In t,his country, al; least, injections a.re nsually given 2 to 4 times weekly. Intramuscular injections are notpleasurable. Any estrogenic substance, then, t,hat would control menopausal spmpt,oms and that which could be given with a minimal frcqnency would be desirable. In view of the enhanced potency and prolonged physiologic effect of estradiol dipropionate in the experimental animal, it was thought worth while to determine the clinical value of this substance in the treatment of menopausal symptoms in the human female. METHODS
AND
RESULTS
Sixt,y-two menopausal patients have been treated with estradiol dipropionate.” Only 55 of these patients will be considered in this report. The remaining 7 patients are not included either because they had been observed over too short a period of time (un.der three months) or because their clinic attendance was so poor that it was not possible to estimate their maintenance dosage. The symptoms of the menopausal patient are many and varied. However, such patients have one common symptom, the hot flush. In view of this fact, the patients were instructed to keep an accurate record of the frequency and severity of the hot flushes. These data were used to a large ext,ent as the index of the success of therapy. It was noted that with disappearance or return of the hot flushes there was a corresponding subsidence or exacerbation of such symptoms as nervousness, irritability, fatigue, headaches, etc. *E&radio1 through the Incorporated.
dipropionate courtesy of
under the trade name Dr. Ernst Oppenheimer
“IX-ovocyclin” has been of Cibn Pharmaceutical
furnished Products
460
AMERICAN
JOURNAL
UF
OLlSTETRlCY
ANI)
GYNECOLOQY
The dispensary patients were seen once a week, the few private patients occa. sionally at more frequent intervals. It was found that patients were rendered symptom-free more rapidly by giving large doses ( 2.0 to 5.0 mg.) for the first few treatments. No patient was treated more often than once a week. After a patient was free from the hot flushes (usually one to three weeks) an att,empt vvas made to determine her maintenance dosage. This was a rather difficult procedure, being largely a matter of trial and error. However, by gr:rtlually lowering the dose, and prolonging the interval between treatments, at least the approximate maintenance dosage was determined which would keep each patient either entirely symptom-free or having not more than 1 or 2 hot flushes during the t’ourse of a week. A slight diminution in necessary dosage KS observed in only a few patients during the experimental period. This is probably clue tu the fact that only a relatively short Patients included in this series period of treatment is considered in this stully. are limited to those treated from three to nine months only. Slight and temporary reappearance of i;pmptoms was noted in :I few patients, or periods of unusual emotional stress. associated with upper respiratory infections. The ages of the patients in this series varied from 29 to 59 years, with an average age of forty-three years. Twenty-nine vver~ ’ ’ normal ’ ’ menopausal patients, 2:: The average age of the patients and the average postoperative and 3 postradiation. correlation duration of the symptoms are shown in Table T. There was no definite of these factors. The total between the neressnry maintenance dosage and either but no definite correlation dosage per month per patient has also been calculated was found with the age or length of symptoms. In theory, at least, one would expect that the necessary maintenance dosage would be less in patients whose symptoms had been present a long time in contrast t,o those In a larger seCrs of patients such a in whom the symptoms were of recent origin. correlation might be present.
--~ INTERVAT, IN WEEKS
DOSE IN MG.
AVERAGE LENGTH OF SYMPTOMS MONTHS
NITMBER OF PATIENTS -..-
0.2 o.5
-
-1.0----1.0 1.0 1.0 _-
__..-
2 5.0 5.0 5.0 5.0 5.0 TABLE
~--~~-..2 1 1 2 I> l 1 3 1.0 1.71 2.0 “.O I.0 II.
1
.-,
.._~~____
12 2 1 i 6 3 7 2 1 NECESSARY
___ FREQUENCY
AVERAGE AGE YEARS
36.0 49.7 41.0 42.3 42.5 48.0 45.0 37.3 42.0 43.6 43.0 40.5 59.0
fin
6.0 7.8 12.3 6.5 12.0 37.0 14.25 10.0 19.5 38.0 30.0 12.0
__--..
--
OF TREATMENT
-__
Number Per cent
of patients of patients
TREATED ONCE A WEEK
TREATED EVERY 10 DAYS
21 38.18
3 5.45
TREATED EVERY 7 TO 10 DAYS
Number of patients Per cent of patients
24 43.64
___--
TREATED EVERY 2 WEEKS
25 45.45 TREATED EVERY 2 TO 4 WEEKS
31 56.36
TREATED EVERY 3-4 WEEKS
6 10.92
TOTALS
55 100 TOTALS
55 100
The necessary frequency of treatment is shown in Table 11. ‘l’went,y-one oi’ t.h(t 33 patients had to be treated once a week for maintenance therapy, 3 every ten days. 25 every second week, and the remaining 6 every third or fourth week. A further analysis of these data shows that 43.64 per cent of the patients could be maintained with treatment once every seven or ten days and .Tti.Z(i per cent of the patients 1)) treatment once every second to fourth week. These data indicate that estradiol dipropionate is clinically valuable in that treatment may be given at relatively infrequent interrxlx. The individual dosages may seem quite high but t,he dosage when considered on a mont,hly basis is not rer! large in the majority of patients (Table III I. The maintenancze dosage per four weeks in the 55 patients was 2.0 mg. or less in 21, 4.0 to 5.0 mg. in 10, 7.5 to 10.0 rug. in 15 and 15.0 to 20.0 mg. in 9; 5ti.36 per c+ent of the patients received 3.0 mg. 01 less per month and 27.27 per cent received i.5 to 10.0 mg. per month; 76.37 per cc’nt received what may be considered a fairly high tlosagr of 1.5.0 to 20 mg. per mnntll.
