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Use of Androgen-Estrogen Combination to Prevent Pain and Lactation in the Puerperium
USE OF
.ANDROGEN~BSTltOGEN
OOMBINATION TO PREVENT PAIN .AND LACTATION IN TJIE PUDPBBIUM BERTRAM KATZMAN, :M.D., HARRISBURG, PA. (From the Keystone Hospital)
usefulness of either androgenic or estrogenic hormones in the ;,.;uppressim1 TofHElactation and relief of painful breast engorgement in the early postpartum period has frequently been reported in the literature. However, much disagreement exists as to the identity of the more effective of these hormones and as to the proper time for initiating therapy. In the present series, study and evaluation have been made of the usefulness of an androgen-estrogen combination. 'fhis was undertaken using the rationale of the physiologic occurrence of both androgen and estrogen in norma] human males and females. In the author's experience, a single injection of combined androgen-estrogen has been effective in controlling functional bleeding in 96 per cent of cases. 1 Good results haYe been obtained with combined hormone therapy in studies of geriatrics2 • 3 and the menopausal state. 4 • ' Reports on the use of estrogens in suppression of lactation showed effectiveness ranging from 66 per cent6 to 98.5 per cent. 7 Numerous side effects have been reported.s-n The most frequent of these is nausea and the most distressing .are withdrawal bleeding and return of breast engorgement. Testosterone has been shown to be free of such undesirable actions12 and to have been effective in inhibiting lactation in from 60 per cent13 to 100 per centH of cases. Apparently more effective than estrogens in relief of breast engorgement, testosterone failed to accompliRh this end in 6 per cent 15 to over 20 per cent 16 of cases. The exact timing of doses and the dosage are, however, matters of dispute. Arrhenomimetic effects have not been observed by investigators who employed testosterone in therapeutic dosages for the inhibition of lactation. However, the potentiality of masculinizing effects is well known and is feared by most physicians. There has been a marked hesitancy to employ testosterone in female patients, unless the condition were of such a magnitude that masculinizing effects would be unimportant in eomparison. In considering any treatment in which hormones are employed, it is simple, but not precise, to speak of ''male'' and ''female'' hormones. Both are present in individuals of either sex. 17 In addition, the gonadal hormones are not exclusively sex hormones, but exert numerous effects on extragonadal activities and psychic attitudes. Margolese 18 observed that a specific ratio of androgen to estrogen, causing neither bleeding nor masculinization, was found to exist for each individuaL Variations from this ratio were not marked, thus a specific ratio was found to be therapeutically effective for a majority of cases. The most satisfactory proportion was found to be 1 part of estradiol by weight to 20 parts of testosterone propionate. Newman 19 recently confirmed this figure. Barsantini and Masson 20 determined the relative activity of numerous steroids in lactating animals. They found estradiol to be the most active compound, followed closely 1338
ANDROGEN-ESTROGEN COMBINATION TO PREVENT LACTATION
Volume 63 Number 6
133<1 iJ
by testosterone. Since estradiol and testosterone were found to be the most biologically active steroids, and a 20 :1 ratio the most physiologic proportion, we employed in our series an androgen-estrogen combination of testosterone propionate, 20 mg., plus estradiol benzoate, 1 mg. per cubic centimeter. • Comprehensive search of the literature has failed to disclose published reports on the effect of an androgen-estrogen combination on lactation. However, studies of such combinations in menopausal therapy have brought forth several interesting facts. Glass 4 reported that the effective dosage of androgenestrogen in combination was markedly less than that of either hormone given separately. In his series, withdrawal bleeding or andromimetic effects were rarely seen and then only after prolonged maintenance therapy. He remarked that the anabolic synergism of the androgen-estrogen combination provided an optimum sense of well-being. With such obvious advantages in mind, we employed an androgen-estrogen combination in one series to relieve painful lactation; and, in a second series, to suppress lactation.
