Current Development
Luteal phase deficiency: Effect of treatment on pregnancy rates Lisa M. Karamardian, MD, and David A. Grimes, MD Los Angeles, California Luteal phase deficiency is thought to be a cause of female infertility. Nevertheless, little agreement exists concerning either its diagnosis or its treatment. To address the latter question, we reviewed the English literature and examined the effect of treatment on pregnancy rates. One randomized controlled trial found a statistically insignificant benefit of treatment with progesterone suppositories or oral dehydrogesterone versus no treatment (relative risk 1.9; 95% confidence interval 0.4 to 8.1). Three other comparative studies also showed no statistically significant benefit. Case-series reports (before-after studies) claiming benefit failed to account for the effect of regression to the mean. The benefit of treatment for luteal phase deficiency has not been established. Uniform case definitions and randomized controlled trials of adequate power are needed to resolve this problem. (AM J OSSTET GYNECOL 1992;167:1391-8.)
Key words: Luteal phase deficiency, infertility, pregnancy, progesterone, pregnancy com plications Luteal phase deficiency is widely held to be a cause of female infertility.lo, Estimates of the prevalence of luteal phase deficiency as a cause of infertility range from 3.5% to 20%.' It is even more commonly seen in women with recurrent abortions (23% to 60%).' In the most recent National Survey of Family Growth 6 about 4.9 million women of reproductive age had an impaired ability to have children. If then 3% to 4% of women had luteal phase deficiency as the cause, L7 150,000 to 200,000 women may have this condition in the United States alone. In spite of this potentially large burden, both the diagnosis and the treatment of luteal phase deficiency remain unclear. Although much has been written on the diagnosis of luteal phase deficiency,"oll there is little agreement on diagnostic criteria. A recent reviews concluded that whereas the endometrial biopsy has not been validated as a diagnostic test, it remains the "best" current method for diagnosing luteal phase deficiency when the "standard" guidelines are used. Other methods include luteal phase duration, basal body temperature charts, serum progesterone measurements, ultrasonographic determination of follicle size, and serum prolactin measurements. From the Department of Obstetrics and Gynecology, University of Southern California School of Medicine. Reprint requests: Dr. David A. Grimes, Department of Obstetrics and Gynecology, Women's Hospital, 1240 North Mission Road, Los Angeles, CA 90033.
611140253
The question of therapy is equally unsettled. Furthermore, the choice of therapy and evaluation of results have received far less attention in the literature than has diagnosis.' The most popular treatment is progesterone supplementation, as either a vaginal suppository or an intramuscular ilBection. Other treatments include clomiphene citrate,I2 16 follicle-stimulating hormone,I7 I" bromocriptine,20 24 human chorionic gonadotropin, IS. 20 gonadotropin-releasing hormone pulse therapy,"' human menopausal gonadotropins,26 epimestrol,27 monoamine oxidase inhibitors,2S phenytoin,28 and tamoxifen. 29 Few studies, however, have appropriately evaluated the effectiveness of therapy. Because of the scope of this problem and the lack of consensus concerning management, we conducted this review to evaluate the results of treatment. 0
0
0
Material and methods We conducted a MEDLINE search of publications in English from January 1966 to July 1991 related to luteal phase deficiency with the medical subject headings "luteal phase," "pregnancy," "progesterone," and "pregnancy complications." We sought further publications by searching through reference lists, review articles, and textbook chapters and by consultations with infertility experts. To be included in this analysis, each study must have provided a case definition of luteal phase deficiency and sufficient data to calculate pregnancy rates. We limited this analysis of treatment efficacy to pregnancy rates, because changes in endometrial his1391
1392 Karamardian and Grimes
tologic type or hormone levels are only indirect measures of treatment efficacy. There are a number of studies showing statistically significant changes in endometrial biopsy specimens,,0.32; however, pregnancy is the ultimate outcome of interest and also the only one of concern to the couple. We categorized each report by study design and then grouped these publications by type of treatment. Each randomized controlled trial was analyzed for methodologic soundness with standard criteria33-"5 for such trials. Relative risks with 95% confidence intervals and the power of each study to identify differences were calculated according to standard methods. If a 95% confidence interval overlaps 1.0, then the difference is not statistically significant at the 0.05 level. The X2 or Fisher's exact test was used as appropriate. We also determined the 95% confidence limits for pregnancy rates in case-series reports (before-after studies) by means of the binomial distribution. 36 For the analysis of comparative studies we defined a case of luteal phase deficiency as including a patient with two endometrial biopsies (performed in the luteal phase) displaying at least a 2-day lag between the histologic pattern and that expected for the biopsy day of the menstrual cycle. We accepted a less-stringent definition of luteal phase deficiency for the case-series reports. Basal body temperature rises of < 12 days, abnormally low serum progesterone values in the luteal phase, or any combination of the above-mentioned diagnostic methods were accepted for inclusion. A different case definition was used for the case-series reports to include a larger number of reports and to accommodate the variability in definition that exists in the literature. Results