2.0 JIG.
4.0
OR LESS
Number of patients Per cent of patients 5.0
Number of patients Per cent of patients -~-
5.0
~-___-..--
.-.___7.5
TO 1 IO.0 MG.
TO xc.
21
10
15
38.18
18.18
27.27
MG.
OR
LESS
31 56.36
Patients were observed and questioned Twelve patients had some recurrence patients the bleeding was rather profuse for a short interval or when the dosage
i.5
T O 20.0
"4 43.64
-~.
.-.
15.0 l’O’l’.\i.S
TO
--
“0.0
MC.
9 16.37
MC:.
------r =I
.Ja 100
TOTALS
-
55 700
for systemic, reactions but none were noted. or exaggeration of uterine bleeding. In 3 but ceased when treatment was discontinued was lowered.
A comparison of the clinical effectiveness of identical amounts of estradiol dipropionate and estrone has been made. Eleven patients of this series whose maintenance dosage of estradiol dipropionate had been determined, have been given tltc, same amount in milligrams of estrone at the same time intervals. The patients were not informed of this substitution. Ten of the 11 patients had a recurrence of symp t,orns under treatment with estrone. When &radio1 llipropionate was again given, the symptoms disappeared. One patient of this group (Fig. 1) had a maintenance dosage of 2.0 mg. of e&radio1 dipropionate once a week. When estrone was substituted symptoms recurred in five days. Six patients had a maintenance dosage of 1.0 mg. of estrndiol dipropionate once a week. When estrone was substituted symptom s recurred in 5 of 6 patients in one to t,wo weeks (average 1.6 weeks). Findings in the sixth paGent are considered inconclusive because of irregular attendance to the clinic. Three patients had a maintenance dosage of 1 mg. of estradiol dipropionate every two weeks. With estrone symptoms recurred after two to four weeks (average 2.66) of treatment. One patient had previously been treated with 0.2 mg. of estrone a week with some improvemenr but not complete cessation of hot flushes. Her maintenance dosage of estradiol dipropionate for complete relief of symptoms was found to be 0.2 mg. of estradiol When e&one was substituted flushes rec.urred at tkck dipropionate every two weeks. end of the third week. One week after the return to estrxdiol dipropionatc, symptoms ceased. Weekly vaginal smears have been examined on ti of there menopausal patients. The smears have heen interpreted according to the criteria of Papanicolaou (Fig. He has shown that in the human being the menopausal smear is characterized 1). by few or no squamous epithelial cells and with varying proportions of small rounc? epithelial cells with large nuclei and leucocytes. Under adequate estrogenic therapy the vaginal smear consists almost exclusively of large flattened squamous epithelial cells with small darkly staining, ppknotic nuclei.
462
AMERICAN
JOURNAL
OF
OBSTFlRICS
AND
GYNECOLOGY
‘T’wo of these paCents received 1.0 mg. once every two weeks and their smearb were consistently of the menopausal type under treatment with both estradiol dipropionatr and e&one. In the other 4 patienm with tlosages of 1.0 or 2.0 mg. of estradiol dipropionate per week the smears were of thtb estrus or follicular type. When estrone was substituted after a lag of one or two weeks the smears regressed toward the menopausal types containing varying proportions of squamous epithelial cells, small round epitlielial cells and leucocytex. One to two weeks after e&radio1 dipropionate was resumed, the smears again returned to the estrus type. In addition to these menopausal patients, vaginal smears were made weekly on 4 patients who had been treated and cured of a vaginitis with e&radio1 dipropionate. One patient with senile vaginitis had been found to maintain a consistent smear of squamous epithelial cells on 1.0 mg. of cstradiol dipropionate once a week. When c&one was substituted, there was a gra~lual rrgression of the smear to t,he menoAt the end of the third week of estrone the smear consisted of equal pausal type. proportions of squamous epithelial cells, small round epithelial cells and leucocytex.
