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Excretion of hormones in a case of habitual abortion
PALMER
:
EXCRETION
OF
HORMONES
IN
HABITUAL
1005
ABORTION
M. c.:
Human Biol. 6: 431, 1934. (5) Evans, H. N., and SujeBy, 0.: Mem. Univ. California 9: 119, 1931. (6) Fraenkel, I,.: Zentralbl. f. Gynak. 35: 1591, 1911. (7) Hurtman, C. G.: Contributions to Embryol. 23: 1, 1932. (8) Idem: AX J. OBST. & GYNEC. 26: 600, 1932. (9) Idem: Time of Ovulation in Women, a Study on the Fertile Period in the Menstrual Cycle, Baltimore, 1936, Williams & Wilkins. (10) Idem: J. Contraception 2: 51, 1937. (11) Harvey, D. L., and Crockett, H. E.: Human Biol. 4: 453., 1932. (12) Enaus, N.: Zentralbl. f. Gynak. 53: 2193, 1929. (13) Idem: Perrodic Fertility and Sterility in Woman: a Natural Method of Birth Control, Tr. by D. H. and K. Kitchen, Vienna, Moudrich, following the German edition in 1934. (14) Ogino, E.: Zentralbl f. GynHk. 54: 464, 1930. (15) Idem: Zentralbl. f. GynLk. 56: 721, 1932. (16) Papanicolaozl, G. I?.: Am. J. Anat. 52: 519, 1933. (17) Rubenstein, B. B.: J. Contraception 2: 171, 1937. (18) Schroeder, Robert: In Handbuch d. Gynakologie, 1928 (VeitStoeckel), vol. 1. (19) Pan de B&e, 2’. H.: fiber den Zusammenhang zwischen Ovarialfunction, Wellenbewegung, und Menstrualblutung und iiber die Enstehung des sogenannten Mittel-Schmerzes, 1904, Haarlem. (20) Idem: Ideal Marriage, Its Physiology and Technique. London, 1929, Heinemann.
EXCRETION
(From
OF
HORMONES IN ABORTION”
A CASE
ALLAN PALMER, M.D., SAN FRANCISCO, the Department of Obstetrics and Gynecology, California Medical School)
OF HABITUAL CALIF,
T
Uiversity
of
HE purpose of this report is twofold; first to present the urinary estrogenic and gonadotropic hormone findings in a carefully followed ease of abortion, and second, to confirm the findings of a report by Cohen and others1 and Marrian2 in which an association between the sudden excretion of free fat-soluble estrogen&z hormone and the onset of labor was demonstrated. The patient studied was a woman of 36 years, anxious to have a child but with the history of two spontaneous abortions at 1.5 and 5 months and one premature labor at 6.5 months in the order noted. The latter pregnancy terminated spontaneously Jan. 8, 1936. It was planned at that time that the patient should collect complete twenty-four-hour urine specimens regularly at weekly intervals during the ensuing year and bring them to the laboratory for the assay of estrogenic and gonadotropic hormones. She was to avoid pregnancy for the first six months of this experiment. This plan was carefully followed. A daily record of intercourse and menstrual periods was kept. The intervals at which coitus occurred, the date of abortion, and the size of the fetus were such that the probable date of conception could be quite accurately calculated. Unfortunately for the patient the pregnancy under investigation was multiple (twins) and an examination within a few hours after the earliest symptoms of abortion revealed a bulging amnion filling the vaginal vault. The patient promptly aborted twins and subsequently recovered after a stormy four-day febrile reaction. *Supported
by
the
Christine
Breon
Fund
for
Medical
Research.
