- Email: [email protected]
Androgen Therapy of Menopausal Symptoms in Cancer Patients*
G02 and have had them look into the stereo~eope hut they eouldn 't ~eP anything tiHtt wa~ 1111 to the <'onelu~ion, as far a~ I was roneerned, that it was a hopelP's propo~ition. I believe the qualitative method of ('aldwell and Moloy 1' tit•• )lPHt ll1<'1111Jd W<' !J:n-.. l'·>l studying cephalopelvie disproportion, but ,Y1l in lH;l:;! baek at thP !Pwl of the s:wrum all!! took :1 picture in the erect posturP. \\'p u'e a nwtal ru]p and put it lwtwe\'Il thP patient·~ leg~. I am not entirely prepared to ('omhat Dr. Moloy'' criti<'imt of the standing lateral. We took standing lateral' for a good many years aml I was unimpressed hy any ht'ads jumping in the pelvis that wen• out of the pelvis when the patient was lying down. T alRo think that if any patient in whom you are interestPd has eephalopelvie 1lisproportion, there i~ going to be very little desrent of the head, irresjwl'ti n~ of its position, bdore going into labor. Dr. Maloy told me that lw was going to quE'stion the lying down lateral position. L feel you should take both pietures with the p:ttient in the same position, whether l~·ing down or standing up, but not take one lying down and one standing up :md transpose from one to the other. I feel that in our lateral picture if tlw head is at or near thp pelvie brim, you •·an get a fairly good estimate of whether or not the head is going to go through. We are very cautious in our prognostications because too many factor~ PntPr into thp <·oursP of labor besides the size of the head and the size of tlrz' f.'lvis.
AND&OGEN THDA.PY 01' MliHOP.A.UI.AL SYMPTOJIS IN OANOBR PATIBNTS* S. B. GuSBERG, M.D., NEw YoRK, N.Y. (From the Sloane Hospital for Women and the Department of Obstetrics and Gynecology, Columbia UniFet·sity)
Introduction REATMENT of the menopausal patient with estrogenic substances is a well-established and effective method of controlling the uncomfortable symptoms which sometimes occur with the decline and cessation of ovarian activity. The explanation for the effectiveness of this therapy has been studied for many years; some observers suggest that this efficiency in relation to the vasomotor symptoms of the menopause is probably due to inhibition of overactivity of the anterior pituitary gland. This explanation would be in accord with the well-known reciprocal interaction of the pituitary gland and the various glands of internal secretion whi~h it governs. We have been dissatisfied with the use of stilbestrol in a certain group of menopausal patients in whom we believed the stimulating effect of estrogen was contraindicated. This includes those who have been treated for some form of cancer of the reproductive organs and also some of those in whom estrogenic therapy has provoked uterine bleeding. It is not within the province or this presentation to discuss the possible relationship between estrogens and carcinogenesis. This relationship has been studied and debated by numerous careful observers for many years; our own data and conclusions will be presented elsewhere. Suffice it to say that in the human species whose genetic
T
*Presented at the New York Academy of Medicine, Section of Obstetrics and Gynecology, Jan. 23, 1945.
GUSBERG:
ANDROGEN THERAPY OF ME~OPAUSAL SYMPTOMS
503
pattern is so complex, we think it unwise to subject susceptible tissue to a stimulating substance; those individuals who have already demonstrated the responsiveness of one of the reproductive organs to whatever abnormal stimulus develops carcinoma would seem especially unfavorable subjects in whom to administer a cell-proliferating substance like estrogen. We have also become impressed with the fundamental error in continuing estrogenic therapy in any postmenopausal individual for long periods of time for it creates a habit which is difficult to break; we have sought a method to remedy this condition. These eonsiderations, together with the occasional production of abnormal endometrial patterns in patients who have developed stilbestrol bleeding led ·Js to the use of androgen therapy for this selected group of menopausal patients. In animals, a variety of uterine and vaginal responses have been produced by androgens (Salmon, Geist, et al.I), some of a stimulating nature, others of an inhibitory nature. There is a suggestion in some of this work that mature animals most co=only 11how an inhibitory response, especially with small doses. Inhibition of reproductive tract activity in animals by androgens has been demonstrated by many workers, among them Ihrke and D'Amour,2 Robson,3 Zuckerman,4 and Hartman.5 Inhibitory action on menstruation has aiso been demonstrated in humans by Papanicolaou, Ripley, and Shorr,s Loeser,7 Geist, Salmon, and their associates,! Huffman,s Greenblatt,9 and others. In the increasing literature concerning the use of androgens for abnormal uterine bleeding, it would appear that doses of testosterone propionate under 400 to 500 mg. monthly will reduce bleeding effectively without changing the endometrial pattern, while doses higher than this are required to produce endometrial regression. There are no reports of stimulation of the human endometrium by androgens. Engle and SmithiO working with castrated mature Rhesus monkeys were able to maintain endometria primed by the use of estrogens and progesterone, with short courses of testosterone propionate treatment. They suggest, however, that this sequence of administration may not inhibit the pituitary as androgens are believed to do when given throughout the menstrual cycle. It has been suggested by other workers (Salmon, Geist, et al.,l Huffman,s Greenhill and Freed,n and Aub2S) that inhibition of the pituitary is the probable mode of action of androgen therapy in the control of uterine bleeding. In menopausal patients there bas been more direct evidence that androgen therapy can reduce anterior pituitary hyperactivity. Nathanson and Townel2 and Salmon1 3 clearly demonstrated reduction in urinary gonadotropins as treatment proceeded and symptoms were ameliorated. Similar findings were obtained by Shorr, Papanicolaou, and Stimmel,H Laroche, et al.,I5 and Rotbermicb and ]'oltz.lS The use of androgen therapy for the menopausal syndrome has been suggested by several workers since 1936. In that year Mocquot and Moricard,17 and Margeil and Zwillingls reported the effectiveness of this therapy. Since that time there have been several small groups of cases reported, including those of Kurzrok, Birnberg and Livingston,I9 Mandy and Mandy,2o McCullagh and McGurl,21 Geist and Salmon,22 Kurzrok and Rothbart,23 Silberman, Radman, and Abarbanel,24 Greenhill,25 .Joe1,2s Loeser,27 and Greenblatt.9 For the most part these investigators used testosterone propionate parenterally, though several mention the U:le of methyl testosterone by mouth; in some instances a combined stilbestrol-androgen therapy was given. In general the results of treatment were excellent. In none of these reports is there any evidence of uterine stimulation by this androgen therapy.
