CME INFORMATION

Examining the Evidence: Progesterone Supplementation During Fresh

and Frozen Embryo Transfer

CME Objectives

After completing this educational activity, you should be able to:

• Demonstrate a clinical understanding of the rationale for progesterone supplementation after fresh and
frozen-embryo transfer;
• Distinguish between progesterone formulation choices and its impact on efficacy;
• Recognize the role of patient preference on the selection of progesterone formulation (i.e. convenience,
tolerability, compliance).

Statement of Need and Purpose

Assisted reproductive technologies have evolved over time such that frozen-thawed embryo transfer (FET) is
now a frequently performed and successful option. During the last decade, cryopreservation techniques have
received considerable interest, whereas interest in the priming and preparation of the endometrium prior to and
after embryo transfer was more limited. The available evidence, largely based on fresh embryo transfer data,
for the rationale and timing of progesterone supplementation as well as an understanding of the differences
among progesterone formulations with respect to efficacy, optimum use, and patient preference is worth
examining. A Summit was convened to critically review the literature on progesterone supplementation in
assisted reproductive transfer cycles in general, and after FET and to provide guidance on the most clinically
relevant issues. Utilizing a unique and innovative consensus-building learning model to examine the current
evidence, Summit faculty drafted potential summit statements prior to the meeting, completed an extensive
literature search, and created a presentation based on this research. At the conclusion of their discussion,
the entire faculty developed final summit statements, evaluating the strength of the evidence supporting
each statement, and rating their level of support for each statement. The clinically relevant topical areas
were the rationale for progesterone supplementation, timing and appropriate dosing regimen of progesterone
administration, whether progesterone serum levels reflect outcomes, and distinguishing among progesterone
formulations with respect to efficacy, tolerability, and patient preference/satisfaction.

Accreditation Statement

This activity has been planned and implemented in accordance with the accreditation requirements and policies
of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Penn
State College of Medicine and CORE Medical Education, LLC. Penn State College of Medicine is accredited by the
ACCME to provide continuing medical education for physicians.

Credit Designation

Penn State College of Medicine designates this enduring material for a maximum of 1.5 AMA PRA Category 1
Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the
activity.

Date of Original Release/Review

This supplement was published in Reproductive BioMedicine Online. The original release date is 30 December
2014 and is eligible for AMA PRA Category 1 Credit™ through 30 December 2015.
Faculty

Chairman:
Daniel B. Shapiro, MD
Reproductive Biology Associates – Atlanta, Georgia

Faculty:
Robert Boostanfar, MD
Clinical Assistant Professor at the Keck School of Medicine, Department of Obstetrics and Gynecology, University
of Southern California – Los Angeles, California

Kaylen M. Silverberg, MD
Texas Fertility Center – Austin, Texas

Elena H. Yanushpolsky, MD
Assistant Professor, Harvard Medical School
Director, Center for Infertility and Reproductive Surgery at South Shore Hospital – Boston, Massachusetts

Disclosure of Conflicts of Interest

According to the disclosure policy of the Penn State College of Medicine, faculty, editors, managers, and other
individuals who are in a position to control content are required to disclose any relevant financial relationships
with the commercial companies related to this activity. All relevant relationships that are identified are reviewed
for potential conflicts of interest. If a conflict of interest is identified, it is the responsibility of the Penn
State College of Medicine to initiate a mechanism to resolve the conflict(s). The existence of these interests
or relationships is not viewed as implying bias or decreasing the value of the presentation. All educational
materials are reviewed for fair balance, scientific objectivity of studies reported, and levels of evidence.

The following faculty has reported real or apparent conflicts of interest that have been resolved:

• Dan Shapiro is a consultant/advisor to Merck, Merck-Serono and OvaScience. He is on the speakers’ bureau
of Actavis, Merck and Merck-Serono and received a research grant from Actavis
• Robert Boostanfar is a consultant/advisor to Actavis, Merck and Ferring. He is on the speakers’ bureau of
Actavis, Merck and Ferring, and received a research grant from Activis and Merck
• Kaylen Silverberg is on the speakers’ bureau of Actavis and received a research grant from Actavis
• Elena H. Yanushpolsky has nothing to disclose

The following reviewers/planners/authors have reported real or apparent conflicts of interest:

• Otto Ratz, MD has nothing to disclose

• Christina Culbert, MSc has nothing to disclose
• P. Susan Jordan has nothing to disclose

Penn State faculty and staff involved in the planning and reviews of this material have nothing to disclose.

Provider

For questions about CME credits, contact Penn State College of Medicine, Continuing Education at 717-531-6483
or ContinuingEd@hmc.psu.edu and reference course #G5483-14-R.

Commercial Support

This CME activity is supported by an educational grant from Actavis Pharmaceuticals.

Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not
approved or indicated by the FDA. Neither Penn State College of Medicine nor CORE Medical Education, LLC
recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational
activity are those of the faculty and do not necessarily represent the views of Penn State College of Medicine or
CORE Medical Education, LLC. Please refer to the official prescribing information for each product for discussion
of approved indications, contraindications, and warnings.

Instruction for Participation

The estimated time to complete is 90 minutes. There are no fees for participating in and receiving CME credit
for this online activity. During the period of 30 December 2014– 30 December 2015 participants must 1) read the
learning objectives and faculty disclosures; 2) read the full content of the activity and reflect upon its teachings;
3) successfully complete the post-test with a passing score of 75% and the evaluation at the end of the activity.