Method A parenteral preparation of androgen-estrogen (testosterone propionate, 20 mg., plus estradiol benzoate, 1 mg. per cubic centimeter) was administered to an unselected group of 50 patients. All patients received a single intramuscular injection during the first 24 hours post partum. To establish painless lactation without suppression of the flow of milk, a single injection of 1 c.c. was administered during the first 24 hours post partum. To inhibit lactation an injection of 2 c.c. was administered during the first 24 hours. Two patients received an additional dose of 1 c.c. No other treatment of any type was employed.
Results Of 17 patients treated to ensure painless lactation, results were good in 15 patients (88 per cent). One patient experienced minimal discomfort. In TABLE
I.
RELIEF OF PAINFUI, LACTATION WITH C'O.MBINED ANDROGEN~ESTROGEN THERAPY
F.Z. E.M.
J.E. J.W. C. H. B.Y. W.F. M.J. I. s. J.B. J.B. D. B. C. D. A.W. M.S. C. B.
•Plus 1 c. c.
ii
24
17
iii i i
ii ii ii ii ii i v 3
21 22 2a 21 21 17 29 39
31
22 28
3() 21
c.e. 1 c.c. 1 c.c. 1 c.c. 1 c.c. 1 c.c. '1 c.c. 1 c.c. 1 c.c. 1 c.e. 1 c.c. 1 c.c. 1 c.e. 1 C.(';.* 1 c.e.
1 c.c. 1 c.c.
Slight pain Painless lactation Painless lactation Painless lactation. Painless lactation Painless lactation. Painless lactation. Painless lactation Painless lactation Painless lactation Painless lactation Painless Poor Painless Painless PainlORR
Excellent Good Good
Pain 48 hours post partum for 10 hours
bctation lactation lactation lactation
days later.
•Testosterone propionate, 20 mg., plus estradiol benzoate, 1 mg. per cubic centimeter supplied as Gynetone Injection, through the courtesy of Scherlng corporation, Bloomfteld, N. l
1340
Am.]. Obst. & Gynec. June, 1952
KATZMAN
the other, the result was poor even with a repeat injeetion of 1 e.e. on the fom·th postpartum day. There was no diminution of milk secretion in any case. No nursing difficulties were encountered (Table I). Of 33 patients in whom lactation was inhibited, excellent results occurred in 9 and good results occurred in 19. Results were fair in 4. One of these patients received a 1 c.c. dose; after 2 days of lactation, a second dose of 1 c.c. Gynetone was administered and lactation ceased 48 hours later. Results were poor in one ease (3 per cent). Successful results occurred in 97 per cent (Table II). TABLE II. PATIENT
J.P. G.Q. M.K. FJ. D. M.T. .T. D. H. D. .T. B. H.S. R. s. ,J. H.
M.W.
w.w.
c. s. s. W.R. w.w.
R.
SUPPP..ESSION OF LACTATION WITH COMBINED ANDROGEN-ESTROGEN THERAPY GRAv'ID.\ iv v iv iii iii vi vi iv
v ii v
ii i i v
I'.U.
(YEARS) 30
41 28 30 26
31 39 26
2 c.c.
21
2 c.c.
38
2 c.c. 2 c.c. 2 c.c. 2 c.c. 2 e.c. 2 c.r. 3 e.e~
30
20 39 35 :1:{ 21
:n
2 r.c. 2 ('.{',,
ii
W.M. R.N.
.r. c.
ii v
2R :..!8
ii
l\LN. B. B. F. T.
ii ii
23 0.:)') -" 29
.r. s.
ii
ii
28 25 25 22 19
26
*IJactation stopped in: +-1 day ++--2 days +++-3 days ++n-4 days t I c. c. first 24 hours. 1 c.c. after 2 days' lactation.
~
('.('.
2 c.c. 2 e.e. ~ r.c. 2 e.c. 2 c.c. 2 r.<:. 2 P..('.
Excellent Excellent Good Good Good
+++ ++ ++ ++ ++
Fair
+++
Good
+
Fairt
++ 1+ + ++
Good Goo'!
