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Transient decline in serum progesterone levels during prostaglandin F2α infusion in the midluteal phase of the normal human menstrual cycle
Transient decline in serum progesterone levels during prostaglandin Fza infusion in the midluteal phase of the normal human menstrual cycle SERGE JEREMY
P.
COUDERT, S.
CHARLES Winnipeg,
D.
D.V.M.,
WINTER,
FAIMAN, Manitoba,
M.Sc.
M.D., M.D.,
F.R.C.P.(C)*
M.Sc.,
F.R.C.P.(C)**
Canada
Intravenous infusion of PGF,,,, 0.75 pg per kilogram per minute for 3.5 to 6 hours, during the midluteal phase of the normal menstrual cycle, resulted in a transient diminution in circulating progesterone and estradiol levels in four out of secven subjects. This effect did not result in a significant shortening of the menstrual interval or luteal phase. The eflect appeared to be directly at the ovarian level since there was no correlation of alterations in steroid values with LH or FSH changes. Because of serious gastrointestinal side effects and only transient effects on luteal function, it does not appear that systemically administered PGF:, can be used as a luteolytic agent during the normal menstrual cycle.
p R 0
S T A G L A N D I N
Fpa
(Pc&)
iS
of luteolytic agents has been the timing of drug administration during the luteal phase due to inherent variability in the menstrual cycle. Short-term observation also failed to account for the pulsatile nature of hormone release.3s 4 Therefore this study was undertaken to examine the potential luteolytic effects of intravenously administered PGF,, ensuring that the treatment took place during the midluteal phase of the cycle and that stable pretreatment hormone levels prior to drug administration were documented. Circulating progesterone and estradiol levels were monitored as indices of luteal function. Concomitant determinations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were performed to ascertain whether or not steroid hormone alterations might be secondary to PGF2, effects on pituitary gonadotropin secretion.
h-
teolytic in rhesus monkeys during early pregnancy’ and is an effective abortifacient in early human pregnancy when a functioning corpus luteum is required for pregnancy maintenance.2 Thus, it appeared important to delineate whether PGF,, interfered with human corpus luteum function. One of the problems with previous studies From the Departments of Physiology Paediatrics,. University of Manitoba, the Endocrme-Metabolic Laboratory, Health Sciences Gentle. This study was supported a grant from the Upjohn Canada and by M.R.C. MA-2997. Received 1973. Revised Accepted
in part by Company of Canada Grant
for publication November December
and and
September
1 I,
20, 1973. 17, 1973.
Reprint requests: Dr. C. Faiman, G-449, Health Sciences Centre. 700 William Ave., Winnipeg, Manitoba, Canada R3E 023. *Queen **M.R.C.
Elizabeth Canada
Materials
and
methods
Subjects. Seven healthy
II Scientist,
19 and
Scholar. 755
subjects, between 23 years of age, with normal men-
756
Coudert,
Winter,
and
July 15, 1974 Am. J. Obstet. Gynecol.
Faiman
F A.
01,
-2
I
;
0
I
I
I
,
M.L.
I
I-
2 4 6 -2 TIME FROM INJECTION (Hours)
Fig. 1. Serum levels of progesterone (P), estradiol (IX,), LH and FSH before, during and following PGF., infusion in subjects F. A. and M. L. Circled progesterone dots indicate the level the day prior to and the day following the test infusion. Letters in LH panels in this and in subsequent figures indicate times of urination (17) and major side effects: C = abdominal cramps ; H = headache; D = diarrhea: F = fainting; N = nausea; NB = nosebleed; I/ = vomiting; Ch = coughing; + = marked. .4sterisks in the upper right hand corner of each panel indicate statistically significant differences between mean levels durine PGF,, vs. saline infusions as assessed by nonpaired t test, * p < 0.05; ** = p < 0.01; ibsence-of asterisk = not significant, p > 0.1.