Fig. I.-Solid line shows number of hot flushes per day. Dotted line shows state of vaginal smear. This patient had been standardized at 2 mg. of e&radio1 dipropionate for six months. 4, Smear of squamous epithelial cells. 8, Smear of .aquamous epithelial cells and small round epithelial cells, 2, Smear of few squamous, many small round epithelial cells and a few leucocytes. 1, Smear of small round epithelial cells and leucocytes in equal proportions. 0, Smear of mostly leucocytes and a few small round epithelial cells. Three other patients had been treated for infantile vaginitis. In these patients it had been found that an estrus smear could be maintained for two weeks with 1.0 mg. of estradiol dipropionate. When estrone was substituted and the smear examined one week later, in addition to squamous epithelial cells, a few small round epithelial cells and leucocytes were found in 2 of these patients. At the end of the second week the smears in both had regressed almost completely to the infantile type. In the third patient, it was found that estrone would maintain the estrus smear for one week, but at the end of the second week the smear was made up of small round cells and leucocytes. On the basis, then, of recurrence of subjective symptoms in 10 of 11 menopausal patients and objective vaginal smear changes in 8 patients, estradiol dipropionate is clinically more effective per milligram in the human being than is estrone. DISCUSSIOK
This clinical study must not be interpreted as presenting data as to the absolute minimal, total dosages of e&radio1 dipropionate necessary to
DORR
AND
GREENE
:
ESTRADIOL
DIPROPIONA’Tlt
-Hi:l
control symptoms in menopausal patients. The emphasis has rather* been on an attempt to determine if this substance would be clinically valuable when given in moderate dosages at infrequent intervals. 1t. is quite possible that some of the patients who received treatment of 1.0, 2.0, or 5.0 mg. at two- to four-week intervals could have been maintained with smaller, total monthly dosages if treated at more frequent intervals. At any rate, this particular substance has a prolonged effect in the human being similar to that observed in the rat. This prolonged clinical effectiveness is qualitative. It is not (3~ merely to the dosages used. This is indicated by the fact that estronc, a substance that is supposed to have the same minimal effective dosic or rat unit has been subjectively and objectively inadequate when substituted for estradiol dipropionate. We do not, however, wish to indicate that WC consider this method the only way to treat patients with estrogenie substances or that estradiol dipropionate is the one and only ideal estrogenic hormone. It is possible that in the near future the natural estrogens (estrone, estradiol, estriol) will become sufficiently inexpensive for all such therapy to be given 1)~ mouth. This oral route would probably be preferred by many patients. lt is also possible, though, that some would prefer an intramuscular injection once every one or four weeks rather than a pill by mouth 3 times each day. Another possibility is that the use of the natural estrogens in the free or esterified forms will be completely supplanted by the new potent, estrogens of a more simple chemical structure as discovered by Dodds and his co-workers.15-1’ One of these synthetics, di-ethyl stilboestrol, has heen used for estrogenic therapy in human beings by several English workers.‘s-23 These workers have reported, however, nausea with occasional vomiting and epigastric pain in 9 per cent to 67.7 per cent, of treatr>d patients. It remains to be seen whether this complication is merely due to the method of administration or is inherent in the ccmpound. SUMMARY
AND
CONCLUSIONS
Estradiol dipropionate has been shown by previous workers to have a very prolonged estrogenic effect in the experimental animal. Evidence is presented that this compound also has a prolonged effect in the human being It is of unusual clinical value in that, injections may be given at infrequent intervals. A comparison with chst,ronr has shown estradinl c1ipropionat.e to be clinically more effective. REFERESCES
(1 J XacCorqtcdale, D. W,, Thayer, S. A., and Daisy, R. A.: J. Biol. Chem. 115: 435, 1936. (2) Daisy, E. d., Veler, C. D., and Thayer, S. A.: Am. J. Physiol. SO: Proc. Calif. Acad. Med. 1: 38, 1931. (4) P&us, G., 329, 1929. (3) Collip, 6. B.: ml Zahl,. P. A. : J. Gen. Physiol. 20: 879, 1937. (5) Pincus, G.: Symposia of Quantitative Biology 5: 44, 1937. (6) WesterJield, W. W., and Do&y, E. A.: Ann. Chim. Acta 20: Int. Med. 11: 267, 1937. (7) Miescher, K., and Scholz, C. : Helv. 263, 1937. (8) Miescher, E., Tschopp, E., and Scholz, C.: B&hem. J. 32: 725, Endocrinology 22: 28,1938. (10) Zondek, 19:3X. (9) Greene, R. R., and I%y, A. C.: 8.: Lancet 1: 1107, 1938. (11) Jadahson, Neplinger, and Zzlercher: Helv. Med. J. Obst. & Gynaec,. Brit. Emp. 44: 701, 1937. Acta 4: 199, 1937. (12) Lwsser, A.: Proc. Sot. Exper. Biol. & Med. 38: 439, 1938. (14) Dodds, K. (13) Salmon, U. 8.:
(‘.) FilzyL~trl(l, Jf. I<‘. Il.. tr~cti. I,~rcc’soi~. II’.: N:,l~lrc~ 140: iL’L’, 1Wi. (1.5) Ihllls, 1:‘. (‘., mcd Lnwso~t, 7V.: Ibid. 139: til’i, I!)::;. ( Iii) Itl6,h: Ibitl. 139: lO(i8, IYS’i. (17) Dotids, I:‘. C., Boldb~q, L., I~tr~r~.\oii. II’., ic,r~/ I;obi~~.w~r, I:.: Ibid. 141: 247, X., %rlc~l;rrmcrn, S.: I,anwt 1: 3, J939. (,19! 1938. (18) Bishop, Ii. X. F., f;o!ymtt. Whtertion, 7F. Ii., am1 XacGrc~,c/or, I’. ,\-.: lii,it. AI. .I. 1: 10. 1989. (20) Loes.Wr, .1. :7.: Ibid. 1: 112, 1929. (21) T’o~trrs.~/ot. .I.: Lancet 1: 296, ICILY. ( ?!I IZish07~. I’. 31. F.: Ibid. 1: ::54, 19::9. (2 ) N.i~tr t,fif~~, 77.. I;. : Ibitl. 1: -116, 19.W. -l)1~scIJ,ssl(~)~ DR. Ivl. ED\VARD l)AVlS.-This rellort on the treatment of the menopause with estradiol dipropionate emphasizes the inlpoktwe of choosing the proper available estrogenic substance. The prolonged and more pronounced effect of this estrogenic hormone which probably represents the t.rue f’ollicular substance simplifies therapy and provides more favorahlc result>. Our work confirms all of the observations of the authors. Some time ago we began the use of estrogens in suitable ointments for local application. This method of therapv shoul~l I liroretically be ideal for it obviates the necessity of hypodermk administration an11 provides a constant hormonal effect. 1Vr have used this preparation in approximately .JIJ patients with menopausal symptorllb and have found that it was of value in lesh than half of this group of women. In a number of our patients this type ol’ medication proviclell only partial relief. From these preliminary observations, \ve hare ccmclude[l that estrogens cannot be providcll the patient as readily hy the percutaneou,~ route as by ltypo(lermic administration. Lawson, and their co-workers ha\-e more rrl>ently introduced synthetit Dodds, compounds with estrogenic aetirity. During the last year these compounds have hrcn available for animal experimentatiun anrl clinical WC. Most o-f these synthetics organic compountls are derived front a eliemical compound designated as stilboestrol It has l~cn fount1 that these substances are several times more by Dodds and others. active than the natural e;;trogens, that tlnsy protluce all of the changes that can be ascribed t,o the use of natural suhstanr~es. anrl that they are as effective by oral administration as when nrlministc~re~l l~arentr~~:~11~. Thebe substances provide us with a new type of medication. for ora1 :l~lriiiiliht~r:~lioll is most de.sirahle. These synthetic compoundt; will likewise re~laie t~~enlcnil(lnsl~ tlic cost, of cstrogenic medication. with these artiDuring the past four monthh we leave t rtsatr11 :I nun~ber of patients ficial estrogens an11 have rrenrcll esWllrWt wru1tr. The only undesirable manifcstatious which we have noted hare been occasional nausea, vomiting, and headxvhe. Onl? additional observations will determine \\-hc~lrcr these manifestations occur too often to make the use of these preparationr u~l~lesi~xhlr. 1 t ix our inlpression tllat these ne\\ h,vntltetic organil, ~~oml~ounds will simplify as well :I$ Tile treatment of all other con~litionx vvllerc the therapy of the rr~eiu~pnu~c~ estrogens have been fount1 effect ire. DR. H. R. (+RJ:E:NF2 (closing).--lip1 * rlatural estrogens,” we meant the natural estrogens found only in the liuman being. ‘lYit~rc :LI’P several other estrogens found in animals, as for example in the l)reynant inat’c. We have hat1 ILO espericilvc with the ~till~~~estml referred to 1,~ Dr. Davis. The matter of nausea and vomiting with t1ri.s l~artieular substance is an observation not only on the part of I7r. Davis but nl+n in tlie English literature, where there are One man gave it hy ti reports concerning patients \\-I10 were given it by mouth. subcutaneous injection. am1 he also reported nausea and vomiting. The amount of nausea and vomiting v:rrie
OF THE MENOPAUSE DIPROPIONATE”
WITH
ESTRADIOL
EDWARD M. DORR, M.D., AND R. R. GREENE, MS., CHICAGO, ILL. (Prom the Departments of Gynecology and Obstetrics, Pharmacology of Northwestern University Me&cd School Service of St. Luks Hospital)
and
M.D., Physiology
a%d
and the Gynecology
N ESTROGENIC substance is any substance which has activities similar to those exhibited by the hormone of the ovarian follicle. In the human being, 3 chemically dist,inct and biologically active estroEstradiol has been genie substances have thus far been isolated. separated from follicular fluid in crystalline form and presumably is the true follicular horm0ne.l Estrone (theelin) and estriol (theelol) are found in pregnancy urine,* placenta” and presumably in nonpregnant urine. They probably represent excretion forms of the metabolized estradioL4e6 Various observers do not agree as to the exact potency of these 3 compounds, but do agree that estradiol is more potent than estrone and that estriol is the least potent of the 3 substances. It has been demonstrated by various workers that esterification of estradiol or estrone leads to a more prolonged physiologic effect on parenteral administration. This enhanced effect is due, presumably, to slower absorption of the compound.
A
In 1937 Miescher and Scholz; synthesized &radio1 dipropionate, which is the In this compound the 2 hydroxyl groups on the doubly esterified form of eatradiol. molecule have been replaced by propionic acid radicles. Miescher, Tsehopp and Scholzs have investigated the relative potency of this substance, with other esterified forms and with free estrone and estradiol. According to these workers the minimal rffertive dose or rat unit of estrone, estradiol benzoate, and estradiol dipropionate is the same, 0.00075 mg. Other workers agree fairly well on this rat unit for estrone but believe the rat unit for e&radio1 benzoate to be lower. Miescher and his coworkers found a marked difference in physiologic effect between these compounds. If 0.05 mg. of estrone, estradiol benzoate, or e&radio1 dipropionate were injected into castrate rats, the animals would go into e&us. In the estrone injected animals this estrus would persist for four or five days. In the animals injected with estradiol benzoate, estrus would persist for fourteen days. In animals injected with estradiol dipropionate, estrus would persist for forty-two days. Similar differences were noted when growth of the rat uterus was used as the criterion of estrogenic effectiveness. With the same dosage (0.05 mg.) the effect of estrone persisted eight days, with estradiol benzoate twenty-four day s, and with estradiol dipropionate, sixty days.