Good Good Good Good
+
·'
Excellent
Excellent
Good
Fairt i
Poor Good f'.ood
H
2 c.e. 2 c.e.
2 c.c.
Good C'.ood
t + ++
~ f'~.{~.
17 20
RESULTS
++ 1· + + ++
2 (',(,,
:21
L.M. W.M. L.W. R. S.
LACTATION*
2 c.c.
2!1
:!H
C.M. O.K. M.S. A. B.
DOSAGE 2 c.c. 2 c.c. 2 e.e. 2 c.c. 2 c.c. 2 e.c. 2 c.c.
+t
+
Excellent Excellent
+ +++ ++ +
Good
Fair l
++
Uood
++ ++
Excellent Good
+
-
:FJxcellent
++
---~~--~-~---
Hood -~
----~--~-~""-
--,.·------~--------
Lactation ceased 48 hours later.
Of 12 patients who had in previous pregnancies received stilbestrol, all preferred the present androgen-estrogen combination therapy. Many had previously suffered nausea from stilbestrol. In the present series, there were no instances of nausea, vomiting, fever, malaise, urticaria, or any of the other side effects reported as having occurred with estrogenic therapy. There were no increased bleeding tendencies, nor did any patient complain of engorged breasts, either during treatment or upon withdrawal of medication.
Volume 63 Number 6
ANDROGEN-ESTROGEN COMBINATION TO PREVENT LACTA'riON
1341
Summary Painless lactation in 88 per cent of patients resulted from a 1 c.c. intramuscular dosage of androgen-estrogen combination (testosterone propionate, 20 mg., plus estradiol benzoate, 1 mg. per cubic centimeter) during the first 24 hours post partum. Inhibition of lactation in 97 per cent of patients resulted from a single 2 c.c. intramuscular dose of this same androgen-estrogen combination. No side actions,were observed. No supportive therapy or other measures of any kind were employed. It is concluded that in the prevention of lactation and painful postpartum breast engorgement an androgen-estrogen combination (testosterone propionate, 20 mg., plus estradiol benzoate, 1 mg. per cubic centimeter as Gynetone injection) offers therapeutic advantages as well as greater convenience to both patient and physician.
References 1. Katzman, B.:
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
M. Times, New York 78: 89, 1950. Benjamin, H.: J. Gerontol. 4: 222, 1949. Benjamin, II.: J. Insurance Med. 6: 12, 1951. Glass, S. J.: J. Clin. Endocrinol. 10: 1616, 1950. Greenblatt, R. B., et al.: J. Clin. Endocrinol. 10: 1547, 1950. Lubin, S.: AM. J. OBST. & GYNEC. 51: 225, 1946. Bloom, 0. H.: AM. J. 0BST. & GYNEC. 47: 693, 1944. Gershenfeld, D. B., and Perlmutter, I. K.: J. Olin. Endocrinol. 8: 875, 1948. Berlowe, L.: Yale J. Biol. & Med. 14: 631, 1941-42. Kurzrok, L., Birnberg, C. H., and Livingston, S.: J. C'lin. Endoerinol. 2: 471, 1942. Jeffcoate, T. N. A., Lister, U. M., Hargreaves, B., and Roberts, H.: Brit. M. J. 2: 4583, 1948. Kurzrok, R., and 0 'Connell, 0. P.: Endocrinology 23: 476, 1938. Waters, E. G.: Pennsylvania M. J. 54: 217, 1951. Parker, J. C.: Virginia M. Monthly 77: 543, 1950. Siegler, S. L., and Silverstein, L. M.: AM. J. OBST. & GYNEC. 39: 109, 1940. Birnberg, C. H., Kurzok, L., and Klor, S. J.: AM. J. OBST. & GYNEC. 39: 107, 1940. Gallagher, T. F.: et al.: J. Olin. Investigation 16: 695, 1937. Margolese, M. S.: J. Clin. Endocrinol. 4: 394, 1944. Newman, G. T.: AM. J. OBST. & GYNEC. 62: 607, 1951. Barsantini, J. C., and Masson, G. M. C.: Endocrinology 41: 229, 1947.
