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Effect of progesterone and 17-hydroxyprogesterone caproate on normal corpus luteum function
Effect of progesterone and 17 -hydroxy progesterone caproate on normal corpus luteum function SEZER AKSEL,
M.D.
Durham, North Carolina
GEORGEANNA S. JONES, M.D. Baltimore, Maryland A group of infertility patients were evaluated by an endometrial biopsy, timed with a basal body temperature chart, serum /luteinizing hormone radioimmunassay to pinpoint ovulation, and daily serum progesterone values durin·g a control and a treatment cycle. Progesterone in the suppository or intramuscular form and 17hydroxyprogesterone caproate* were administered during the luteal phase to a group of volunteer patients with normal corpus luteum function to determine if these compounds would depress serum progesterone levels as do certain progestational agents. There was no apparent inhibition of corpus luteum function as no decrease in progesterone production occurred. Despite the additive effect of progesterone administration demonstrated by elevated serum levels, endometrial biopsies remained in phase when dated from the estimated day of ovulation.
C L I N I C A L S I G N I F I C A N C E of adequate luteal function for normal trophoblastic implantation and development is well recognized. Steroidogenic potential of the corpus luteum can be satisfactorily evaluated by daily serial collection of serum or urine for progesterone or pregnanediol assays. However, a timed endometrial biopsy used as a bioassay during the second half of the cycle has been shown to be a practical method to determine steroidogenesis and the adequacy of the endometrial response. Certain compounds such as progestational
agents, diethylstilbestrol, H and oxymetholone4 cause a reduction in serum progesterone levels and a shortening of the luteal phase when administered after ovulation, creating an iatrogenic corpus luteum defect, reversible with supplemental human chorionic gonadotropin. It has been postulated that progesterone itself may inhibit progesterone synthesis, either by a central feedback causing luteinizing hormone (LH) inhibition or, perhaps, through an inhibition of the 3-betaol dehydrogenase enzyme system. 5 Also, 17hydroxyprogesterone is noted to inhibit progesterone synthesis in bovine adrenals, apparently through an inhibition of the conversion of pregnenolone to progesterone. 6 In high dosages, 500 mg. of 17-hydroxyprogesterone caproate has been shown to decrease progesterone production m the human subject. 7 The effects of progesterone administration on corpus luteum progesterone production in the woman have not been investigated. This study was designed to determine if these steroids given in thera-
From the Department of Obstetrics and Gynecology, Duke University Medical Center, and the Department of Obstetrics and Gynecology, The johns Hopkins Hospital. Received for publication july II, I973. Accepted August 20, I973. Reprint requests: Sezer Aksel, M.D., Duke University Medical Center, Department of Obstetrics-Gynecology, Durham, North Carolina 277IO. *Delalutin, E. R. Squibb, P. 0. Box 4000, Princeton, New jersey 08544.
466
Steroids on corpus luteum function 467
Volume 118 Number 4
Prog . - - - - - - - - - - - - - - - - - - - - - , ng/ml
101-
5-
0
e?il~
Baselmes
~
Voginal Rectal Prog. NoRx Supp. Supp. in oil 25 mg. 25 mg. 12.5mgiM
Progesterone Administration 2 Hrs. Before Sampling
Fig. 1. Base-line progesterone levels in an anovulatory patient are less than 1 ng. per milliliter. Progesterone was administered on 3 successive days, 25 mg. suppositories twice daily, vaginally the first day and rectally the second day. Intramuscular progesterone, 12.5 mg., was administered the third day. Blood sampling was performed 2 and 24 hours later. Suppositories gave serum values in the range of 6 ng. per milliliter while the intramuscular progesterone was apparently absorbed more slowly and showed a comparable value the next day.