The value of estrogenic substances in the treatment of menopausal symptoms is quite well established. However there is little a,greement of opinion as to which substance should be used, or the method or freWe are well aware of the fact that desiccated quency of administration. thyroid or sedatives may be of value in some menopausal patients. Some individuals may even be improved by suggestion therapy. However, it *PrcsentPcl
at
:I
nlrrting
of
thP
ChiCRfi.o Gynecological Rooiety. March 17, lg$$l, 453
DORR
AND
GREENE:
ESTRADIOL
DIPROPIONATE
459
is very doubtful whether true menopausal symptoms such as the hot flush can be relieved in all patients by such means. Estrogens, if given The one in adequate dosage, will relieve these symptoms in all patients. qualification that must be added to this statement is that the symptoms the estrogens are expected to relieve must truly be menopausal symptoms and not entirely independent or even unrelated symptoms present in the woman of menopausal age. Estrogens are effective by a variety of routes: the oral, the percutaneous or the parenteral. With the exception of estriol glucuronide (emmenin) g which is of low potency, natural estrogens are many times more effective by parenteral administration than when given orally. Estrogens are at the present time quite costly. Their price per effective mout,h unit is such that treatment of the ordinary patient with dosages adequate to control menopausal symptoms is financially prohibitive. Several workers have shown that estrogens are absorbed through the skin and have systemic effects after percutaneous administration.l”-l” According to Zondek’O estrone in solution in alcohol, benzene, or ethel is as effective percutaneously in the experimental animal as it is snhcutaneously in oil. In oil or ointment solution it is only one-seventh as potent percutaneously as it is subcutaneously. Whether this relativcl cffect.iveness by percutaneous administration is equally as true in the human being has yet to be shown. A report by Salmon’” and experime& in progress by one of us (R. R. G.) would indicate that this is dollht~ful.
At, the present time the majority of patients are given estrogenic therapy by the intramuscular route. In t,his country, al; least, injections a.re nsually given 2 to 4 times weekly. Intramuscular injections are notpleasurable. Any estrogenic substance, then, t,hat would control menopausal spmpt,oms and that which could be given with a minimal frcqnency would be desirable. In view of the enhanced potency and prolonged physiologic effect of estradiol dipropionate in the experimental animal, it was thought worth while to determine the clinical value of this substance in the treatment of menopausal symptoms in the human female. METHODS
AND
RESULTS
Sixt,y-two menopausal patients have been treated with estradiol dipropionate.” Only 55 of these patients will be considered in this report. The remaining 7 patients are not included either because they had been observed over too short a period of time (un.der three months) or because their clinic attendance was so poor that it was not possible to estimate their maintenance dosage. The symptoms of the menopausal patient are many and varied. However, such patients have one common symptom, the hot flush. In view of this fact, the patients were instructed to keep an accurate record of the frequency and severity of the hot flushes. These data were used to a large ext,ent as the index of the success of therapy. It was noted that with disappearance or return of the hot flushes there was a corresponding subsidence or exacerbation of such symptoms as nervousness, irritability, fatigue, headaches, etc. *E&radio1 through the Incorporated.
dipropionate courtesy of
under the trade name Dr. Ernst Oppenheimer
“IX-ovocyclin” has been of Cibn Pharmaceutical
furnished Products
460
AMERICAN
JOURNAL
UF
OLlSTETRlCY
ANI)
GYNECOLOQY
The dispensary patients were seen once a week, the few private patients occa. sionally at more frequent intervals. It was found that patients were rendered symptom-free more rapidly by giving large doses ( 2.0 to 5.0 mg.) for the first few treatments. No patient was treated more often than once a week. After a patient was free from the hot flushes (usually one to three weeks) an att,empt vvas made to determine her maintenance dosage. This was a rather difficult procedure, being largely a matter of trial and error. However, by gr:rtlually lowering the dose, and prolonging the interval between treatments, at least the approximate maintenance dosage was determined which would keep each patient either entirely symptom-free or having not more than 1 or 2 hot flushes during the t’ourse of a week. A slight diminution in necessary dosage KS observed in only a few patients during the experimental period. This is probably clue tu the fact that only a relatively short Patients included in this series period of treatment is considered in this stully. are limited to those treated from three to nine months only. Slight and temporary reappearance of i;pmptoms was noted in :I few patients, or periods of unusual emotional stress. associated with upper respiratory infections. The ages of the patients in this series varied from 29 to 59 years, with an average age of forty-three years. Twenty-nine vver~ ’ ’ normal ’ ’ menopausal patients, 2:: The average age of the patients and the average postoperative and 3 postradiation. correlation duration of the symptoms are shown in Table T. There was no definite of these factors. The total between the neressnry maintenance dosage and either but no definite correlation dosage per month per patient has also been calculated was found with the age or length of symptoms. In theory, at least, one would expect that the necessary maintenance dosage would be less in patients whose symptoms had been present a long time in contrast t,o those In a larger seCrs of patients such a in whom the symptoms were of recent origin. correlation might be present.