.ANDROGEN~BSTltOGEN
OOMBINATION TO PREVENT PAIN .AND LACTATION IN TJIE PUDPBBIUM BERTRAM KATZMAN, :M.D., HARRISBURG, PA. (From the Keystone Hospital)
usefulness of either androgenic or estrogenic hormones in the ;,.;uppressim1 TofHElactation and relief of painful breast engorgement in the early postpartum period has frequently been reported in the literature. However, much disagreement exists as to the identity of the more effective of these hormones and as to the proper time for initiating therapy. In the present series, study and evaluation have been made of the usefulness of an androgen-estrogen combination. 'fhis was undertaken using the rationale of the physiologic occurrence of both androgen and estrogen in norma] human males and females. In the author's experience, a single injection of combined androgen-estrogen has been effective in controlling functional bleeding in 96 per cent of cases. 1 Good results haYe been obtained with combined hormone therapy in studies of geriatrics2 • 3 and the menopausal state. 4 • ' Reports on the use of estrogens in suppression of lactation showed effectiveness ranging from 66 per cent6 to 98.5 per cent. 7 Numerous side effects have been reported.s-n The most frequent of these is nausea and the most distressing .are withdrawal bleeding and return of breast engorgement. Testosterone has been shown to be free of such undesirable actions12 and to have been effective in inhibiting lactation in from 60 per cent13 to 100 per centH of cases. Apparently more effective than estrogens in relief of breast engorgement, testosterone failed to accompliRh this end in 6 per cent 15 to over 20 per cent 16 of cases. The exact timing of doses and the dosage are, however, matters of dispute. Arrhenomimetic effects have not been observed by investigators who employed testosterone in therapeutic dosages for the inhibition of lactation. However, the potentiality of masculinizing effects is well known and is feared by most physicians. There has been a marked hesitancy to employ testosterone in female patients, unless the condition were of such a magnitude that masculinizing effects would be unimportant in eomparison. In considering any treatment in which hormones are employed, it is simple, but not precise, to speak of ''male'' and ''female'' hormones. Both are present in individuals of either sex. 17 In addition, the gonadal hormones are not exclusively sex hormones, but exert numerous effects on extragonadal activities and psychic attitudes. Margolese 18 observed that a specific ratio of androgen to estrogen, causing neither bleeding nor masculinization, was found to exist for each individuaL Variations from this ratio were not marked, thus a specific ratio was found to be therapeutically effective for a majority of cases. The most satisfactory proportion was found to be 1 part of estradiol by weight to 20 parts of testosterone propionate. Newman 19 recently confirmed this figure. Barsantini and Masson 20 determined the relative activity of numerous steroids in lactating animals. They found estradiol to be the most active compound, followed closely 1338
ANDROGEN-ESTROGEN COMBINATION TO PREVENT LACTATION
Volume 63 Number 6
133<1 iJ
by testosterone. Since estradiol and testosterone were found to be the most biologically active steroids, and a 20 :1 ratio the most physiologic proportion, we employed in our series an androgen-estrogen combination of testosterone propionate, 20 mg., plus estradiol benzoate, 1 mg. per cubic centimeter. • Comprehensive search of the literature has failed to disclose published reports on the effect of an androgen-estrogen combination on lactation. However, studies of such combinations in menopausal therapy have brought forth several interesting facts. Glass 4 reported that the effective dosage of androgenestrogen in combination was markedly less than that of either hormone given separately. In his series, withdrawal bleeding or andromimetic effects were rarely seen and then only after prolonged maintenance therapy. He remarked that the anabolic synergism of the androgen-estrogen combination provided an optimum sense of well-being. With such obvious advantages in mind, we employed an androgen-estrogen combination in one series to relieve painful lactation; and, in a second series, to suppress lactation.