peutic dosages will depress serum progesterone levels during the luteal phase and to correlate the serum progesterone levels with endometrial biopsies in women with normal corpus luteum function. Material and methods
Eight infertility patients between the ages of 26 and 35 with no etiologic factor found to explain the infertility volunteered to participate in the study. All had regular menstrual cycles and normal corpus luteum function as determined by an endometrial biopsy prior to the study cycles. A control cycle and a treatment cycle were evaluated by an endometrial biopsy, histologically dated according to the criteria of Noyes and associates 8 timed with a basal body temperature chart. Serum LH was assayed by the double-isotope-dilution technique of Midgely9 to pinpoint ovulation. Daily serum progesterone assays were done by a modification10 of the protein-binding method of Murphy. Blood samples were obtained through venipuncture at the same time, daily, whenever feasible, and 2 hours after the progesterone administration during the treatment cycles to obtain uniformity. Serum was separated and frozen, and all samples of a particular patient were run in the same
assay. During the treatment cycle, attempts were made to start each patient on a selected steroid, i.e., progesterone or 17-hydroxyprogesterone caproate,* 3 days after the postovulatory rise in the basal body temperature chart could be determined. The actual day of ovulation was subsequently determined by the LH surge, and this was taken into account for the final analysis. Progesterone suppositories were prepared by The Johns Hopkins Hospital Pharmacy according to the following formula: progesterone powder, 44 Gm.; polyethylene glycol 400, 2,096 Gm.; polyethylene glycol 6,000, 1,392 Gm. This will produce 1,760 suppositories with a progesterone concentration of 25 mg. in each 2 Gm. suppository. Progesterone in oil,t 25 mg. per milliliter, was used for intramuscular administration in predetermined dosages, i.e., 12.5 or 25 mg. daily. Injections were given deep into the gluteal muscle. 17-hydroxyprogesterone caproate was used intramuscularly, 125 mg. on Days 3 and 10 after the postovulatory rise in the basal body temperature chart was evident. *Delalutin, E. R. Squibb, P. 0. Box 4000, Princeton, New Jersey 08544. tProluton, Schering Corp., lOll Morris Ave., Union, New Jersey 07083.
February 15, 1974 Am. ]. Obstet. Gynecol.
468 Aksel and Jones
LW
AR
ssrcr--------------=~
XX X
XX X
X
LH ffill
\~100
23 25 27 29 31 Aug
Fig. 2. Control (top) and treatment (bottom) cycles of Patient L. W. Ovulations are depicted by the LH surge. Endometrial biopsies are in phase. Comparison of the areas outlined by the two curves show an increase of 32 per cent during the treatment cycle. Maximum difference in progesterone levels is observed beginning on the seventh Discharge. P. Supp postovulatory day. D Progesterone suppository.
=
=
An anovulatory patient, scheduled for progesterone withdrawal bleeding, volunteered for evaluation of progesterone absorption by different modes of administration. Base-line progesterone values were obtained, and serum progesterone assays were performed on 4 consecutive days, 2 hours after progesterone administration vaginally and rectally, and 2 and 24 hours after an intramuscular injection of 12.5 mg. of progesterone in oil. Results
Fig. represents our findings in an anovulatory patient who received progesterone by various routes on 3 separate days to evaluate the absorption of this steroid by different modes of administration. Base-line progesterone values were less than 1 ng. per milliliter. Blood levels assayed 2 hours after
Fig. 3. Control (top) and treatment (bottom) cycles of Patient A. R. Intramuscular progesterone, 12.5 mg. was started on the fifth postovulatory day. The treatment curve represents a marked rise in progesterone levels and covers 62 per cent more area than the control curve. P = Progesterone in oil.