strual histories and normal basal body temperature (BBT) curves for at least the past two cycles, were studied. Based on BBT records, the PGF,, infusion was scheduled on days six to nine after ovulation, assuming that ovulation occurs one day prior to the rise in BBT.” The midluteal phase was chosen since this is the time that the corpus luteum is fully functioning and when dayto-day serum progesterone levels are relatively stable.” In order to ensure adequate corpus luteum function prior to study, a serum progesterone level of greater than 5 ng. per milliliter on the morning prior to the scheduled infusion was a prerequisite. Test procedure. On the day of the test. subjects reported to the Clinical Investigation Unit at 8 to 9 A.M. following an overnight fast. Two indwelling forearm-vein catheters (opposite arms-one for sampling. one for infusion) were established and kept
open with a slow drip infusion of saline. Subjects were recumbent throughout the study except during use of bathroom facilities. They were allowed fruit juices only by mouth. A two-hour control period of observation (saline infusion only) was followed by a 3.5 to 6 hour infusion of PGF,,. in 1.5 ml. ampoules PGFzru was supplied containing 7.5 mg. of the tris (hydroxymethyl) aminomethane salt dissolved in benzyl alcohol and water. The test substance \vas diluted in 600 ml. of isotonic saline and infused at a dose rate of 0.75 /kg per kilogram per minute (16.2 mg. for a 60 kilogram subject over 6 hours). Blood samples of 12 ml. were collected every 20 minutes throughout the study. Additional samples were obtained during the hour following discontinuation of the PGF,,, infusion and a single sample was also obtained in five of the subjects the following
Volume 119 Number 6
Decline
in
progesterone
during
PGFza
infusion
757
C.Z. PGFru
PGF2u
E
41’ ()
4j -2
Fig. 2. Serum
0
/ 2 4 TIME FROM
6 -2 INJECTION
0 b-loun)
2
4
6
hormone levels in subjects J. M. and C. Z. Format as for Fig. 1.
morning. Samples were allowed to clot at room temperature and the sera removed and kept at -20’ C. until analyzed. Pulse rate, brachial blood pressure, and oral temperature were recorded by the same attending nurse before each blood collection. Electrocardiograms were continuously monitored during the study. Four complete ( 12 lead) tracings were obtained from each subject: one during the control infusion (20 minutes prior to PGF,, infusion) : two during the PGF,, infusion, at approximately +60 and +320 minutes; and the last during the postinfusion period. All tracings were read without prior knowledge as to the order of each by a single individual of the Cardiology Unit. Laboratory methods. All samples from individual tests for the following hormones were analyzed in the same assay run in duplicate. Progesterone was quantitated by a radioimmunoassay technique which utilized an antiserum against progesterone-6-P-bovine serum albumin. Standards and unknowns were extracted with methylene chloride and
run through the entire radioimmunoassay method in identical fashion. Since the antiserum is relatively specific for progesterone and shows cross-reactivity only with pregnenolone (3.4 per cent), 17a-hydroxyprogesterone (0.3 per cent), and 1 la-hydroxyprogesterone (0.9 per cent), the samples were not further purified by chromatographic means. Estradiol was quantitated by a radioimmunoassay procedure.” FSH and LH levels were analyzed by puriradioimmunoassay’, * with the partially fied human pituitary preparation LER-907 used as the assay standard. The coefficients of variation between duplicates for all the above assays were in the five to eight per cent range. Results
Hormone levels are shown in Figs. 1 to 4. Progesterone. Values were relatively stable in all subjects (except subject E. K.) during the control (saline infusion only) observation period. Four of the seven subjects (F. A., M. L., J. M., and C. Z.) showed a statisti-
758
Coudert,
Winter,
and
July 15, 1974 Am. J. Obstct. Gynccol.
Faiman
J.W.
0
Fig.
, -2
3. Serum
i 0
,
,
hormone
( , I 1 , 2 4 6 -2 TIME FROM INJECTION levels
in subjects
r---==l
CCh
J. Mr.
”
ject
01 -2 TIME Fig. 4. Serum Format as for
r
8 I 0 FROM
hormone Fig. 1.
1 I
I
I
1
2 4 6 INJECTION (Hours) levels
in
subject
,
0 Woun)
I
1 2
1
r 4
and B. P. Format
I
6
as for Fig.
1.
tally significant decline in mean progesterone levels during the PGF,, infusion period as compared to the control period. Only the change in subject J. M. appeared marked. This effect on progesterone levels was transitory as shown by the return toward preinfusion levels during the recovery period or by the next day in three of these four subjects (M. L., J. M., and C. Z.). A possible decline was also noted in subject E. K. toward the end of the infusion period. However, the apparent pulsatile pattern of progesterone levels in this subject makes a firm interpretation difficult. Values remained unchanged in subject J. MC. Interpretation of the apparent stimulatory response in sub-
E.K.
:
BP.
E.
K.