The fear of untoward symptoms and masculinization has deterred many gynecologists from the use of androgen therapy. This healthy regard for the patient's complete safety is readily understandable when one studies the undesirable effects produced by large or prolonged dosage. Our interest in the possible use of this type of endocrine preparation led us to a series of preliminary observations which convinced us of the safety of this technique in the relatively small dosage required for the treatment of the menopausal syndrome. We therefore proceeded to its use in selected patients.
'l'.
/38198
M.G.
ljti/553
U.K.
D. f'. 1)83ii90
1158198
c.
549137
H.\'.
678012
S.Q.
}~. 1-'. 713316
710670
P.M.
699551
'I'. H.
5S036
M.Q.
562742
D.W.
I 50
I 49
40
47
2ll
45
29
31
51
50
24
61
~
520851
AGE (YR.)
NAME NO.
I
a:_____ j_
I
I
I
PRINCIPAL SYMPTOMS
I
I
1_
I
I
.I PRESENT TREATMENT
I
ANDROGEN TREATMENT OF MENOPAUSAL SYMPTOMS
PREVIOUS TREATMENT
I.
RESULT
0
SIDE EFFECTS
R11dium and hysterec· Hot flashes Androgen, /Methyl testosterone 10-20 mg.l Improved markedly. Not per0 small amount O.D. 2 x 1 mo. courses manent. Appetite and tomy 2 years ago weight increased for corpus carcinoma Testosterone propionate, 75 mg. Excellent. Flashes gone. Radium and hysterec· Flashes, faStilbestrol Slight hirsutism of lip and tomy for corpus tigue, loss of per week for 1 month. Weight, strength, appetite chin. Slight engorgement carcinoma 1 year appetite Methyl testosterone, 10 mg. markedly improved. Slight of clitoris. No change in daily for () weekR return of symptoms. More ago libido. Oeca,.;ional leg cramps effective relief than stilbestrol 0 Methyl testosterone 10 mg.IExcellent. Flashes, nervous· /Radium for fibroids,jFlashes. Nerv- !Stilbestrol ousness recent daily for 4 weeks ness, strength all improved. No return. More effective than stilbestrol !Flashes !None Methyl testosterone 10 mg.IExcellent. Flashes gone, no 0 !Hysterectomy and radiation 1 year daily for 4 weeks return ago for primary carcinoma of tube Carcino-1 E'laRhes Radiation. !None 0 Methyl testosterone 10 mg.IExcellent. Flashes gone. Very ma of cerYix, recent daily for S weeks slight return when off · merlieation Ca rcino-1 Flashes Methyl testosteronp ~0 mg. Exeellent. Flashes gonP. .\p Ir symptoms !<~!ashe~. JaiMueh ,.;tilbes~ !Te,.;to,terone propionatf', 1;)0 11arked impron•ment. Strength! Slight bn•a,;t paill. QuP"· Oophorectomy 5 tigue 1 I rol. Relief ' mg. Methyl te,tosterone, ~01 an
DESCRIPTION OF MENOPAUSE
TABLE
--:
9
7,
__..
~
:J5
,-.
::0
j ~
1
'""' ;;:j
:.--
~
s;:::;
'...:
>
;::_;
...
;:; "-' ::0
:..• ~
c.~.
34
48
46
46
D. F. 563292
E.G. 708360
E.P. 700065
M.B. 321196 E.W. 712508
48
53
28
46
H.M.
R.G. 334513
K.H. 680757
M.S.
P. 0. G. I.
Flashes, nervousness Flashes, fa· tigue, nervousness
Flashes, headaches, poor appetite Flashes
Flashes
dizzi · ness, head· aches Flashes
}~lashes,
Flashes, nervousness
Radiation for car· Flashes, nerv· cinoma of cervix 2 ousness years ago Oophorectomy, hys· Flashes, terectomy for carnervousness, cinoma of ovary, fatigue recent
Spontaneous meno· pause, recent
Radiation for ( ~) Flashes, nervcarcinoma of cervix ousness, fa7 years ago tigue, de· pression Spontaneous menoFlashes, nervpause 5 years ago ousness, fatigue
Radiation for carcinoma of cervix 1 year ago Radium menopause. Fibroids 8 months ago Spontaneous meno· pause. Fibroids Radiation for car· cinoma of cervix 4 years ago
Oophorectomy with hysterectomy, recent Oophorectomy 6 months ago
Spontaneous, recent
= Gastrointestinal.
= Postoperative.
0. D. := Daily.
41
Mrs.T.
52
47
54
P.S. 639300
465049
testosterone, for 2 weeks, for 2 weeks testosterone, for 4 weeks, for 2 weeks testosterone, for 2 weeks, for 2 weeks testosterone, for 4 weeks
-
20
20 mg. Excellent
mg. Excellent. lieved
20 mg. Excellent. 10 mg.
20 mg. Excellent 10 mg.
20 mg. Excellent 10 mg.
return
All symptoms
Slight
0
re- General stimulation
0
0
General stimulation
--···-···-
--------·-
- -
Moderate return
-
0
-
mg. Excellent result. All symptoms General stimulation. relieved. More effective than Marked increase in stilbestrol weight, appetite, and strength
mg. Improved.