administration of 25 mg. of progesterone in suppository form by the vaginal route on Day 1 and by the rectal route the following day gave serum values in the range of 6 ng. per milliliter, while intramuscular progesterone, 12.5 mg., administered the third day was apparently absorbed more slowly and showed a comparable level only after 24 hours. Table I summarizes the findings in the 8 "normal infertile" women studied. Four received dosages of progesterone considered to be physiologic, that is, 50 mg. suppositories daily or 25 mg. twice daily and 12.5 mg. of progesterone daily, intramuscularly. Two patients received progesterone dosages thought to be excessive, that is, 50 mg. suppositories twice daily or 25 mg. daily intramuscularly. In these patients, treatment was stopped after 12 days. Two patients received a pro-
Volume 118 Number 4
Steroids on corpus luteum function
469
Table I. Patients with normal corpus luteum function. Effects of progesterone and 17-hydroxyprogesterone caproate on the luteal phase Control cycle Patient
L. W.
Luteal days
I
S. B. S.M.
16 14 13 14
In In In In
A. R.
12
In phase
M. B.
12
In phase
T. H.
13
In phase
E. 0.
14-
In phase
w. J.
Average
Treatment cycle
Endometrial biopsy phase phase phase phase
Agent used Progesterone suppository, 50 mg. per day Progesterone suppository, 25 mg. twice daily Progesterone suppository, 50 mg. twice daily Progesterone in oil, 12.5 mg. intramuscularly per day Progesterone in oil, 12.5 mg. intramuscularly per day Progesterone in oil, 25 mg. intramuscularly per day 17-Hydroxyprogesterone caproate, 125 mg. on days 3 and 10 17-Hydroxyprogesterone caproate, 125 mg. on days 3 and 10
13.5
gestational agent, 17-hydroxyprogesterone caproate. It was of interest that the biopsy findings in both the control and treatment cycles were in phase as judged by ovulation. The luteal span was prolonged on an average of only 1 day. Statistical comparison of the difference between the luteal phase lengths of the control and treatment cycles did not show a significant change. (T 14 = 1.6, P = > > 0.05) . Among the 4 patients who received physiologic dosage of progesterone, Figs. 2 and 3 are representative. The treatment cycles show augmentation of serum progesterone levels after utilization of progesterone in either suppository or intramuscular form. When areas of the treatment cycles were compared to areas of the control cycles, 32 per cent (Fig. 2) and 62 per cent (Fig. 3) increases, respectively, were noted. To investigate the effects of progesterone administered in higher than physiologic doses, one volunteer with a normal 30 day cycle was started on 25 mg. of intramuscular progesterone daily on the fourth day post ovulation. Fig. 4 represents the cycles of this patient which show a marked additive progesterone effect in the treatment cycle. The area under the curve of the treatment cycle shows an 82 per cent increase when compared to the area under the control cycle (Fig. 5). It is evident that this dosage
Luteal days
IEndometrial biopsy
17 14 14 16
In In In In
phase phase phase phase
13
In phase
16
In phase
13
In phase
14
In phase
14.6
Fig. 4. The control (top) and treatment (bottom) cycles of Patient M. B. Intramuscular progesterone, 25 mg., was started on the fnurth postovulatory day. The treatment was stopped 12 days later on October 5. Normally, the patient expected her period on October 4.
of progesterone will not only cause a significant rise in daily serum progesterone levels but will override the menses (Fig. 5). This patient had a luteal span prolonged by
February 15, 1974
470 Aksel and Jones
Am.
J. Obstet. Gynecol.
M.B Prog nqlml
30
,--11
Control Cycle Rx Cycle •--•
I I
I
I
I I
I
I
! \ r~3d_o2~xd I
11
\
1
1 I
I/ \
Menses= X
I
.
\I I /
tl.
I '
\
II
\
\ \
\..- ............
Cycle Days Fig. 5. Comparison of the control and treatment cycles of Patient M. B. The maximum difference in progesterone levels was observed beginning on the seventh postovulatory day. There is an 82 per cent increase in the area covered by the treatment cycle progesterone curve when compared to the control cycle.
TH
T H. BBTCXXX
Prog X
ng/ml
Control Cycle-
Rx Cycle
.. _.
97° Prog
Fig. 7. Comparison of the progesterone values during T. H.'s control and treatment cycles. No augmentation or depression in serum progesterone levels was observed. No significant change could be demonstrated in the overlapping curves.
