FERTILITY AND STERILITYt

VOL. 71, NO. 1, JANUARY 1999

Copyright © 1998 American Society for Reproductive Medicine
Published by Elsevier Science Inc.
INFERTILITY AND
Printed on acid-free paper in U.S.A.
IN VITRO FERTILIZATION
Administration of progesterone before
oocyte retrieval negatively affects the
implantation rate
Sae H. Sohn, M.D., Alan S. Penzias, M.D.,* Adelina M. Emmi, M.D.,†
Anil K. Dubey, Ph.D., Lawrence C. Layman, M.D.,‡ Richard H. Reindollar, M.D.,§ and
Alan H. DeCherney, M.D.\
Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Tufts University School of
Medicine, New England Medical Center, Boston, Massachusetts

Objective: To compare the efficacy of two clinically accepted methods of progesterone supplementation
during IVF.
Received March 18, 1997; Design: Prospective randomized trial.
revised and accepted
September 3, 1998. Setting: A university-based IVF program.
Presented at the 50th Patient(s): Three hundred fourteen stimulated IVF cycles between January 1993 and October 1994.
Annual Meeting of the Intervention(s): Patients were assigned to one of two luteal phase progesterone regimens by a random
American Fertility Society, permuted block design. In protocol A, 12.5 mg of IM progesterone was given 12 hours before oocyte retrieval;
San Antonio, Texas,
November 5–10, 1994.
in protocol B, 25 mg of IM progesterone was given on the day of oocyte retrieval.
Reprint requests and Main Outcome Measure(s): Clinical pregnancy.
present address: Sae H. Result(s): Patient demographic characteristics, including age, diagnosis, number of oocytes retrieved and
Sohn, M.D., Pacific Fertility fertilized, and number of embryos transferred, were not different between the two groups. There was no
Medical Center, 55 difference in the rate of cycle cancellation between the groups. One hundred forty ETs were performed in
Francisco Street, Suite
500, San Francisco,
patients assigned to protocol A and 142 in patients assigned to protocol B. The clinical pregnancy rate in group
California 94133 (FAX: 415- A was 12.9% compared with 24.6% in group B.
834-3099). Conclusion(s): The administration of progesterone before oocyte retrieval is associated with a lower
* Present address: pregnancy rate than the administration of progesterone after oocyte retrieval. (Fertil Sterilt 1999;71:11– 4.
Department of Obstetrics ©1998 by American Society for Reproductive Medicine.)
and Gynecology, Beth
Israel Hospital, Harvard
Key Words: In vitro fertilization, luteal support, progesterone, randomized clinical trial
University, Boston,
Massachusetts.
†
Present address: The Luteal phase support in stimulated IVF cy- the attendant risk of ovarian hyperstimulation
Fertility Center of York, cles is well accepted and widely used. Despite syndrome (OHSS), which limits its utility. For
York, Pennsylvania.
‡
its widespread use, there is no consensus with those patients who are given luteal support, the
Present address:
Department of Obstetrics regard to the ideal agent or protocol of admin- type of preparation used varies between paren-
and Gynecology, Division istration. The timing, dosage, and route of ad- teral, oral, vaginal suppository, and, more re-
of Reproductive ministration of hormones for luteal support has cently, vaginal gel formulations.
Endocrinology, University
of Chicago, Chicago, been the subject of numerous publications (1–
Illinois.
Pregnancy rates (PRs) do not appear to vary
6). Several investigators have reported the su-
§
Present address: appreciably despite the marked differences in
periority of hCG over progesterone (1, 2),
Department of Obstetrics these compounds and their routes of adminis-
and Gynecology, George whereas others have found no difference (3–5).
tration. We compared two clinically accepted
Washington University,
Washington, D.C. A recent meta-analysis by Soliman et al. (6) methods of progesterone administration that
\ suggested that both progesterone and hCG are differed primarily with regard to their timing
Present address:
Department of Obstetrics beneficial for routine luteal support in IVF. The and relative dose in relation to oocyte retrieval.
and Gynecology, University
of California, Los Angeles, analysis also revealed no difference in the In one of these regimens, progesterone was
Los Angeles, California. spontaneous abortion rate between the proges- given before oocyte retrieval; in the other, pro-
terone-supported and hCG-supported groups. gesterone was administered after oocyte re-
0015-0282/98/$19.00
PII S0015-0282(98)00404-X One major drawback to the use of luteal hCG is trieval to determine whether exposure of the

11
 TABLE 1 TABLE 2

Protocols for progesterone administration. Patient demographics, including primary diagnosis.

