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Treatment of Menstrual Disorders with Pregnant Mares' Serum
VOGT, JR., AND SEXTON:
TREATMENT OF MENSTRUAl, DISORDERS
81
2. The most frequent cause of rupture of the uterus was previous cesarean section. The trauma of internal podalic version and uncorrected transverse presentation also were prominent causative factors. 3. Supracervical hysterectomy or suture of the uterine laceration gave equally good results in the treatment of cases where rupture followed a previous cesarean section~ 4. Supracervical hysterectomy was the treatment of choice in the nonsection cases of uterine rupture. 5. There is a definite danger of uterine rupture before the onset of labor, particularly in patients where previous cesarean section had been performed. 6. Internal podalic version was responsible for 60 per cent of the uterine ruptures occurring during the time of delivery. 7. Complete rupture of the uterus is far more serious than the incomplete variety. 8. Hemorrhage and shock was the most common immediate cause of death. 9. The maternal mortality rate for the entire series was 37 per cent: total fetal mortality rate was 69 per cent. REFERENCES
DeLee, J. B.: Principles and Practice of Obstetrics, ed. 7, Philadelphia, W. B. Saunders Co., p. 859. Davis, .dsa B.: AM. J. OBST. & GYNEC. 13: 5;;!2, 1927. Weber, G. H.: Tilinois :M:. J. 47: 39, 1925, Kerr, Mcintyre, and Hendry: Brit. :M:.•J. 1: 1093, 1924. .dudebert,-J. L.: Gynec. et obst. 7: 487, 1923. McNeile, L., and .McBurney, E.: Calif. & West. :M:ed. 42: 73, 1935. Skeel, .d . .!., and Jordan, F. F.: AM. J. 0BST. & GYNEC~ 23: 172, 1932. Gelle, P.: Bull. So<>, d'obst. et gynec. 21: 62,1932. Woodward, H. L.: J. :M:ed. 20: 106,1939. 10515 CARNEGIE AVENUE
TREATMENT OF MENSTRUAL DISORDERS WITH PREGNANT MARES' SERUM WILLIAM
H. VoGT, JR., A.B., M.D., AND DANIELL. SEXTON, B.S., M.D., ST.
I,ours,
:Mo.
(From The Departments of Obstetrics and Gynecology and Internal Medioine, St. Louis University S'chool of Medicine)
P
REGNANT mares' serum was shown by Cole and Hart1 to possess a powerful stimulating effect on the ovaries of the immature rat, producing ovulation and corpus luteum formation. Evans 2 and Reichert, 3 in their studies on hypophysectomized rats, showed the contrast between pregnant mares' serum and chorionic gonadotropin: The pregnant mares' serum is effective in bringing about structural restoration of the female reproductive system, and chorionic gonadotropin is not. Also, pregnant mares' serum is not excreted by the kidney; therefore, the total dose is available for stimulation. Clinical studies on pregnant mares' serum by Bowes4 and Frank, 5 Davis and Koff, 6 Dodds and his associates, 7 and Kurzrok, 8 gave indifferent or incondusive results. While interest in this hormone centered mostly about its use in overcoming sterility, it has been used· in all forms of menstrual disturbances with varying success. 9 • 13
82
AMERICAN JOURNAL OF OBSTF.TRICS AND GYNECOLOGY
Because of these conflicting reports, further clinical experiences with this hormone are here recorded. Seventeen patients with menstrual disturbances were treated: 13 suffered from amenorrhea or oligomenorrhea, and 4 had menorrhagia or metromenorrhagia. In 12 of the 17 patients endometrial biopsies were performed with a suction curette and 4 of the remaining 5 were followed with vaginal smears:
( '" .
A.
B.
Fig. 1.-A, Endometrial biopsy showing atrophy in patient (H. N .) with amenorrhea of ten months' duration. B , Proliteratlve phase after 3,000 international units of gonadin. Regular monthly p eriods have occurred for eight months after treatment discontinued. ( X l25.)
A.
B.
Fig. 2. -A , Endometrial biopsy showing Cullen's hyperplasia In patient (H. M.) with menorrhagia after three w eeks' flow. B , Proliferative phase after 3,000 International units of gonadin. R egular three- to seven-da y p eriods have occurred for eight months. ( X125.)