Fig. 6. Control (top) and treatment (bottom) cycles of Patient T. H. 17-Hydroxyprogesterone caproate was administered on the fourth and eleventh days of the luteal phase. Endometrial biopsies performed one day before the onset of menses were in phase. Duration of the luteal phase was unchanged.
5 days, and bleeding occurred 36 hours after discontinuation of the hormone. Fig. 6 represents the control and treatment cycles of a volunteer receiving 17-hydroxyprogesterone caproate. No significant change in serum progesterone values was noted in the comparative assays of the control and treatment cycles (Fig. 7). Among the patients who received progesterone during the luteal phase, no aberration of menses was noted in the following cycles.
ng/ml 2
-
Steroids on corpus luteum function 471
Volume 118 Number 4
'
.
Normal Luteal Phose Prog Rx in Normal Luteal Phose •--.. Prog ng/ml
-I Cycie Days Fig. 8. Mean progesterone values in 28 normal cycles and 6 progesterone-treated cycles which show an additive effect. The difference in the areas covered by the 2 curves is statistically significant (T., 14.4, P 0.001). standard error of the mean.
=
=
I=
Among the 2 patients who received 17hydroxyprogesterone caproate, one reported an anovulatory period following the treatment cycle. This was diagnosed on the basis of a basal body temperature chart which was monophasic. However, the subsequent periods appear to be ovulatory. Comment
... _.
When the composite findings of serum progesterone values of 28 normal cycles are compared to the augmented progesterone values of 6 treated cycles (Fig. 8), an additive progesterone effect is observed. Statistically, the difference is significant (T 32 = 13.4, P = 0.(>01 level). The increase in progesterone values is most marked after the sixth luteal day (Fig. 8). Similar findings are observed in the individual treatment cycles (Figs. 2, 3, and 5) . Therefore, progesterone supplementation of the luteal phase can be accomplished with the use of progesterone suppositories given rectally or vaginally or by intramuscular injections . Absorption is adequate through either route of administration. Augmentation of the luteal
phase with physiologic levels of progesterone or 17-hydroxyprogesterone does not seem to advance the endometrial biopsy dating. When progesterone supplementation of the luteal phase is carried out with the use of higher doses than those required for physiologic replacement therapy, the luteal phase is prolonged (Fig. 5) and pseudopregnancy results unless therapy is terminated. However despite markedly elevated serum progesterone values with this mode of treatment, an endometrial biopsy is still not advanced with respect to the day of ovulation but is actually in phase. Several progestational agents and stilbestrol have been shown to be luteolytic when administered during the postovulatory phase of the cycle, causing a significant decline of serum progesterone values and shortening of the luteal phase. When administered in the dosages and manner described in the study, neither progesterone nor 17-hydroxyprogesterone caproate seems to have a luteolytic effect on corpus luteum function or to cause a significant change in the duration of the luteal phase.
472
February 15, 1974 Am. J. Obstet. Gynecol.
Aksel and Jones
REFERENCES
1. Johanson, E. D. B.: Acta Endocrinol. 68: 779, 1971. 2. Gore, B. Z., Caldwell, B. V., and Speroff, L.: J. Clin. Endocrinol. Metab. 36: 615, 1973. 3. Morris, J. M., .and van Wagenen, G.: AM. J. OBsTET. GvNECOL. 115: 101, 1973. 4. Klaiber, E. L., Henzl, M. R., and Lloyd, C. W.: J. Clin. Endocrinol. Metab. 36: 142, 1973. 5. Jones, G. S.: Luteal phase defect, in Behrman, S. J., and Kistner, R. W., editors: Progress
6. 7. 8. 9. 10.
in infertility, Boston, 1972, Little, Brown & Company. Patwardhan, V. V., and Lanthier, A.: Steroids 17: 219, 1971. Johanson, E. D. B.: Acta Obstet. Gynecol. Scand. 52: 37, 1973. Noyes, R. W., Hertig, A., and Rock, J.: Fertil. Steril. 1: 3, 1950. Midgely, A. R., Jr.: Endocrinology 79: 10, 1966. Yoshimi, T., and Lipsett, M. B.: Steroids 11: 527, 1968.
