THE EFFECT OF INTRA-UTERINE PROSTAGLANDIN F ON 2a CORPUS LUTEUM FUNCTION IN THE HUMAN Robert C. Lyneham, Andrew R. Korda, Donald A. Shutt, lan D. Smith and Rodney P. Shearman Queen Elizabeth Ii Research Institute for Mothers and Infants Department of Obstetrics and Gynaecology, University of Sydney New South Wales, 2006, Australia
ABSTRACT Prostaglandin F2 (PGF2 ) was administered via a Foley catheter over a 12 hour period to 8 healthy volunteers awa,hng laparoscoptc stenhsatton. The amount of PGF2 infused varied between 500 i~g and 2000 i~g every 2 hours for 6 doses, Plasmaaprogeshns . and oestradlol . 176, and urinary estrogens and pregnanedlol were assayed throughout the study period. O
•
•
•
i
•
•
There was no evidence of luteolysis in any patient although vaginal bleeding of varying duration occurred in all women within 36 hours of administration of PGF2a.
ACKNOWLEDGEMENTS We wish to thank Dr. R. Seamark for assistance with assaysof plasma progesfins and Mr. Gregory McMahon for skilled technical assistanca. This study was supported by grants from the World Health Organlsafion and the Laura Bushell Trust. The PGF2a was generously supplied by the Upjohn Company.
PROSTAGLANDINS MARCH 1975
VOL. 9 NO. 3
431
PROSTAGLANDINS
INTRODUCTION The~ is good evidence that the uterine luteolysin in those animals possessing this physiological mechanism is PGF,, (1); intra-uterine administration of PGF,~ in these species during the early lute~(~phase is luteolytic (2). Eviden~afor an intrinsic luteolysin in the human is lacking (3). This paper reports, the effects of intra-uterlne ~nfus,on"over a twelve hour period of PGF.,.a on peripheral venous estradlol-1 713and progestins and urinary estrogens and pregnanediol. MATERIALS AND METHODS Eight women who were to undergo laparoscoplc tubal diathermy for sterillsatlon co--operated in this study. Each had a history of regular menstrual cycles which, as judged by basal body temperature recordings, were ovulatory. All patients were admitted to hospital 2 days before administration of prostaglandlns. Twenty four hour urine collections for assay of total estrogens (4) and pregnanediol (5) were collected throughout the study. Plasma progestlns and estradiol-1713 were assayed by competitive protein binding (6,7); plasma for assay was collected daily or twice daily for 2 days before administration of prostagland~ns, two or three times daily during administration and for at least 48 hours afterwards. PGF^ was injected through a small Foley catheter left in sltu after insertion thr~t~gh the cervical canal. The amount given varied from 500 pg to 2000 pg in 2 ml. normal saline every 2 hours for 6 doses. Following each administration the catheter was flushed with 1.5 ml. normal saline. RESULTS These may be divided into 4 groups. •
Three patients in the mid-luteal phase
2.
Two patients in the early luteal phase
3.
One patient in the late luteal phase
4.
Two patients who were anovulatory
Mid-luteal phase These 3 patients were admitted for study on day 1 7 or 18 of their cycle. The dose administered was 500 isg, 1000 tsg and 2000 tsg every 2 hours for 6 doses. No effect was noted on either plasma or urinary steroid levels. However "menstrualllke" bleeding occurred within 48 hours of prostaglandln administration and either continued or recurred despite normal hormonal function of the corpora lutea. The results from one patient are shown in Figure 1. Details of plasma steroid levels, 432
M A R C H 1975
VOL. 9 NO. 3
PROSTAGLANDINS side effects and bleeding are shown for each patient in Tables I, II and III.
PGF2a COMMENCED
~
r63624
I I
J, I'illl' III
ii'i ii iiiii ;ii C
i"i k_.
PGF2 0 * 5 ~ p 2 HOURLy
Figure 1.
Response, seen in one patient t to intra-uterlne PGF2a during mid luteal phase.
M A R C H 1975
VOL. 9 NO. 3
433
PROSTAGLANDINS
TABLE
I
DAY OF CYCLE No. 163424
17
20
19
18
21
22
23
500pg PGF2a
~,,-ly_xj__.]
Plasma Estradlol pg/ml
116
l i b 104
Plasma Progestlns 27.3
21.9 22.4
38~62 !