--·····-----
20
20
Methyl testosterone, 20 mg. Excellent result. All symptoms General stimulation. Ap relieved. Very slight return. petite and weight indaily for 4 weeks, 10 mg. More effective and more per· crease daily for 2 weeks manent than stilbestrol Methyl testosterone, 20 mg. Excellent. More effective than General stimulation stilbestrol daily for 2 weeks
All symptoms re· 0 testosterone, 20 mg. Excellent. for 4 weeks lieved. Mild return testosterone, 20 mg. Good. Nervousness and flashes Libido increased due to Occa improved. Fatigue some· local receptivity. for 6 weeks, 10 mg. sional leg cramps what better. Slightly more for 2 weeks than effective stilbestrol; probably more permanent Methyl testosterone, 20 mg. Questionable benefit. Possible 0 slight improvement. Trial daily for 6 weeks inadequate Methyl daily Methyl daily daily
Methyl testosterone, daily for 4 weeks
Methyl daily daily Methyl daily daily Methyl daily daily Methyl daily
Stilbestrol caused spotting Methyl testosterone, Much stil· bestrol. G.I. daily for 4 weeks symptoms Methyl testosterone, Stilbestrol. daily for 4 weeks G.I. symp· toms
Much stilbestrol. Bleeding
Stilbestrol
Stilbestrol
0
0
0
0
0
0
C)1
0
C)1
rn
~ "1:1 o-3 0 ~
~
(Fl
F
(Fl
q>
~
z
~ trl
0 ""::
~
"1:1
~
.... :i t'1
z
0 0 M
~
z
:--
2
t'1
gj
~
0
506
AMERICAN JOURNAL OF OBSTE'l'RICS AND GYNECOLOGY
Methods and Data We have confined our study for the most part to a selected group of patients who have been subjected to surgery, radiation, or both, for neoplastic dise:tse or dysfunctional bleeding from the reproductive tract. Our group is composed of 24 ptltieuts treated for menopausal symptoms by androgens. This number is small. but we believe tlw uniformity of the results enhance their significance. It is our opinion tltat the penentage o£ menopausal women who require endocrine treatment is small; the majority of patients undergoing Pit her a spontaneous or an artificial menopause require no treatment. A small additional group whieh is symptomatic can be relieved with small doses o£ sedative.29 ln addition, the effectiveness and safety of stilbestrol for many patients who do require endocrine treatment leaves a :;mall group for whom other therapy may be indicated. Unfortunately, our controls arp incomplete, but half our patients had receiveu previou~ stilbestrol treatment. TABI,E
II.
Sn~I ~fARY OF RESUI/rs
24 Cases
Symptomatic menopausal patients
23 Cases
Benefited from androgen therapy 16 Cases Early menopausal patients. Uniformly excellent result
I
Ii I
I
6 Cases
I I
Late menopausal patients
I
II Improved I II
I
I
I I
2 Cases 1 Case Possible slight hirsutism. Oral and Late unimparenteral proved. therapy Large psychoneurotic element
'Ve have used methyl testosterone* for the most part, though an occasional patient was given testosterone propionate early in the study. The course of therapy which we found most effeetive extended over approximately six to eight weeks: 20 ing. of methyl testosterone by mouth daily for four weeks, then 10 mg. daily for two weeks thereafter. This therapy was usually enough to control symptoms. We usually allow several intervals of one week without treatment during the course. Our results are tabulated in Tables I, II, and III. *Methyl testosterone (Metandren) and testosterone propionate (Perandren) were supplied to Dr. E. T. Engle by the Ciba Company, through the courtesy of Mr. R. H. Mautner.
GUSBERG:
ANDROGEN THERAPY OF MENOPAUSAL SYMPTOMS
507
Discussion of Results Androgen therapy has strikingly benefited the vaso.motor symptoms of the menopause in 23 of our 24 cases. For those patients whose menopause was recent, in whom one might reasonably postulate a significant endocrine imbalance, results were excellent and uniform. For late cases in whom one might postulate a greater functional than chemical imbalance, results were less striking, though we observed some benefit in all patients who received an adequate course of treatment. TABLE
III.
COMPARISON:
STILBESTROL AND ANDROGEN THERAPY
12 Cases Previous treatment with stilbestrol !
10 Cases Greater benefit from androgens
7 Cases Untoward effects from stilbestrol. Vaginal bleeding or gastrointestinal symptoms 2 Cases
-
2 Cases
Large psychoPossible slight neurotic element hirsutism. Oral and parenteral therapy
Of 12 patients who had had previous stilbestrol therapy, ten were benefitea to a greater degree by the androgens. The other two had taken stilbestrol for years and the habit was difficult to break. We found it possible in some instances to achieve this withdrawal from 3,11 endocrine therapy by a course of androgen treatment, but in others the functional orientation of the patient to her bottle of stilbestrol tablets had come to play too protective a role in her psychic well-being. We have no explanation for the apparent greater permanence of the result with androgen therapy. It may have some relation to our plan of management which never sought to completely obliterate vasomotor symptoms but simply to reduce them to the point of tolerance. This m,ay allow more natural endocrine readjustment. Frequently also, it will be noted that symptoms recurred to a minor degree when therapy was stopped. 'l'his rarely called for renewal of therapy, for the recurring symptoms were usually· of a degree which produced little discomfort. However, our follow-up is not long enough as yet to evaluate this permanence completely. We have noted that with male sex hormone therapy many patients experience a feeling o:E stimulation and general well-being. There was frequently marked loss of nervousness, increase in appetite, weight, and strength, and at times a marked sense of exhilaration. These effects have also been noted by other observers of androgen-treated patients. They may be partially dependent on the well-known nitrogen-sparing action of androgens. We have not seen untoward reactions of any significant degree in this group of patients. This is in accord with published data which place the limit of safety in relation to masculin· izing symptoms considerably above the amount we have found it necessary to use. We have encountered slight increase in lip hirsuties in two of our cases, both of whom were given testosterone propionate in addition to methyl testosterone. We have also noted slight in· crease in the size of the clitoris in one of these cases. Another patient who had been given
508
AMERICAN ,JOURNAL OE' OBSTETRICS AND OYNECOLOGY
methyl testosterone alone volunteered the information that she had noted a sense of engorgement about the clitoris and some increase in libido. Two patients in our group al~o noted oecasional mild leg cramps during the course of therapy, but these were never striking enough or persistent enough for us to be eertain tlwv were definitely a~~or·iated with the androgen administration. . . If the vasomotor symptoms of the menopauHe are presumed to bexpel'ted that either estrogen or androgen therapy will climini~h it and HO eontrol thc~e symptoms.