B. P. is particularly
difficult
since
values
were below normal luteal levels5 on the day of infusion (despite a normal value the previous day), rose during the PGF,, infusion, and fell slightly thereafter. Estradiol. In general, the serum estradiol responses tended to parallel those for progesterone. There was a statistically significant decline in the same four subjects (F. A., M. L., J. M., and C. Z.), again most marked in subject J. M. There was a suggestion of
Decline
Table I. Analysis of menstrual PGF,, in seven subjects
Subject
F. M. J. c.
cycle data before, during,
Pre-B
*Mean
values
tValue for of this cyclr).
for
cycle
two
evaluation
$Statistical
evaluation
by
27 34 24 24
28.0 37.0 28.3 30.7
27 34 29 28.4
cycles
prior
following factorial
by pailed
to treatment
treatment analysis
of
cycle variance
(a) (BBT (N.S.
PGFzCr
infusion
759
of
Luteal Post-&f
N.S.$ ~~
to four
immediately
$Statistical
27.7 38.5 28.8 26.5
during
and after infusion
Menstrual interval (days) / s /
mean*
A. L. M. z.
; FE: K. Mean p value vs. pre-Q mean
in progesterone
interval (days) mean* 1
Pre-S
R
36 35 25 27
12.7 15.5 14.3 12.5
15 16 12 13
46 37 36 34.6 <0.05$
11.0 13.0 15.0 13.4
12 11 13 13.1 NAP
cycle. CUIWS =
not
obtained
50 that
no
data
obtained
for
lutral
interval
p > 0.1).
t test.
a decline toward the end of the infusion in subject E. K. No change in levels in subject J. MC. was seen. In contrast, subject B. P. showed a significant decline in estradiol levels during the infusion period whereas the progesterone response was stimulatory. LH. In contrast to progesterone and estradiol levels, which appeared stable during the control period, LH levels appeared to decline during this time in the majority of subjects. This was most marked in subjects C. Z. and J. MC. Thus the finding of significantly lower values for LH during the PGF2, infusion in five of the subjects (F. A., J. M., C. Z., J. MC., and E. K.) may simply represent a continuation of the decline during the control period rather than a PGF,, effect. There appeared to be no temporal relationship of changing LH levels to variations in progesterone or estradiol values (see for example the over-all patterns in subject J. MC., Fig. 3, and the lack of a change in progesterone or estradiol levels associated with the pulsatile LH peaks in subject F. A., Fig. 1, at 2.5 and 5 hours). FSH. There was no significant change in over-all FSH levels during the PGF,, infusion in any of the subjects except for a small decline in subject J. MC., not associated in this instance with a change in progesterone or estradiol levels.
Menstrual cycle data. These data are summarized in Table I. None of the subjects reported vaginal spotting during the study or during the next 24 hours. The subsequent menses occurred closely at the expected time in all subjects. There was no significant difference between the mean menstrual interval and luteal interval before and during the PGF2, infusion. An unexplained finding was the statistically significant lengthening of the mean menstrual interval in the cycle following the test infusion (34.6 vs. 30.7 days). The duration of menses was not altered and averaged 5.5 days in the cycles prior to and the cycle immediately following drug administration. Electrocardiograms. No significant departure from normality nor difference among the four tracings (one before, two during, and one after the infusion) was observed in any of the subjects. In subject C. Z. n slight elevation of the ST segment was observed in Leads V,, V:,, aVp, V,, and V,; following 60 minutes of the PGFz,? infusion. By 320 minutes the electrocardiogram was normal. Side effects. The major side effects encountered (noted by symbols in Figs. 1 to 4) were the following: nausea within 20 to 40 minutes in three subjects; vomiting in one subject; diarrhea in three subjects, profuse in two and requiring discontinuation of the
760
Coudert,
Winter,
and
infusion in subject B. P. and in subject J. M. (who also became hypotensive and fainted); abdominal cramps mimicking normal menstrual cramps in six subjects; occasional bouts of coughing, chest pressure, and shortness of breath in one subject; headache in one subject; epistaxis in one subject; and local pain and erythema at the infusion site in all. All untoward effects disappeared within 30 to 90 minutes following cessation of the infusion. No fever (oral temperature range 36.6 to 37.5’ C.) or consistent changes in blood pressure (except for that noted in J. M. above) and pulse rate were noted in any of the subjects. Comment
The present study clearly shows a transient diminution in both circulating progesterone and estradiol levels following PGF,, infusion during the midluteal phase in four out of seven subjects studied. Assuming that the metabolic clearance rate of these steroids is not altered by PGF,,, then diminution in serum levels must reflect a decrease in corpus luteum function. That this effect is transitory is shown by the return toward preinfusion levels by the following day and a failure to result in the premature onset of the next expected menses. The effect on corpus luteum function appears to be primary, since there was no change in FSH levels and no correlation between alterations in LH and steroid levels. The diminution in LH levels seen during the study cannot be directly ascribed to a PGF,, effect since values were declining during the control observation period. PGF,, infusions in men up to 2.0 pg per kilogram per minute for 30 minutes also had no significant effect upon FSH levels but a similarly unexplained decline in LH levels during the control and experimental infusions was noted.Q
1.
