The use of stilbestrol in the menopause and other conditions

THE USE OF STILBESTROL IN THE MENOPAUSE AND OTHER CONDITIONS* CHARLES S. BIRNBERG, M.D.

LAWRENCE KURZROK, M.D., Associate Assistant

Associate

Obstetrician and GynecoIogist, Greenpoint Hospital; Obstetrician and Endocrinologist, Jewish HospitaI

Obstetrician and EndocrinoIogist, Jewish HospitaI

AND HENRY Assistant

Obstetrician

WEBER,

M.D.

and Endocrinologist,

BROOKLYN,

NEW

ODDS, Lawson and NobIe, GoIdberg and Robinson, MacGregor, and Winterton and Loeser have brought to the fore a drug, identified chemicahy as 4, 4-dihydroxy-aIpha-betadiethy stiIbene. This substance, caIIed stiIbestro1, is capabIe of repIacing in every way the action of estrone or estradiol, despite the fact that the moIecuIar structure is entireIy different from that of natura1 estrone. The amount of I mg. of diethyIstiIbestro1 is equivaIent to 25,000 internationa1 units of estrone, according to observers. NobIe demonstrated that administration of aqueous soIutions of stilbestrol oraIIy was foIIowed by reduction of growth of the animaIs, with a dosage of 2 to 3 mg. Inhibition of the gonadotropic hormone of the anterior pituitary gIand, with resuIting atrophy of the gonads, was observed when Iarger amounts of stiIbestro1 were given. In Iactating rats as Iow a dose as 2 to 3 mg. per day appreciabIy reduced the growth of their Iitters. That the mammary gIands were in a condition to yieId more miIk was shown by their increased secretion when treatment was discontinued. It was not found possibIe to inhibit Iactation compIeteIy, even when stiIbestro1 was administered to the femaIe rat before parturition. MeIIish, Baer, and Macias reported that stiIbestro1 and stiIbestro1 dipropionate were at Ieast as effective as an equa1 weight of

Jewish

HospitaI

YORK

estrone in producing growth and deveIopment of the immature rabbit uterus and in sensitizing it to progesterone. Subcutaneous impIants of IO mg. of stiIbestro1 and stiIbestro1 dipropionate in animaIs inhibited body growth and growth of the gonads. Treatment with the stiIbene derivatives increased the weight of the pituitary, but did not cause a significant change in the weight of the adrenaIs. It has been shown by Zondek and SuIman that approximateIy $0 per cent of the stiIbestro1 given is excreted, and can be recovered from the urine and feces, in approximately equa1 amounts. In contrast stiIbestro1 is onIy rendered to estrone, inactive in the organism to a smaI1 extent, resembIing, in this respect, the hormone esters. StiIbestroI remains deposited at the site of injection for a considerable time (depot formation) and from there it is sIowIy absorbed, similar to the hormone esters. In the excreta Iarge amounts of the active substance are found. The fact that the organism is unabIe to inactivate considerabIe amounts of stiIbestro1 may expIain its possible toxic activity. IXeIIar used stiIbestro1 in a group of over twenty women. In six patients suffering from severe menopausa1 symptoms, he was abIe to contro1 the symptoms fuIIy. In three cases of senile vaginitis and two of IeucopIakia vulvae, the patients benefited to a marked degree. Three cases of secondary

D

* From the GynecoIogicaI Endocrine Clinic, Department of Obstetrics and GynecoIogy, Greenpoint Hospital, the FemaIe Sex EndocrinoIogy Clinic, Department of EndocrinoIogy, Jewish Hospital, BrookIyn. 311