Only four comparative studies met our criteria for inclusion. These included one randomized controlled trial, one nonrandomized study that mixed treatments, and two retrospective cohort studies (Table I). Investigators in Barcelona 37 randomized 44 patients with luteal phase deficiency to 3 months of treatment with either progesterone vaginal suppositories (25 mg twice daily), dehydrogesterone (20 mg orally daily, starting 3 days after the basal body temperature rise and continuing for 10 days), or no treatment. The pregnancy rates associated with both treatments (each 31 %) were higher than that without treatment (17%), but this difference was not statistically significant (Fisher's exact test, two-tailed p ~ 0.66). However, the power of this trial to detect important differences in pregnancy rates was very low. For example, to show that progesterone treatment was associated with a 50% higher pregnancy rate than dehydrogesterone treatment (a = 0.05,
November 1992 Am J Obstet Gynecol
power 80%, and equal numbers of subjects in both groups), a total of 334 patients would have been required (Table II). To show a 50% lower pregnancy rate, the corresponding number would be 256 su~jects. Another investigator 3S in Rochester, New York, began a "randomized" trial but then mixed the exposures in the analysis. In this analysis, he compared progesterone vaginal suppositories (25 mg twice daily) with oral clomiphene citrate (50 mg daily for 5 days starting on cycle day 5). The clomiphene dose was increased to a maximum of 150 mg daily in subsequent cycles if correction of the endometrial biopsy specimen did not occur. Pregnancy rates were not significantly different (Table I). Moreover, to show a statistically significant difference of this magnitude (a = 0.05, power 80%, and equal numbers of subjects in both groups), 778 subjects would be required (Table II). Two groups of investigators compared progesterone suppositories with clomiphene citrate in retrospective cohort studies'" 39 The group in Baltimore 39 studied 65 patients. Thirty-five received progesterone suppositories (25 mg twice daily), and 30 received oral clomiphene citrate (50 mg twice daily for 5 days starting on cycle day 2, with subsequent increases to 100 mg daily). Life-table analysis showed that pregnancy rates at 12 months were not significantly different (89% vs 77%, respectively) (Table I). However, only those patients whose endometrial biopsy specimens after treatment were "in phase" were included in the study; four subjects having received clomiphene were excluded by this criterion. To demonstrate a significant difference of this size (with the same assumptions as before), a total of 338 subjects would be required. The group' in Nashville compared progesterone suppositories (54 patients) versus clomiphene citrate (6 patients). These investigators also treated seven patients with a combination of agents; eight patients had no treatment. The pregnancy rate in women having received progesterone was 43% versus 33% in those having received clomiphene (Table I). The rate with combined treatment was 71 %, whereas with no treatment the rate was 38%. As shown in Table II, substantially larger sample sizes would be necessary to demonstrate the superiority of anyone of these treatments over the others. Numerous descriptive studies of the treatment ofluteal phase deficiency have been published 12·25,10-44 (Table Ill). All have used a "before-after" design, except for one study,I6 which was deemed a randomized controlled trial. However, this study provided insufficient detail to allow classification as a randomized controlled trial, and it failed to meet the reporting requirements for such a study.31 Treatment with progestational agents was common;
Luteal phase deficiency
Volume 167 Number 5
1393
Table I. Relative risks of pregnancy in comparative studies of treatment of luteal phase deficiency Author
Type of study
Balasch et al.,'" 1982
Randomized controlled trial
No. of subjects
Method of diagnosis
44
Two endometrial biopsies
Huang," 1986
Nonrandomized trial
82
Two endometrial biopsies (2:2day lag)
Murray et al.,"" 1989
Retrospective cohort study
65
Two endometrial biopsies (>2day lag)
Wentz et al.,' 1984
Retrospective cohort study
79
Variable
Treatment Comparison
95%
Relative risk*
Confidence interval
1.9
0.4-8.1
1.0
0.4-2.8
0.7
0.4-1.3
0.9
0.7-1.1
l.l
0.4-2.9
0.9
0.2-3.8
1.9
0.7-5.2
1.3
0.4-4.1
0.6
0.3-1.1
0.5
0.1-1.6
Progesterone suppository 25 mg b.i.d. vs no treatment Progesterone suppository 25 mg b.i.d. vs dehydrogesterone Clomiphene citrate 50 mg q.d. vs progesterone suppository 25 mg b.i.d. Clomiphene citrate 50 mg q.d. vs progesterone suppository 25 mgb.i.d. Progesterone suppository vs no treatment Clomiphene citrate vs no treatment Progesterone suppository and clomiphene citrate vs no treatment Progesterone suppository vs clomiphene citrate Progesterone suppository vs progesterone suppository and clomiphene citrate Clomiphene citrate vs progesterone suppository and clomiphene citrate
*Based on an index pregnancy rate for the second treatment in each comparison.