Protocol A (oocytes exposed in vivo to exogenous progesterone) Variable Protocol A Protocol B

12 hours before oocyte retrieval: 12.5 mg of progesterone IM
Evening of oocyte retrieval: 12.5 mg of progesterone IM Age (y) 35.3 6 0.4 35.8 6 0.4
Day after oocyte retrieval: 25 mg of progesterone IM Cause of infertility
Protocol B (no in vivo exposure of oocytes to exogenous progesterone) Oligomenorrhea 11 18
Evening of oocyte retrieval: 25 mg of progesterone IM Tubal disease 64 51
Day after oocyte retrieval: 25 mg of progesterone IM Endometriosis 28 33
Uterine factor 9 10
Male factor 24 21
Unexplained 22 23
oocyte to progesterone in vivo affects cycle outcome. No. of oocytes retrieved 10.4 6 0.5 9.7 6 0.5
No. of oocytes fertilized 5.1 6 0.3 4.9 6 0.3
No. of embryos transferred 3.5 6 0.1 3.4 6 0.1
MATERIALS AND METHODS Sperm concentration (raw) 3
106/mL 86.1 6 5.7 85.8 6 5.9
A total of 314 stimulated cycles of IVF performed be- Percent motility (raw) 56.3 6 1.7 54.6 6 1.8
tween January 1993 and October 1994 at the Tufts Univer- Morphology (strict, raw) 12.1 6 0.8 14.0 6 0.9
Sperm concentration (prepared)
sity School of Medicine were randomized by a permuted
3 106/mL 15.2 6 1.1 17.2 6 1.6
block design at the time of hCG administration. Ovulation Percent motility (prepared) 93.7 6 0.6 92.0 6 0.8
induction and oocyte retrieval were performed as previously Percent morphology (strict,
reported (7). prepared) 17.4 6 1.0 18.8 6 1.0

At the time of hCG administration, the patients were Note: All values are means 6 SEM unless otherwise indicated. All values
were not statistically significant.
randomized into two groups (Table 1). In protocol A, the
patients received an IM injection of 12.5 mg of progesterone
in oil 12 hours before oocyte retrieval. Another IM dose of tween the groups revealed no differences (primary diagnosis
12.5 mg was administered on the evening after oocyte re- only) (Table 2).
trieval. The dose of progesterone then was increased to 25 A total of 314 stimulated cycles were randomized during
mg the next day and continued daily until the date of the the study period, 158 to protocol A and 156 to protocol B.
pregnancy test, which was performed approximately 14 days There were a total of 176 patients in the study. Of the 314
after oocyte retrieval. cycles performed, 107 were initial cycles and 207 were
repeated cycles. Of the repeated cycles, 108 were in patients
In protocol B, no medication was administered after hCG
assigned to protocol A and 99 were in patients assigned to
administration until oocyte retrieval had been performed. In
protocol B. The difference was not statistically significant.
this group, 25 mg of progesterone was administered IM on
Success was defined as an ultrasound-documented clinical
the evening of the day of oocyte retrieval. Subsequently, 25
pregnancy. There were 18 clinical pregnancies in patients
mg of progesterone was given daily as described for protocol
assigned to protocol A and 35 in patients assigned to proto-
A. In both groups, progesterone supplementation was con-
col B. The clinical PR per ET for protocol A was 12.9%,
tinued through the first trimester. The main outcome measure
compared with 24.6% for protocol B (P 5 .011) (Table 3).
was the presence of a clinical pregnancy as documented by
pelvic ultrasound examination. Before this study, our group
used both these protocols. For this study, randomization was DISCUSSION
performed in accordance with the Helsinki declaration. Despite universal support for the use of luteal phase
x analysis and the Student’s unpaired t-test were used as
2 supplementation in IVF, the ideal agent, dose, and route of
appropriate. P,.05 was defined as statistically significant.
TABLE 3
RESULTS
Comparison of protocol A with protocol B.
Patient demographic characteristics, including age, pri-
mary diagnosis, number of oocytes retrieved and fertilized, Protocol A Protocol B Significance*
and number of embryos transferred, were not different be-
Cycles initiated 158 156 NS
tween the two groups. In addition, the male partner’s sperm Transfers performed 140 142 NS
concentration, motility, and morphology before and after Cycles cancelled 18 14 NS
sperm preparation were not different between the groups Clinical pregnancy rate 12.9% 24.6% P 5 0.011
(Table 2). x2 analysis of the distribution of diagnoses be- * Chi squared analysis.