Following the suggestion of Novak, patients with amenorrhea and hypomenorrhea were primed with estrone, 16,000 units being the usual preliminary dosage. All of the patients were given a careful physical, endocrinologic and gynecologic examination before pregnant mares' serum was given. All other medication was discontinued. The plan of treatment was to administer 200 international units of pregnant mares'
VOGT, JR., AND SEXTON:
TREATMENT OF MENSTRUAL DISORDERS
83
serum• intramuscularly, every other day, until 15 injections or 3,000 international units were administered. A rest period followed the injections and, if there was no clinical response, the course was repeated. At intervals, depending upon the progress of the individual patient, endometrial biopsies were again taken. Results of treatment are shown in Table I. DISCUSSION
Seven of the 17 patients with amenorrhea anti oligomenorrhea were affected by treatment during the period of injections. \V11en these patients were interviewed eight months later, 2 of the 7 had more than temporary benefit, and in a thhd patient (A. R.), the four- to six-month menstrual interval was reduced to an interval of three months. Of significant interest is the case of R. z... aged 17 years, the only case of primary amenorrhea in the series, who failed to show any immediate clinical benefit from treatment, arul whose endometrial biopsies showed atrophy before and aftilr treatment. One month after the injections were discontinued she
A.
B.
Fig. 3.-A, Endometrial biopsy showing secretory phase in patient (P. M.) with menorrhagia after nine weeks' flow. B, Proliferative phase after 4,200 international units of gonadln. Normal menses occurred for four months; then menorrhagia recurred. ( Xl25.)
menstruated and has continued to have regular monthly periods after eight months. Of further interest is the patient (J. H.) who had acromegaly with an enlarged sella turcica. Since there has been speculation that a
ol
L.M. 27
~ol
I»
Massive doses of estrone
None 6,000 I.U.
6,000 LU
5,400 I.U.
None
Interval 6 wk. in i mo. Sell>nt flow
M.O.
22
fl,OOO I.U.
Irreg.. interval 2-3 mo. None Last menstrual period 10 mo. previous
H.N. 20
G,OOO I.U.
Irreg., 3-6 periods a yr. Desiccated thyroid Last menstrual period 3 mo. previous
M.S. 17
6,000 I.U. 4,200 I.U.
None
Interval 3-6 mo. 1 day None duration past 10 yr.
Sudden cessation 3 yr. previous
Interval of 6 mo.; vary· Series of estrone and 6,000 LU. ing periods of menor- progestin rhagia and metrorrhagia
Primary amenorrhea
flow
Seant
PKEVIOUS TREATMENT
AMOUNT P.M.S.
0
Prolifera· tion
Atrophy
Atrophy
Atrophy
Menses more Not heard from Atrophy regular during treatment
Menstruated Regular monthly pe· riods
Menses more About same as Atrophy regular formerly during treatment
Menstruated Regular monthly periods
0
Atrophy
BE~'ORE
Proli:feraation
Prolifera· at ion
Prolifera· ation
Prolifera· ation
Atrophy
Atrophy
Atrophy
1Atrophy
AFTER
ENDOMETRIUM
Regular periods Atrophy began 1 mo. after treatment
AFTER 8 MONTHS 0
2 periods at No further 30-day in· period terval
0
0
IMMEDIATE
CLIN!OAL RESULTS
RESUME OF CASES 'fREATEIJ WITH PREGNANT MARES' SERUM (P.M. S.)
C.P. 27
32
"" ~ J.H.
a 0
al
0
1l"'
R.Z. 17
29
interval
MENSTRUAL HISTORY
-- ~ 13~-day
NA!\iE AGE
1'ABLE l.
---
---
---
---
BEb'ORE
---
---
---
---
---
---
AFTER
- - - ------
VAGINAL SMEARS
"::
§
~
zl:':J
~
0
~
00
~
~
g
0
~
z
~
'-< 0
~
l.l
~
~
>
~
)1
"'
g
:J,OOO I.U.
H.M. 30
T>
H. A. 24
23
\'.D.
H
Rest; oral medication 4,200 I.U.
Flowed 2 wk.