2.
July 15, 1974 Am. J. Obstet. Gynecol.
Faiman
Previous studies of the possible luteolytic effects of both PGF,,l’-‘” and PGE,lG in women have by and large been negative. More recent observations suggest that PGF2, administration during the mid to late luteal phase may result in a transient diminution of circulating progesterone levels,l”, I73 I8 in keeping with our own observations. However, critical evaluation of those studies in which serial determinations of circulating progesterone levels were obtained during the infusion period has proved difficult because of the inherent variability in levels, the failure to obtain sufficient preinfusion control determinations, and the infrequent sampling during the infusion period.‘l. I23 15-18 The dosages of PGF,, used in the present and in previous studies have approached the limits of tolerance and are associated with serious side effects, particularly of a gastrointestinal nature.“-13, I8 C oupled with the finding of transitory effects, at most, on corpus luteum function, it is doubtful that systemically administered PGF,, can be used as a satisfactory contraceptive agent in the human subject. We
thank
Masson the PGF,,
Drs.
E.
of the Upjohn and
for
their
M.
Southern
Company generous
and
E.
I,.
for providing assistance.
The
progesterone antiserum was provided by Dr. G. D. Niswender, Colorado State University, Fort Collins,
Colorado.
The
estradiol
antiserum
was
by Dr. B. V. Caldwell, Yale University, New Haven, Connecticut. The LER-907 gonadoprovided
tropin standard was a gift of the National Pituitary Agency. We thank Dr. T. E. Cuddy, Section of Cardiology, for interpretation of the electrocardiograms, Mrs. J. Kippen for nursing assistance, and Mr. D. Grant, Mr. I. Riyaz, Mrs. R. Poturnak, and Mrs. E. Dudeck for technical assistance.
REFERENCES
3.
Kirton, K. T., Pharriss, B. B., and Forbes, A. D.: Proc. Sot. Exp. Biol. Med. 133: 314, 1970. Wiqvist, N., and Bygdeman, M.: Lancet 1: 889, 1970.
4. 5.
West, C. D., Nabors, C. Endocrinol. Naftolin, F., Nature New Ross, G. T.,
Mahajan, D. K., Chavrt, V. J., J. and Tyler, F. H.: J. Clin. Metab. 36: 1230, 1973. Yen, S. S. C., and Tsai, C. C.: Biol. 236: 92, 1972. Cargille, C. M., Lipsett, M. B.,
Volume Number
6.
7. 8. 9. 10.
11.
119 6
Rayford, P. L., Marshall, J. R., Strott, C. A., and Rodbard, D.: Recent Progr. Horm. Res. 26: 1, 1970. Winter, J. S. D., Taraska, S., and Faiman, C.: J. Clin. Endocrinol. Metab. 34: 348, 1972. Faiman, C., and Ryan, R. J.: J. Clin. Endocrinol. Metab. 27: 444, 1967. Faiman, C., and Ryan, R. J.: Proc. Sot. Exp. Biol. Med. 125: 1130, 1967. Coudert, S. P., and Faiman, C.: Prostaglandins 3: 89, 1973. Wiqvist, N., Bygdeman, M., and Kirton, K. T.: In Diczfalusy, E., and Borell, V., editors: Nobel Symposium, New York, 1970, John Wiley & Sons, Vol. 15, p. 137. LeMaire, W. J., and Shapiro, A. G.: Prostaglandins 1: 259, 1972.
Decline
12.
13. 14.
15.
16.
17. 18.
in progesterone
during
PGF,,
infusion
761
Jewelewicz, R., Cantor, B., Dyrenfurth, I., Warren, M. P., and Vande Wiele, R. L.: Prostaglandins 1: 443, 1972. Jones, G. S., and Wentz, A. C.: AM. J. OBSTET. GYNECOL. 114: 393, 1972. Tom, W. K. C., Sribyatta, B., Thorneycroft, I. H., and Mishell, D. R., Jr.: Contraception 6: 479, 1972. Hillier, K., Dutton, A., Corker, C. S., Singer, A., and Embrey, M. P.: Br. Med. J. 4: 333, 1972. Hen& M. R., Ortega, E., Cortes-Gallegos, V., Tomlinson, R. V., and Segre, E. J.: J, Clin. Endocrinol. Metab. 36: 784. 1973. Wentz, A. C., and Jones, G. S.: Obstet. Gynecol. 42: 172, 1973. Hillier, K., Dutton, A., and Corker, C. S.: Adv. Biosci. 9: 673, 1973.