1006
AMEjXJCAN
JOURNAL
OF
OBSTETRICS
AND
QYNECOLOGY
METHODS
Estrogenic hormone determinations were done exactly as described in previous 4 The urine was not extracted for “free” estrogenic hormone, however, until the sixth week of pregnancy. In all instances the estrogenic hormone was calculated as estrone in gamma excreted per day. Gonadotropic hormone determinations were done each week according to a concentration method described by Freed and Hechter,s until the hormone characteristic of pregnancy first became evident. After pregnancy was established the whole and diluted urine was tested for its gonadotropin content. A mouse unit of the gonadotropic hormone characteristic of pregnancy is the least amount of hormone necessary to produce at least one corpus luteum in at least one ovary of a nineteen to twentyone-day-old female mouse 100 hours after injection. The amount excreted per day was calculated from the tmentp-four-hour volume of urine.
reports.3,
DISCUSSION
As noted in the chart the first posit.ive pregnancy reaction was obtained at the end of the second week of pregnancy, which date should have been the day of onset of the first, missed menstrual period. The first demonstrable excess in the excretion of estrogenic hormone occurred at the end of the sixth week of pregnancy. The early appearance of the gonadotropic hormone characteristic of pregnancy as compared with the later appearance of increased amounts of estrogenic hormone is of importance in understanding why pregnancy tests which depend upon the detection of gonadotropic hormone arc of greater value in early pregnancy than those tests which depend upon the detection of increased excretion of estrogenic hormone. The peak of gonadotropic hormone excretion occurred at the end of the sixth week of pregnancy. The amount is in agreement with the reports of other investigators.G-Q Although the patient experienced morning nausea, the latter did not seem to have a, clear-cut association with the peak of gonadotropie hormone excretion.G This marked excretion of gonadotropic hormone demonstrates the impossibility of making a diagnosis of hydatidiform mole and chorioepithelioma on the basis of quantitative hormone escretion during the Arst trimester. The fall of gonadotropic hormone excretion during the eighth and uinth weeks, followed by a second rise, ha,s not been report,ed previously. Similar studies of habitual abortion may help to determine whether or not this phenomenon may be associated with a patient’s tendency to abort. The urine concentration procedure failed to reveal any of the gonadotropic hormone in the urine later than the fifth day post partum. Five days before the patient aborted, the exeretion of estrogenic hormone fell far below the expected gradually rising level known to occur in normal pregnancy. Could this have been known on the day of its occurrence, some form of hormone therapy might have prevented the termination of pregnancy. Chemical tests for estrogenic hormone which may be done quite rapidly are not, as yet, of definite value so early in pregnancy. With referenee to the second point in the purpose of this report, namely the confirmation of findings reported by Cohen and others,l the
PALM=
:
EXCRETION
OF
HORMONES
IN
HABITUAL
ABORTION
1007
Chart I.-Estrogenic Hormcme: The columns represent the total excretion of estrogenic hormone per twenty-four hours on the days indicated. The solid portion of the column represents the “combined” fat-insoluble hormone, and the shaded portion of “free” fat-soluble hormone. Each is calculated as estrone. Golzadotropic Hormone: The columns represent the total excretion of the gonadotropic characteristic of pregnancy per twenty-four hours on the days indicated. In every instance the assay was done on a portion of the same twenty-four-hour urine specimen used for estrogenic hormone determination. A mouse unit is the least amount of hormone necessary to produce at least one corpus luteum in at least one ovary of a nineteen to twenty-one-day-old female mouse 100 hours after injectron. The amount excreted per day was calculated from the twenty-four-hour volume of urine.