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amenorrhea bIeed after courses of &Ibestro1, but biopsies reveaIed onIy a proIiferative endometrium with numerous mitoses. Attempts at treatment of inertia type of Iabor and therapeutic abortion faiIed to revea1 any concIusive resuhs as to sensitization of the uterus or improvement of uterine contractions. OccasionaIIy there was, however, a striking success. Inhibition of Iactation was induced by administration of 3 mg. of stiIbestro1 daiIy for a few days. There were three cases of nausea in this series. Shorr, Robinson and PapanicoIaou treated forty-four patients with stiIbestro1. In eight cases, fuI1 foIIicuIar vagina1 smears were obtained, whiIe in seventeen others advanced prefoIIicuIar smears were shown. However, there was faiIure of increasing doses of stiIbestro1 to bring about progressive changes in the smears. BIeeding after cessation of treatment occurred in severa cases of menopause and amenorrhea. There was reIief from symptoms of menopause in twenty-eight cases. Toxic manifestations occurred as foIIows : nausea in thirty-seven, vomiting in fourteen, abdomina1 distress in thirty-one, diarrhea in seven, Iassitude in thirty-two, skin rashes in eight, psychotic reaction in one, vertigo in six, marked thirst in one and paresthesias in two. These toxic symptoms persisted in some instances as Iong as three weeks after cessation of the treatment. The concept of IocaI irritation of the gastric and intestina1 mucosa is contradicted by the Iarge number of severe reactions encountered when the drug was given intramuscuIarIy. Buxton and EngIe reported improvement of symptoms in seventeen patients treated with stiIbestro1. Nausea and vomiting occurred in four cases and bore no reIationship to the amount of the drug used. One patient deveIoped aIbuminuria and casts in the urine, whereas previousIy no such findings had been observed. Liver function tests were inconcIusive. Winterton and MacGregor treated fifty-one patients with stiIbestro1 and obtained good resuIts in treatment of menopause and amenorrhea, simiIar to those

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obtainabIe with estrogens. There were six patients who suffered by-effects, mostIy nausea, with onIy two cases of actua1 sickness. Inhibition of Iactation occurred in three patients with doses of 5 mg. daiIy in whom the drug was used before Iactation had set in, and was of IittIe advantage once Iactation had begun. Karnaky used stiIbestro1 in over one hundred patients, with gonorrhea1 vaginitis, pruritus vuIvae and seniIa vaginitis. He gave doses up to I mg. without any harmfu1 symptoms, but obtained nausea and vomiting with I mg. or over, occasionaIIy. He states that he gave 5 to 90 mg. at one injection without iII effects. Vagina1 PH changed from 6 to 7.2 to PH of 4.0 with 5 to 7 mg. of the parentera medication. The patients were greatIy benefited. EquaI effects were obtained by mouth, by injection and by suppository. The vagina1 mucosa became aduIt in type. Functiona uterine bIeeding was improved or stopped in fourteen cases. There was an improvement in the character of the endometrium on biopsy, the endometria1 gIands were smaIIer in some cases and the cystic endometrium returned to the resting stage. Three cases of amenorrhea were made to bIeed by giving 2 mg. twice a week for three weeks. One case of dysmenorrhea was reIieved. Geist and SaImon used stiIbestro1 in thirty-eight menopause cases. When given by injection, estrogen smear changes appeared after administration of IO to 20 mg. FIushes, in particuIar, were reIieved by tota dosages of from 15 to 25 mg. Nausea and anorexia occurred in 20 per cent of the women. In tweIve patients who had ora administration, ten deveIoped toxic symptoms on doses of I to 5 mg. daiIy. OnIy eight patients were abIe to continue the drug more than a week. It is interesting to note that two of the cases which did not respond cIinicaIIy showed vagina1 smears indicating an estrogen effect. Resnik’s work with stiIbestro1 yieIded good cIinica1 resuIts in most cases with about 23 per cent toxic by-effects noted.

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Biship, BoycoII and Zuckerman noted nausea and vomiting in three of forty-six patients. Varangot found severe gastrointestina1 reactions in eight of eighteen women. Ehrhardt, Kramson and Schafer also reported a Iarge number of unpIeasant side effects which, however, they incIine to attribute to overdosage of stiIbestro1. R. Kurzrok, WiIson, and PerIoff reported a number of toxic symptoms resulting from the use of stiIbestro1. Lack of agreement is seen in the reports of toxicity studiesi n animaIs. They uniformly confirm the estrogenic activity of the compound and revea1 an extraordinary similarity in action to the natura1 estrogens. But in contrast to the earIy indications of its harmIessness, Loeser noted in rats, decreased appetite, epistaxis, vaginal and intestina1 hemorrhages, fatty degeneration with subsequent necrosis of the Iiver, enIargement of the adrenals with arteria1 hyperemia and bIeeding and enIargement of the spIeen with hemorrhagic reaction in the isIands. According to Krietmair and Siechmann the administration of from 0.5 to I mg. per Gm. to mice resuIted in death in from IO to 16 days. In rats I .s to 5 mg. per Gm. resuIted in paraIysis and death in an hour. TisIowitz observed a disturbance of the hyeIogenic system, and granuIocytopenia and anemia in dogs receiving 5 mg. by injection for from twenty-five to fifty days. MorreII, on the other hand, has faiIed to observe any pathoIogic changes in the tissues of rats, rabbits and monkeys. A series of 122 women treated by the administration of diethyIstiIbestro1 and diethyIstiIbestro1 dipropionate is herein reported. Since these two syntheticaIIy prepared compounds have shown much the same effects and benefits, as we11 as byeffects, and the effect on the vagina appears to be aImost identica1, we do not differentiate in the resuIts obtained. The indications for treatment were as foIIows : menopause, I I 2 cases; arthraIgia (menopausaI), eight cases; migraine, two cases; and premenstrua1 tension, four cases.