P.
COUDERT, S.
CHARLES Winnipeg,
D.
D.V.M.,
WINTER,
FAIMAN, Manitoba,
M.Sc.
M.D., M.D.,
F.R.C.P.(C)*
M.Sc.,
F.R.C.P.(C)**
Canada
Intravenous infusion of PGF,,,, 0.75 pg per kilogram per minute for 3.5 to 6 hours, during the midluteal phase of the normal menstrual cycle, resulted in a transient diminution in circulating progesterone and estradiol levels in four out of secven subjects. This effect did not result in a significant shortening of the menstrual interval or luteal phase. The eflect appeared to be directly at the ovarian level since there was no correlation of alterations in steroid values with LH or FSH changes. Because of serious gastrointestinal side effects and only transient effects on luteal function, it does not appear that systemically administered PGF:, can be used as a luteolytic agent during the normal menstrual cycle.
p R 0
S T A G L A N D I N
Fpa
(Pc&)
iS
of luteolytic agents has been the timing of drug administration during the luteal phase due to inherent variability in the menstrual cycle. Short-term observation also failed to account for the pulsatile nature of hormone release.3s 4 Therefore this study was undertaken to examine the potential luteolytic effects of intravenously administered PGF,, ensuring that the treatment took place during the midluteal phase of the cycle and that stable pretreatment hormone levels prior to drug administration were documented. Circulating progesterone and estradiol levels were monitored as indices of luteal function. Concomitant determinations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were performed to ascertain whether or not steroid hormone alterations might be secondary to PGF2, effects on pituitary gonadotropin secretion.
h-
teolytic in rhesus monkeys during early pregnancy’ and is an effective abortifacient in early human pregnancy when a functioning corpus luteum is required for pregnancy maintenance.2 Thus, it appeared important to delineate whether PGF,, interfered with human corpus luteum function. One of the problems with previous studies From the Departments of Physiology Paediatrics,. University of Manitoba, the Endocrme-Metabolic Laboratory, Health Sciences Gentle. This study was supported a grant from the Upjohn Canada and by M.R.C. MA-2997. Received 1973. Revised Accepted
in part by Company of Canada Grant
for publication November December
and and
September
1 I,
20, 1973. 17, 1973.
Reprint requests: Dr. C. Faiman, G-449, Health Sciences Centre. 700 William Ave., Winnipeg, Manitoba, Canada R3E 023. *Queen **M.R.C.
Elizabeth Canada
Materials
and
methods
Subjects. Seven healthy
II Scientist,
19 and
Scholar. 755
subjects, between 23 years of age, with normal men-
756
Coudert,
Winter,
and
July 15, 1974 Am. J. Obstet. Gynecol.
Faiman
F A.
01,
-2
I
;
0
I
I
I
,
M.L.
I
I-
2 4 6 -2 TIME FROM INJECTION (Hours)
Fig. 1. Serum levels of progesterone (P), estradiol (IX,), LH and FSH before, during and following PGF., infusion in subjects F. A. and M. L. Circled progesterone dots indicate the level the day prior to and the day following the test infusion. Letters in LH panels in this and in subsequent figures indicate times of urination (17) and major side effects: C = abdominal cramps ; H = headache; D = diarrhea: F = fainting; N = nausea; NB = nosebleed; I/ = vomiting; Ch = coughing; + = marked. .4sterisks in the upper right hand corner of each panel indicate statistically significant differences between mean levels durine PGF,, vs. saline infusions as assessed by nonpaired t test, * p < 0.05; ** = p < 0.01; ibsence-of asterisk = not significant, p > 0.1.