1008
BW3RICAN
JOURNAL
OF
OBSTETRICS
AND
GYNECOLOGY
sudden excretion of increased amounts of “free” fat-soluble estrogeuic hormone preceded and accompanied part,urition. Cohen fractionated the fat-soluble estrogen&z hormone into estrone and estriol for purposes of chemical identification This procedure does not, at the present time, lend itself well to biologic means of testing. The “free” estrogenic hormone shown in the accompanying chart represents both estrone and estriol whose joint estrogenic activity is calculated as estrone. It should be stated that the small amounts of “free” hormone excreted from the seventh week unt,il t,hc week during which parturition occurred are probably of no significance. Although each specimen was extracted within twenty-four hours of its collection, slight bacterial hydrolysis of “ combined ” hormone is known t,o occur in t,he urine upon st,anding at room temperature. The time factor is a constant one in this laboratory. The rather marked fall in urinary hormone excretion at the onset of labor is in keeping with a suggestion made in a previous reporL4 namely that the uterus may be considered an excretory organ for estrogenic hormone. SUMMARI-
The quantitative hormone determinations and discussion pertaining to them in a case of habitual abortion are presented. The relationship of estrogenic hormone excretion to parturition is demonstrated. COI\‘CLUSIOXS
1. Parturition is accompanied by a sudden urinary excretion of “free” fat-soluble estrogenic hormone. 2. The diagnosis of hydatidiform mole or chorionepithelioma cannot be made from the quantitative determination of gonadotropic hormone excretion in the urine during the first, trimester. REFFRENCES 2
(1) Cohen, S. L., Marrian, G. F., ancl Watson, M. : Lancet 228: &far&an, 0. F.: Diplomate 8: 147, 1936. (3) Palmer, A.: Proc. (5) & Med. 36: 123, 193’7. (4) Palmer, A.: Ibid. 37: 273, 1937. Hechter, 0. : Endocrinology 20: 396, 1936. (6) E’hrhardt, 3X.: (7) Browne, J. S. L., and Fenning, E. M. : ,4m. 15: 514, 1936. 18, 1936. (8) Browne, J. S. L., and Penning, E. M.: Lnncet (9) Evans, H. M., Eohls, C. L., and Wonder, D. H.: J. A. M. A.
MacRae,
D.
J. 1: 849,
J.:
Antenatal
Care
and
Some
Complications
674, 1935. (2) Sot. Exper. Bi01. Freed, S. C., and Klin. Wchnschr. J. Physiol. 116: 231: 1507, 1936. 108: 287, 1937.
of Labour,
Brit.
M.
1938.
The author feels that the first stage of labor begins not when uterine pains begin but during the last few weeks of pregnancy, with a glow and gradual formation of the lower uterine segment. Undivided control over the latter weeks of p and the succeeding labor would serve greatly to lessen eomplioatiuns. CODlQuirri mended fur prophylactic use where a uterine inertia is threatened iu the first s@e. He recommends Diihrssen’s incisions or spinal anesthesia and manual dilatation for the slowly dilating cervix. I?. L. ADAIR AND JOHN A. HAUOEN.
:
EXCRETION
OF
HORMONES
IN
HABITUAL
1005
ABORTION
M. c.:
Human Biol. 6: 431, 1934. (5) Evans, H. N., and SujeBy, 0.: Mem. Univ. California 9: 119, 1931. (6) Fraenkel, I,.: Zentralbl. f. Gynak. 35: 1591, 1911. (7) Hurtman, C. G.: Contributions to Embryol. 23: 1, 1932. (8) Idem: AX J. OBST. & GYNEC. 26: 600, 1932. (9) Idem: Time of Ovulation in Women, a Study on the Fertile Period in the Menstrual Cycle, Baltimore, 1936, Williams & Wilkins. (10) Idem: J. Contraception 2: 51, 1937. (11) Harvey, D. L., and Crockett, H. E.: Human Biol. 4: 453., 1932. (12) Enaus, N.: Zentralbl. f. Gynak. 53: 2193, 1929. (13) Idem: Perrodic Fertility and Sterility in Woman: a Natural Method of Birth Control, Tr. by D. H. and K. Kitchen, Vienna, Moudrich, following the German edition in 1934. (14) Ogino, E.: Zentralbl f. GynHk. 54: 464, 1930. (15) Idem: Zentralbl. f. GynLk. 56: 721, 1932. (16) Papanicolaozl, G. I?.: Am. J. Anat. 52: 519, 1933. (17) Rubenstein, B. B.: J. Contraception 2: 171, 1937. (18) Schroeder, Robert: In Handbuch d. Gynakologie, 1928 (VeitStoeckel), vol. 1. (19) Pan de B&e, 2’. H.: fiber den Zusammenhang zwischen Ovarialfunction, Wellenbewegung, und Menstrualblutung und iiber die Enstehung des sogenannten Mittel-Schmerzes, 1904, Haarlem. (20) Idem: Ideal Marriage, Its Physiology and Technique. London, 1929, Heinemann.