--~ INTERVAT, IN WEEKS
DOSE IN MG.
AVERAGE LENGTH OF SYMPTOMS MONTHS
NITMBER OF PATIENTS -..-
0.2 o.5
-
-1.0----1.0 1.0 1.0 _-
__..-
2 5.0 5.0 5.0 5.0 5.0 TABLE
~--~~-..2 1 1 2 I> l 1 3 1.0 1.71 2.0 “.O I.0 II.
1
.-,
.._~~____
12 2 1 i 6 3 7 2 1 NECESSARY
___ FREQUENCY
AVERAGE AGE YEARS
36.0 49.7 41.0 42.3 42.5 48.0 45.0 37.3 42.0 43.6 43.0 40.5 59.0
fin
6.0 7.8 12.3 6.5 12.0 37.0 14.25 10.0 19.5 38.0 30.0 12.0
__--..
--
OF TREATMENT
-__
Number Per cent
of patients of patients
TREATED ONCE A WEEK
TREATED EVERY 10 DAYS
21 38.18
3 5.45
TREATED EVERY 7 TO 10 DAYS
Number of patients Per cent of patients
24 43.64
___--
TREATED EVERY 2 WEEKS
25 45.45 TREATED EVERY 2 TO 4 WEEKS
31 56.36
TREATED EVERY 3-4 WEEKS
6 10.92
TOTALS
55 100 TOTALS
55 100
The necessary frequency of treatment is shown in Table 11. ‘l’went,y-one oi’ t.h(t 33 patients had to be treated once a week for maintenance therapy, 3 every ten days. 25 every second week, and the remaining 6 every third or fourth week. A further analysis of these data shows that 43.64 per cent of the patients could be maintained with treatment once every seven or ten days and .Tti.Z(i per cent of the patients 1)) treatment once every second to fourth week. These data indicate that estradiol dipropionate is clinically valuable in that treatment may be given at relatively infrequent interrxlx. The individual dosages may seem quite high but t,he dosage when considered on a mont,hly basis is not rer! large in the majority of patients (Table III I. The maintenancze dosage per four weeks in the 55 patients was 2.0 mg. or less in 21, 4.0 to 5.0 mg. in 10, 7.5 to 10.0 rug. in 15 and 15.0 to 20.0 mg. in 9; 5ti.36 per c+ent of the patients received 3.0 mg. 01 less per month and 27.27 per cent received i.5 to 10.0 mg. per month; 76.37 per cc’nt received what may be considered a fairly high tlosagr of 1.5.0 to 20 mg. per mnntll.
2.0 JIG.
4.0
OR LESS
Number of patients Per cent of patients 5.0
Number of patients Per cent of patients -~-
5.0
~-___-..--
.-.___7.5
TO 1 IO.0 MG.
TO xc.
21
10
15
38.18
18.18
27.27
MG.
OR
LESS
31 56.36
Patients were observed and questioned Twelve patients had some recurrence patients the bleeding was rather profuse for a short interval or when the dosage
i.5
T O 20.0
"4 43.64
-~.
.-.
15.0 l’O’l’.\i.S
TO
--
“0.0
MC.
9 16.37
MC:.
------r =I
.Ja 100
TOTALS
-
55 700
for systemic, reactions but none were noted. or exaggeration of uterine bleeding. In 3 but ceased when treatment was discontinued was lowered.
A comparison of the clinical effectiveness of identical amounts of estradiol dipropionate and estrone has been made. Eleven patients of this series whose maintenance dosage of estradiol dipropionate had been determined, have been given tltc, same amount in milligrams of estrone at the same time intervals. The patients were not informed of this substitution. Ten of the 11 patients had a recurrence of symp t,orns under treatment with estrone. When &radio1 llipropionate was again given, the symptoms disappeared. One patient of this group (Fig. 1) had a maintenance dosage of 2.0 mg. of e&radio1 dipropionate once a week. When estrone was substituted symptoms recurred in five days. Six patients had a maintenance dosage of 1.0 mg. of estrndiol dipropionate once a week. When estrone was substituted symptom s recurred in 5 of 6 patients in one to t,wo weeks (average 1.6 weeks). Findings in the sixth paGent are considered inconclusive because of irregular attendance to the clinic. Three patients had a maintenance dosage of 1 mg. of estradiol dipropionate every two weeks. With estrone symptoms recurred after two to four weeks (average 2.66) of treatment. One patient had previously been treated with 0.2 mg. of estrone a week with some improvemenr but not complete cessation of hot flushes. Her maintenance dosage of estradiol dipropionate for complete relief of symptoms was found to be 0.2 mg. of estradiol When e&one was substituted flushes rec.urred at tkck dipropionate every two weeks. end of the third week. One week after the return to estrxdiol dipropionatc, symptoms ceased. Weekly vaginal smears have been examined on ti of there menopausal patients. The smears have heen interpreted according to the criteria of Papanicolaou (Fig. He has shown that in the human being the menopausal smear is characterized 1). by few or no squamous epithelial cells and with varying proportions of small rounc? epithelial cells with large nuclei and leucocytes. Under adequate estrogenic therapy the vaginal smear consists almost exclusively of large flattened squamous epithelial cells with small darkly staining, ppknotic nuclei.