M.D.
Durham, North Carolina
GEORGEANNA S. JONES, M.D. Baltimore, Maryland A group of infertility patients were evaluated by an endometrial biopsy, timed with a basal body temperature chart, serum /luteinizing hormone radioimmunassay to pinpoint ovulation, and daily serum progesterone values durin·g a control and a treatment cycle. Progesterone in the suppository or intramuscular form and 17hydroxyprogesterone caproate* were administered during the luteal phase to a group of volunteer patients with normal corpus luteum function to determine if these compounds would depress serum progesterone levels as do certain progestational agents. There was no apparent inhibition of corpus luteum function as no decrease in progesterone production occurred. Despite the additive effect of progesterone administration demonstrated by elevated serum levels, endometrial biopsies remained in phase when dated from the estimated day of ovulation.
C L I N I C A L S I G N I F I C A N C E of adequate luteal function for normal trophoblastic implantation and development is well recognized. Steroidogenic potential of the corpus luteum can be satisfactorily evaluated by daily serial collection of serum or urine for progesterone or pregnanediol assays. However, a timed endometrial biopsy used as a bioassay during the second half of the cycle has been shown to be a practical method to determine steroidogenesis and the adequacy of the endometrial response. Certain compounds such as progestational
agents, diethylstilbestrol, H and oxymetholone4 cause a reduction in serum progesterone levels and a shortening of the luteal phase when administered after ovulation, creating an iatrogenic corpus luteum defect, reversible with supplemental human chorionic gonadotropin. It has been postulated that progesterone itself may inhibit progesterone synthesis, either by a central feedback causing luteinizing hormone (LH) inhibition or, perhaps, through an inhibition of the 3-betaol dehydrogenase enzyme system. 5 Also, 17hydroxyprogesterone is noted to inhibit progesterone synthesis in bovine adrenals, apparently through an inhibition of the conversion of pregnenolone to progesterone. 6 In high dosages, 500 mg. of 17-hydroxyprogesterone caproate has been shown to decrease progesterone production m the human subject. 7 The effects of progesterone administration on corpus luteum progesterone production in the woman have not been investigated. This study was designed to determine if these steroids given in thera-
From the Department of Obstetrics and Gynecology, Duke University Medical Center, and the Department of Obstetrics and Gynecology, The johns Hopkins Hospital. Received for publication july II, I973. Accepted August 20, I973. Reprint requests: Sezer Aksel, M.D., Duke University Medical Center, Department of Obstetrics-Gynecology, Durham, North Carolina 277IO. *Delalutin, E. R. Squibb, P. 0. Box 4000, Princeton, New jersey 08544.
466
Steroids on corpus luteum function 467
Volume 118 Number 4
Prog . - - - - - - - - - - - - - - - - - - - - - , ng/ml
101-
5-
0
e?il~
Baselmes
~
Voginal Rectal Prog. NoRx Supp. Supp. in oil 25 mg. 25 mg. 12.5mgiM
Progesterone Administration 2 Hrs. Before Sampling
Fig. 1. Base-line progesterone levels in an anovulatory patient are less than 1 ng. per milliliter. Progesterone was administered on 3 successive days, 25 mg. suppositories twice daily, vaginally the first day and rectally the second day. Intramuscular progesterone, 12.5 mg., was administered the third day. Blood sampling was performed 2 and 24 hours later. Suppositories gave serum values in the range of 6 ng. per milliliter while the intramuscular progesterone was apparently absorbed more slowly and showed a comparable value the next day.