To obtain credit, participants must complete the Post-Test and Evaluation Form and submit it to: Penn State
College of Medicine, Continuing Education, (G220), 44 E Granada Ave., Rm 1108, PO Box 851, Hershey, PA 17033
USA or fax to 717-531-5604 or send via email to ContinuingEd@hmc.psu.edu and reference course #G5483-14-R.

Review Process
The entire faculty discussed the content at a peer-review planning session; the chair reviewed the activity for
accuracy and fair balance, and a member of the External CME Advisory Board, who is without conflict of interest,
reviewed the activity to determine whether the material is evidence-based, objective and demonstrated fair
balance.

Acknowledgment
This Supplement is derived from a planning teleconference series which was held December 2013 through
February 2014 and was independently developed by Penn State College of Medicine and CORE Medical Education
LLC, pursuant to an educational grant from Actavis Pharmaceuticals (formerly known as Watson Pharmaceuticals).
The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME
provider and publisher, or the commercial supporter.

Disclaimer
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes
and their own professional development. The information presented in this activity is not meant to serve as
a guideline for patient management. Any procedure, medications, or other courses of diagnosis or treatment
discussed or suggested in this activity should not be used by clinicians without the evaluation of their patients’
conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product
information, and comparison with recommendations of other authorities.
Reproductive BioMedicine Online (2014) 29, S4–S14

ARTICLE

Examining the evidence: progesterone

supplementation during fresh and frozen embryo
transfer
Daniel Shapiro a, *, Robert Boostanfar b , Kaylen Silverberg c ,
Elena Hesina Yanushpolsky d

a
Medical Director, Reproductive Biology Associates, Atlanta, GA, USA; b Director of Clinical Research, HRC Fertility, Los
Angeles, CA, USA; c Texas Fertility Center Austin, TX and San Antonio, TX, USA; d Center for Infertility and Reproductive
Surgery, Brigham and Woman’s Hospital, Harvard Medical School, Boston, MA, USA
* Corresponding author: Daniel Shapiro, MD. 1100 Johnson Ferry Rd Ste 200, Atlanta, GA 30342, USA.
E-mail address: daniel.shapiro@rba-online.com (D. Shapiro).
Dan Shapiro is a native of Miami, Florida and currently a resident of Atlanta, Georgia. Dr. Shapiro is a Phi Beta
Kappa graduate of Bowdoin College and Emory University School of Medicine. He completed residency training at
the Pennsylvania Hospital in Philadelphia and Fellowship training at the University of Connecticut.
Dr. Shapiro is Board Certified in OB/GYN and REI. He is an author of over 50 peer-reviewed publications. He has a
special interest in egg donation and cryopreservation and is the medical director of the USAŠs largest frozen donor
egg bank network, MyEggBank-North America. He is also the medical director of Reproductive Biology Associates
in Atlanta.

Abstract ART has evolved over time and frozen-thawed embryo transfer (FET) is now a frequently performed, successful option.
During the last decade, cryopreservation techniques have received considerable interest, whereas interest in the priming and
preparation of the endometrium prior to and after embryo transfer was more limited. The available evidence for the rationale
and timing of progesterone supplementation as well as an understanding of the differences among progesterone formulations with
respect to efficacy, optimum use, and patient preference is worth examining. A Summit was convened to review the literature on
progesterone supplementation in ART and after FET and to provide guidance on the most clinically relevant issues. Utilizing an
innovative consensus-building model to examine the evidence, Summit faculty drafted summit statements prior to the meeting,
completed a literature search, and created a presentation based on this. At the conclusion of their discussion the faculty developed
final summit statements, evaluating the strength of the evidence supporting each statement, and rating their level of support for
each statement. The clinically relevant topic areas were the rationale for progesterone supplementation, timing and appropriate
dosing, whether progesterone serum levels reflect outcomes, and distinguishing among progesterone formulations with respect to
efficacy, tolerability, and patient preference/satisfaction.
© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. Allrights reserved.

KEYWORDS: frozen embryo transfer, implantation, in vitro fertilization, progesterone supplementation, timing