EXCRETION
(From
OF
HORMONES IN ABORTION”
A CASE
ALLAN PALMER, M.D., SAN FRANCISCO, the Department of Obstetrics and Gynecology, California Medical School)
OF HABITUAL CALIF,
T
Uiversity
of
HE purpose of this report is twofold; first to present the urinary estrogenic and gonadotropic hormone findings in a carefully followed ease of abortion, and second, to confirm the findings of a report by Cohen and others1 and Marrian2 in which an association between the sudden excretion of free fat-soluble estrogen&z hormone and the onset of labor was demonstrated. The patient studied was a woman of 36 years, anxious to have a child but with the history of two spontaneous abortions at 1.5 and 5 months and one premature labor at 6.5 months in the order noted. The latter pregnancy terminated spontaneously Jan. 8, 1936. It was planned at that time that the patient should collect complete twenty-four-hour urine specimens regularly at weekly intervals during the ensuing year and bring them to the laboratory for the assay of estrogenic and gonadotropic hormones. She was to avoid pregnancy for the first six months of this experiment. This plan was carefully followed. A daily record of intercourse and menstrual periods was kept. The intervals at which coitus occurred, the date of abortion, and the size of the fetus were such that the probable date of conception could be quite accurately calculated. Unfortunately for the patient the pregnancy under investigation was multiple (twins) and an examination within a few hours after the earliest symptoms of abortion revealed a bulging amnion filling the vaginal vault. The patient promptly aborted twins and subsequently recovered after a stormy four-day febrile reaction. *Supported
by
the
Christine
Breon
Fund
for
Medical
Research.
1006
AMEjXJCAN
JOURNAL
OF
OBSTETRICS
AND
QYNECOLOGY
METHODS
Estrogenic hormone determinations were done exactly as described in previous 4 The urine was not extracted for “free” estrogenic hormone, however, until the sixth week of pregnancy. In all instances the estrogenic hormone was calculated as estrone in gamma excreted per day. Gonadotropic hormone determinations were done each week according to a concentration method described by Freed and Hechter,s until the hormone characteristic of pregnancy first became evident. After pregnancy was established the whole and diluted urine was tested for its gonadotropin content. A mouse unit of the gonadotropic hormone characteristic of pregnancy is the least amount of hormone necessary to produce at least one corpus luteum in at least one ovary of a nineteen to twentyone-day-old female mouse 100 hours after injection. The amount excreted per day was calculated from the tmentp-four-hour volume of urine.
reports.3,
DISCUSSION
As noted in the chart the first posit.ive pregnancy reaction was obtained at the end of the second week of pregnancy, which date should have been the day of onset of the first, missed menstrual period. The first demonstrable excess in the excretion of estrogenic hormone occurred at the end of the sixth week of pregnancy. The early appearance of the gonadotropic hormone characteristic of pregnancy as compared with the later appearance of increased amounts of estrogenic hormone is of importance in understanding why pregnancy tests which depend upon the detection of gonadotropic hormone arc of greater value in early pregnancy than those tests which depend upon the detection of increased excretion of estrogenic hormone. The peak of gonadotropic hormone excretion occurred at the end of the sixth week of pregnancy. The amount is in agreement with the reports of other investigators.G-Q Although the patient experienced morning nausea, the latter did not seem to have a, clear-cut association with the peak of gonadotropie hormone excretion.G This marked excretion of gonadotropic hormone demonstrates the impossibility of making a diagnosis of hydatidiform mole and chorioepithelioma on the basis of quantitative hormone escretion during the Arst trimester. The fall of gonadotropic hormone excretion during the eighth and uinth weeks, followed by a second rise, ha,s not been report,ed previously. Similar studies of habitual abortion may help to determine whether or not this phenomenon may be associated with a patient’s tendency to abort. The urine concentration procedure failed to reveal any of the gonadotropic hormone in the urine later than the fifth day post partum. Five days before the patient aborted, the exeretion of estrogenic hormone fell far below the expected gradually rising level known to occur in normal pregnancy. Could this have been known on the day of its occurrence, some form of hormone therapy might have prevented the termination of pregnancy. Chemical tests for estrogenic hormone which may be done quite rapidly are not, as yet, of definite value so early in pregnancy. With referenee to the second point in the purpose of this report, namely the confirmation of findings reported by Cohen and others,l the
PALM=
:
EXCRETION
OF
HORMONES
IN
HABITUAL
ABORTION
1007
Chart I.-Estrogenic Hormcme: The columns represent the total excretion of estrogenic hormone per twenty-four hours on the days indicated. The solid portion of the column represents the “combined” fat-insoluble hormone, and the shaded portion of “free” fat-soluble hormone. Each is calculated as estrone. Golzadotropic Hormone: The columns represent the total excretion of the gonadotropic characteristic of pregnancy per twenty-four hours on the days indicated. In every instance the assay was done on a portion of the same twenty-four-hour urine specimen used for estrogenic hormone determination. A mouse unit is the least amount of hormone necessary to produce at least one corpus luteum in at least one ovary of a nineteen to twenty-one-day-old female mouse 100 hours after injectron. The amount excreted per day was calculated from the twenty-four-hour volume of urine.
