- Email: [email protected]
Serum Relaxin and Human Chorionic Gonadotropin Concentrations in Spontaneous Abortions*
FERTILITY AND STERIUTY Copyright e 1981 The American Fertility Society
Vol. 36, No.3, September 1981 Printed in U.SA.
SERUM RELAXIN AND HUMAN CHORIONIC GONADOTROPIN CONCENTRATIONS IN SPONTANEOUS ABORTIONS*
JOHN QUAGLIARELLO, M.D.t NELLY SZLACHTER, M.D. t JEROME S. NISSELBAUM, PH.D.* MORTON K. SCHWARTZ, PH.D.* BERNARD STEINETZ, PH.D.§ GERSON WEISS, M.D.*~ Department of Obstetrics and Gynecology and Department of Physiology, New York University School of Medicine, New York, New York, Ciba-Geigy Corp., Ardsley, New York, and Memorial Hospital, New York, New York
from 82 women with normal first trimester pregnancies. heG concentrations were determined from 47 of these samples. Relaxin was assayed in serum in a radioimmunoassay (RIA) previously described. 3 The sensitivity of the assay was 50 pg. The interassay coefficient of variation was 14.1%, and the intraassay coefficient of variation was 2.7%. The average precision of the assay was 13.9%. heG was assayed in an RIA specific for the beta subunit and native hormone but not luteinizing hormone (LH).4 The sensitivity of the assay was 0.4 ng/ml. The interassay coefficient of variation was 9.7%. The intraassay coefficient of variation was 9.3%. All samples from normal and abnormal patients were assayed in the same RIA.
Relaxin is a peptide hormone produced by the corpus luteum of pregnancy. 1 In women, there are no extraluteal sources of circulating serum relaxin,2 making serum relaxin a unique index of luteal function in pregnancy. This study was designed for the simultaneous observation of serum relaxin and chorionic gonadotropin (heG) in spontaneously aborting first trimester pregnancies to determine whether luteal or placental function decrease was the initial event.
MATERIALS AND METHODS
Eighteen women had serum samples drawn at the time of first trimester spontaneous abortion. Dilatation and curettage revealed chorionic villi in all. Seven apparently normal women were sampled 2 to 6 weeks prior to subsequent spontaneous abortion, at a time when there were no signals of abortion. To establish normal values, relaxin concentrations were measured in serum
RESULTS
Relaxin was detectable (> 0.2 ng/ml) in 14 of 18 spontaneously aborting first trimester patients (Fig. 1). Nine of 18 were within two standard deviations of the mean previously calculated for normal human pregnancy; the remaining 9 were below two standard deviations of the mean. heG was subnormal in 14 of 18 spontaneously aborting first trimester patients (Fig. 2). Fifteen of 18 had heG levels below 260 ng/ml; 10 were 100 ng/ml or below. No patient whose relaxin values were below two standard deviations of the mean had heG values in the normal range. No patient with normal heG values had subnormal relaxin values. Four of seven asymptomatic, ap-
Received January 8, 1981; revised and accepted May 8, 1981. *Supported in part by United Cerebral Palsy grant R-288-79 and NIH grant HD-12395. tDepartment of Obstetrics and Gynecology, New York University School of Medicine, New York, New York. *Memorial Hospital, New York, New York. §Department of Physiology, New York University School of Medicine, New York, New York. ~Reprint requests: Gerson Weiss, M.D., Department of Obstetrics and Gynecology, New York University School of Medicine, 550 First Avenue, New York, New York 10016.
399
COMMUNICATIONS-IN-BRIEF
400
September 1981 3000
Serum 2.5 Relaxin ng/ml
HCG 2000 ng/ml
2.0
Serum 2.5 Relaxin ng/ml
1.5
1000
2.•
~I
1.5
1.0
:1
1.•
0.5
•
• 7
8
9
10
11
•.5
12
We8ksfromL.M.P.
FIG. 1. Serum relaxin levels in 18 first.trimester spontaneous abortions. Open circles with' bars are mean.± SE of 82 normal pregnancies; shaded area. represents ± 2 SD. Relaxin was detectable (> 0.2 nglml) in 14 of 18 spontaneously aborting first-trimester patients.
parently normal women, destined to abort in 2 to 6 weeks, had subnormal hCG levels at a time when relaxin levels were normal (Fig. 3). No patients with high hCGlevels had low relaxin levels (Fig. 4). DISCUSSION
The role of the corpus luteum in first-trimester spontaneous abortion is unclear: ~ study of serum progesterone levels has suggested that luteal failure maybe the cause; rather than the effect, of .spontaneous abortion. 5 Serum relaxin is a specific index ofluteal function in pregnancy,since it has no extraluteal sources in women, in contrast to progesterone, which is also secreted by the placenta. 2
HCG ng/ml
•
~r~~ 5
WeekslromL.M.P.