1472-6483/© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. Allrights reserved.
Examining the evidence: progesterone supplementation during fresh and frozen embryo transfer
Introduction
Assisted reproductive technologies have evolved from those
used in the early days of in vitro fertilization (IVF)-embryo
transfer. As the rates of successful fertilization resulted in
increasing pregnancy rates, successful cryopreservation of
embryos followed. Frozen-thawed embryo transfer (FET) is
now a commonly performed and successful option for IVF.
Progesterone supplementation for luteal phase support is
important for successful implantation in programmed cycles
of FET. With the introduction of formulations of proge-
sterone other than intramuscular, which was first used in
IVF-embryo transfer, physicians and patients have additional
options for supplementation. However, it is important to
recognize the differences among formulations with respect
to efficacy, tolerability, and patient satisfaction. Given
the choices now available, everyone involved with assisted
reproductive techniques (ART) need to be aware of the
evidence in order to make an informed decision regarding
choice of therapy and to optimize delivery rates.
A Summit was therefore convened to address several
questions regarding progesterone supplementation in ART
cycles (Table 1). Summit faculty presented the available
evidence, evaluated the strengths and weaknesses of the
studies and data, and sought to achieve consensus regarding
the use of progesterone in frozen embryo transfer (FET)
cycles to increase implantation and delivery rates. Their
discussion included an assessment of differences in efficacy,
safety, and patient satisfaction among various progesterone
formulations that are now available for use. In this publica-
tion, a review of the data for each topical area is presented
first followed by the consensus statements developed by the
faculty including their assessment of the strength of the
supporting evidence.
Role of progesterone in implantation and early
pregnancy
It is well established that progesterone is necessary to
maintain early pregnancy. A study of 57 pregnant women
who underwent tubal ligation at approximately 7 weeks
gestational age (control group) maintained their plasma
progesterone levels and continued their pregnancy, whereas
plasma progesterone levels plummeted to near zero within
5 days and the pregnancy was aborted in those women
who underwent tubal ligation and luteectomy at approxi-
mately 7 weeks gestational age (Csapo et al., 1978; Csapo,
Table 1 Questions regarding progesterone supplementation in
assisted reproduction cycles.
• What is the role of progesterone in assisted reproduction
cycles?
• Is an artificial cycle better than a natural cycle?
• Is progesterone supplementation required?
• What is the optimum timing for initiation of progesterone
supplementation?
• What is the optimum route of administration for
progesterone?
• What is the optimum dose of progesterone?
S5
1977). In another group of women who underwent tubal
ligation and luteectomy at 8 weeks gestational age, plasma
progesterone levels decreased at day 4, but then increa-
sed to pretreatment levels with successful continuation of
pregnancy. Similarly, pregnancies were continued in women
who underwent tubal ligation and luteectomy at approxi-
mately 7 weeks gestational age and received progesterone
replacement.
The need for progesterone supplementation in ART cycles
is now well accepted. There are several lines of evidence
that establish the need for progesterone. The cyclic se-
cretion of estrogen and progesterone by the ovaries leads
to morphological and physiological changes in the endome-
trium that create a suitable endometrial environment for
embryo implantation and maintenance of early pregnancy
(Nardo and Sallam, 2006). Administration of progesterone
receptor antagonists within the first 7 weeks of pregnancy
induces abortion (Peyron et al., 1993). The potential for
implantation is lessened if there is a decrease in the amount
or duration of progesterone production by the corpus lute-
um or if there is poor endometrial response to progesterone
(Jones, 1991; Ginsburg, 1992), which may lead to pregnancy
failure (Porter and Scott, 2005).
Successful implantation involves complex mechanisms
that require hormonal synchronization. A preovulatory in-
crease in estrogen secretion stimulates proliferation and
differentiation of endometrial epithelial cells, while pro-
duction of progesterone by the corpus luteum stimulates
proliferation and/or differentiation of endometrial glands
and stromal cells (Norwitz et al., 2001). Since progesterone
prepares the endometrium for blastocyst implantation and
induces endometrial development, it has been termed the
’hormone of pregnancy.’ While successful pregnancy can
occur in the relative absence of estrogen, especially after
ovulation, it cannot occur without adequate progesterone
production until the luteal placental shift is well under-
way (Norwitz et al., 2001). Endometrial morphology is an
appropriate predictor of receptivity for implantation, and
hormonal control of endometrial receptivity includes an
estrogen priming phase followed by progesterone secreti-
on, which leads to the necessary endometrial changes (de
Ziegler et al., 1998).
Progesterone in in vitro fertilization
In the pre-gonadotropin-releasing hormone (GnRH)-agonist
era, women undergoing in vitro fertilization (IVF) were
found to have higher estrogen levels in the periovulatory
phase as well as in the early, mid, and late luteal phases
in conception cycles compared with nonconception cycles,
while progesterone levels were higher from the midlute-
al phase onward (Dlugi et al., 1984). A decline in both
serum estrogen and progesterone levels in the midluteal
phase in conception cycles also was noted suggesting some
degree of corpus luteum deficiency. However, both serum
estrogen and progesterone levels increased markedly after
the establishment of pregnancy. Corpus luteum deficiency
was also noted in patients undergoing IVF stimulated with
human menopausal gonadotrophin (hMG) alone or hMG with
clomiphene citrate (Gronow et al., 1985). To overcome cor-