'Ve have encountered no in.-.tanee of androgen-induced uterine bleeding in our
seriP~.
Summary and Conclusions 1. The rationale and literature of androgen therapy of the menopausal syndrome are discussed. 2. A group of menopausal patients treated with methyl testosterone is presented. ·we have found this a safe and effective means of controlling menopausal symptoms. In a small group of patients who have had both medications, we have observed a somewhat greater benefit from androgens. 3. .F'or the small number of menopausal women who require endocrine therapy we have urged the use of androgens rather than estrogens in the following groups : a. Patients who have been treated for cancer of the reproductive tract or breast. b. Patients who have been treated for abnormal uterine bleeding during the climacteric. c. Patients who have developed uterine bleeding while under treatment with estrogenic substances. d. Patients who require endocrine therapy for vasomotor symptoms before their menses have completely ceased. e. Patients who have become addicted to stilbestrol by long-continued usage. The author wishes to acknowledge the advice and encouragement of Dr. B. P. Watson and Dr. W. E. Studdiford in this work. Also, to Dr. J. A. Corscaden and Dr. Earl T. Engle, the author wishes to express his indebtedness for their constant aid in the supervision and study of these patients.
References 1. Salmon, U. J., Geist, S. H., Gaines, J. A., and Walter, R. I.: AM .•J. OBST. & GYNEc. 41: 990, 1941. 2. Ihrke, I. A., and D'Amour, F.: Am. J. Physiol. 96: 289, 1931. 3. Robson, J. M.: Proc. Soc. Exper. Biol. & Med. 35: 49, 1936. 4. Zuckerman, S.: Lancet 2: 676, 1937. 5. Hartman, C. G.: Proc. Soc. Exper. Biol. & Med. 37: 8i, 1937. 6. Papanicolaou, G. N., Ripley, H. S., and Shorr, E.: Endocrinology 24: 339, 193!). 7. Loeser, A. A.: Lancet 1: 373, 1938. 8. Huffman, J. W.: AM. J. 0BST. & GYNEC. 40: 675, 1940. 9. Greenblatt, R.: J. A.M. A. 121: 17, 1943. 10. Engle, E. T., and Smith, P. E.: Endocrinology 25: 1, 1939. 11. Greenhill, J. P., and Freed, S. C.: AM. J. 0BsT. & GYNEC. 39: 636, 1940. 12. Nathanson, I. T., and Towne, L. E.: Endocrinology 25: 754, 1939. 13. Salmon, U. J.: Proc. Soc. Exper. Bioi. & Med. 37: 488, 1937. 14. Shorr, E., Papanicolaou, G. N., and Stimmel, B. F.: Proc. Soc. Exper. Bioi. & Mecl. 38: 758, 1938. 15. Laroehe, G., Simmonet, H., and Bompanl, E.: Compt. rend Soc. de biol. 129: 953, 1938. 16. Rothermich, N. 0., and Foltz, L. M.: Eudocrinology Zl: 37, 1940. 17. Mocquot, P., and Moricard, R.: Bull. Soc. d'obst. et de gynec. 25: 787, 1936. 18. Margeil, E., and Zwilling, G.: Polska gaz. lek. 15: 81fi, 1936. 19. Kurzrok, L., Birnberg, C. H., antl Livingston, S.: Endocrinology 24: 347, 1939. 20. Mandy, T. E., and Mandy, A. J.: We.st .T. Surg. 48: 604, 1940. 21. McCullagh, E. P., and McGurl, F. J.: .T. Ural. 42: 1265, 1939. 22. Geist, S. H., and Salmon, U ..T.: .T. A. M. A. 117: 2207, l!l41.
BRADY
AND
REID:
LACTOBACILLUS THERAPY IN VAGINITIS
50-9
23. Kurzrok, L., and Rothbart, H.: Am. J. Surg. 56: 636, 1942. 24. Silberman, D., Radman, H. M., and Abarbanel, A. R.: Allf. J. OBST. & GYNEC. 39: 332, 1940. . 25. Greenhill, J. P., ed.: Year Book of Obstetnes and Gynecology, 1943. 26. Joel, C. A.: J. Olin. Endocrinol. 2: 116, 1942. 27. Loeser, A. A.: Med. Press. 210: 240, 1943. 28. Aub, J. C.: New England J. Med. 222: 877, 1940. 29. Buxton, C. L.: J. Olin. Endocrinol. 4: 592, 1944.
LACTOBACILLUS THERAPY IN VAGINITIS DUE TO TRICHOMONAS LEo BRADY, M.D., AND RoGER D. REID, PH.D., BALTIMORE, MD. (From the Department of Gynecology of the Johns Hopkins Hospital and University)
N
the authors of this report read a paper before the annual meeting of I the1941Southern Surgieal Association on the treatment of Trichomonas vaginalis 1
vaginitis with the lactobacillus. That report was based on the study of 50 patients treated with tablets containing viable lactic acid forming bacilli. We now wish to present our results in a second series of cases treated in this manner. In our first paper we stated that this method of treatment usually gave quick relief from symptoms, and in the great majority of instances, the vagina became free of trichomonas and remained so. At the time of our first report, we already had many patients who had been examined monthly for at least six months after treatment had been discontinued, and who remained free of trichomonads. There were, however, as we emphasized at that time, a few recurrences, or reinfestations, so, in spite of what we considered markedly good results in most cases, no claim was made that this method of treatment would completely eliminate recurrences or that it would even temporarily relieve the symptoms in ·~very case. The tablets used are prepared ·for us under the careful supervision of the bacteriologist, Dr. John H. Brewer. The strain of lactobacillus used in this work was obtained from the United States Department of Agriculture and is known as Hansen's strain of Lactobacillus bulgaricus. The actual preparation of the tablets is as follows: Sterile skim milk is inoculated with the culture. After forty-eight hours' incubation, each 1,000 c.c. of this culture is mixed with 325 grams of XXXX sugar and milk sugar. This is thoroughly dissolved in the milk and the mixture is spread in thin layers on enamel pans and dried. The mixture is scraped from the pans, broken into bits, and replaced in a drier to complete desiccation. When completely dried, 6 c.c. of white mineral oil and 38 Gm. of starch are added. The mixture is then pressed into tablets. Each one weighs 1.3 Gm., and represents 1.28 c.c. of original culture.