FIG. 3. Serum relaxin and heG levels in seven patients who subsequently aborted within 2 to 6 weeks after sampling (none showed signals' of abortion when sampled). The shaded area represents.± 2 SD. Open circles with vertical bars are mean .± SE. The single marks or connected marks represent individual patients. Four of seven patients had subnormal heG levels at a time when relaxin levels were normal.
Although human term placenta has recently been shown to contain immunohistochemical evidence of relaxin, there is no evidence suggesting that it contributes to circulating serum relaxin levels in ·women. 6 Relaxin is detectable in the sera of pregnant women around the time of the missed menses. 7 First trimester levels are higher than second and third trimester levels, a pattern similar to that described for hCG. 8 hCG has been shown to induce relaxin secretion in nonpregnant women when administered late in the luteal phase. 9 hCG levels have been shown previously to be subnormal in spontaneously aborting pregnancies. 10 This finding was confirmed in this stUdy: 14 of 18 patients had subnormal hCG levels. Relaxin was detectable in 14 of 18, although normal in only 9 of 18, suggesting that the corpus luteum continues to function in many spontaneously aborting
Serum 2.0 Relaxin ng/ml 1.5
1.0
0.5
•.. 100 200 300 400 500 800 700 800 900 1000 1100 1200 1300 1400 1500
FIG. 2. Serum heG levels in 18 first-trimester spontaneous abortions. heG was subnormal in 14 of 18 spontaneously
aborting first-trimester patients. Open circles with bars are mean ± SE of 47 normal pregnancies. The shaded area represents ± 2 SD. e, Represents spontaneously aborting patients.
Serum HCG
ng/ml
FIG. 4. Serum heG and relaxin levels in 18 first-trimester spontaneous abortions. Low heG levels were associated with low or normal relaxin levels; no patient with a high heG level had a low relaxin level.
r.
Vol. 36, No.3
·COMMUNICATIONS:IN.BRlEF
pregnancies. These observations suggest that decreases in placental activity seem to precede a decrease in luteal activity. Thus, in most of the patients studied, luteal failure appears to be the result of low placental luteotropic stimulus by the failing placenta. The seven women who aborted 2 to 6 weeks after serum was obtained provided a. good opportunity to study the endocrine milieu prior to spontaneous abortion. Since four of seven had subnormal heG levels at a time when luteal relaxin was normal, it appears that in these pa:tients luteal failure is a consequence of, rather than a cause of, the abortion process. It is of note that low heG levels « 300 ng/ml) were associated with low or normal relaxin levels. This finding suggests that even small amounts of heG may be luteotropic in some patients, or that other luteotropins are present of which we are unaware. No patients, however, with high heG levels had low relaxin levels, suggesting that luteal failure does not occur in the absence of placental failure.
401 REFERENCES
1. Weiss G, O'Byrne EM, Steinetz BG: Relaxin: a product of
2. 3. 4.
5.
6. 7. 8.
9.
10.
the human corpus luteum of pregnancy. Science 194:948, 1976 Weiss G, O'Byrne EM, Hochman J, Steinetz BG, Goldsmith L, Flitcraft JG: Distribution of relaxin in women during pregnancy. Obstet Gynecol 52:569,1978 O'Byrne EM, Steinetz BG: Radioimmunoassay of relaxin in sera of various species using an antiserum to porcine relaxin. Proc Soc Exp BioI 152:272, 1976 Vaitukaitis JL, Braunstein GD, Ross GT: A radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone. Am J Obstet Gynecol 113:751, 1972 Hensleigh P A, Fainstat T: Corpus luteum dysfunction: serum progesterone levels in diagnosis and assessment of therapy for recurrent and threatened abortion. Fertil Steril 32:396, 1979 Fields P A, Larkin LH: Purification and immunohistochemical localization of relaxin in the human term placenta. J Clin Endocrinol Metab 52:79, 1981 Quagliarello J, Steinetz BG, Weiss G: Relaxin secretion in early pregnancy. Obstet Gyneco153:62, 1979 Quagliarello J, Szlachter N, Steinetz BG, Goldsmith LT, Weiss G: Serial relaxin concentrations in human pregnancy. Am J Obstet Gynecol 135:43, 1979 Quagliarello J, Goldsmith LT, Steinetz BG, Lustig DS, Weiss G: Induction of relaxin secretion in non-pregnant women by human chorionic gonadotropin. J Clin Endocrinol Metab 51:74, 1980 Schweditsch MO, Dubin NH, Jones GS, Wentz AC: Hormonal considerations in early normal pregnancy and blighted ovum syndrome. Fertil Steril 31:252, 1979
Vol. 36, No.3, September 1981 Printed in U.SA.