pus luteum deficiency, progesterone supplementation was
recommended.
S6
Following the introduction of GnRH agonists, luteal phase
deficiency in IVF cycles stimulated with a GnRH agonist and
hMG but no luteal supplementation was reported (Smitzet
al., 1988). The inadequate production of progesterone by
the corpus luteum is presumably due to sustained inhibition
of pituitary gonadotrophin secretion, which occurs with
both long and short protocols and when the GnRH agonist is
discontinued before human chorionic gonadotrophin (hCG)
administration (Nardo and Sallam, 2006; Smitz et al., 1988).
It also occurs regardless of the drug used to induce terminal
oocyte maturation. Aspiration of luteinized granulosa cells
also can result in luteal phase deficiency and inadequate
progesterone secretion.
This body of data supports the notion that progesterone
supplementation is necessary, and several meta-analyses of
randomized controlled trials indicate that progesterone sup-
plementation significantly raises pregnancy rates in IVF. A
meta-analysis of 18 trials conducted between 1971 and 1993
demonstrated that, when either hCG (with GnRH agonist)
or progesterone was used for luteal phase support in IVF
cycles, pregnancy rates increased (Soliman et al., 1994). A
second meta-analysis of 59 studies conducted between 1971
and 2003 found a significant increase in pregnancy rates
(odds ratio [OR], 1.34) with progesterone use for luteal
phase support (Daya and Gunby, 2004). The largest meta-
analysis included 69 trials with a total of 16,327 women (Van
der Linden et al., 2011). In eight of these trials (n = 875)
that compared progesterone with placebo or no treatment,
progesterone administration for luteal phase support
significantly increased the clinical pregnancy rate (Peto OR,
1.83), as well as the live birth rate (Peto OR, 2.95).
Progesterone in frozen embryo transfer cycles
The data for progesterone use for luteal phase support
in FET cycles are more complex and less conclusive. The
evidence that does exist is from retrospective studies as
well as randomized controlled studies and meta-analyses of
randomized trials.
A retrospective study of FET in natural (n = 212) or estro-
gen/progesterone supplemented (n = 205) cycles found no
significant difference in implantation rates (14.1% vs 13.5%,
natural vs estrogen/progesterone supplemented) or clinical
pregnancy rates (11.6% vs 10.2%; Gelbaya et al., 2006). A
meta-analysis of seven randomized, controlled trials also
demonstrated no difference in pregnancy rates in estro-
gen/progesterone supplemented versus natural FET cycles
(Ghobera and Vandekerckhove, 2008). A second meta-
analysis of 20 studies found no differences in clinical pre-
gnancy rates, continuing pregnancy rates, or live birth rates
between natural FET cycles and estrogen/progesterone
supplemented cycles (Groenewoud et al., 2013).
A recent retrospective cohort study, however, found that
luteal support with progesterone during a natural cycle was
associated with the best live birth rate after FET when
compared with natural cycles without progesterone or with
estrogen/progesterone supplemented cycles (Veleva et al.,
2013). The benefit of progesterone for luteal phase support
was confirmed in a prospective, randomized, controlled trial
of 435 women undergoing FET in natural cycles (Bjuresten et
al., 2011). The live birth rate was significantly higher in the
women who received vaginal progesterone (400 mg twice
D. Shapiro et al.
daily, micronized; n = 219) starting on the day of embryo
transfer than in the group that did not receive progesterone
(30% vs 20%).
Progesterone: route of administration
The effect of the route of administration of progesterone
for luteal phase support in FET on serum progesterone levels
and pregnancy rates has been studied. In one retrospective
chart review of 96 women, progesterone treatment was
initiated on cycle day 15, 2 days before embryo trans-
fer, with either vaginal gel (90 mg twice daily), capsules
administered vaginally (200 mg three times daily), or intra-
muscular progesterone (50 mg daily) during a programmed
FET cycle (Williams et al., 2000). There was no statistically
significant difference in the pregnancy rate among the three
groups (39% vs 30% vs 23%, gel vs capsule vs intramuscular),
but, as expected, the serum progesterone level was signi-
ficantly higher in the intramuscular group (15.5 ng/mL vs
15.7 ng/mL vs 45.6 ng/mL). The small number of patients
in the analysis prohibits drawing any conclusion regarding
differences among progesterone treatment groups. Another
retrospective chart review that included 279 FET recipients
also found no significant difference in the clinical pregnancy
rate (34% vs 35%) between progesterone vaginal gel (90 mg
twice daily) and intramuscular progesterone (50 mg daily)
initiated 4 or 6 days prior to FET based on either a cycle
day 3 or 5 (blastocyst) embryo transfer (Berger and Phillips,
2008). In addition, there was no significant difference in
the total pregnancy loss rate (16.9% vs 18.3%, progesterone
vaginal gel vs intramuscular progesterone). A prospective
randomized trial in 60 women undergoing assisted reproduc-
tive techniques compared progesterone supplementation
administered as either an oral tablet (400 mg daily), vaginal
gel (90 mg daily), or intramuscularly (50 mg daily) initiated
one day before embryo transfer (Saucedo et al., 2000).
The clinical pregnancy rate was statistically the same with
vaginal and intramuscular administration of progesterone
(35% and 40%), but the rate following oral administration
(15%) was significantly less.
A large retrospective analysis of 1,034 ART cycles eva-
luated vaginal micronized progesterone insert (100 mg 3
times daily) monotherapy with a combination of vaginal
micronized progesterone insert (100 mg 3 times daily) and
progesterone in oil intramuscular injection (50 mg at least
once every 3 days) in FET cycles (n = 194), donor oocyte
cycles (n = 159), and autologous fresh IVF cycles (n = 681)
(Feinberg et al., 2013). The analysis found that the clinical
pregnancy rate was significantly higher with combination
progesterone therapy than with monotherapy (47.9% vs
23.5%; P = 0.0004) as was the live birth rate (37.5% vs 17.3%;