12 Sohn et al. Progesterone supplementation in IVF Vol. 71, No. 1, January 1999
administration remain elusive. Although hCG has proven
effective as a means of supporting the endometrium after
IVF, it has the distinct disadvantage of carrying an increased
risk for the development of OHSS (8). This necessarily
limits the number of patients for whom this therapy can be
prescribed.
The alternate agent available for luteal supplementation is
progesterone, which has no such restrictions. Progesterone is
advantageous in that it can be administered by any of three
common routes: IM injection, vaginal suppository or gel, or
oral micronized form. Comparative studies of different
routes of progesterone administration have been performed.
Smitz et al. (9) compared IM progesterone administration
(50 mg/d) with vaginal administration (600 mg/d) in 262
women undergoing assisted reproductive techniques. In both
protocols, progesterone was administered at least 12 hours
before oocyte retrieval. No difference in PRs was seen
between the groups.
Miles et al. (10) evaluated the pharmacokinetics and
endometrial tissue levels of progesterone after IM or vaginal
administration. The subjects in their study received 50 mg of
IM progesterone twice daily or 200 mg of micronized pro-
gesterone vaginally four times daily. They observed that
endometrial progesterone concentrations were higher with
vaginal administration, whereas IM progesterone adminis-
tration yielded higher serum levels. In the former study, all
patients received progesterone before oocyte retrieval,
whereas the latter study was not intended to evaluate the
effect of progesterone administration on cycle outcome.
We undertook the current study to evaluate the timing of
progesterone administration with regard to the time of oo-
cyte retrieval. Before this study was begun, clinicians within
our group prescribed progesterone supplementation using
either protocol A or protocol B according to personal bias
from prior training or loosely following evaluation of prior
ovarian stimulation cycles. A search of the literature with the
use of MEDLINE revealed no prospective, randomized clin-
ical trials that compared the administration of progesterone
before and after oocyte retrieval.
In the current study, we found that prospective random-
ization of patients yielded similar groups as evidenced by the
lack of statistically significant differences in demographic
data, distribution of diagnoses, initial or repeated cycles, and
outcomes with regard to number of oocytes retrieved and
fertilized and number of embryos transferred. In addition,
the male partners’ semen parameters before and after prep-
aration were not different. The only statistically significant
difference was observed in relation to the achievement of
clinical pregnancy. Patients assigned to protocol B had
nearly double the clinical PR of patients assigned to protocol
A.
Pregnancy rates for patients given IM or vaginal proges-
terone before oocyte retrieval in the study by Smitz et al.
FERTILITY & STERILITYt
were higher than the rates reported for both our groups. We
believe that this likely reflects differences in patient demo-
graphics. For example, our study included all age groups; the
mean age of our patients was 35 years and the mean age of
the patients in the study by Smitz et al. was 32 years.
Reports that characterize IVF cycle outcome on the basis
of progesterone levels before oocyte retrieval primarily ad-
dress the issue of premature luteinization. Silverberg et al.
(11) reported that a serum progesterone level of $0.9 ng/mL
on the day of hCG administration was associated with a
diminished PR in IVF cycles stimulated with leuprolide
acetate and hMG. However, in a subsequent publication by
the same investigators (12), they reported that when the PRs
from frozen embryos obtained from cycles in which the
progesterone level was .0.9 ng/mL were compared with
those from embryos obtained from cycles in which the
progesterone level was ,0.9 ng/mL, no difference was ob-
served.
Although patients who received progesterone only after
oocyte retrieval had a significantly higher PR, the mecha-
nism of this effect remains unclear. Another factor that is
critically involved in pregnancy outcome is the endometrium
(13). Zarutskie et al. (14) evaluated 72 stimulated IVF cycles
in which the progesterone levels were ,12 ng/mL on the day
before ET. Of those women, 42 were started on progesterone
supplementation 1 day before ET and 30 were started on
progesterone after ET. The investigators reported that they
were unable to improve clinical outcome by earlier proges-
terone supplementation.
Chang et al. (15) evaluated immediate versus delayed
progesterone supplementation after GIFT. They studied a
total of 86 GIFT cycles, in 42 of which patients received 25
mg of IM progesterone beginning on the day of the GIFT
procedure that was increased to 50 mg daily 2 days later, and
in 44 of which patients received progesterone supplementa-
tion 4 days after GIFT according to the same dosing sched-
ule. The investigators reported no difference in PRs between
the two groups.
Whether the difference in PRs seen in our study reflects
the effect of exogenous progesterone on an oocyte before
ovum capture or an endometrial effect is unclear. However,
for patients with the demographic characteristics of those in
our study, providing progesterone supplementation before
oocyte retrieval significantly adversely affected outcome.
Because of the recent arrival of new forms of progester-
one for use in luteal support, a great deal of interest has again
been focused on this aspect of assisted reproductive technol-
ogy. Despite the fact that PRs are much higher today than at
the time of our study, the dramatic difference associated with
the timing of progesterone administration remains significant.
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Vol. 71, No. 1, January 1999