Table II. Actual versus required sample sizes in comparative studies of treatment of luteal phase deficiency Pregnancy rate Author
Treatment A (1)
I
Sample size* Treat/llent B (2)
Required (3)
I
Actual (4)
I
Diffetence
Percentage of required size (413)
(3 - 4)
Progesterone suppository: 31 %
No treatment: 17%
318
28
290
9
Progesterone suppository: 31 %
Dehydrogesterone: 31 %
Clomiphene citrate: 21 %
302 224 696
II
Murrayet al.,"" 1989 Wentz et aI., I 1984
Clomiphene citrate: 77%
Progesterone suppository: 30% Progesterone suppository: 89% No treatment: 38% No treatment: 38% No treatment: 38%
32 32 82
10 13
Huang," 1986
334t 256:j: 778 338
65
273
19
3104 2952 80
62 14 15
3042 2938 65
2 0.5 19
776
60
716
8
1I0
61
49
55
62
13
49
21
Balasch et al.,"71982
Progesterone suppository: 43% Clomiphene citrate: 33% Progesterone suppository and clomiphene citrate: 71 % Progesterone suppository: 43% Progesterone suppository: 43% Clomiphene citrate: 33%
Clomiphene citrate: 33% Progesterone suppository and clomiphene citrate: 71 % Progesterone suppository and clomiphene citrate: 71 %
*With Ol = 0.05, power of 80%, and equal numbers of subjects in both treatment groups. tNumber of subjects necessary to show a 50% increase in rate. :j:Number of subjects necessary to show a 50% reduction in rate.
1394 Karamardian and Grimes
November 1992 Am J Obstet Gynecol
Table III. Descriptive studies of treatment of luteal phase deficiency
Aut/lOr
No. of Type of study subjects Method of diagnosis
Treatment with progestational agents
Check and Adelson."o 1987
Before-after design
50
Rosenberg et al., 41 1980
Before-after design
32
Soules et aI., 42 1977 Before-after design
Treatment with clomiphene citrate
70
55-82
35/50 Patients conceived within 6 mo and 29/50 had normal babies; 15% abortion rate
70
39-91
16
Two endometrial Progesterone suppository 25 mg biopsies (>2day lag) b.i.d or progesterone intramuscularly 12.5 mg q.d.
50
25-75
9/13 Patients with no other infertility factors conceived within 6 mo and 7/ 13 carried to term 8/16 Patients conceived
Two endometrial Clomiphene citrate biopsies (;0:350 mg q.d. (cycle day lag), or one days 5-9) endometrial biopsy and serum progesterone Serum progester- Clomiphene citrate one 4-14 ng/ml 50 mg q.d. (cycle days 3-7) BBT rise :;;10 Clomiphene citrate 50 mg q.d. (cycle dayst days 5-9) Two endometrial Various doses of biopsies (;0:2clomiphene ciday lag) trate Two endometrial Clomiphene citrate biopsies (;0:2100 mg q.d. or placebo (cycle day lag):j: days 5-7)
39
24-56
45
33-57
Before-after design
41
Hammond and Talbert,13 1982
Before-after design
69
QuagliareJIo and Weiss,14 1979
Before-after design
8
Garcia et aI., 15 1977 Before-after design
26
Echt et al.,16 1969
19
Treatment with FSH
Comments
Two endometrial Progesterone suppository 25 mg biopsies (>2b.i.d. day lag) and follicle between 18 and 24 mm in diameter Two endometrial Progesterone supbiopsies (;0:2pository 25 mg b.i.d. day lag)
Downs and Gibson,12 1983
Randomized controlled trial (?)