P = 0.0015), The FET cycles represented <20% of the total
number of ART cycles. Although the findings were statisti-
cally significant, they may represent a treatment bias since
combination therapy was offered only by a select group of
physicians.
In summary, while the studies are not large and the data
are not uniform, the preponderance of data for FET indicate
that adequate endometrial exposure to progesterone before
and after the actual transfer is necessary. Oral administra-
tion of progesterone is associated with inferior outcomes
compared with intramuscular and vaginal administration.
Examining the evidence: progesterone supplementation during fresh and frozen embryo transfer
Dose and timing of progesterone
administration
The dose of progesterone is very important and varies by the
route of administration and progesterone formulation (Ta-
ble 2). Because of pharmacokinetic differences (e.g., endo-
metrial absorption) among different vaginal formulations of
progesterone, it is important to note the differences in dose
and frequency of administration for vaginal formulations to
achieve good success rates. A meta-analysis of nine studies
comparing therapeutic doses of vaginal (90 mg daily of a
bioadhesive gel formulation; 200 mg three times daily of an
oil-in-capsule formulation) and intramuscular (50 mg daily)
progesterone administration found that, overall, in stimu-
lated cycles with GnRH agonist administration, vaginal and
intramuscular administration of progesterone had a compa-
rable effect on clinical pregnancy (OR, 0.91; 95% confidence
intervals [CI], 0.74–1.13; Fig. 1; Zarutskie et al., 2009).
Timing of progesterone administration: stimulated
cycles
Different protocols for initiation of progesterone supple-
mentation are reported, ranging from before oocyte re-
trieval to 6 days after oocyte retrieval. The data suggest
that there is an optimum window for initiating progesterone
administration to maximize clinical outcomes.
Table 2 Therapeutic doses of progesterone for luteal support
in stimulated cycles.
• Intramuscular
– 25 mg to 100 mg once daily (usual dose: 50 mg once daily)
• Vaginal
– Insert or capsule: 100 mg to 200 mg two to three times a
day
– Bioadhesive gel: 90 mg once daily
Figure 1 Intramuscular versus vaginal progesterone (P) administration: clinical pregnancy per in vitro fertilization-embryo
transfer (ET) in gonadotropin-releasing hormone (GnRH) agonist cycles (Zarutskie et al., 2009, p. 166. Reprinted with permissi-
on).
S7
Clinical outcomes of IVF-embryo transfer in GnRH ant-
agonist cycles were compared for vaginal gel (90 mg twice
daily; n = 209) and intramuscular (100 mg daily; n = 217) pro-
gesterone supplementation initiated 24 hours after oocyte
retrieval in a randomized controlled study (Kahraman et al.,
2010). There were no significant differences between the
two groups in the clinical pregnancy rate per embryo trans-
fer cycle (53.1% vs 54.8%, vaginal vs intramuscular), the
percent of ongoing pregnancies per embryo transfer cycle
(45.9% vs 47.9%), or the implantation rate (35.1% vs 33.4%).
A second randomized controlled study compared vaginal
(90 mg once daily, 8% gel formulation; n = 206) with intra-
muscular (50 mg once daily; n = 201) progesterone in GnRH
agonist cycles (Yanushpolsky et al., 2010). Intramuscular
progesterone was initiated 24 hours after oocyte retrieval,
whereas vaginal progesterone gel was initiated 48 hours
after retrieval to account for higher endometrial tissue
bioavailability and to prevent premature endometrial ad-
vancement. There were no significant differences between
the two progesterone formulation groups in the rates of cli-
nical pregnancy (66.5% vs 62.2%, vaginal vs intramuscular),
ongoing/delivered pregnancy (45.2% vs 42.2%), or pregnancy
loss rate (32.1% vs 32.0% of pregnancies).
The above studies noted equivalent efficacy of a vagi-
nal progesterone gel formulation administered either once
or twice daily with intramuscular progesterone. Another
randomized controlled study compared a 90-mg dose of a
vaginal gel formulation of progesterone administered either
once (n = 137) or twice (n = 137) daily with a 50 mg once
daily dose of intramuscular progesterone (n = 138) initiated
24 hours after oocyte retrieval in GnRH agonist cycles (Dal
Prato et al., 2008). There were no significant differences
among the three progesterone administration groups in the
clinical pregnancy rate (36.3% vs 37.2% v 32.6%, once daily
vaginal vs twice daily vaginal vs intramuscular) as well as
other clinical outcome measures (e.g., implantation rate,
ongoing pregnancy rate). This study demonstrates that both
once and twice daily vaginal progesterone administration
S8
initiated 24 hours after oocyte retrieval in stimulated cycles
provided an endometrial hormonal milieu that is equally
effective to intramuscular progesterone, which has been
the mainstay of progesterone supplementation regimens.
Another prospective trial compared a vaginal gel for-
mulation (n = 172) with intramuscular (n = 302) progesterone
initiated 48 hours after oocyte retrieval (Silverberg et al.,
2012). It is of interest that clinical outcomes in this study
were better with vaginal than with intramuscular progeste-
rone administration: total pregnancy rate (70.9% vs 64.2%,
vaginal vs intramuscular; P = NS) and live birth rate (51.7%
vs 45.4%; P < 0.05).
A multivariate analysis of data from a large retrospective
trial that compared vaginal (90 mg daily, 8% gel formulation;
n = 310) with intramuscular (250 mg every 3 days; n = 617)
progesterone initiated the night of oocyte retrieval found
that vaginal was superior to intramuscular progesterone for
β-hCG positivity (OR, 1.97; 95% CI, 1.28–3.03; P = 0.002)
and clinical pregnancy rates (OR, 1.66; 95% CI, 1.07–2.60;
P = 0.03), but not for biochemical pregnancy rates (OR, 1.85;
95% CI, 1.00–3.41;P = NS) or ongoing pregnancy rates (OR,
1.43; 95% CI, 0.89–2.30; P = NS; Satir et al., 2013). Univa-
riate analysis showed no significant differences between the
two progesterone administration groups for any clinical out-
come. The trial included women who underwent IVF-embryo
transfer between October 1999 and August 2009.
A prospective randomized trial that compared admini-