SERUM RELAXIN AND HUMAN CHORIONIC GONADOTROPIN CONCENTRATIONS IN SPONTANEOUS ABORTIONS*
JOHN QUAGLIARELLO, M.D.t NELLY SZLACHTER, M.D. t JEROME S. NISSELBAUM, PH.D.* MORTON K. SCHWARTZ, PH.D.* BERNARD STEINETZ, PH.D.§ GERSON WEISS, M.D.*~ Department of Obstetrics and Gynecology and Department of Physiology, New York University School of Medicine, New York, New York, Ciba-Geigy Corp., Ardsley, New York, and Memorial Hospital, New York, New York
from 82 women with normal first trimester pregnancies. heG concentrations were determined from 47 of these samples. Relaxin was assayed in serum in a radioimmunoassay (RIA) previously described. 3 The sensitivity of the assay was 50 pg. The interassay coefficient of variation was 14.1%, and the intraassay coefficient of variation was 2.7%. The average precision of the assay was 13.9%. heG was assayed in an RIA specific for the beta subunit and native hormone but not luteinizing hormone (LH).4 The sensitivity of the assay was 0.4 ng/ml. The interassay coefficient of variation was 9.7%. The intraassay coefficient of variation was 9.3%. All samples from normal and abnormal patients were assayed in the same RIA.
Relaxin is a peptide hormone produced by the corpus luteum of pregnancy. 1 In women, there are no extraluteal sources of circulating serum relaxin,2 making serum relaxin a unique index of luteal function in pregnancy. This study was designed for the simultaneous observation of serum relaxin and chorionic gonadotropin (heG) in spontaneously aborting first trimester pregnancies to determine whether luteal or placental function decrease was the initial event.
MATERIALS AND METHODS
Eighteen women had serum samples drawn at the time of first trimester spontaneous abortion. Dilatation and curettage revealed chorionic villi in all. Seven apparently normal women were sampled 2 to 6 weeks prior to subsequent spontaneous abortion, at a time when there were no signals of abortion. To establish normal values, relaxin concentrations were measured in serum
RESULTS
Relaxin was detectable (> 0.2 ng/ml) in 14 of 18 spontaneously aborting first trimester patients (Fig. 1). Nine of 18 were within two standard deviations of the mean previously calculated for normal human pregnancy; the remaining 9 were below two standard deviations of the mean. heG was subnormal in 14 of 18 spontaneously aborting first trimester patients (Fig. 2). Fifteen of 18 had heG levels below 260 ng/ml; 10 were 100 ng/ml or below. No patient whose relaxin values were below two standard deviations of the mean had heG values in the normal range. No patient with normal heG values had subnormal relaxin values. Four of seven asymptomatic, ap-
Received January 8, 1981; revised and accepted May 8, 1981. *Supported in part by United Cerebral Palsy grant R-288-79 and NIH grant HD-12395. tDepartment of Obstetrics and Gynecology, New York University School of Medicine, New York, New York. *Memorial Hospital, New York, New York. §Department of Physiology, New York University School of Medicine, New York, New York. ~Reprint requests: Gerson Weiss, M.D., Department of Obstetrics and Gynecology, New York University School of Medicine, 550 First Avenue, New York, New York 10016.
399
COMMUNICATIONS-IN-BRIEF
400
September 1981 3000
Serum 2.5 Relaxin ng/ml
HCG 2000 ng/ml
2.0
Serum 2.5 Relaxin ng/ml
1.5
1000
2.•
~I
1.5
1.0
:1
1.•
0.5
•
• 7
8
9
10
11
•.5
12
We8ksfromL.M.P.
FIG. 1. Serum relaxin levels in 18 first.trimester spontaneous abortions. Open circles with' bars are mean.± SE of 82 normal pregnancies; shaded area. represents ± 2 SD. Relaxin was detectable (> 0.2 nglml) in 14 of 18 spontaneously aborting first-trimester patients.
parently normal women, destined to abort in 2 to 6 weeks, had subnormal hCG levels at a time when relaxin levels were normal (Fig. 3). No patients with high hCGlevels had low relaxin levels (Fig. 4). DISCUSSION
The role of the corpus luteum in first-trimester spontaneous abortion is unclear: ~ study of serum progesterone levels has suggested that luteal failure maybe the cause; rather than the effect, of .spontaneous abortion. 5 Serum relaxin is a specific index ofluteal function in pregnancy,since it has no extraluteal sources in women, in contrast to progesterone, which is also secreted by the placenta. 2
HCG ng/ml
•
~r~~ 5
WeekslromL.M.P.