Treatment
Pregnancy 95% rate per Confidence 100 interval*
88
31/69 Patients conceived; 23% abortion rate 47-100 7/8 Patients conceived
19
7-39
21
6-46
Balasch et al.,17 1990 Before-after design, singleblind
15
Two endometrial "Pure" FSH 150 IV biopsies (;0:2intramuscuday lag), within larly x 4 days 1-3 days before (cycle days 1-4) menses
40
5-85
Minassian et al.,18 1988
Before-after design
18
39
17-64
Huang et al.,19 1984 Before-after design
15
One endometrial Human urinary biopsy (>2-day FSH 75 mIU intramusculag) and BBT lariy x 5 days rise nt> trt>r1tmt>nt wt>rt> 1C}o/,; to RRo/,; Trt>r1t-
16/41 Patients conceived and 13/41 had normal babies
5/26 Patients conceived and 3 miscarried 4/19 Patients conceived; one had ectopic pregnancy and one baby was born with multiple congenital anomalies 2/5 Patients without any other infertility factors except luteal phase deficiency conceived and had normal babies 7/18 Patients conceived and had normal babies
5115 Patients conceived; 3/15 carried to term and had normal babies
studies l7 . 19 was associated with pregnancy rates ranging from 33% to 40%. Treatment with bromocriptine 2024 w,,~ r1~~orirltt>rl with rrltt>~ from 00/,; to h~o/r, HiCThpr nrpCT-
Luteal phase deficiency
Volume 167 Number 5
1395
Table III-Cont'd
Author
No. of Type of study subjects Method of diagnosis
Treatment
Pregnancy 95% mte per Confidence interval* 100
Treatment with bromocriptine in hyperprolactinemic and euprolactinemic luteal phase deficiency Borenstein et al.;o Before-after 41 BBT rise 25 hMG and heG nglml Andersen et al.,2! Before-after 12 BBT rise :5 12Bromocriptine 2.5 0 day, progester1979 design mgb.i.d. one peak 2-day lag) Del Pozo et al.,22 Before-after 8 BBT rise
Luteal phase deficiency: Effect of treatment on pregnancy rates Lisa M. Karamardian, MD, and David A. Grimes, MD Los Angeles, California Luteal phase deficiency is thought to be a cause of female infertility. Nevertheless, little agreement exists concerning either its diagnosis or its treatment. To address the latter question, we reviewed the English literature and examined the effect of treatment on pregnancy rates. One randomized controlled trial found a statistically insignificant benefit of treatment with progesterone suppositories or oral dehydrogesterone versus no treatment (relative risk 1.9; 95% confidence interval 0.4 to 8.1). Three other comparative studies also showed no statistically significant benefit. Case-series reports (before-after studies) claiming benefit failed to account for the effect of regression to the mean. The benefit of treatment for luteal phase deficiency has not been established. Uniform case definitions and randomized controlled trials of adequate power are needed to resolve this problem. (AM J OSSTET GYNECOL 1992;167:1391-8.)
Key words: Luteal phase deficiency, infertility, pregnancy, progesterone, pregnancy com plications Luteal phase deficiency is widely held to be a cause of female infertility.lo, Estimates of the prevalence of luteal phase deficiency as a cause of infertility range from 3.5% to 20%.' It is even more commonly seen in women with recurrent abortions (23% to 60%).' In the most recent National Survey of Family Growth 6 about 4.9 million women of reproductive age had an impaired ability to have children. If then 3% to 4% of women had luteal phase deficiency as the cause, L7 150,000 to 200,000 women may have this condition in the United States alone. In spite of this potentially large burden, both the diagnosis and the treatment of luteal phase deficiency remain unclear. Although much has been written on the diagnosis of luteal phase deficiency,"oll there is little agreement on diagnostic criteria. A recent reviews concluded that whereas the endometrial biopsy has not been validated as a diagnostic test, it remains the "best" current method for diagnosing luteal phase deficiency when the "standard" guidelines are used. Other methods include luteal phase duration, basal body temperature charts, serum progesterone measurements, ultrasonographic determination of follicle size, and serum prolactin measurements. From the Department of Obstetrics and Gynecology, University of Southern California School of Medicine. Reprint requests: Dr. David A. Grimes, Department of Obstetrics and Gynecology, Women's Hospital, 1240 North Mission Road, Los Angeles, CA 90033.