The idea of trying to free the vagina of trichomonads by implanting lactic acid-forming bacilli occurred to us after we had made a careful study of the normal defensive mechanism of the vagina which depends primarily on the three following conditions: First, that the vaginal secretion remains at its normal low pH; second, that the Doderlein or vaginal lactobacilli are present in sufficient numbers to form lactic acid; and finally, that there is sufficient carbohydrate, perhaps in the form of glycogen, in the vaginal epithelial cells or spaces between
AND&OGEN THDA.PY 01' MliHOP.A.UI.AL SYMPTOJIS IN OANOBR PATIBNTS* S. B. GuSBERG, M.D., NEw YoRK, N.Y. (From the Sloane Hospital for Women and the Department of Obstetrics and Gynecology, Columbia UniFet·sity)
Introduction REATMENT of the menopausal patient with estrogenic substances is a well-established and effective method of controlling the uncomfortable symptoms which sometimes occur with the decline and cessation of ovarian activity. The explanation for the effectiveness of this therapy has been studied for many years; some observers suggest that this efficiency in relation to the vasomotor symptoms of the menopause is probably due to inhibition of overactivity of the anterior pituitary gland. This explanation would be in accord with the well-known reciprocal interaction of the pituitary gland and the various glands of internal secretion whi~h it governs. We have been dissatisfied with the use of stilbestrol in a certain group of menopausal patients in whom we believed the stimulating effect of estrogen was contraindicated. This includes those who have been treated for some form of cancer of the reproductive organs and also some of those in whom estrogenic therapy has provoked uterine bleeding. It is not within the province or this presentation to discuss the possible relationship between estrogens and carcinogenesis. This relationship has been studied and debated by numerous careful observers for many years; our own data and conclusions will be presented elsewhere. Suffice it to say that in the human species whose genetic
T
*Presented at the New York Academy of Medicine, Section of Obstetrics and Gynecology, Jan. 23, 1945.
GUSBERG:
ANDROGEN THERAPY OF ME~OPAUSAL SYMPTOMS
503
pattern is so complex, we think it unwise to subject susceptible tissue to a stimulating substance; those individuals who have already demonstrated the responsiveness of one of the reproductive organs to whatever abnormal stimulus develops carcinoma would seem especially unfavorable subjects in whom to administer a cell-proliferating substance like estrogen. We have also become impressed with the fundamental error in continuing estrogenic therapy in any postmenopausal individual for long periods of time for it creates a habit which is difficult to break; we have sought a method to remedy this condition. These eonsiderations, together with the occasional production of abnormal endometrial patterns in patients who have developed stilbestrol bleeding led ·Js to the use of androgen therapy for this selected group of menopausal patients. In animals, a variety of uterine and vaginal responses have been produced by androgens (Salmon, Geist, et al.I), some of a stimulating nature, others of an inhibitory nature. There is a suggestion in some of this work that mature animals most co=only 11how an inhibitory response, especially with small doses. Inhibition of reproductive tract activity in animals by androgens has been demonstrated by many workers, among them Ihrke and D'Amour,2 Robson,3 Zuckerman,4 and Hartman.5 Inhibitory action on menstruation has aiso been demonstrated in humans by Papanicolaou, Ripley, and Shorr,s Loeser,7 Geist, Salmon, and their associates,! Huffman,s Greenblatt,9 and others. In the increasing literature concerning the use of androgens for abnormal uterine bleeding, it would appear that doses of testosterone propionate under 400 to 500 mg. monthly will reduce bleeding effectively without changing the endometrial pattern, while doses higher than this are required to produce endometrial regression. There are no reports of stimulation of the human endometrium by androgens. Engle and SmithiO working with castrated mature Rhesus monkeys were able to maintain endometria primed by the use of estrogens and progesterone, with short courses of testosterone propionate treatment. They suggest, however, that this sequence of administration may not inhibit the pituitary as androgens are believed to do when given throughout the menstrual cycle. It has been suggested by other workers (Salmon, Geist, et al.,l Huffman,s Greenhill and Freed,n and Aub2S) that inhibition of the pituitary is the probable mode of action of androgen therapy in the control of uterine bleeding. In menopausal patients there bas been more direct evidence that androgen therapy can reduce anterior pituitary hyperactivity. Nathanson and Townel2 and Salmon1 3 clearly demonstrated reduction in urinary gonadotropins as treatment proceeded and symptoms were ameliorated. Similar findings were obtained by Shorr, Papanicolaou, and Stimmel,H Laroche, et al.,I5 and Rotbermicb and ]'oltz.lS The use of androgen therapy for the menopausal syndrome has been suggested by several workers since 1936. In that year Mocquot and Moricard,17 and Margeil and Zwillingls reported the effectiveness of this therapy. Since that time there have been several small groups of cases reported, including those of Kurzrok, Birnberg and Livingston,I9 Mandy and Mandy,2o McCullagh and McGurl,21 Geist and Salmon,22 Kurzrok and Rothbart,23 Silberman, Radman, and Abarbanel,24 Greenhill,25 .Joe1,2s Loeser,27 and Greenblatt.9 For the most part these investigators used testosterone propionate parenterally, though several mention the U:le of methyl testosterone by mouth; in some instances a combined stilbestrol-androgen therapy was given. In general the results of treatment were excellent. In none of these reports is there any evidence of uterine stimulation by this androgen therapy.