76
32.4 24.3
17.1
76
68
71 88
87
21.9
22.6 10.2
87
[ 24.5
21.4
19.9
ng/ml Lower abdominal colicky pain Nausea
SYMPTOMS
BLEEDING
Nil
"NORMAL
Nil
Nil
Nil
PEfl O D "
TABLE II
DAY OF CYCLE No.165189
18
20
19
21
22
23
24-30
1000 pg PGF2aj Plasma Estra~iol pg/ml
Plasma Progestlns ng/ml
2 hourly x 6 96
106
74
82
68
78
89 100
24.3
24.6
~17.2
17.2
15.7
!16.3
16.8 11.7
ii
SYMPTOMS '
BLEEDING[
434
J
Lower abdomina I ~ colicky pain Flatus -HNil
Nil
Nil
BLEEDINGi:
LIKE
MARCH 1975
"NORMAL
PERIOD "
VOL. 9 NO. 3
PROSTAGLANDINS
PGF2o COt,~AEIVCED
I
300
I 1 250
f I I
200
I
0
I
1600 24OO mOO 1400 2,100 g~O liO0
r I
I I
~
'~
.
,
i,llllll
I
0
PGF2 tmlj Z HCCItLy FC~ ~ DOSES
Figure 2.
MARCH
Response seen in one patient to intra-uterine PGF2a during early luteal phase.
1975
VOL. 9 NO. 3
435
PROSTAGLANDINS
TABLE Ill
DAY OF CYCLE No. 045610
lg
20
19
2000 ~g
23
22
21
28
24-27
i
PGE2a
2 hourly x 6
Plasma Estmdlol pg/ml
133
147
260
Plasma Progestlns ng/ml
9.0
B.O
9.3
226
226
10.4
66
160
9.3
3.6
L Salivation
SYMPTOMS
BLEEDING
Vomiting Lower abdominal colicky pain Nil
Nil
Nil
Sli'li t
L
~ht
N|l
Nil
Nil
"Normal period"
Earl), luteal phase These 2 patients were admitted on day 19 of their cycle and PGF2a administered dur|ng the 21st day. It was obvious from analysis of their steroid results that each had ovulated later than expected. The dose administered to one patient was 1000 IJg every 2 hours, to the other 500 IJg every 2 hours for 6 doses. Plasma progestlns and urinary pregnanedlol increased after administration of prostaglandins. In each patient "menstrual-llke" bleeding occurred within 36 hours of infusion, continued for 36-48 hours and then stopped. After a further 1-5 days without bleeding, apparently normal menstruation followed. The results for one patient are shown in Figure 2. Details of plasma steroid levels, side effects and bleeding are shown for each patient in Tables IV and V.
436
M A R C H 1975
VOL. 9 NO. 3
PROSTAGLANDINS TABLE IV DAY OF CYCLE No. I 10672
20
19
21
PJosmo Estradlol pg/ml
265
PJasma Progestlns ng/ml
1000 Hg PGF2a I 2 hourly x 6 i
281i332
2~1148
1.6
3.0 4.3
118
3.1
SYMPTOMS
BLEEDING
22
23
29-34
!
126
~8
;'5 125i145
7.1
6.6
5.6 6.7 !7.6
Hot flushes Lower abdominal colicky pain NauSea ~ Nil
24-28
i
t
Nil
7.7
6.8
I
He~y
Nil
I;,5
HeavI
Nil
Nil
"Normal period"
TABLE V DAY OF CYCLE No. 163422 Pla~m Estradiol
pg/ml Plasma Progestlns ng/ml
19
16
2.9
20
32
6.9
21
149
16.7
i500Hg PGF2a I 12 hourly x 6 I 40 47
9.4
SYMPTOMS
BLEEDING
11.6
35
22
23
26
40166 40 I
i I i~ 9.5 9.ej11.8
24-26
27
Slight
Nil
28-31
54
17.2
Flatus Lower abdominal colick-y pain Dyt~noea Nil
M A R C H 1975
Nil
NH
VOL. 9 NO. 3
Nil
Slight
Heavy
437
PROSTAGLANDINS Late luteal phase This patient had PGF,~ administered during the 23rd day of the cycle O in a dose of 1500 pg every 2~ours for 6 doses. Progesterone and pregnanecl;ol levels were falllng before administration and continued to do so afterwards. An apparently normal period began on day 24. (Figure 3) Details of plasma steroid levels, side effects and bleeding are shown in Table VI.
I
PGF2a COMMENCED I
T t I
'
i,
]'-'~ •
,,$
I
:::ti'I ;'ii,ilii"21" W380930 2045'
i(1~ 1615
i l~l~ 2a~02200~9~T~q~
0900103018~
I I i i
I
I
I2t
I i I
I
I
I
.
24
25
I I i
I22
I
~Y OFCYC~ pGF2 1.Se~g2 HOURLY For ~ 0oses
Figure 3.
Response during
438
seen late
in
one
patient
to
intra-uterine
PGF2a
luteal phase.