611140253
The question of therapy is equally unsettled. Furthermore, the choice of therapy and evaluation of results have received far less attention in the literature than has diagnosis.' The most popular treatment is progesterone supplementation, as either a vaginal suppository or an intramuscular ilBection. Other treatments include clomiphene citrate,I2 16 follicle-stimulating hormone,I7 I" bromocriptine,20 24 human chorionic gonadotropin, IS. 20 gonadotropin-releasing hormone pulse therapy,"' human menopausal gonadotropins,26 epimestrol,27 monoamine oxidase inhibitors,2S phenytoin,28 and tamoxifen. 29 Few studies, however, have appropriately evaluated the effectiveness of therapy. Because of the scope of this problem and the lack of consensus concerning management, we conducted this review to evaluate the results of treatment. 0
0
0
Material and methods We conducted a MEDLINE search of publications in English from January 1966 to July 1991 related to luteal phase deficiency with the medical subject headings "luteal phase," "pregnancy," "progesterone," and "pregnancy complications." We sought further publications by searching through reference lists, review articles, and textbook chapters and by consultations with infertility experts. To be included in this analysis, each study must have provided a case definition of luteal phase deficiency and sufficient data to calculate pregnancy rates. We limited this analysis of treatment efficacy to pregnancy rates, because changes in endometrial his1391
1392 Karamardian and Grimes
tologic type or hormone levels are only indirect measures of treatment efficacy. There are a number of studies showing statistically significant changes in endometrial biopsy specimens,,0.32; however, pregnancy is the ultimate outcome of interest and also the only one of concern to the couple. We categorized each report by study design and then grouped these publications by type of treatment. Each randomized controlled trial was analyzed for methodologic soundness with standard criteria33-"5 for such trials. Relative risks with 95% confidence intervals and the power of each study to identify differences were calculated according to standard methods. If a 95% confidence interval overlaps 1.0, then the difference is not statistically significant at the 0.05 level. The X2 or Fisher's exact test was used as appropriate. We also determined the 95% confidence limits for pregnancy rates in case-series reports (before-after studies) by means of the binomial distribution. 36 For the analysis of comparative studies we defined a case of luteal phase deficiency as including a patient with two endometrial biopsies (performed in the luteal phase) displaying at least a 2-day lag between the histologic pattern and that expected for the biopsy day of the menstrual cycle. We accepted a less-stringent definition of luteal phase deficiency for the case-series reports. Basal body temperature rises of < 12 days, abnormally low serum progesterone values in the luteal phase, or any combination of the above-mentioned diagnostic methods were accepted for inclusion. A different case definition was used for the case-series reports to include a larger number of reports and to accommodate the variability in definition that exists in the literature. Results
Only four comparative studies met our criteria for inclusion. These included one randomized controlled trial, one nonrandomized study that mixed treatments, and two retrospective cohort studies (Table I). Investigators in Barcelona 37 randomized 44 patients with luteal phase deficiency to 3 months of treatment with either progesterone vaginal suppositories (25 mg twice daily), dehydrogesterone (20 mg orally daily, starting 3 days after the basal body temperature rise and continuing for 10 days), or no treatment. The pregnancy rates associated with both treatments (each 31 %) were higher than that without treatment (17%), but this difference was not statistically significant (Fisher's exact test, two-tailed p ~ 0.66). However, the power of this trial to detect important differences in pregnancy rates was very low. For example, to show that progesterone treatment was associated with a 50% higher pregnancy rate than dehydrogesterone treatment (a = 0.05,
November 1992 Am J Obstet Gynecol