None
rettage 4,200 I.U.
Flow ht::;t·iug· 7 tu 21 Uays 2 dilatation and cu- 3,000 I.U.
Flowing 9 wk.
6,000 I.U.
Irregular fast 2 yr. Last Estrone 3,800 I.U. menstrua period 3 mo. previous Flowing 3 wk. 3 dilatation and cu- 3,000 I.U. rettage; ''shots''
Estrone, two long series
M.P. 33
30
Scant flow. Last men.'!trual period 10 yr. previous
L.R.
1,500 I.U.
Always irregular. Last Thyroid; estrone; menstrual period 15 mo. gonadotropic horprevious mone; urinary gonadotropin
ol ..:::: ... 27
...
None
Fairly regular until last Estrone for 9 mo. pe- 4,800 I.U. menstrual period 12 mo. riod previous
Interval 4 to 6 mo. Scant flow
P.B. 25
M.A. 20
'b.J P.M.
ol
--
~
~
0
,<:I
......"' "'
ol
A.R. 18
Pregnant
Benefited
Benefited
Benefited
0
0
0
Vaginal bleeding one time
---
---
---
---
Proliferaation
Proliferaation
---
---
---
---
---
---
ProliferaCullen's hyperplasia at ion Full term preg- Prolifernancy ation
Regular, 4-8 days' duration
Secretory Improvement for 4 mo. only phase
3-7 davs' dura- Cullen's tion. ·Regular hyperplasia
0
0
0
0
Menstruated Regular for 4 Atrophy mo. No period since
---
---
---
---
Neg.
Weak Pos.
---
Neg.
---
---
---
---
-----
Neg.
Neg.
---
Pos.
---
<1 0
·:..-'"1
CD
::>;l 00
trl
t:)
::>;l
0
00
H
t:)
~
rj
::>;l
>-3
z 00
~ trl
"J
0
z>-3
>-3 ~ trl
~
trl
::>;l
>-3
z0
>< >-3
trl
00
t:)
z~
J'
<:...,
Q _,..,
~
~ '~
~
~
'~
l
<
I
I
~
I
i
86
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY SUl\1l\1ARY
Thirteen patients with amenorrhea and oligomenorrhea were treated with pregnant mares' serum. After eight months' observation, regular monthly periods have continued in 3 of the 13, 1 of the 3 having been a case of primary amenorrhea. Four patients with menorrhagia were treated; all 4 of whom showed evidence of immediate improvement. One of the 4 became pregnant after a sterile marriage of five years, and has gone on to full term. Two of the remaining 3 have shown continued benefit after eight months. Endometrial changes in the cases of amenorrhea and oligomenorrhea were inconstant, while in the cases of menorrhagia, the pattern changed from one of hyperplasia to one of proliferation. The authors wish to express their indebtedness to Dr. Wm. H. Yogt, Sr., Director of the Department of Obstetrics and Gynecology, for his suggestions and invaluable ald in carrying out these studies.
REFERENCES
(1) Cole, H. H., and Hart, G. H.: Am. J. Physiol. 93: 57, 1930. (2) EvaM, H. M.: West. J. Surg. 44: 175, 1936. (3) llei
THE EF:r'ECT OF ORAL ADMINISTRATION OF ALPHA BSTRADIOL AND PRBGNBNINOLONE UPON THE HUMAN CASTRATE UTERUS THEODORE
M.D., F.A.C.S., L.M. NEW YORK, N.Y.
lrlEUSTAEDTER,
(DUBLIN),
(From the Departmrnt of Gyneoology, New York Post-Grad'l#(].te Medical School and Hospital, Columbia University)
HE oral effect of estrin, 1 and the combined effect of oral estrin and parenteral progestin2 upon the human castrate endometrium have been previously demonstrated. This presentation eon~erns itself with the application of oral estrin ( dimenformon) • and an oral synthetic progestin derivative (pregneninolone)• upon the endometrium of the human castrate uterus. In addition, an attempt has been made to determine the standard for a human unit of these two ovarian hormones, i.e., the approximate amounts utilized, in milligrams, of crystalline substance during a normal menstrual cycle. •we are indebted to Roche-Organon, Inc. for a supply of dlmentormon and preg-
T
neninolone ( progestoral).