M A R C H 1975
VOL. 9 NO. 3
PROSTAGLANDINS
TABLE VI DAY OJ: CYCLE No.066906 Plasma
21
22
L93
65
i
79186
78
24
23 1500IJgPGF2a 2 haurlvx 6 54 41
25
26
38
42 20
ABSTRACT Prostaglandin F2 (PGF2 ) was administered via a Foley catheter over a 12 hour period to 8 healthy volunteers awa,hng laparoscoptc stenhsatton. The amount of PGF2 infused varied between 500 i~g and 2000 i~g every 2 hours for 6 doses, Plasmaaprogeshns . and oestradlol . 176, and urinary estrogens and pregnanedlol were assayed throughout the study period. O
•
•
•
i
•
•
There was no evidence of luteolysis in any patient although vaginal bleeding of varying duration occurred in all women within 36 hours of administration of PGF2a.
ACKNOWLEDGEMENTS We wish to thank Dr. R. Seamark for assistance with assaysof plasma progesfins and Mr. Gregory McMahon for skilled technical assistanca. This study was supported by grants from the World Health Organlsafion and the Laura Bushell Trust. The PGF2a was generously supplied by the Upjohn Company.
PROSTAGLANDINS MARCH 1975
VOL. 9 NO. 3
431
PROSTAGLANDINS
INTRODUCTION The~ is good evidence that the uterine luteolysin in those animals possessing this physiological mechanism is PGF,, (1); intra-uterine administration of PGF,~ in these species during the early lute~(~phase is luteolytic (2). Eviden~afor an intrinsic luteolysin in the human is lacking (3). This paper reports, the effects of intra-uterlne ~nfus,on"over a twelve hour period of PGF.,.a on peripheral venous estradlol-1 713and progestins and urinary estrogens and pregnanediol. MATERIALS AND METHODS Eight women who were to undergo laparoscoplc tubal diathermy for sterillsatlon co--operated in this study. Each had a history of regular menstrual cycles which, as judged by basal body temperature recordings, were ovulatory. All patients were admitted to hospital 2 days before administration of prostaglandlns. Twenty four hour urine collections for assay of total estrogens (4) and pregnanediol (5) were collected throughout the study. Plasma progestlns and estradiol-1713 were assayed by competitive protein binding (6,7); plasma for assay was collected daily or twice daily for 2 days before administration of prostagland~ns, two or three times daily during administration and for at least 48 hours afterwards. PGF^ was injected through a small Foley catheter left in sltu after insertion thr~t~gh the cervical canal. The amount given varied from 500 pg to 2000 pg in 2 ml. normal saline every 2 hours for 6 doses. Following each administration the catheter was flushed with 1.5 ml. normal saline. RESULTS These may be divided into 4 groups. •
Three patients in the mid-luteal phase
2.
Two patients in the early luteal phase
3.
One patient in the late luteal phase
4.
Two patients who were anovulatory
Mid-luteal phase These 3 patients were admitted for study on day 1 7 or 18 of their cycle. The dose administered was 500 isg, 1000 tsg and 2000 tsg every 2 hours for 6 doses. No effect was noted on either plasma or urinary steroid levels. However "menstrualllke" bleeding occurred within 48 hours of prostaglandln administration and either continued or recurred despite normal hormonal function of the corpora lutea. The results from one patient are shown in Figure 1. Details of plasma steroid levels, 432
M A R C H 1975
VOL. 9 NO. 3
PROSTAGLANDINS side effects and bleeding are shown for each patient in Tables I, II and III.
PGF2a COMMENCED
~
r63624
I I
J, I'illl' III
ii'i ii iiiii ;ii C
i"i k_.
PGF2 0 * 5 ~ p 2 HOURLy
Figure 1.
Response, seen in one patient t to intra-uterlne PGF2a during mid luteal phase.
M A R C H 1975
VOL. 9 NO. 3
433
PROSTAGLANDINS
TABLE
I
DAY OF CYCLE No. 163424
17
20
19
18
21
22
23
500pg PGF2a
~,,-ly_xj__.]
Plasma Estradlol pg/ml
116
l i b 104
Plasma Progestlns 27.3
21.9 22.4
38~62 !
76
32.4 24.3
17.1
76
68
71 88
87
21.9
22.6 10.2
87
[ 24.5
21.4
19.9
ng/ml Lower abdominal colicky pain Nausea
SYMPTOMS
BLEEDING
Nil
"NORMAL
Nil
Nil
Nil
PEfl O D "
TABLE II
DAY OF CYCLE No.165189
18
20
19
21
22
23
24-30
1000 pg PGF2aj Plasma Estra~iol pg/ml
Plasma Progestlns ng/ml
2 hourly x 6 96
106
74
82
68
78
89 100
24.3
24.6
~17.2
17.2
15.7
!16.3
16.8 11.7
ii
SYMPTOMS '
BLEEDING[
434
J
Lower abdomina I ~ colicky pain Flatus -HNil
Nil
Nil
BLEEDINGi:
LIKE
MARCH 1975
"NORMAL
PERIOD "
VOL. 9 NO. 3
PROSTAGLANDINS
PGF2o COt,~AEIVCED
I
300
I 1 250
f I I
200
I
0
I
1600 24OO mOO 1400 2,100 g~O liO0
r I
I I
~
'~
.