power 80%, and equal numbers of subjects in both groups), a total of 334 patients would have been required (Table II). To show a 50% lower pregnancy rate, the corresponding number would be 256 su~jects. Another investigator 3S in Rochester, New York, began a "randomized" trial but then mixed the exposures in the analysis. In this analysis, he compared progesterone vaginal suppositories (25 mg twice daily) with oral clomiphene citrate (50 mg daily for 5 days starting on cycle day 5). The clomiphene dose was increased to a maximum of 150 mg daily in subsequent cycles if correction of the endometrial biopsy specimen did not occur. Pregnancy rates were not significantly different (Table I). Moreover, to show a statistically significant difference of this magnitude (a = 0.05, power 80%, and equal numbers of subjects in both groups), 778 subjects would be required (Table II). Two groups of investigators compared progesterone suppositories with clomiphene citrate in retrospective cohort studies'" 39 The group in Baltimore 39 studied 65 patients. Thirty-five received progesterone suppositories (25 mg twice daily), and 30 received oral clomiphene citrate (50 mg twice daily for 5 days starting on cycle day 2, with subsequent increases to 100 mg daily). Life-table analysis showed that pregnancy rates at 12 months were not significantly different (89% vs 77%, respectively) (Table I). However, only those patients whose endometrial biopsy specimens after treatment were "in phase" were included in the study; four subjects having received clomiphene were excluded by this criterion. To demonstrate a significant difference of this size (with the same assumptions as before), a total of 338 subjects would be required. The group' in Nashville compared progesterone suppositories (54 patients) versus clomiphene citrate (6 patients). These investigators also treated seven patients with a combination of agents; eight patients had no treatment. The pregnancy rate in women having received progesterone was 43% versus 33% in those having received clomiphene (Table I). The rate with combined treatment was 71 %, whereas with no treatment the rate was 38%. As shown in Table II, substantially larger sample sizes would be necessary to demonstrate the superiority of anyone of these treatments over the others. Numerous descriptive studies of the treatment ofluteal phase deficiency have been published 12·25,10-44 (Table Ill). All have used a "before-after" design, except for one study,I6 which was deemed a randomized controlled trial. However, this study provided insufficient detail to allow classification as a randomized controlled trial, and it failed to meet the reporting requirements for such a study.31 Treatment with progestational agents was common;
Luteal phase deficiency
Volume 167 Number 5
1393
Table I. Relative risks of pregnancy in comparative studies of treatment of luteal phase deficiency Author
Type of study
Balasch et al.,'" 1982
Randomized controlled trial
No. of subjects
Method of diagnosis
44
Two endometrial biopsies
Huang," 1986
Nonrandomized trial
82
Two endometrial biopsies (2:2day lag)
Murray et al.,"" 1989
Retrospective cohort study
65
Two endometrial biopsies (>2day lag)
Wentz et al.,' 1984
Retrospective cohort study
79
Variable
Treatment Comparison
95%
Relative risk*
Confidence interval
1.9
0.4-8.1
1.0
0.4-2.8
0.7
0.4-1.3
0.9
0.7-1.1
l.l
0.4-2.9
0.9
0.2-3.8
1.9
0.7-5.2
1.3
0.4-4.1
0.6
0.3-1.1
0.5
0.1-1.6
Progesterone suppository 25 mg b.i.d. vs no treatment Progesterone suppository 25 mg b.i.d. vs dehydrogesterone Clomiphene citrate 50 mg q.d. vs progesterone suppository 25 mg b.i.d. Clomiphene citrate 50 mg q.d. vs progesterone suppository 25 mgb.i.d. Progesterone suppository vs no treatment Clomiphene citrate vs no treatment Progesterone suppository and clomiphene citrate vs no treatment Progesterone suppository vs clomiphene citrate Progesterone suppository vs progesterone suppository and clomiphene citrate Clomiphene citrate vs progesterone suppository and clomiphene citrate
*Based on an index pregnancy rate for the second treatment in each comparison.
Table II. Actual versus required sample sizes in comparative studies of treatment of luteal phase deficiency Pregnancy rate Author
Treatment A (1)
I
Sample size* Treat/llent B (2)
Required (3)
I
Actual (4)
I
Diffetence
Percentage of required size (413)
(3 - 4)
Progesterone suppository: 31 %
No treatment: 17%
318
28
290
9
Progesterone suppository: 31 %
Dehydrogesterone: 31 %
Clomiphene citrate: 21 %
302 224 696
II
Murrayet al.,"" 1989 Wentz et aI., I 1984
Clomiphene citrate: 77%
Progesterone suppository: 30% Progesterone suppository: 89% No treatment: 38% No treatment: 38% No treatment: 38%
32 32 82
10 13
Huang," 1986
334t 256:j: 778 338
65
273
19
3104 2952 80
62 14 15
3042 2938 65
2 0.5 19
776
60
716
8
1I0
61
49
55
62
13
49
21
Balasch et al.,"71982
Progesterone suppository: 43% Clomiphene citrate: 33% Progesterone suppository and clomiphene citrate: 71 % Progesterone suppository: 43% Progesterone suppository: 43% Clomiphene citrate: 33%
Clomiphene citrate: 33% Progesterone suppository and clomiphene citrate: 71 % Progesterone suppository and clomiphene citrate: 71 %
*With Ol = 0.05, power of 80%, and equal numbers of subjects in both treatment groups. tNumber of subjects necessary to show a 50% increase in rate. :j:Number of subjects necessary to show a 50% reduction in rate.