TREATMENT OF MENSTRUAl, DISORDERS
81
2. The most frequent cause of rupture of the uterus was previous cesarean section. The trauma of internal podalic version and uncorrected transverse presentation also were prominent causative factors. 3. Supracervical hysterectomy or suture of the uterine laceration gave equally good results in the treatment of cases where rupture followed a previous cesarean section~ 4. Supracervical hysterectomy was the treatment of choice in the nonsection cases of uterine rupture. 5. There is a definite danger of uterine rupture before the onset of labor, particularly in patients where previous cesarean section had been performed. 6. Internal podalic version was responsible for 60 per cent of the uterine ruptures occurring during the time of delivery. 7. Complete rupture of the uterus is far more serious than the incomplete variety. 8. Hemorrhage and shock was the most common immediate cause of death. 9. The maternal mortality rate for the entire series was 37 per cent: total fetal mortality rate was 69 per cent. REFERENCES
DeLee, J. B.: Principles and Practice of Obstetrics, ed. 7, Philadelphia, W. B. Saunders Co., p. 859. Davis, .dsa B.: AM. J. OBST. & GYNEC. 13: 5;;!2, 1927. Weber, G. H.: Tilinois :M:. J. 47: 39, 1925, Kerr, Mcintyre, and Hendry: Brit. :M:.•J. 1: 1093, 1924. .dudebert,-J. L.: Gynec. et obst. 7: 487, 1923. McNeile, L., and .McBurney, E.: Calif. & West. :M:ed. 42: 73, 1935. Skeel, .d . .!., and Jordan, F. F.: AM. J. 0BST. & GYNEC~ 23: 172, 1932. Gelle, P.: Bull. So<>, d'obst. et gynec. 21: 62,1932. Woodward, H. L.: J. :M:ed. 20: 106,1939. 10515 CARNEGIE AVENUE
TREATMENT OF MENSTRUAL DISORDERS WITH PREGNANT MARES' SERUM WILLIAM
H. VoGT, JR., A.B., M.D., AND DANIELL. SEXTON, B.S., M.D., ST.
I,ours,
:Mo.
(From The Departments of Obstetrics and Gynecology and Internal Medioine, St. Louis University S'chool of Medicine)
P
REGNANT mares' serum was shown by Cole and Hart1 to possess a powerful stimulating effect on the ovaries of the immature rat, producing ovulation and corpus luteum formation. Evans 2 and Reichert, 3 in their studies on hypophysectomized rats, showed the contrast between pregnant mares' serum and chorionic gonadotropin: The pregnant mares' serum is effective in bringing about structural restoration of the female reproductive system, and chorionic gonadotropin is not. Also, pregnant mares' serum is not excreted by the kidney; therefore, the total dose is available for stimulation. Clinical studies on pregnant mares' serum by Bowes4 and Frank, 5 Davis and Koff, 6 Dodds and his associates, 7 and Kurzrok, 8 gave indifferent or incondusive results. While interest in this hormone centered mostly about its use in overcoming sterility, it has been used· in all forms of menstrual disturbances with varying success. 9 • 13
82
AMERICAN JOURNAL OF OBSTF.TRICS AND GYNECOLOGY
Because of these conflicting reports, further clinical experiences with this hormone are here recorded. Seventeen patients with menstrual disturbances were treated: 13 suffered from amenorrhea or oligomenorrhea, and 4 had menorrhagia or metromenorrhagia. In 12 of the 17 patients endometrial biopsies were performed with a suction curette and 4 of the remaining 5 were followed with vaginal smears:
( '" .
A.
B.
Fig. 1.-A, Endometrial biopsy showing atrophy in patient (H. N .) with amenorrhea of ten months' duration. B , Proliteratlve phase after 3,000 international units of gonadin. Regular monthly p eriods have occurred for eight months after treatment discontinued. ( X l25.)
A.
B.
Fig. 2. -A , Endometrial biopsy showing Cullen's hyperplasia In patient (H. M.) with menorrhagia after three w eeks' flow. B , Proliferative phase after 3,000 International units of gonadin. R egular three- to seven-da y p eriods have occurred for eight months. ( X125.)