strual histories and normal basal body temperature (BBT) curves for at least the past two cycles, were studied. Based on BBT records, the PGF,, infusion was scheduled on days six to nine after ovulation, assuming that ovulation occurs one day prior to the rise in BBT.” The midluteal phase was chosen since this is the time that the corpus luteum is fully functioning and when dayto-day serum progesterone levels are relatively stable.” In order to ensure adequate corpus luteum function prior to study, a serum progesterone level of greater than 5 ng. per milliliter on the morning prior to the scheduled infusion was a prerequisite. Test procedure. On the day of the test. subjects reported to the Clinical Investigation Unit at 8 to 9 A.M. following an overnight fast. Two indwelling forearm-vein catheters (opposite arms-one for sampling. one for infusion) were established and kept
open with a slow drip infusion of saline. Subjects were recumbent throughout the study except during use of bathroom facilities. They were allowed fruit juices only by mouth. A two-hour control period of observation (saline infusion only) was followed by a 3.5 to 6 hour infusion of PGF,,. in 1.5 ml. ampoules PGFzru was supplied containing 7.5 mg. of the tris (hydroxymethyl) aminomethane salt dissolved in benzyl alcohol and water. The test substance \vas diluted in 600 ml. of isotonic saline and infused at a dose rate of 0.75 /kg per kilogram per minute (16.2 mg. for a 60 kilogram subject over 6 hours). Blood samples of 12 ml. were collected every 20 minutes throughout the study. Additional samples were obtained during the hour following discontinuation of the PGF,,, infusion and a single sample was also obtained in five of the subjects the following
Volume 119 Number 6
Decline
in
progesterone
during
PGFza
infusion
757
C.Z. PGFru
PGF2u
E
41’ ()
4j -2
Fig. 2. Serum
0
/ 2 4 TIME FROM
6 -2 INJECTION
0 b-loun)
2
4
6
hormone levels in subjects J. M. and C. Z. Format as for Fig. 1.
morning. Samples were allowed to clot at room temperature and the sera removed and kept at -20’ C. until analyzed. Pulse rate, brachial blood pressure, and oral temperature were recorded by the same attending nurse before each blood collection. Electrocardiograms were continuously monitored during the study. Four complete ( 12 lead) tracings were obtained from each subject: one during the control infusion (20 minutes prior to PGF,, infusion) : two during the PGF,, infusion, at approximately +60 and +320 minutes; and the last during the postinfusion period. All tracings were read without prior knowledge as to the order of each by a single individual of the Cardiology Unit. Laboratory methods. All samples from individual tests for the following hormones were analyzed in the same assay run in duplicate. Progesterone was quantitated by a radioimmunoassay technique which utilized an antiserum against progesterone-6-P-bovine serum albumin. Standards and unknowns were extracted with methylene chloride and
run through the entire radioimmunoassay method in identical fashion. Since the antiserum is relatively specific for progesterone and shows cross-reactivity only with pregnenolone (3.4 per cent), 17a-hydroxyprogesterone (0.3 per cent), and 1 la-hydroxyprogesterone (0.9 per cent), the samples were not further purified by chromatographic means. Estradiol was quantitated by a radioimmunoassay procedure.” FSH and LH levels were analyzed by puriradioimmunoassay’, * with the partially fied human pituitary preparation LER-907 used as the assay standard. The coefficients of variation between duplicates for all the above assays were in the five to eight per cent range. Results
Hormone levels are shown in Figs. 1 to 4. Progesterone. Values were relatively stable in all subjects (except subject E. K.) during the control (saline infusion only) observation period. Four of the seven subjects (F. A., M. L., J. M., and C. Z.) showed a statisti-
758
Coudert,
Winter,
and
July 15, 1974 Am. J. Obstct. Gynccol.
Faiman
J.W.
0
Fig.
, -2
3. Serum
i 0
,
,
hormone
( , I 1 , 2 4 6 -2 TIME FROM INJECTION levels
in subjects
r---==l
CCh
J. Mr.
”
ject
01 -2 TIME Fig. 4. Serum Format as for
r
8 I 0 FROM
hormone Fig. 1.
1 I
I
I
1
2 4 6 INJECTION (Hours) levels
in
subject
,
0 Woun)
I
1 2
1
r 4
and B. P. Format
I
6
as for Fig.
1.
tally significant decline in mean progesterone levels during the PGF,, infusion period as compared to the control period. Only the change in subject J. M. appeared marked. This effect on progesterone levels was transitory as shown by the return toward preinfusion levels during the recovery period or by the next day in three of these four subjects (M. L., J. M., and C. Z.). A possible decline was also noted in subject E. K. toward the end of the infusion period. However, the apparent pulsatile pattern of progesterone levels in this subject makes a firm interpretation difficult. Values remained unchanged in subject J. MC. Interpretation of the apparent stimulatory response in sub-
E.K.
:
BP.
E.
K.
B. P. is particularly
difficult
since
values
were below normal luteal levels5 on the day of infusion (despite a normal value the previous day), rose during the PGF,, infusion, and fell slightly thereafter. Estradiol. In general, the serum estradiol responses tended to parallel those for progesterone. There was a statistically significant decline in the same four subjects (F. A., M. L., J. M., and C. Z.), again most marked in subject J. M. There was a suggestion of
Decline
Table I. Analysis of menstrual PGF,, in seven subjects
Subject
F. M. J. c.
cycle data before, during,
Pre-B
*Mean
values
tValue for of this cyclr).
for
cycle
two
evaluation
$Statistical
evaluation
by
27 34 24 24
28.0 37.0 28.3 30.7
27 34 29 28.4
cycles
prior
following factorial
by pailed
to treatment
treatment analysis
of
cycle variance
(a) (BBT (N.S.