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Administration of stiIbestro1 was by intramuscuIar injection in doses of I to 5 mg. twice weekIy or parenteraIIy in amounts of 2 to 3 mg. daiIy. SimiIar resuIts were obtained with the two modes of therapy. Vagina1 PH determinations and vagina1 smears were done routineIy at weekIy intervaIs during and after cessation of stiIbestro1 treatment. Cases previousIy treated with estrogens reveaIed a vaginal PH of 4 to 5 and a vagina1 smear of pIus 3 to 4, according to the technic of Papanicolaou and Shorr. Untreated patients usuaIIy showed a vagina1 smear of pIus I to 2, and an acidity of PH 6 to 7. After administration of I mg. of stiIbestro1, for a period of two to three weeks, the vagina1 acidity ranged between pw 5 to 6 generaIIy with a pIus 2 to 3 vagina1 smear. After administration of 2 to 5 mg. of stiIbestro1 for a period of two to three weeks, the vagina1 acidity was between PH 4 to 5 with a pIus 3 to 4 smear. A number of cases showed considerabIe inconsistency between the vagina1 smear and PH determination, such as a fuI1 estrogenic smear with PH of 6 to 8. Five weeks after cessation of stiIbestro1 medication, the genera1 picture was that of reversion to the untreated state. There were severa exceptions, in which fuI1 foIIicuIar smears and PH of 4 to 5 were found. A number of these patients compIained of moderate menopausa1 symptoms, even though fuI1 estrogenic vagina1 effect was noted, a finding in accord with other reports. Biopsies of the endometrium in cases of bIeeding varied from hyperpIasia during menorrhagia to insuffIcient materia1 in a postradium menorrhagia, to a secretory endometrium in a thirty-seven year old woman with premenstrua1 tension and menopausa1 complaints. SuccessfuI resuIts were obtained in seventy-eight cases or 64 per cent, with dosage of 2 to 5 mg. administered by injection, biweekIy, or z to 3 mg. given parenteraIIy daiIy. A few patients were benefited by doses of I mg. daiIy. The two cases of

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premenstrua1 migraine were aided. Five of the cases of arthraIgia were improved. Four women with premenstrua1 tension were heIped in various degree. There were twenty-eight cases, or 35 per cent, who were intoIerant to stiIbestro1 and in whom medication had to be discontinued aImost immediateIy. Total dosage in some instances was 200 mg. given over a period of two to three months. Reactions to stiIbestro1 therapy occurred as foIIows : No. of Cases Locate reaction to injection or genIO eralized rash with pruritus Nausea......................... 37 Vomiting. 20 Epigastric distress.. IO 7 Diarrhea.. 4 Weakness or faintness.. I Aching joints.

Among the toxic by-effects, nausea usuaIIy Iasted for two to three days and diarrhea for the same Iength of time. In no instance was there any tenderness over the Iiver or jaundice. MastaIgia did not occur. There was no bIeeding in postsurgica1 menopause cases. Increased vagina1 secretion occurred in severa patients. Moderate bIeeding occurred in thirteen cases, in women stiI1 menstruating with menopausa1 compIaints during treatment with stiIbestro1. BIeeding occurred in one patient six years postmenopause Iasting fourteen days. The effect of stiIbestro1 upon Iactation wiI1 be reported at a Iater date. SUMMARY I. StiIbestroI of 122 women compIaints.

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was used in a series mainly with menopausa1

2. Vagina1 smears generaIIy showed a good estrogenic effect. 3. VaginaI PH determinations frequentIy did not coincide with the cytoIogic changes. 4. SuccessfuI resuIts were obtained in 64 per cent of cases. 5. Toxic manifestations occurred in a considerable number of patients, the most frequent being nausea, which took pIace in thirty-seven cases, or 30 per cent. 6. Toxic manifestations did not seem to depend on tota dosage. 7. StiIbestroI shouId be used only on direction of a physician and the patient foIIowed carefuIIy. We wish to thank the Winthrop Company and the Endo Products for their co-operation in supplying bestrol used in this series.

ChemicaI Company the stiI-

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