The fear of untoward symptoms and masculinization has deterred many gynecologists from the use of androgen therapy. This healthy regard for the patient's complete safety is readily understandable when one studies the undesirable effects produced by large or prolonged dosage. Our interest in the possible use of this type of endocrine preparation led us to a series of preliminary observations which convinced us of the safety of this technique in the relatively small dosage required for the treatment of the menopausal syndrome. We therefore proceeded to its use in selected patients.
'l'.
/38198
M.G.
ljti/553
U.K.
D. f'. 1)83ii90
1158198
c.
549137
H.\'.
678012
S.Q.
}~. 1-'. 713316
710670
P.M.
699551
'I'. H.
5S036
M.Q.
562742
D.W.
I 50
I 49
40
47
2ll
45
29
31
51
50
24
61
~
520851
AGE (YR.)
NAME NO.
I
a:_____ j_
I
I
I
PRINCIPAL SYMPTOMS
I
I
1_
I
I
.I PRESENT TREATMENT
I
ANDROGEN TREATMENT OF MENOPAUSAL SYMPTOMS
PREVIOUS TREATMENT
I.
RESULT
0
SIDE EFFECTS
R11dium and hysterec· Hot flashes Androgen, /Methyl testosterone 10-20 mg.l Improved markedly. Not per0 small amount O.D. 2 x 1 mo. courses manent. Appetite and tomy 2 years ago weight increased for corpus carcinoma Testosterone propionate, 75 mg. Excellent. Flashes gone. Radium and hysterec· Flashes, faStilbestrol Slight hirsutism of lip and tomy for corpus tigue, loss of per week for 1 month. Weight, strength, appetite chin. Slight engorgement carcinoma 1 year appetite Methyl testosterone, 10 mg. markedly improved. Slight of clitoris. No change in daily for () weekR return of symptoms. More ago libido. Oeca,.;ional leg cramps effective relief than stilbestrol 0 Methyl testosterone 10 mg.IExcellent. Flashes, nervous· /Radium for fibroids,jFlashes. Nerv- !Stilbestrol ousness recent daily for 4 weeks ness, strength all improved. No return. More effective than stilbestrol !Flashes !None Methyl testosterone 10 mg.IExcellent. Flashes gone, no 0 !Hysterectomy and radiation 1 year daily for 4 weeks return ago for primary carcinoma of tube Carcino-1 E'laRhes Radiation. !None 0 Methyl testosterone 10 mg.IExcellent. Flashes gone. Very ma of cerYix, recent daily for S weeks slight return when off · merlieation Ca rcino-1 Flashes Methyl testosteronp ~0 mg. Exeellent. Flashes gonP. .\p I
DESCRIPTION OF MENOPAUSE
TABLE
--:
9
7,
__..
~
:J5
,-.
::0
j ~
1
'""' ;;:j
:.--
~
s;:::;
'...:
>
;::_;
...
;:; "-' ::0
:..• ~
c.~.
34
48
46
46
D. F. 563292
E.G. 708360
E.P. 700065
M.B. 321196 E.W. 712508
48
53
28
46
H.M.
R.G. 334513
K.H. 680757
M.S.
P. 0. G. I.
Flashes, nervousness Flashes, fa· tigue, nervousness
Flashes, headaches, poor appetite Flashes
Flashes
dizzi · ness, head· aches Flashes
}~lashes,
Flashes, nervousness
Radiation for car· Flashes, nerv· cinoma of cervix 2 ousness years ago Oophorectomy, hys· Flashes, terectomy for carnervousness, cinoma of ovary, fatigue recent
Spontaneous meno· pause, recent
Radiation for ( ~) Flashes, nervcarcinoma of cervix ousness, fa7 years ago tigue, de· pression Spontaneous menoFlashes, nervpause 5 years ago ousness, fatigue
Radiation for carcinoma of cervix 1 year ago Radium menopause. Fibroids 8 months ago Spontaneous meno· pause. Fibroids Radiation for car· cinoma of cervix 4 years ago
Oophorectomy with hysterectomy, recent Oophorectomy 6 months ago
Spontaneous, recent
= Gastrointestinal.
= Postoperative.
0. D. := Daily.
41
Mrs.T.
52
47
54
P.S. 639300
465049
testosterone, for 2 weeks, for 2 weeks testosterone, for 4 weeks, for 2 weeks testosterone, for 2 weeks, for 2 weeks testosterone, for 4 weeks
-
20
20 mg. Excellent
mg. Excellent. lieved
20 mg. Excellent. 10 mg.
20 mg. Excellent 10 mg.
20 mg. Excellent 10 mg.
return
All symptoms
Slight
0
re- General stimulation
0
0
General stimulation
--···-···-
--------·-
- -
Moderate return
-
0
-
mg. Excellent result. All symptoms General stimulation. relieved. More effective than Marked increase in stilbestrol weight, appetite, and strength
mg. Improved.