PGFzCr
infusion
759
of
Luteal Post-&f
N.S.$ ~~
to four
immediately
$Statistical
27.7 38.5 28.8 26.5
during
and after infusion
Menstrual interval (days) / s /
mean*
A. L. M. z.
; FE: K. Mean p value vs. pre-Q mean
in progesterone
interval (days) mean* 1
Pre-S
R
36 35 25 27
12.7 15.5 14.3 12.5
15 16 12 13
46 37 36 34.6 <0.05$
11.0 13.0 15.0 13.4
12 11 13 13.1 NAP
cycle. CUIWS =
not
obtained
50 that
no
data
obtained
for
lutral
interval
p > 0.1).
t test.
a decline toward the end of the infusion in subject E. K. No change in levels in subject J. MC. was seen. In contrast, subject B. P. showed a significant decline in estradiol levels during the infusion period whereas the progesterone response was stimulatory. LH. In contrast to progesterone and estradiol levels, which appeared stable during the control period, LH levels appeared to decline during this time in the majority of subjects. This was most marked in subjects C. Z. and J. MC. Thus the finding of significantly lower values for LH during the PGF2, infusion in five of the subjects (F. A., J. M., C. Z., J. MC., and E. K.) may simply represent a continuation of the decline during the control period rather than a PGF,, effect. There appeared to be no temporal relationship of changing LH levels to variations in progesterone or estradiol values (see for example the over-all patterns in subject J. MC., Fig. 3, and the lack of a change in progesterone or estradiol levels associated with the pulsatile LH peaks in subject F. A., Fig. 1, at 2.5 and 5 hours). FSH. There was no significant change in over-all FSH levels during the PGF,, infusion in any of the subjects except for a small decline in subject J. MC., not associated in this instance with a change in progesterone or estradiol levels.
Menstrual cycle data. These data are summarized in Table I. None of the subjects reported vaginal spotting during the study or during the next 24 hours. The subsequent menses occurred closely at the expected time in all subjects. There was no significant difference between the mean menstrual interval and luteal interval before and during the PGF2, infusion. An unexplained finding was the statistically significant lengthening of the mean menstrual interval in the cycle following the test infusion (34.6 vs. 30.7 days). The duration of menses was not altered and averaged 5.5 days in the cycles prior to and the cycle immediately following drug administration. Electrocardiograms. No significant departure from normality nor difference among the four tracings (one before, two during, and one after the infusion) was observed in any of the subjects. In subject C. Z. n slight elevation of the ST segment was observed in Leads V,, V:,, aVp, V,, and V,; following 60 minutes of the PGFz,? infusion. By 320 minutes the electrocardiogram was normal. Side effects. The major side effects encountered (noted by symbols in Figs. 1 to 4) were the following: nausea within 20 to 40 minutes in three subjects; vomiting in one subject; diarrhea in three subjects, profuse in two and requiring discontinuation of the
760
Coudert,
Winter,
and
infusion in subject B. P. and in subject J. M. (who also became hypotensive and fainted); abdominal cramps mimicking normal menstrual cramps in six subjects; occasional bouts of coughing, chest pressure, and shortness of breath in one subject; headache in one subject; epistaxis in one subject; and local pain and erythema at the infusion site in all. All untoward effects disappeared within 30 to 90 minutes following cessation of the infusion. No fever (oral temperature range 36.6 to 37.5’ C.) or consistent changes in blood pressure (except for that noted in J. M. above) and pulse rate were noted in any of the subjects. Comment
The present study clearly shows a transient diminution in both circulating progesterone and estradiol levels following PGF,, infusion during the midluteal phase in four out of seven subjects studied. Assuming that the metabolic clearance rate of these steroids is not altered by PGF,,, then diminution in serum levels must reflect a decrease in corpus luteum function. That this effect is transitory is shown by the return toward preinfusion levels by the following day and a failure to result in the premature onset of the next expected menses. The effect on corpus luteum function appears to be primary, since there was no change in FSH levels and no correlation between alterations in LH and steroid levels. The diminution in LH levels seen during the study cannot be directly ascribed to a PGF,, effect since values were declining during the control observation period. PGF,, infusions in men up to 2.0 pg per kilogram per minute for 30 minutes also had no significant effect upon FSH levels but a similarly unexplained decline in LH levels during the control and experimental infusions was noted.Q
1.