,
i,llllll
I
0
PGF2 tmlj Z HCCItLy FC~ ~ DOSES
Figure 2.
MARCH
Response seen in one patient to intra-uterine PGF2a during early luteal phase.
1975
VOL. 9 NO. 3
435
PROSTAGLANDINS
TABLE Ill
DAY OF CYCLE No. 045610
lg
20
19
2000 ~g
23
22
21
28
24-27
i
PGE2a
2 hourly x 6
Plasma Estmdlol pg/ml
133
147
260
Plasma Progestlns ng/ml
9.0
B.O
9.3
226
226
10.4
66
160
9.3
3.6
L Salivation
SYMPTOMS
BLEEDING
Vomiting Lower abdominal colicky pain Nil
Nil
Nil
Sli'li t
L
~ht
N|l
Nil
Nil
"Normal period"
Earl), luteal phase These 2 patients were admitted on day 19 of their cycle and PGF2a administered dur|ng the 21st day. It was obvious from analysis of their steroid results that each had ovulated later than expected. The dose administered to one patient was 1000 IJg every 2 hours, to the other 500 IJg every 2 hours for 6 doses. Plasma progestlns and urinary pregnanedlol increased after administration of prostaglandins. In each patient "menstrual-llke" bleeding occurred within 36 hours of infusion, continued for 36-48 hours and then stopped. After a further 1-5 days without bleeding, apparently normal menstruation followed. The results for one patient are shown in Figure 2. Details of plasma steroid levels, side effects and bleeding are shown for each patient in Tables IV and V.
436
M A R C H 1975
VOL. 9 NO. 3
PROSTAGLANDINS TABLE IV DAY OF CYCLE No. I 10672
20
19
21
PJosmo Estradlol pg/ml
265
PJasma Progestlns ng/ml
1000 Hg PGF2a I 2 hourly x 6 i
281i332
2~1148
1.6
3.0 4.3
118
3.1
SYMPTOMS
BLEEDING
22
23
29-34
!
126
~8
;'5 125i145
7.1
6.6
5.6 6.7 !7.6
Hot flushes Lower abdominal colicky pain NauSea ~ Nil
24-28
i
t
Nil
7.7
6.8
I
He~y
Nil
I;,5
HeavI
Nil
Nil
"Normal period"
TABLE V DAY OF CYCLE No. 163422 Pla~m Estradiol
pg/ml Plasma Progestlns ng/ml
19
16
2.9
20
32
6.9
21
149
16.7
i500Hg PGF2a I 12 hourly x 6 I 40 47
9.4
SYMPTOMS
BLEEDING
11.6
35
22
23
26
40166 40 I
i I i~ 9.5 9.ej11.8
24-26
27
Slight
Nil
28-31
54
17.2
Flatus Lower abdominal colick-y pain Dyt~noea Nil
M A R C H 1975
Nil
NH
VOL. 9 NO. 3
Nil
Slight
Heavy
437
PROSTAGLANDINS Late luteal phase This patient had PGF,~ administered during the 23rd day of the cycle O in a dose of 1500 pg every 2~ours for 6 doses. Progesterone and pregnanecl;ol levels were falllng before administration and continued to do so afterwards. An apparently normal period began on day 24. (Figure 3) Details of plasma steroid levels, side effects and bleeding are shown in Table VI.
I
PGF2a COMMENCED I
T t I
'
i,
]'-'~ •
,,$
I
:::ti'I ;'ii,ilii"21" W380930 2045'
i(1~ 1615
i l~l~ 2a~02200~9~T~q~
0900103018~
I I i i
I
I
I2t
I i I
I
I
I
.
24
25
I I i
I22
I
~Y OFCYC~ pGF2 1.Se~g2 HOURLY For ~ 0oses
Figure 3.
Response during
438
seen late
in
one
patient
to
intra-uterine
PGF2a
luteal phase.
M A R C H 1975
VOL. 9 NO. 3
PROSTAGLANDINS
TABLE VI DAY OJ: CYCLE No.066906 Plasma
21
22
L93
65
i
79186
78
24
23 1500IJgPGF2a 2 haurlvx 6 54 41
25
26
38
42 20