Following the suggestion of Novak, patients with amenorrhea and hypomenorrhea were primed with estrone, 16,000 units being the usual preliminary dosage. All of the patients were given a careful physical, endocrinologic and gynecologic examination before pregnant mares' serum was given. All other medication was discontinued. The plan of treatment was to administer 200 international units of pregnant mares'
VOGT, JR., AND SEXTON:
TREATMENT OF MENSTRUAL DISORDERS
83
serum• intramuscularly, every other day, until 15 injections or 3,000 international units were administered. A rest period followed the injections and, if there was no clinical response, the course was repeated. At intervals, depending upon the progress of the individual patient, endometrial biopsies were again taken. Results of treatment are shown in Table I. DISCUSSION
Seven of the 17 patients with amenorrhea anti oligomenorrhea were affected by treatment during the period of injections. \V11en these patients were interviewed eight months later, 2 of the 7 had more than temporary benefit, and in a thhd patient (A. R.), the four- to six-month menstrual interval was reduced to an interval of three months. Of significant interest is the case of R. z... aged 17 years, the only case of primary amenorrhea in the series, who failed to show any immediate clinical benefit from treatment, arul whose endometrial biopsies showed atrophy before and aftilr treatment. One month after the injections were discontinued she
A.
B.
Fig. 3.-A, Endometrial biopsy showing secretory phase in patient (P. M.) with menorrhagia after nine weeks' flow. B, Proliferative phase after 4,200 international units of gonadln. Normal menses occurred for four months; then menorrhagia recurred. ( Xl25.)
menstruated and has continued to have regular monthly periods after eight months. Of further interest is the patient (J. H.) who had acromegaly with an enlarged sella turcica. Since there has been speculation that a
ol
L.M. 27
~ol
I»
Massive doses of estrone
None 6,000 I.U.
6,000 LU
5,400 I.U.
None
Interval 6 wk. in i mo. Sell>nt flow
M.O.
22
fl,OOO I.U.
Irreg.. interval 2-3 mo. None Last menstrual period 10 mo. previous
H.N. 20
G,OOO I.U.
Irreg., 3-6 periods a yr. Desiccated thyroid Last menstrual period 3 mo. previous
M.S. 17
6,000 I.U. 4,200 I.U.
None
Interval 3-6 mo. 1 day None duration past 10 yr.
Sudden cessation 3 yr. previous
Interval of 6 mo.; vary· Series of estrone and 6,000 LU. ing periods of menor- progestin rhagia and metrorrhagia
Primary amenorrhea
flow
Seant
PKEVIOUS TREATMENT
AMOUNT P.M.S.
0
Prolifera· tion
Atrophy
Atrophy
Atrophy
Menses more Not heard from Atrophy regular during treatment
Menstruated Regular monthly pe· riods
Menses more About same as Atrophy regular formerly during treatment
Menstruated Regular monthly periods
0
Atrophy
BE~'ORE
Proli:feraation
Prolifera· at ion
Prolifera· ation
Prolifera· ation
Atrophy
Atrophy
Atrophy
1Atrophy
AFTER
ENDOMETRIUM
Regular periods Atrophy began 1 mo. after treatment
AFTER 8 MONTHS 0
2 periods at No further 30-day in· period terval
0
0
IMMEDIATE
CLIN!OAL RESULTS
RESUME OF CASES 'fREATEIJ WITH PREGNANT MARES' SERUM (P.M. S.)
C.P. 27
32
"" ~ J.H.
a 0
al
0
1l"'
R.Z. 17
29
interval
MENSTRUAL HISTORY
-- ~ 13~-day
NA!\iE AGE
1'ABLE l.
---
---
---
---
BEb'ORE
---
---
---
---
---
---
AFTER
- - - ------
VAGINAL SMEARS
"::
§
~
zl:':J
~
0
~
00
~
~
g
0
~
z
~
'-< 0
~
l.l
~
~
>
~
)1
"'
g
:J,OOO I.U.
H.M. 30
T>
H. A. 24
23
\'.D.
H
Rest; oral medication 4,200 I.U.
Flowed 2 wk.
None
rettage 4,200 I.U.