stration of intramuscular progesterone beginning 12 hours
before oocyte retrieval with initiation 24 hours after retrie-
val found that the clinical pregnancy rate was significantly
lower when progesterone was started before oocyte re-
trieval (12.9% vs 24.6%, before vs 24 hours after oocyte
retrieval; P = 0.011; Sohn et al., 1999). The results suggest
that starting progesterone administration too early is not
beneficial because of a potential for premature endometrial
advancement.
Delaying initiation of progesterone administration also
is associated with decreased pregnancy rates after IVF. A
prospective randomized study of vaginal progesterone (200
mg three times daily, micronized formulation) beginning on
either day 3 or day 6 after oocyte retrieval in GnRH-agonist
stimulated cycles found that rates of clinical pregnancy
(61.0% vs 44.8%, day 3 vs day 6; P < 0.05) and implantation
(27.0% vs 20.0%) were statistically lower when progesterone
was started on day 6 (Williams et al., 2001).
In summary, the timing of progesterone supplementation
in stimulated IVF cycles should not be too early or too late.
The optimal timing appears to be within 24 to 72 hours after
oocyte retrieval, and the clinical outcomes with vaginal
progesterone administration are at least equivalent to those
with intramuscular progesterone.
Timing of progesterone administration: frozen
embryo transfer cycles
The evidence in frozen or donor egg transfer cycles is more
limited, and adequately powered prospective, randomized
studies are needed to answer outstanding questions. The
authors of a Cochrane Database Review of a limited num-
ber of small prospective randomized trials concluded that
starting progesterone at a time equivalent to the day of
or the day after oocyte retrieval results in a significantly
D. Shapiro et al.
higher pregnancy rate (OR, 1.87; 95% CI, 1.13–3.08) than
if progesterone is started the day before oocyte retrieval
(Glujovsky et al., 2010). Findings from the review also
suggested that vaginal and intramuscular progesterone ad-
ministration result in equivalent clinical pregnancy rates
(OR 1.07; 95% CI 0.61–1.89). These data from prospective
randomized studies are consistent with fresh IVF-embryo
transfer data.
Data from retrospective studies of FET cycles are conflic-
ting. A retrospective analysis compared clinical outcomes
following vaginal (90 mg twice daily, gel formulation;
n = 105) or intramuscular (50 mg daily; n = 120) progesterone
started on the afternoon of oocyte retrieval and embryo
transfer performed on day 4 of progesterone supplementa-
tion (Berger and Phillips, 2012). There were no significant
differences between the two progesterone administration
groups for any clinical outcome. A second retrospective stu-
dy did find significant differences in some clinical outcome
measures in a comparison of vaginal (90 mg twice daily,
gel formulation; n = 298) and intramuscular (25 to 50 mg
daily; n = 440) initiated 3 days before cryopreserved/thawed
embryo transfer (Kaser et al., 2012). The clinical pregnancy
(36.9% vs 51.1%, vaginal vs intramuscular; P < 0.01) and
live birth (24.4% vs 39.1%; P < 0.01) rates were significantly
lower with vaginal progesterone administration. Other out-
come measures were not significantly different between the
groups.
A retrospective study of autologous embryos vitrified in
the blastocyst stage found significant differences between
vaginal (n = 209) and intramuscular (n = 1515) progesterone
administration for age at cryopreservation (34.8 vs 33.6;
P < 0.001), number of embryos transferred (1.5 vs 1.6;
P < 0.05), and the live birth rate (36.1% vs 45.3%; P < 0.05),
but not for the implantation (43.1% vs 47.2%; P = NS) or
clinical pregnancy (51.7% vs 58.5%; P = NS) rates (Heitmann
et al., 2013). Another retrospective analysis of transfer of
vitrified blastocysts comparing progesterone supplementati-
on with progesterone vaginal gel 8% (n = 238 FET cycles) with
intramuscular progesterone (n = 682 FET cycles)found no si-
gnificant differences between progesterone vaginal gel and
intramuscular progesterone for implantation rates (45.6%
vs 46.4%; P = NS), clinical pregnancy rates (60.5% vs 61.7%;
P = NS), or live birth rates (48.9% vs 49.1%; P = NS) (Shapiro
et al., 2014).
It is possible that various confounding factors, such as
differences in the cryopreservation system, quality of the
embryo, and IVF cycle, as well as treatment bias, the
many other variables involved in FET, and the lack of
randomization to luteal support contributed to differences
in the significance of clinical outcomes in the retrospective
studies.
In summary, the timing of progesterone supplementa-
tion in FET cycles is less clearly established. Treatment
regimens studied include embryo age plus 1 day (day 3
embryo transfer on day 4 of progesterone administration
or day 5 embryo transfer on day 6 of progesterone) and
embryo age plus 0 days (day 3 embryo transfer on day 3
of progesterone administration or day 5 embryo transfer on
day 5 of progesterone). There may be differences in the
timing of vaginal compared with intramuscular progesterone
supplementation as there is no endogenous progesterone
present in FET cycles. The optimal protocol for progestero-
Examining the evidence: progesterone supplementation during fresh and frozen embryo transfer
ne supplementation for FET cycles that could be universally
applied is not known, but it must be efficacious, convenient,
have minimal side effects, and be affordable. A multicenter,
properly powered, prospective randomized study is necessa-
ry to identify the optimal timing and route of administration
for progesterone supplementation in FET cycles. As more
programs move toward vitrification of blastocysts, any fu-
ture study on this subject, to be clinically relevant, should
be conducted with vitrified blastocysts.
Progesterone formulations: serum and
endometrial levels
An apparent disconnect exists between serum and endome-
trial progesterone levels when intramuscular administration
of progesterone is compared with vaginal administration.
There were limited data comparing intramuscular and vagi-
nal progesterone formulations until the late 1980s. One of