peutic dosages will depress serum progesterone levels during the luteal phase and to correlate the serum progesterone levels with endometrial biopsies in women with normal corpus luteum function. Material and methods
Eight infertility patients between the ages of 26 and 35 with no etiologic factor found to explain the infertility volunteered to participate in the study. All had regular menstrual cycles and normal corpus luteum function as determined by an endometrial biopsy prior to the study cycles. A control cycle and a treatment cycle were evaluated by an endometrial biopsy, histologically dated according to the criteria of Noyes and associates 8 timed with a basal body temperature chart. Serum LH was assayed by the double-isotope-dilution technique of Midgely9 to pinpoint ovulation. Daily serum progesterone assays were done by a modification10 of the protein-binding method of Murphy. Blood samples were obtained through venipuncture at the same time, daily, whenever feasible, and 2 hours after the progesterone administration during the treatment cycles to obtain uniformity. Serum was separated and frozen, and all samples of a particular patient were run in the same
assay. During the treatment cycle, attempts were made to start each patient on a selected steroid, i.e., progesterone or 17-hydroxyprogesterone caproate,* 3 days after the postovulatory rise in the basal body temperature chart could be determined. The actual day of ovulation was subsequently determined by the LH surge, and this was taken into account for the final analysis. Progesterone suppositories were prepared by The Johns Hopkins Hospital Pharmacy according to the following formula: progesterone powder, 44 Gm.; polyethylene glycol 400, 2,096 Gm.; polyethylene glycol 6,000, 1,392 Gm. This will produce 1,760 suppositories with a progesterone concentration of 25 mg. in each 2 Gm. suppository. Progesterone in oil,t 25 mg. per milliliter, was used for intramuscular administration in predetermined dosages, i.e., 12.5 or 25 mg. daily. Injections were given deep into the gluteal muscle. 17-hydroxyprogesterone caproate was used intramuscularly, 125 mg. on Days 3 and 10 after the postovulatory rise in the basal body temperature chart was evident. *Delalutin, E. R. Squibb, P. 0. Box 4000, Princeton, New Jersey 08544. tProluton, Schering Corp., lOll Morris Ave., Union, New Jersey 07083.
February 15, 1974 Am. ]. Obstet. Gynecol.
468 Aksel and Jones
LW
AR
ssrcr--------------=~
XX X
XX X
X
LH ffill
\~100
23 25 27 29 31 Aug
Fig. 2. Control (top) and treatment (bottom) cycles of Patient L. W. Ovulations are depicted by the LH surge. Endometrial biopsies are in phase. Comparison of the areas outlined by the two curves show an increase of 32 per cent during the treatment cycle. Maximum difference in progesterone levels is observed beginning on the seventh Discharge. P. Supp postovulatory day. D Progesterone suppository.
=
=
An anovulatory patient, scheduled for progesterone withdrawal bleeding, volunteered for evaluation of progesterone absorption by different modes of administration. Base-line progesterone values were obtained, and serum progesterone assays were performed on 4 consecutive days, 2 hours after progesterone administration vaginally and rectally, and 2 and 24 hours after an intramuscular injection of 12.5 mg. of progesterone in oil. Results
Fig. represents our findings in an anovulatory patient who received progesterone by various routes on 3 separate days to evaluate the absorption of this steroid by different modes of administration. Base-line progesterone values were less than 1 ng. per milliliter. Blood levels assayed 2 hours after
Fig. 3. Control (top) and treatment (bottom) cycles of Patient A. R. Intramuscular progesterone, 12.5 mg. was started on the fifth postovulatory day. The treatment curve represents a marked rise in progesterone levels and covers 62 per cent more area than the control curve. P = Progesterone in oil.
administration of 25 mg. of progesterone in suppository form by the vaginal route on Day 1 and by the rectal route the following day gave serum values in the range of 6 ng. per milliliter, while intramuscular progesterone, 12.5 mg., administered the third day was apparently absorbed more slowly and showed a comparable level only after 24 hours. Table I summarizes the findings in the 8 "normal infertile" women studied. Four received dosages of progesterone considered to be physiologic, that is, 50 mg. suppositories daily or 25 mg. twice daily and 12.5 mg. of progesterone daily, intramuscularly. Two patients received progesterone dosages thought to be excessive, that is, 50 mg. suppositories twice daily or 25 mg. daily intramuscularly. In these patients, treatment was stopped after 12 days. Two patients received a pro-
Volume 118 Number 4
Steroids on corpus luteum function
469
Table I. Patients with normal corpus luteum function. Effects of progesterone and 17-hydroxyprogesterone caproate on the luteal phase Control cycle Patient
L. W.
Luteal days
I
S. B. S.M.
16 14 13 14
In In In In
A. R.
12
In phase
M. B.
12
In phase
T. H.
13
In phase
E. 0.
14-
In phase
w. J.