--·····-----
20
20
Methyl testosterone, 20 mg. Excellent result. All symptoms General stimulation. Ap relieved. Very slight return. petite and weight indaily for 4 weeks, 10 mg. More effective and more per· crease daily for 2 weeks manent than stilbestrol Methyl testosterone, 20 mg. Excellent. More effective than General stimulation stilbestrol daily for 2 weeks
All symptoms re· 0 testosterone, 20 mg. Excellent. for 4 weeks lieved. Mild return testosterone, 20 mg. Good. Nervousness and flashes Libido increased due to Occa improved. Fatigue some· local receptivity. for 6 weeks, 10 mg. sional leg cramps what better. Slightly more for 2 weeks than effective stilbestrol; probably more permanent Methyl testosterone, 20 mg. Questionable benefit. Possible 0 slight improvement. Trial daily for 6 weeks inadequate Methyl daily Methyl daily daily
Methyl testosterone, daily for 4 weeks
Methyl daily daily Methyl daily daily Methyl daily daily Methyl daily
Stilbestrol caused spotting Methyl testosterone, Much stil· bestrol. G.I. daily for 4 weeks symptoms Methyl testosterone, Stilbestrol. daily for 4 weeks G.I. symp· toms
Much stilbestrol. Bleeding
Stilbestrol
Stilbestrol
0
0
0
0
0
0
C)1
0
C)1
rn
~ "1:1 o-3 0 ~
~
(Fl
F
(Fl
q>
~
z
~ trl
0 ""::
~
"1:1
~
.... :i t'1
z
0 0 M
~
z
:--
2
t'1
gj
~
0
506
AMERICAN JOURNAL OF OBSTE'l'RICS AND GYNECOLOGY
Methods and Data We have confined our study for the most part to a selected group of patients who have been subjected to surgery, radiation, or both, for neoplastic dise:tse or dysfunctional bleeding from the reproductive tract. Our group is composed of 24 ptltieuts treated for menopausal symptoms by androgens. This number is small. but we believe tlw uniformity of the results enhance their significance. It is our opinion tltat the penentage o£ menopausal women who require endocrine treatment is small; the majority of patients undergoing Pit her a spontaneous or an artificial menopause require no treatment. A small additional group whieh is symptomatic can be relieved with small doses o£ sedative.29 ln addition, the effectiveness and safety of stilbestrol for many patients who do require endocrine treatment leaves a :;mall group for whom other therapy may be indicated. Unfortunately, our controls arp incomplete, but half our patients had receiveu previou~ stilbestrol treatment. TABI,E
II.
Sn~I ~fARY OF RESUI/rs
24 Cases
Symptomatic menopausal patients
23 Cases
Benefited from androgen therapy 16 Cases Early menopausal patients. Uniformly excellent result
I
Ii I
I
6 Cases
I I
Late menopausal patients
I
II Improved I II
I
I
I I
2 Cases 1 Case Possible slight hirsutism. Oral and Late unimparenteral proved. therapy Large psychoneurotic element
'Ve have used methyl testosterone* for the most part, though an occasional patient was given testosterone propionate early in the study. The course of therapy which we found most effeetive extended over approximately six to eight weeks: 20 ing. of methyl testosterone by mouth daily for four weeks, then 10 mg. daily for two weeks thereafter. This therapy was usually enough to control symptoms. We usually allow several intervals of one week without treatment during the course. Our results are tabulated in Tables I, II, and III. *Methyl testosterone (Metandren) and testosterone propionate (Perandren) were supplied to Dr. E. T. Engle by the Ciba Company, through the courtesy of Mr. R. H. Mautner.
GUSBERG:
ANDROGEN THERAPY OF MENOPAUSAL SYMPTOMS
507
Discussion of Results Androgen therapy has strikingly benefited the vaso.motor symptoms of the menopause in 23 of our 24 cases. For those patients whose menopause was recent, in whom one might reasonably postulate a significant endocrine imbalance, results were excellent and uniform. For late cases in whom one might postulate a greater functional than chemical imbalance, results were less striking, though we observed some benefit in all patients who received an adequate course of treatment. TABLE
III.
COMPARISON:
STILBESTROL AND ANDROGEN THERAPY
12 Cases Previous treatment with stilbestrol !
10 Cases Greater benefit from androgens
7 Cases Untoward effects from stilbestrol. Vaginal bleeding or gastrointestinal symptoms 2 Cases
-
2 Cases
Large psychoPossible slight neurotic element hirsutism. Oral and parenteral therapy
Of 12 patients who had had previous stilbestrol therapy, ten were benefitea to a greater degree by the androgens. The other two had taken stilbestrol for years and the habit was difficult to break. We found it possible in some instances to achieve this withdrawal from 3,11 endocrine therapy by a course of androgen treatment, but in others the functional orientation of the patient to her bottle of stilbestrol tablets had come to play too protective a role in her psychic well-being. We have no explanation for the apparent greater permanence of the result with androgen therapy. It may have some relation to our plan of management which never sought to completely obliterate vasomotor symptoms but simply to reduce them to the point of tolerance. This m,ay allow more natural endocrine readjustment. Frequently also, it will be noted that symptoms recurred to a minor degree when therapy was stopped. 'l'his rarely called for renewal of therapy, for the recurring symptoms were usually· of a degree which produced little discomfort. However, our follow-up is not long enough as yet to evaluate this permanence completely. We have noted that with male sex hormone therapy many patients experience a feeling o:E stimulation and general well-being. There was frequently marked loss of nervousness, increase in appetite, weight, and strength, and at times a marked sense of exhilaration. These effects have also been noted by other observers of androgen-treated patients. They may be partially dependent on the well-known nitrogen-sparing action of androgens. We have not seen untoward reactions of any significant degree in this group of patients. This is in accord with published data which place the limit of safety in relation to masculin· izing symptoms considerably above the amount we have found it necessary to use. We have encountered slight increase in lip hirsuties in two of our cases, both of whom were given testosterone propionate in addition to methyl testosterone. We have also noted slight in· crease in the size of the clitoris in one of these cases. Another patient who had been given
508
AMERICAN ,JOURNAL OE' OBSTETRICS AND OYNECOLOGY
methyl testosterone alone volunteered the information that she had noted a sense of engorgement about the clitoris and some increase in libido. Two patients in our group al~o noted oecasional mild leg cramps during the course of therapy, but these were never striking enough or persistent enough for us to be eertain tlwv were definitely a~~or·iated with the androgen administration. . . If the vasomotor symptoms of the menopauHe are presumed to be
'Ve have encountered no in.-.tanee of androgen-induced uterine bleeding in our
seriP~.
Summary and Conclusions 1. The rationale and literature of androgen therapy of the menopausal syndrome are discussed. 2. A group of menopausal patients treated with methyl testosterone is presented. ·we have found this a safe and effective means of controlling menopausal symptoms. In a small group of patients who have had both medications, we have observed a somewhat greater benefit from androgens. 3. .F'or the small number of menopausal women who require endocrine therapy we have urged the use of androgens rather than estrogens in the following groups : a. Patients who have been treated for cancer of the reproductive tract or breast. b. Patients who have been treated for abnormal uterine bleeding during the climacteric. c. Patients who have developed uterine bleeding while under treatment with estrogenic substances. d. Patients who require endocrine therapy for vasomotor symptoms before their menses have completely ceased. e. Patients who have become addicted to stilbestrol by long-continued usage. The author wishes to acknowledge the advice and encouragement of Dr. B. P. Watson and Dr. W. E. Studdiford in this work. Also, to Dr. J. A. Corscaden and Dr. Earl T. Engle, the author wishes to express his indebtedness for their constant aid in the supervision and study of these patients.