FIG. 3. Serum relaxin and heG levels in seven patients who subsequently aborted within 2 to 6 weeks after sampling (none showed signals' of abortion when sampled). The shaded area represents.± 2 SD. Open circles with vertical bars are mean .± SE. The single marks or connected marks represent individual patients. Four of seven patients had subnormal heG levels at a time when relaxin levels were normal.
Although human term placenta has recently been shown to contain immunohistochemical evidence of relaxin, there is no evidence suggesting that it contributes to circulating serum relaxin levels in ·women. 6 Relaxin is detectable in the sera of pregnant women around the time of the missed menses. 7 First trimester levels are higher than second and third trimester levels, a pattern similar to that described for hCG. 8 hCG has been shown to induce relaxin secretion in nonpregnant women when administered late in the luteal phase. 9 hCG levels have been shown previously to be subnormal in spontaneously aborting pregnancies. 10 This finding was confirmed in this stUdy: 14 of 18 patients had subnormal hCG levels. Relaxin was detectable in 14 of 18, although normal in only 9 of 18, suggesting that the corpus luteum continues to function in many spontaneously aborting
Serum 2.0 Relaxin ng/ml 1.5
1.0
0.5
•.. 100 200 300 400 500 800 700 800 900 1000 1100 1200 1300 1400 1500
FIG. 2. Serum heG levels in 18 first-trimester spontaneous abortions. heG was subnormal in 14 of 18 spontaneously
aborting first-trimester patients. Open circles with bars are mean ± SE of 47 normal pregnancies. The shaded area represents ± 2 SD. e, Represents spontaneously aborting patients.
Serum HCG
ng/ml
FIG. 4. Serum heG and relaxin levels in 18 first-trimester spontaneous abortions. Low heG levels were associated with low or normal relaxin levels; no patient with a high heG level had a low relaxin level.
r.
Vol. 36, No.3
·COMMUNICATIONS:IN.BRlEF
pregnancies. These observations suggest that decreases in placental activity seem to precede a decrease in luteal activity. Thus, in most of the patients studied, luteal failure appears to be the result of low placental luteotropic stimulus by the failing placenta. The seven women who aborted 2 to 6 weeks after serum was obtained provided a. good opportunity to study the endocrine milieu prior to spontaneous abortion. Since four of seven had subnormal heG levels at a time when luteal relaxin was normal, it appears that in these pa:tients luteal failure is a consequence of, rather than a cause of, the abortion process. It is of note that low heG levels « 300 ng/ml) were associated with low or normal relaxin levels. This finding suggests that even small amounts of heG may be luteotropic in some patients, or that other luteotropins are present of which we are unaware. No patients, however, with high heG levels had low relaxin levels, suggesting that luteal failure does not occur in the absence of placental failure.
401 REFERENCES
1. Weiss G, O'Byrne EM, Steinetz BG: Relaxin: a product of
2. 3. 4.
5.
6. 7. 8.
9.
10.
the human corpus luteum of pregnancy. Science 194:948, 1976 Weiss G, O'Byrne EM, Hochman J, Steinetz BG, Goldsmith L, Flitcraft JG: Distribution of relaxin in women during pregnancy. Obstet Gynecol 52:569,1978 O'Byrne EM, Steinetz BG: Radioimmunoassay of relaxin in sera of various species using an antiserum to porcine relaxin. Proc Soc Exp BioI 152:272, 1976 Vaitukaitis JL, Braunstein GD, Ross GT: A radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone. Am J Obstet Gynecol 113:751, 1972 Hensleigh P A, Fainstat T: Corpus luteum dysfunction: serum progesterone levels in diagnosis and assessment of therapy for recurrent and threatened abortion. Fertil Steril 32:396, 1979 Fields P A, Larkin LH: Purification and immunohistochemical localization of relaxin in the human term placenta. J Clin Endocrinol Metab 52:79, 1981 Quagliarello J, Steinetz BG, Weiss G: Relaxin secretion in early pregnancy. Obstet Gyneco153:62, 1979 Quagliarello J, Szlachter N, Steinetz BG, Goldsmith LT, Weiss G: Serial relaxin concentrations in human pregnancy. Am J Obstet Gynecol 135:43, 1979 Quagliarello J, Goldsmith LT, Steinetz BG, Lustig DS, Weiss G: Induction of relaxin secretion in non-pregnant women by human chorionic gonadotropin. J Clin Endocrinol Metab 51:74, 1980 Schweditsch MO, Dubin NH, Jones GS, Wentz AC: Hormonal considerations in early normal pregnancy and blighted ovum syndrome. Fertil Steril 31:252, 1979