Average
Treatment cycle
Endometrial biopsy phase phase phase phase
Agent used Progesterone suppository, 50 mg. per day Progesterone suppository, 25 mg. twice daily Progesterone suppository, 50 mg. twice daily Progesterone in oil, 12.5 mg. intramuscularly per day Progesterone in oil, 12.5 mg. intramuscularly per day Progesterone in oil, 25 mg. intramuscularly per day 17-Hydroxyprogesterone caproate, 125 mg. on days 3 and 10 17-Hydroxyprogesterone caproate, 125 mg. on days 3 and 10
13.5
gestational agent, 17-hydroxyprogesterone caproate. It was of interest that the biopsy findings in both the control and treatment cycles were in phase as judged by ovulation. The luteal span was prolonged on an average of only 1 day. Statistical comparison of the difference between the luteal phase lengths of the control and treatment cycles did not show a significant change. (T 14 = 1.6, P = > > 0.05) . Among the 4 patients who received physiologic dosage of progesterone, Figs. 2 and 3 are representative. The treatment cycles show augmentation of serum progesterone levels after utilization of progesterone in either suppository or intramuscular form. When areas of the treatment cycles were compared to areas of the control cycles, 32 per cent (Fig. 2) and 62 per cent (Fig. 3) increases, respectively, were noted. To investigate the effects of progesterone administered in higher than physiologic doses, one volunteer with a normal 30 day cycle was started on 25 mg. of intramuscular progesterone daily on the fourth day post ovulation. Fig. 4 represents the cycles of this patient which show a marked additive progesterone effect in the treatment cycle. The area under the curve of the treatment cycle shows an 82 per cent increase when compared to the area under the control cycle (Fig. 5). It is evident that this dosage
Luteal days
IEndometrial biopsy
17 14 14 16
In In In In
phase phase phase phase
13
In phase
16
In phase
13
In phase
14
In phase
14.6
Fig. 4. The control (top) and treatment (bottom) cycles of Patient M. B. Intramuscular progesterone, 25 mg., was started on the fnurth postovulatory day. The treatment was stopped 12 days later on October 5. Normally, the patient expected her period on October 4.
of progesterone will not only cause a significant rise in daily serum progesterone levels but will override the menses (Fig. 5). This patient had a luteal span prolonged by
February 15, 1974
470 Aksel and Jones
Am.
J. Obstet. Gynecol.
M.B Prog nqlml
30
,--11
Control Cycle Rx Cycle •--•
I I
I
I
I I
I
I
! \ r~3d_o2~xd I
11
\
1
1 I
I/ \
Menses= X
I
.
\I I /
tl.
I '
\
II
\
\ \
\..- ............
Cycle Days Fig. 5. Comparison of the control and treatment cycles of Patient M. B. The maximum difference in progesterone levels was observed beginning on the seventh postovulatory day. There is an 82 per cent increase in the area covered by the treatment cycle progesterone curve when compared to the control cycle.
TH
T H. BBTCXXX
Prog X
ng/ml
Control Cycle-
Rx Cycle
.. _.
97° Prog
Fig. 7. Comparison of the progesterone values during T. H.'s control and treatment cycles. No augmentation or depression in serum progesterone levels was observed. No significant change could be demonstrated in the overlapping curves.
Fig. 6. Control (top) and treatment (bottom) cycles of Patient T. H. 17-Hydroxyprogesterone caproate was administered on the fourth and eleventh days of the luteal phase. Endometrial biopsies performed one day before the onset of menses were in phase. Duration of the luteal phase was unchanged.