the first comparisons of intramuscular, vaginal, and rectal
administration measured only serum progesterone levels
(Nillius and Johansson, 1971). Intramuscular progesterone
administration resulted in serum levels four times higher
than those after vaginal or rectal administration leading the
authors to conclude that hourly administration of vaginal
or rectal suppositories would be necessary to achieve se-
rum progesterone levels equivalent to those following 100
mg administered intramuscularly. The assumption was that
serum levels of progesterone predicted its effect on the
endometrium.
Subsequent studies noted the lack of a linear relati-
onship between serum levels and histological findings. A
comparison of daily intramuscular (100 mg daily), oral (300
mg micronized progesterone), and vaginal (300 or 600 mg
micronized progesterone) administration of progesterone
evaluated not only the serum progesterone levels but also
endometrial dating by microscopy and morphology using
electron microscopy on day 21 of stimulated luteal pha-
ses in women with absent ovaries (Devroey et al., 1989).
Whereas administration of oral progesterone did not show
evidence of an in-phase endometrium, both intramuscular
and vaginal administration did result in in-phase biopsies
and endometrial architecture by electron microscopy. Se-
rum progesterone levels after intramuscular administration
were five times higher than after vaginal administration.
The authors did not report any correlation between serum
progesterone levels and histological findings.
A subsequent small study compared endometrial mor-
phology on day 21 after intramuscular (50 mg twice daily;
n = 34), oral (100 mg three times daily, micronized; n = 12),
and vaginal (100 mg three times daily, micronized; n = 8)
progesterone administration in women with primary ovarian
Table 3 Comparison of serum levels and endometrial morphology following intramuscular, oral, and vaginal progesterone admini-
stration in women with primary ovarian failure (Bourgain et al., 1990).
Intramuscular
Endpoint (n = 34)
Serum progesterone, mean ± SD (μg/mL) 43.4 ± 0.6
Biopsy results 50% out of phase
Pregnancies/embryo transfer 8/40 (20%)
S9
failure and correlated serum levels with histological findings
(Bourgain et al., 1990). The biopsies were done in a trial cy-
cle with embryo transfer in a subsequent cycle. Endometrial
response most closely matched a natural cycle after vagi-
nal progesterone administration, and as noted in previous
studies, serum progesterone levels were markedly higher
following intramuscular administration (Table 3). This was
the first study to report clinical pregnancies (2/8 embryo
transfers) in replacement cycles with vaginal progesterone
administration as the sole source of progesterone. The
authors concluded that vaginal progesterone administration
is effective for embryo transfer in ovariectomized or func-
tionally menopausal women and that serum levels do not
correlate with clinical outcomes.
Several studies evaluating what was termed the first
uterine pass effect all concluded that the uterine effects
of steroid hormones administered vaginally exceed the re-
sponse that can be reasonably expected from the level of
the circulating hormone (de Ziegler et al., 1992, 1995; Miles
et al., 1994; Pasquale et al., 1997; Cicinelli et al., 1998,
2000; Tourgeman et al., 1999). A pharmacokinetic study
evaluated endometrial progesterone levels after intramus-
cular (50 mg twice daily) and vaginal (100 mg three times
a day, micronized) in functionally agonadal and normally
ovulating women (Miles et al., 1994). In both groups, blood
samples were drawn hourly for 6 hours on the first day of
progesterone administration, and blood and tissue samples
were recovered on day 7 of progesterone administration,
which corresponded to day 21 of a natural cycle. The study
found that vaginal progesterone administration yields higher
endometrial progesterone concentrations compared with
intramuscular administration (11.5 ± 2.60 ng/mg protein vs
1.4 ± 0.4 vs 0.3 ng/mg protein, vaginal vs intramuscular vs
natural cycle), and that the endometrium was considered
synchronous.
A randomized, open-label, three-way crossover study in
20 estrogen-primed postmenopausal women compared three
vaginal doses of micronized progesterone (100 mg/d, 200
mg/d, 400 mg/day [200 mg twice daily]) with respect to
serum progesterone levels and endometrial dating by the
criteria of Noyes on day 11 of progesterone (day 25 biopsy;
Pasquale et al., 1997). The 200 mg/day and the 400 mg/day
vaginal doses of progesterone reliably yielded in-phase biop-
sies and normal bleeding patterns, whereas the 100 mg/day
dose was inadequate with respect to histological findings
or cycle normalcy. This study, therefore, demonstrated that
the vaginal progesterone dose does matter.
Two studies described preferential uptake of proge-
sterone following vaginal administration of a micronized
formulation (Cicinelli et al., 1998, 2000). In the first study
of 20 postmenopausal women undergoing transabdominal
hysterectomy, vaginal progesterone (100 mg, oil-based mi-
Oral Vaginal
(n = 12) (n = 8)
2.79 ± 0.6 6.79 ± 1.28
All out of phase 80% in phase
No transfers 2/8 (25%)
S10
cronized) was applied 45 minutes before the planned
surgery, and parallel blood samples from the uterine and
radial arteries were drawn for progesterone and PaO2 levels
(Cicinelli et al., 1998). Levels of progesterone in samp-
les from the uterine artery were significantly higher than
those from the paired radial artery (9.75 ± 3.21 ng/mL vs
5.12 ± 2.06 ng/mL; P < 0.000001). This finding confirmed
that arterial blood had been sampled and that vaginal
administration of progesterone is distributed preferentially
to the uterus compared with the periphery. The authors
concluded that the mechanism is likely a countercurrent
flow from utero-ovarian veins into local tissue and the
uterine artery. A second study by the same group provided
the first direct clinical evidence that vaginal administration
of a controlled sustained-release progesterone gel formu-
lation (90 mg) achieves higher endometrial concentrations
compared with intramuscular progesterone (50 mg; Cicinelli
et al., 2000). Fourteen postmenopausal women undergoing