1394 Karamardian and Grimes
November 1992 Am J Obstet Gynecol
Table III. Descriptive studies of treatment of luteal phase deficiency
Aut/lOr
No. of Type of study subjects Method of diagnosis
Treatment with progestational agents
Check and Adelson."o 1987
Before-after design
50
Rosenberg et al., 41 1980
Before-after design
32
Soules et aI., 42 1977 Before-after design
Treatment with clomiphene citrate
70
55-82
35/50 Patients conceived within 6 mo and 29/50 had normal babies; 15% abortion rate
70
39-91
16
Two endometrial Progesterone suppository 25 mg biopsies (>2day lag) b.i.d or progesterone intramuscularly 12.5 mg q.d.
50
25-75
9/13 Patients with no other infertility factors conceived within 6 mo and 7/ 13 carried to term 8/16 Patients conceived
Two endometrial Clomiphene citrate biopsies (;0:350 mg q.d. (cycle day lag), or one days 5-9) endometrial biopsy and serum progesterone Serum progester- Clomiphene citrate one 4-14 ng/ml 50 mg q.d. (cycle days 3-7) BBT rise :;;10 Clomiphene citrate 50 mg q.d. (cycle dayst days 5-9) Two endometrial Various doses of biopsies (;0:2clomiphene ciday lag) trate Two endometrial Clomiphene citrate biopsies (;0:2100 mg q.d. or placebo (cycle day lag):j: days 5-7)
39
24-56
45
33-57
Before-after design
41
Hammond and Talbert,13 1982
Before-after design
69
QuagliareJIo and Weiss,14 1979
Before-after design
8
Garcia et aI., 15 1977 Before-after design
26
Echt et al.,16 1969
19
Treatment with FSH
Comments
Two endometrial Progesterone suppository 25 mg biopsies (>2b.i.d. day lag) and follicle between 18 and 24 mm in diameter Two endometrial Progesterone supbiopsies (;0:2pository 25 mg b.i.d. day lag)
Downs and Gibson,12 1983
Randomized controlled trial (?)
Treatment
Pregnancy 95% rate per Confidence 100 interval*
88
31/69 Patients conceived; 23% abortion rate 47-100 7/8 Patients conceived
19
7-39
21
6-46
Balasch et al.,17 1990 Before-after design, singleblind
15
Two endometrial "Pure" FSH 150 IV biopsies (;0:2intramuscuday lag), within larly x 4 days 1-3 days before (cycle days 1-4) menses
40
5-85
Minassian et al.,18 1988
Before-after design
18
39
17-64
Huang et al.,19 1984 Before-after design
15
One endometrial Human urinary biopsy (>2-day FSH 75 mIU intramusculag) and BBT lariy x 5 days rise nt> trt>r1tmt>nt wt>rt> 1C}o/,; to RRo/,; Trt>r1t-
16/41 Patients conceived and 13/41 had normal babies
5/26 Patients conceived and 3 miscarried 4/19 Patients conceived; one had ectopic pregnancy and one baby was born with multiple congenital anomalies 2/5 Patients without any other infertility factors except luteal phase deficiency conceived and had normal babies 7/18 Patients conceived and had normal babies
5115 Patients conceived; 3/15 carried to term and had normal babies
studies l7 . 19 was associated with pregnancy rates ranging from 33% to 40%. Treatment with bromocriptine 2024 w,,~ r1~~orirltt>rl with rrltt>~ from 00/,; to h~o/r, HiCThpr nrpCT-
Luteal phase deficiency
Volume 167 Number 5
1395
Table III-Cont'd
Author
No. of Type of study subjects Method of diagnosis
Treatment
Pregnancy 95% mte per Confidence interval* 100
Treatment with bromocriptine in hyperprolactinemic and euprolactinemic luteal phase deficiency Borenstein et al.;o Before-after 41 BBT rise 25 hMG and heG nglml Andersen et al.,2! Before-after 12 BBT rise :5 12Bromocriptine 2.5 0 day, progester1979 design mgb.i.d. one peak 2-day lag) Del Pozo et al.,22 Before-after 8 BBT rise