Method A parenteral preparation of androgen-estrogen (testosterone propionate, 20 mg., plus estradiol benzoate, 1 mg. per cubic centimeter) was administered to an unselected group of 50 patients. All patients received a single intramuscular injection during the first 24 hours post partum. To establish painless lactation without suppression of the flow of milk, a single injection of 1 c.c. was administered during the first 24 hours post partum. To inhibit lactation an injection of 2 c.c. was administered during the first 24 hours. Two patients received an additional dose of 1 c.c. No other treatment of any type was employed.
Results Of 17 patients treated to ensure painless lactation, results were good in 15 patients (88 per cent). One patient experienced minimal discomfort. In TABLE
I.
RELIEF OF PAINFUI, LACTATION WITH C'O.MBINED ANDROGEN~ESTROGEN THERAPY
F.Z. E.M.
J.E. J.W. C. H. B.Y. W.F. M.J. I. s. J.B. J.B. D. B. C. D. A.W. M.S. C. B.
•Plus 1 c. c.
ii
24
17
iii i i
ii ii ii ii ii i v 3
21 22 2a 21 21 17 29 39
31
22 28
3() 21
c.e. 1 c.c. 1 c.c. 1 c.c. 1 c.c. 1 c.c. '1 c.c. 1 c.c. 1 c.c. 1 c.e. 1 c.c. 1 c.c. 1 c.e. 1 C.(';.* 1 c.e.
1 c.c. 1 c.c.
Slight pain Painless lactation Painless lactation Painless lactation. Painless lactation Painless lactation. Painless lactation. Painless lactation Painless lactation Painless lactation Painless lactation Painless Poor Painless Painless PainlORR
Excellent Good Good
Pain 48 hours post partum for 10 hours
bctation lactation lactation lactation
days later.
•Testosterone propionate, 20 mg., plus estradiol benzoate, 1 mg. per cubic centimeter supplied as Gynetone Injection, through the courtesy of Scherlng corporation, Bloomfteld, N. l
1340
Am.]. Obst. & Gynec. June, 1952
KATZMAN
the other, the result was poor even with a repeat injeetion of 1 e.e. on the fom·th postpartum day. There was no diminution of milk secretion in any case. No nursing difficulties were encountered (Table I). Of 33 patients in whom lactation was inhibited, excellent results occurred in 9 and good results occurred in 19. Results were fair in 4. One of these patients received a 1 c.c. dose; after 2 days of lactation, a second dose of 1 c.c. Gynetone was administered and lactation ceased 48 hours later. Results were poor in one ease (3 per cent). Successful results occurred in 97 per cent (Table II). TABLE II. PATIENT
J.P. G.Q. M.K. FJ. D. M.T. .T. D. H. D. .T. B. H.S. R. s. ,J. H.
M.W.
w.w.
c. s. s. W.R. w.w.
R.
SUPPP..ESSION OF LACTATION WITH COMBINED ANDROGEN-ESTROGEN THERAPY GRAv'ID.\ iv v iv iii iii vi vi iv
v ii v
ii i i v
I'.U.
(YEARS) 30
41 28 30 26
31 39 26
2 c.c.
21
2 c.c.
38
2 c.c. 2 c.c. 2 c.c. 2 c.c. 2 e.c. 2 c.r. 3 e.e~
30
20 39 35 :1:{ 21
:n
2 r.c. 2 ('.{',,
ii
W.M. R.N.
.r. c.
ii v
2R :..!8
ii
l\LN. B. B. F. T.
ii ii
23 0.:)') -" 29
.r. s.
ii
ii
28 25 25 22 19
26
*IJactation stopped in: +-1 day ++--2 days +++-3 days ++n-4 days t I c. c. first 24 hours. 1 c.c. after 2 days' lactation.
~
('.('.
2 c.c. 2 e.e. ~ r.c. 2 e.c. 2 c.c. 2 r.<:. 2 P..('.
Excellent Excellent Good Good Good
+++ ++ ++ ++ ++
Fair
+++
Good
+
Fairt
++ 1+ + ++
Good Goo'!
Good Good Good Good
+
·'
Excellent
Excellent
Good
Fairt i
Poor Good f'.ood
H
2 c.e. 2 c.e.