Flow ht::;t·iug· 7 tu 21 Uays 2 dilatation and cu- 3,000 I.U.
Flowing 9 wk.
6,000 I.U.
Irregular fast 2 yr. Last Estrone 3,800 I.U. menstrua period 3 mo. previous Flowing 3 wk. 3 dilatation and cu- 3,000 I.U. rettage; ''shots''
Estrone, two long series
M.P. 33
30
Scant flow. Last men.'!trual period 10 yr. previous
L.R.
1,500 I.U.
Always irregular. Last Thyroid; estrone; menstrual period 15 mo. gonadotropic horprevious mone; urinary gonadotropin
ol ..:::: ... 27
...
None
Fairly regular until last Estrone for 9 mo. pe- 4,800 I.U. menstrual period 12 mo. riod previous
Interval 4 to 6 mo. Scant flow
P.B. 25
M.A. 20
'b.J P.M.
ol
--
~
~
0
,<:I
......"' "'
ol
A.R. 18
Pregnant
Benefited
Benefited
Benefited
0
0
0
Vaginal bleeding one time
---
---
---
---
Proliferaation
Proliferaation
---
---
---
---
---
---
ProliferaCullen's hyperplasia at ion Full term preg- Prolifernancy ation
Regular, 4-8 days' duration
Secretory Improvement for 4 mo. only phase
3-7 davs' dura- Cullen's tion. ·Regular hyperplasia
0
0
0
0
Menstruated Regular for 4 Atrophy mo. No period since
---
---
---
---
Neg.
Weak Pos.
---
Neg.
---
---
---
---
-----
Neg.
Neg.
---
Pos.
---
<1 0
·:..-'"1
CD
::>;l 00
trl
t:)
::>;l
0
00
H
t:)
~
rj
::>;l
>-3
z 00
~ trl
"J
0
z>-3
>-3 ~ trl
~
trl
::>;l
>-3
z0
>< >-3
trl
00
t:)
z~
J'
<:...,
Q _,..,
~
~ '~
~
~
'~
l
<
I
I
~
I
i
86
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY SUl\1l\1ARY
Thirteen patients with amenorrhea and oligomenorrhea were treated with pregnant mares' serum. After eight months' observation, regular monthly periods have continued in 3 of the 13, 1 of the 3 having been a case of primary amenorrhea. Four patients with menorrhagia were treated; all 4 of whom showed evidence of immediate improvement. One of the 4 became pregnant after a sterile marriage of five years, and has gone on to full term. Two of the remaining 3 have shown continued benefit after eight months. Endometrial changes in the cases of amenorrhea and oligomenorrhea were inconstant, while in the cases of menorrhagia, the pattern changed from one of hyperplasia to one of proliferation. The authors wish to express their indebtedness to Dr. Wm. H. Yogt, Sr., Director of the Department of Obstetrics and Gynecology, for his suggestions and invaluable ald in carrying out these studies.
REFERENCES
(1) Cole, H. H., and Hart, G. H.: Am. J. Physiol. 93: 57, 1930. (2) EvaM, H. M.: West. J. Surg. 44: 175, 1936. (3) llei
THE EF:r'ECT OF ORAL ADMINISTRATION OF ALPHA BSTRADIOL AND PRBGNBNINOLONE UPON THE HUMAN CASTRATE UTERUS THEODORE
M.D., F.A.C.S., L.M. NEW YORK, N.Y.
lrlEUSTAEDTER,
(DUBLIN),
(From the Departmrnt of Gyneoology, New York Post-Grad'l#(].te Medical School and Hospital, Columbia University)
HE oral effect of estrin, 1 and the combined effect of oral estrin and parenteral progestin2 upon the human castrate endometrium have been previously demonstrated. This presentation eon~erns itself with the application of oral estrin ( dimenformon) • and an oral synthetic progestin derivative (pregneninolone)• upon the endometrium of the human castrate uterus. In addition, an attempt has been made to determine the standard for a human unit of these two ovarian hormones, i.e., the approximate amounts utilized, in milligrams, of crystalline substance during a normal menstrual cycle. •we are indebted to Roche-Organon, Inc. for a supply of dlmentormon and preg-
T
neninolone ( progestoral).