462
AMERICAN
JOURNAL
OF
OBSTFlRICS
AND
GYNECOLOGY
‘T’wo of these paCents received 1.0 mg. once every two weeks and their smearb were consistently of the menopausal type under treatment with both estradiol dipropionatr and e&one. In the other 4 patienm with tlosages of 1.0 or 2.0 mg. of estradiol dipropionate per week the smears were of thtb estrus or follicular type. When estrone was substituted after a lag of one or two weeks the smears regressed toward the menopausal types containing varying proportions of squamous epithelial cells, small round epitlielial cells and leucocytex. One to two weeks after e&radio1 dipropionate was resumed, the smears again returned to the estrus type. In addition to these menopausal patients, vaginal smears were made weekly on 4 patients who had been treated and cured of a vaginitis with e&radio1 dipropionate. One patient with senile vaginitis had been found to maintain a consistent smear of squamous epithelial cells on 1.0 mg. of cstradiol dipropionate once a week. When c&one was substituted, there was a gra~lual rrgression of the smear to t,he menoAt the end of the third week of estrone the smear consisted of equal pausal type. proportions of squamous epithelial cells, small round epithelial cells and leucocytex.
Fig. I.-Solid line shows number of hot flushes per day. Dotted line shows state of vaginal smear. This patient had been standardized at 2 mg. of e&radio1 dipropionate for six months. 4, Smear of squamous epithelial cells. 8, Smear of .aquamous epithelial cells and small round epithelial cells, 2, Smear of few squamous, many small round epithelial cells and a few leucocytes. 1, Smear of small round epithelial cells and leucocytes in equal proportions. 0, Smear of mostly leucocytes and a few small round epithelial cells. Three other patients had been treated for infantile vaginitis. In these patients it had been found that an estrus smear could be maintained for two weeks with 1.0 mg. of estradiol dipropionate. When estrone was substituted and the smear examined one week later, in addition to squamous epithelial cells, a few small round epithelial cells and leucocytes were found in 2 of these patients. At the end of the second week the smears in both had regressed almost completely to the infantile type. In the third patient, it was found that estrone would maintain the estrus smear for one week, but at the end of the second week the smear was made up of small round cells and leucocytes. On the basis, then, of recurrence of subjective symptoms in 10 of 11 menopausal patients and objective vaginal smear changes in 8 patients, estradiol dipropionate is clinically more effective per milligram in the human being than is estrone. DISCUSSIOK
This clinical study must not be interpreted as presenting data as to the absolute minimal, total dosages of e&radio1 dipropionate necessary to
DORR
AND
GREENE
:
ESTRADIOL
DIPROPIONA’Tlt
-Hi:l
control symptoms in menopausal patients. The emphasis has rather* been on an attempt to determine if this substance would be clinically valuable when given in moderate dosages at infrequent intervals. 1t. is quite possible that some of the patients who received treatment of 1.0, 2.0, or 5.0 mg. at two- to four-week intervals could have been maintained with smaller, total monthly dosages if treated at more frequent intervals. At any rate, this particular substance has a prolonged effect in the human being similar to that observed in the rat. This prolonged clinical effectiveness is qualitative. It is not (3~ merely to the dosages used. This is indicated by the fact that estronc, a substance that is supposed to have the same minimal effective dosic or rat unit has been subjectively and objectively inadequate when substituted for estradiol dipropionate. We do not, however, wish to indicate that WC consider this method the only way to treat patients with estrogenie substances or that estradiol dipropionate is the one and only ideal estrogenic hormone. It is possible that in the near future the natural estrogens (estrone, estradiol, estriol) will become sufficiently inexpensive for all such therapy to be given 1)~ mouth. This oral route would probably be preferred by many patients. lt is also possible, though, that some would prefer an intramuscular injection once every one or four weeks rather than a pill by mouth 3 times each day. Another possibility is that the use of the natural estrogens in the free or esterified forms will be completely supplanted by the new potent, estrogens of a more simple chemical structure as discovered by Dodds and his co-workers.15-1’ One of these synthetics, di-ethyl stilboestrol, has heen used for estrogenic therapy in human beings by several English workers.‘s-23 These workers have reported, however, nausea with occasional vomiting and epigastric pain in 9 per cent to 67.7 per cent, of treatr>d patients. It remains to be seen whether this complication is merely due to the method of administration or is inherent in the ccmpound. SUMMARY
AND
CONCLUSIONS