5 days, and bleeding occurred 36 hours after discontinuation of the hormone. Fig. 6 represents the control and treatment cycles of a volunteer receiving 17-hydroxyprogesterone caproate. No significant change in serum progesterone values was noted in the comparative assays of the control and treatment cycles (Fig. 7). Among the patients who received progesterone during the luteal phase, no aberration of menses was noted in the following cycles.
ng/ml 2
-
Steroids on corpus luteum function 471
Volume 118 Number 4
'
.
Normal Luteal Phose Prog Rx in Normal Luteal Phose •--.. Prog ng/ml
-I Cycie Days Fig. 8. Mean progesterone values in 28 normal cycles and 6 progesterone-treated cycles which show an additive effect. The difference in the areas covered by the 2 curves is statistically significant (T., 14.4, P 0.001). standard error of the mean.
=
=
I=
Among the 2 patients who received 17hydroxyprogesterone caproate, one reported an anovulatory period following the treatment cycle. This was diagnosed on the basis of a basal body temperature chart which was monophasic. However, the subsequent periods appear to be ovulatory. Comment
... _.
When the composite findings of serum progesterone values of 28 normal cycles are compared to the augmented progesterone values of 6 treated cycles (Fig. 8), an additive progesterone effect is observed. Statistically, the difference is significant (T 32 = 13.4, P = 0.(>01 level). The increase in progesterone values is most marked after the sixth luteal day (Fig. 8). Similar findings are observed in the individual treatment cycles (Figs. 2, 3, and 5) . Therefore, progesterone supplementation of the luteal phase can be accomplished with the use of progesterone suppositories given rectally or vaginally or by intramuscular injections . Absorption is adequate through either route of administration. Augmentation of the luteal
phase with physiologic levels of progesterone or 17-hydroxyprogesterone does not seem to advance the endometrial biopsy dating. When progesterone supplementation of the luteal phase is carried out with the use of higher doses than those required for physiologic replacement therapy, the luteal phase is prolonged (Fig. 5) and pseudopregnancy results unless therapy is terminated. However despite markedly elevated serum progesterone values with this mode of treatment, an endometrial biopsy is still not advanced with respect to the day of ovulation but is actually in phase. Several progestational agents and stilbestrol have been shown to be luteolytic when administered during the postovulatory phase of the cycle, causing a significant decline of serum progesterone values and shortening of the luteal phase. When administered in the dosages and manner described in the study, neither progesterone nor 17-hydroxyprogesterone caproate seems to have a luteolytic effect on corpus luteum function or to cause a significant change in the duration of the luteal phase.
472
February 15, 1974 Am. J. Obstet. Gynecol.
Aksel and Jones
REFERENCES
1. Johanson, E. D. B.: Acta Endocrinol. 68: 779, 1971. 2. Gore, B. Z., Caldwell, B. V., and Speroff, L.: J. Clin. Endocrinol. Metab. 36: 615, 1973. 3. Morris, J. M., .and van Wagenen, G.: AM. J. OBsTET. GvNECOL. 115: 101, 1973. 4. Klaiber, E. L., Henzl, M. R., and Lloyd, C. W.: J. Clin. Endocrinol. Metab. 36: 142, 1973. 5. Jones, G. S.: Luteal phase defect, in Behrman, S. J., and Kistner, R. W., editors: Progress
6. 7. 8. 9. 10.
in infertility, Boston, 1972, Little, Brown & Company. Patwardhan, V. V., and Lanthier, A.: Steroids 17: 219, 1971. Johanson, E. D. B.: Acta Obstet. Gynecol. Scand. 52: 37, 1973. Noyes, R. W., Hertig, A., and Rock, J.: Fertil. Steril. 1: 3, 1950. Midgely, A. R., Jr.: Endocrinology 79: 10, 1966. Yoshimi, T., and Lipsett, M. B.: Steroids 11: 527, 1968.