2 c.c.
Good C'.ood
t + ++
~ f'~.{~.
17 20
RESULTS
++ 1· + + ++
2 (',(,,
:21
L.M. W.M. L.W. R. S.
LACTATION*
2 c.c.
2!1
:!H
C.M. O.K. M.S. A. B.
DOSAGE 2 c.c. 2 c.c. 2 e.e. 2 c.c. 2 c.c. 2 e.c. 2 c.c.
+t
+
Excellent Excellent
+ +++ ++ +
Good
Fair l
++
Uood
++ ++
Excellent Good
+
-
:FJxcellent
++
---~~--~-~---
Hood -~
----~--~-~""-
--,.·------~--------
Lactation ceased 48 hours later.
Of 12 patients who had in previous pregnancies received stilbestrol, all preferred the present androgen-estrogen combination therapy. Many had previously suffered nausea from stilbestrol. In the present series, there were no instances of nausea, vomiting, fever, malaise, urticaria, or any of the other side effects reported as having occurred with estrogenic therapy. There were no increased bleeding tendencies, nor did any patient complain of engorged breasts, either during treatment or upon withdrawal of medication.
Volume 63 Number 6
ANDROGEN-ESTROGEN COMBINATION TO PREVENT LACTA'riON
1341
Summary Painless lactation in 88 per cent of patients resulted from a 1 c.c. intramuscular dosage of androgen-estrogen combination (testosterone propionate, 20 mg., plus estradiol benzoate, 1 mg. per cubic centimeter) during the first 24 hours post partum. Inhibition of lactation in 97 per cent of patients resulted from a single 2 c.c. intramuscular dose of this same androgen-estrogen combination. No side actions,were observed. No supportive therapy or other measures of any kind were employed. It is concluded that in the prevention of lactation and painful postpartum breast engorgement an androgen-estrogen combination (testosterone propionate, 20 mg., plus estradiol benzoate, 1 mg. per cubic centimeter as Gynetone injection) offers therapeutic advantages as well as greater convenience to both patient and physician.
References 1. Katzman, B.:
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
M. Times, New York 78: 89, 1950. Benjamin, H.: J. Gerontol. 4: 222, 1949. Benjamin, II.: J. Insurance Med. 6: 12, 1951. Glass, S. J.: J. Clin. Endocrinol. 10: 1616, 1950. Greenblatt, R. B., et al.: J. Clin. Endocrinol. 10: 1547, 1950. Lubin, S.: AM. J. OBST. & GYNEC. 51: 225, 1946. Bloom, 0. H.: AM. J. 0BST. & GYNEC. 47: 693, 1944. Gershenfeld, D. B., and Perlmutter, I. K.: J. Olin. Endocrinol. 8: 875, 1948. Berlowe, L.: Yale J. Biol. & Med. 14: 631, 1941-42. Kurzrok, L., Birnberg, C. H., and Livingston, S.: J. C'lin. Endoerinol. 2: 471, 1942. Jeffcoate, T. N. A., Lister, U. M., Hargreaves, B., and Roberts, H.: Brit. M. J. 2: 4583, 1948. Kurzrok, R., and 0 'Connell, 0. P.: Endocrinology 23: 476, 1938. Waters, E. G.: Pennsylvania M. J. 54: 217, 1951. Parker, J. C.: Virginia M. Monthly 77: 543, 1950. Siegler, S. L., and Silverstein, L. M.: AM. J. OBST. & GYNEC. 39: 109, 1940. Birnberg, C. H., Kurzok, L., and Klor, S. J.: AM. J. OBST. & GYNEC. 39: 107, 1940. Gallagher, T. F.: et al.: J. Olin. Investigation 16: 695, 1937. Margolese, M. S.: J. Clin. Endocrinol. 4: 394, 1944. Newman, G. T.: AM. J. OBST. & GYNEC. 62: 607, 1951. Barsantini, J. C., and Masson, G. M. C.: Endocrinology 41: 229, 1947.