Estradiol dipropionate has been shown by previous workers to have a very prolonged estrogenic effect in the experimental animal. Evidence is presented that this compound also has a prolonged effect in the human being It is of unusual clinical value in that, injections may be given at infrequent intervals. A comparison with chst,ronr has shown estradinl c1ipropionat.e to be clinically more effective. REFERESCES
(1 J XacCorqtcdale, D. W,, Thayer, S. A., and Daisy, R. A.: J. Biol. Chem. 115: 435, 1936. (2) Daisy, E. d., Veler, C. D., and Thayer, S. A.: Am. J. Physiol. SO: Proc. Calif. Acad. Med. 1: 38, 1931. (4) P&us, G., 329, 1929. (3) Collip, 6. B.: ml Zahl,. P. A. : J. Gen. Physiol. 20: 879, 1937. (5) Pincus, G.: Symposia of Quantitative Biology 5: 44, 1937. (6) WesterJield, W. W., and Do&y, E. A.: Ann. Chim. Acta 20: Int. Med. 11: 267, 1937. (7) Miescher, K., and Scholz, C. : Helv. 263, 1937. (8) Miescher, E., Tschopp, E., and Scholz, C.: B&hem. J. 32: 725, Endocrinology 22: 28,1938. (10) Zondek, 19:3X. (9) Greene, R. R., and I%y, A. C.: 8.: Lancet 1: 1107, 1938. (11) Jadahson, Neplinger, and Zzlercher: Helv. Med. J. Obst. & Gynaec,. Brit. Emp. 44: 701, 1937. Acta 4: 199, 1937. (12) Lwsser, A.: Proc. Sot. Exper. Biol. & Med. 38: 439, 1938. (14) Dodds, K. (13) Salmon, U. 8.:
(‘.) FilzyL~trl(l, Jf. I<‘. Il.. tr~cti. I,~rcc’soi~. II’.: N:,l~lrc~ 140: iL’L’, 1Wi. (1.5) Ihllls, 1:‘. (‘., mcd Lnwso~t, 7V.: Ibid. 139: til’i, I!)::;. ( Iii) Itl6,h: Ibitl. 139: lO(i8, IYS’i. (17) Dotids, I:‘. C., Boldb~q, L., I~tr~r~.\oii. II’., ic,r~/ I;obi~~.w~r, I:.: Ibid. 141: 247, X., %rlc~l;rrmcrn, S.: I,anwt 1: 3, J939. (,19! 1938. (18) Bishop, Ii. X. F., f;o!ymtt. Whtertion, 7F. Ii., am1 XacGrc~,c/or, I’. ,\-.: lii,it. AI. .I. 1: 10. 1989. (20) Loes.Wr, .1. :7.: Ibid. 1: 112, 1929. (21) T’o~trrs.~/ot. .I.: Lancet 1: 296, ICILY. ( ?!I IZish07~. I’. 31. F.: Ibid. 1: ::54, 19::9. (2 ) N.i~tr t,fif~~, 77.. I;. : Ibitl. 1: -116, 19.W. -l)1~scIJ,ssl(~)~ DR. Ivl. ED\VARD l)AVlS.-This rellort on the treatment of the menopause with estradiol dipropionate emphasizes the inlpoktwe of choosing the proper available estrogenic substance. The prolonged and more pronounced effect of this estrogenic hormone which probably represents the t.rue f’ollicular substance simplifies therapy and provides more favorahlc result>. Our work confirms all of the observations of the authors. Some time ago we began the use of estrogens in suitable ointments for local application. This method of therapv shoul~l I liroretically be ideal for it obviates the necessity of hypodermk administration an11 provides a constant hormonal effect. 1Vr have used this preparation in approximately .JIJ patients with menopausal symptorllb and have found that it was of value in lesh than half of this group of women. In a number of our patients this type ol’ medication proviclell only partial relief. From these preliminary observations, \ve hare ccmclude[l that estrogens cannot be providcll the patient as readily hy the percutaneou,~ route as by ltypo(lermic administration. Lawson, and their co-workers ha\-e more rrl>ently introduced synthetit Dodds, compounds with estrogenic aetirity. During the last year these compounds have hrcn available for animal experimentatiun anrl clinical WC. Most o-f these synthetics organic compountls are derived front a eliemical compound designated as stilboestrol It has l~cn fount1 that these substances are several times more by Dodds and others. active than the natural e;;trogens, that tlnsy protluce all of the changes that can be ascribed t,o the use of natural suhstanr~es. anrl that they are as effective by oral administration as when nrlministc~re~l l~arentr~~:~11~. Thebe substances provide us with a new type of medication. for ora1 :l~lriiiiliht~r:~lioll is most de.sirahle. These synthetic compoundt; will likewise re~laie t~~enlcnil(lnsl~ tlic cost, of cstrogenic medication. with these artiDuring the past four monthh we leave t rtsatr11 :I nun~ber of patients ficial estrogens an11 have rrenrcll esWllrWt wru1tr. The only undesirable manifcstatious which we have noted hare been occasional nausea, vomiting, and headxvhe. Onl? additional observations will determine \\-hc~lrcr these manifestations occur too often to make the use of these preparationr u~l~lesi~xhlr. 1 t ix our inlpression tllat these ne\\ h,vntltetic organil, ~~oml~ounds will simplify as well :I$ Tile treatment of all other con~litionx vvllerc the therapy of the rr~eiu~pnu~c~ estrogens have been fount1 effect ire. DR. H. R. (+RJ:E:NF2 (closing).--lip1 * rlatural estrogens,” we meant the natural estrogens found only in the liuman being. ‘lYit~rc :LI’P several other estrogens found in animals, as for example in the l)reynant inat’c. We have hat1 ILO espericilvc with the ~till~~~estml referred to 1,~ Dr. Davis. The matter of nausea and vomiting with t1ri.s l~artieular substance is an observation not only on the part of I7r. Davis but nl+n in tlie English literature, where there are One man gave it hy ti reports concerning patients \\-I10 were given it by mouth. subcutaneous injection. am1 he also reported nausea and vomiting. The amount of nausea and vomiting v:rrie