References 1. Salmon, U. J., Geist, S. H., Gaines, J. A., and Walter, R. I.: AM .•J. OBST. & GYNEc. 41: 990, 1941. 2. Ihrke, I. A., and D'Amour, F.: Am. J. Physiol. 96: 289, 1931. 3. Robson, J. M.: Proc. Soc. Exper. Biol. & Med. 35: 49, 1936. 4. Zuckerman, S.: Lancet 2: 676, 1937. 5. Hartman, C. G.: Proc. Soc. Exper. Biol. & Med. 37: 8i, 1937. 6. Papanicolaou, G. N., Ripley, H. S., and Shorr, E.: Endocrinology 24: 339, 193!). 7. Loeser, A. A.: Lancet 1: 373, 1938. 8. Huffman, J. W.: AM. J. 0BST. & GYNEC. 40: 675, 1940. 9. Greenblatt, R.: J. A.M. A. 121: 17, 1943. 10. Engle, E. T., and Smith, P. E.: Endocrinology 25: 1, 1939. 11. Greenhill, J. P., and Freed, S. C.: AM. J. 0BsT. & GYNEC. 39: 636, 1940. 12. Nathanson, I. T., and Towne, L. E.: Endocrinology 25: 754, 1939. 13. Salmon, U. J.: Proc. Soc. Exper. Bioi. & Med. 37: 488, 1937. 14. Shorr, E., Papanicolaou, G. N., and Stimmel, B. F.: Proc. Soc. Exper. Bioi. & Mecl. 38: 758, 1938. 15. Laroehe, G., Simmonet, H., and Bompanl, E.: Compt. rend Soc. de biol. 129: 953, 1938. 16. Rothermich, N. 0., and Foltz, L. M.: Eudocrinology Zl: 37, 1940. 17. Mocquot, P., and Moricard, R.: Bull. Soc. d'obst. et de gynec. 25: 787, 1936. 18. Margeil, E., and Zwilling, G.: Polska gaz. lek. 15: 81fi, 1936. 19. Kurzrok, L., Birnberg, C. H., antl Livingston, S.: Endocrinology 24: 347, 1939. 20. Mandy, T. E., and Mandy, A. J.: We.st .T. Surg. 48: 604, 1940. 21. McCullagh, E. P., and McGurl, F. J.: .T. Ural. 42: 1265, 1939. 22. Geist, S. H., and Salmon, U ..T.: .T. A. M. A. 117: 2207, l!l41.
BRADY
AND
REID:
LACTOBACILLUS THERAPY IN VAGINITIS
50-9
23. Kurzrok, L., and Rothbart, H.: Am. J. Surg. 56: 636, 1942. 24. Silberman, D., Radman, H. M., and Abarbanel, A. R.: Allf. J. OBST. & GYNEC. 39: 332, 1940. . 25. Greenhill, J. P., ed.: Year Book of Obstetnes and Gynecology, 1943. 26. Joel, C. A.: J. Olin. Endocrinol. 2: 116, 1942. 27. Loeser, A. A.: Med. Press. 210: 240, 1943. 28. Aub, J. C.: New England J. Med. 222: 877, 1940. 29. Buxton, C. L.: J. Olin. Endocrinol. 4: 592, 1944.
LACTOBACILLUS THERAPY IN VAGINITIS DUE TO TRICHOMONAS LEo BRADY, M.D., AND RoGER D. REID, PH.D., BALTIMORE, MD. (From the Department of Gynecology of the Johns Hopkins Hospital and University)
N
the authors of this report read a paper before the annual meeting of I the1941Southern Surgieal Association on the treatment of Trichomonas vaginalis 1
vaginitis with the lactobacillus. That report was based on the study of 50 patients treated with tablets containing viable lactic acid forming bacilli. We now wish to present our results in a second series of cases treated in this manner. In our first paper we stated that this method of treatment usually gave quick relief from symptoms, and in the great majority of instances, the vagina became free of trichomonas and remained so. At the time of our first report, we already had many patients who had been examined monthly for at least six months after treatment had been discontinued, and who remained free of trichomonads. There were, however, as we emphasized at that time, a few recurrences, or reinfestations, so, in spite of what we considered markedly good results in most cases, no claim was made that this method of treatment would completely eliminate recurrences or that it would even temporarily relieve the symptoms in ·~very case. The tablets used are prepared ·for us under the careful supervision of the bacteriologist, Dr. John H. Brewer. The strain of lactobacillus used in this work was obtained from the United States Department of Agriculture and is known as Hansen's strain of Lactobacillus bulgaricus. The actual preparation of the tablets is as follows: Sterile skim milk is inoculated with the culture. After forty-eight hours' incubation, each 1,000 c.c. of this culture is mixed with 325 grams of XXXX sugar and milk sugar. This is thoroughly dissolved in the milk and the mixture is spread in thin layers on enamel pans and dried. The mixture is scraped from the pans, broken into bits, and replaced in a drier to complete desiccation. When completely dried, 6 c.c. of white mineral oil and 38 Gm. of starch are added. The mixture is then pressed into tablets. Each one weighs 1.3 Gm., and represents 1.28 c.c. of original culture.
The idea of trying to free the vagina of trichomonads by implanting lactic acid-forming bacilli occurred to us after we had made a careful study of the normal defensive mechanism of the vagina which depends primarily on the three following conditions: First, that the vaginal secretion remains at its normal low pH; second, that the Doderlein or vaginal lactobacilli are present in sufficient numbers to form lactic acid; and finally, that there is sufficient carbohydrate, perhaps in the form of glycogen, in the vaginal epithelial cells or spaces between