1008
BW3RICAN
JOURNAL
OF
OBSTETRICS
AND
GYNECOLOGY
sudden excretion of increased amounts of “free” fat-soluble estrogeuic hormone preceded and accompanied part,urition. Cohen fractionated the fat-soluble estrogen&z hormone into estrone and estriol for purposes of chemical identification This procedure does not, at the present time, lend itself well to biologic means of testing. The “free” estrogenic hormone shown in the accompanying chart represents both estrone and estriol whose joint estrogenic activity is calculated as estrone. It should be stated that the small amounts of “free” hormone excreted from the seventh week unt,il t,hc week during which parturition occurred are probably of no significance. Although each specimen was extracted within twenty-four hours of its collection, slight bacterial hydrolysis of “ combined ” hormone is known t,o occur in t,he urine upon st,anding at room temperature. The time factor is a constant one in this laboratory. The rather marked fall in urinary hormone excretion at the onset of labor is in keeping with a suggestion made in a previous reporL4 namely that the uterus may be considered an excretory organ for estrogenic hormone. SUMMARI-
The quantitative hormone determinations and discussion pertaining to them in a case of habitual abortion are presented. The relationship of estrogenic hormone excretion to parturition is demonstrated. COI\‘CLUSIOXS
1. Parturition is accompanied by a sudden urinary excretion of “free” fat-soluble estrogenic hormone. 2. The diagnosis of hydatidiform mole or chorionepithelioma cannot be made from the quantitative determination of gonadotropic hormone excretion in the urine during the first, trimester. REFFRENCES 2
(1) Cohen, S. L., Marrian, G. F., ancl Watson, M. : Lancet 228: &far&an, 0. F.: Diplomate 8: 147, 1936. (3) Palmer, A.: Proc. (5) & Med. 36: 123, 193’7. (4) Palmer, A.: Ibid. 37: 273, 1937. Hechter, 0. : Endocrinology 20: 396, 1936. (6) E’hrhardt, 3X.: (7) Browne, J. S. L., and Fenning, E. M. : ,4m. 15: 514, 1936. 18, 1936. (8) Browne, J. S. L., and Penning, E. M.: Lnncet (9) Evans, H. M., Eohls, C. L., and Wonder, D. H.: J. A. M. A.
MacRae,
D.
J. 1: 849,
J.:
Antenatal
Care
and
Some
Complications
674, 1935. (2) Sot. Exper. Bi01. Freed, S. C., and Klin. Wchnschr. J. Physiol. 116: 231: 1507, 1936. 108: 287, 1937.
of Labour,
Brit.
M.
1938.
The author feels that the first stage of labor begins not when uterine pains begin but during the last few weeks of pregnancy, with a glow and gradual formation of the lower uterine segment. Undivided control over the latter weeks of p and the succeeding labor would serve greatly to lessen eomplioatiuns. CODlQuirri mended fur prophylactic use where a uterine inertia is threatened iu the first s@e. He recommends Diihrssen’s incisions or spinal anesthesia and manual dilatation for the slowly dilating cervix. I?. L. ADAIR AND JOHN A. HAUOEN.