2.
July 15, 1974 Am. J. Obstet. Gynecol.
Faiman
Previous studies of the possible luteolytic effects of both PGF,,l’-‘” and PGE,lG in women have by and large been negative. More recent observations suggest that PGF2, administration during the mid to late luteal phase may result in a transient diminution of circulating progesterone levels,l”, I73 I8 in keeping with our own observations. However, critical evaluation of those studies in which serial determinations of circulating progesterone levels were obtained during the infusion period has proved difficult because of the inherent variability in levels, the failure to obtain sufficient preinfusion control determinations, and the infrequent sampling during the infusion period.‘l. I23 15-18 The dosages of PGF,, used in the present and in previous studies have approached the limits of tolerance and are associated with serious side effects, particularly of a gastrointestinal nature.“-13, I8 C oupled with the finding of transitory effects, at most, on corpus luteum function, it is doubtful that systemically administered PGF,, can be used as a satisfactory contraceptive agent in the human subject. We
thank
Masson the PGF,,
Drs.
E.
of the Upjohn and
for
their
M.
Southern
Company generous
and
E.
I,.
for providing assistance.
The
progesterone antiserum was provided by Dr. G. D. Niswender, Colorado State University, Fort Collins,
Colorado.
The
estradiol
antiserum
was
by Dr. B. V. Caldwell, Yale University, New Haven, Connecticut. The LER-907 gonadoprovided
tropin standard was a gift of the National Pituitary Agency. We thank Dr. T. E. Cuddy, Section of Cardiology, for interpretation of the electrocardiograms, Mrs. J. Kippen for nursing assistance, and Mr. D. Grant, Mr. I. Riyaz, Mrs. R. Poturnak, and Mrs. E. Dudeck for technical assistance.
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3.
Kirton, K. T., Pharriss, B. B., and Forbes, A. D.: Proc. Sot. Exp. Biol. Med. 133: 314, 1970. Wiqvist, N., and Bygdeman, M.: Lancet 1: 889, 1970.
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West, C. D., Nabors, C. Endocrinol. Naftolin, F., Nature New Ross, G. T.,
Mahajan, D. K., Chavrt, V. J., J. and Tyler, F. H.: J. Clin. Metab. 36: 1230, 1973. Yen, S. S. C., and Tsai, C. C.: Biol. 236: 92, 1972. Cargille, C. M., Lipsett, M. B.,
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Rayford, P. L., Marshall, J. R., Strott, C. A., and Rodbard, D.: Recent Progr. Horm. Res. 26: 1, 1970. Winter, J. S. D., Taraska, S., and Faiman, C.: J. Clin. Endocrinol. Metab. 34: 348, 1972. Faiman, C., and Ryan, R. J.: J. Clin. Endocrinol. Metab. 27: 444, 1967. Faiman, C., and Ryan, R. J.: Proc. Sot. Exp. Biol. Med. 125: 1130, 1967. Coudert, S. P., and Faiman, C.: Prostaglandins 3: 89, 1973. Wiqvist, N., Bygdeman, M., and Kirton, K. T.: In Diczfalusy, E., and Borell, V., editors: Nobel Symposium, New York, 1970, John Wiley & Sons, Vol. 15, p. 137. LeMaire, W. J., and Shapiro, A. G.: Prostaglandins 1: 259, 1972.
Decline
12.
13. 14.
15.
16.
17. 18.
in progesterone
during
PGF,,
infusion
761
Jewelewicz, R., Cantor, B., Dyrenfurth, I., Warren, M. P., and Vande Wiele, R. L.: Prostaglandins 1: 443, 1972. Jones, G. S., and Wentz, A. C.: AM. J. OBSTET. GYNECOL. 114: 393, 1972. Tom, W. K. C., Sribyatta, B., Thorneycroft, I. H., and Mishell, D. R., Jr.: Contraception 6: 479, 1972. Hillier, K., Dutton, A., Corker, C. S., Singer, A., and Embrey, M. P.: Br. Med. J. 4: 333, 1972. Hen& M. R., Ortega, E., Cortes-Gallegos, V., Tomlinson, R. V., and Segre, E. J.: J, Clin. Endocrinol. Metab. 36: 784. 1973. Wentz, A. C., and Jones, G. S.: Obstet. Gynecol. 42: 172, 1973. Hillier, K., Dutton, A., and Corker, C. S.: Adv. Biosci. 9: 673, 1973.