transabdominal hysterectomy were randomized to one of
the progesterone formulations, which was administered the
morning and evening the day before and the morning of
surgery. The ratios of endometrial to serum levels of pro-
gesterone were markedly higher in women who received
vaginal progesterone. The endometrial progesterone levels
were higher following vaginal administration (1.05 ± 0.67
ng/mg protein vs 0.43 ± 0.19 ng/mg protein, vaginal vs in-
tramuscular), while serum progesterone levels were higher
following intramuscular administration (4.82 ± 2.25 ng/mL
vs 29.42 ± 14.14 ng/mL). The findings demonstrate a first
uterine pass effect.
The relationship between serum progesterone levels and
clinical outcomes were evaluated in an open-label stu-
dy comparing a vaginal 8% gel formulation (90 mg daily;
n = 100) with historical controls who had received intra-
muscular progesterone (100 mg daily; n = 106) for luteal
phase support in IVF-embryo transfer cycles beginning on
the day of oocyte retrieval (Chantillis et al., 1999). Mean
mid-luteal serum progesterone levels were significantly
higher following intramuscular progesterone administration
(94.3 ± 8.8 ng/mL vs 57.7 ± 7.4 ng/mL, intramuscular vs
vaginal; P = 0.0015). There were no differences between
the two progesterone administration groups with respect to
positive β-hCG and ongoing pregnancy rates; biochemical
loss occurred more commonly in the vaginal gel group.
The study concluded that serum progesterone levels do not
correlate with pregnancy outcomes.
In summary, intramuscular administration consistently
yields higher serum progesterone levels compared with
either the oral or vaginal routes of administration. Howe-
ver, serum progesterone levels are neither associated with
endometrial histology nor pregnancy outcome. Measuring
progesterone serum levels only confirms that the patient
is taking progesterone or that ovulation has taken place in
the natural cycle. Vaginal (micronized or 8% gel formula-
tions) administration consistently yields higher endometrial
progesterone concentrations than does intramuscular ad-
ministration. The preferential uptake of progesterone by
the endometrium after vaginal administration is likely the
result of the first uterine pass effect and helps explain the
dissociation between endometrial and serum concentrations
of progesterone.
D. Shapiro et al.
Progesterone formulation selection: patient
satisfaction and luteal bleeding
Most of the data regarding patient satisfaction with re-
spect to progesterone formulations are derived from fresh
IVF-embryo transfer cycles rather than from FET cycles.
However, it is reasonable to extrapolate information from
fresh cycles to frozen cycles.
The three principal routes of administration for progeste-
rone support and replacement are summarized in Table 4.
The dose of intramuscular progesterone is somewhat physi-
cian/center selective, with the100 mg dose used in patients
with higher body mass. Oral progesterone is not generally
used as it undergoes first-pass metabolism in the liver with
very little reaching the uterus; it is also associated with
significant side effects such as somnolence. The twice-daily
dose of the gel formulation is the only regimen approved by
the Food and Drug Administration for replacement in ART
cycles. HCG is not generally used for luteal support as it is
inconvenient, can cause ovarian hyperstimulation syndrome,
and may interfere with the diagnosis of pregnancy.
Patient satisfaction
Patient satisfaction with treatment is an important consi-
deration in ART cycles. Deterrents to patient satisfaction
include the risk of cellulitis with intramuscular injections
and the continuing need for injections if intramuscular
progesterone is used for luteal support in GnRH-analogue
treated IVF-ET cycles. The physical or psychological burden
of treatment has been cited as a major stressor during
ART cycles (Verberg et al., 2008). High satisfaction with
treatment may translate to patients staying in treatment
longer, which in turn, may result in higher cumulative
pregnancy rates. In a study of 4102 cycles in 2130 patients,
investigators found that drop-out rates negatively affect
real cumulative pregnancy rates and result from stress and
frustration (Schröder et al., 2004).
A prospective, randomized, adequately powered study
that evaluated the efficacy of vaginal administration of
progesterone in a gel formulation (n = 206) with intramus-
cular (n = 201) progesterone for luteal phase support in
IVF-embryo transfer cycles included patient satisfaction as
an endpoint (Yanushpolsky et al., 2010). At the completion
Table 4 Progesterone support and replacement options for the
patient undergoing in vitro fertilization.
• Intramuscular
– 25 mg, 50 mg, 100 mg
• Oral
– 200 mg three times daily
• Vaginal
– Gel: Support 90 mg daily
Replacement 90 mg twice daily *
– Insert: Support 100 mg two or three times daily
– Compounded capsule/suppository: Support 200 mg two or
three times daily
* Only formulation and dosage regimen approved by the Food
and Drug Administration for replacement in assisted reproducti-
ve treatment cycles.
Examining the evidence: progesterone supplementation during fresh and frozen embryo transfer
of the cycle, patients were surveyed by telephone regar-
ding their level of satisfaction for ease of administration,
convenience of administration, and discomfort with the
progesterone formulation they had used. Responses were
recorded on a scale of 1 to 5 with 5 being the most satis-
fied. Satisfaction with the gel formulation was significantly
greater than with intramuscular progesterone (4.4 ± 0.9 vs
2.8 ± 1.2, gel vs intramuscular; OR, 13.7; P < 0.01).
Patient satisfaction with different vaginal progesterone
formulations also was studied. A multicenter, randomized,
controlled equivalence trial of vaginal gel (8%, 90 mg;
n = 991) and vaginal tablet (200 mg or 400 mg, microni-
zed; n = 992) formulations of progesterone administered for
luteal support after IVF/intracytoplasmic sperm injection
included a secondary objective of convenience and ease of
use (Bergh et al., 2012). Patients completed a questionnaire
on day 14 after embryo transfer before their pregnancy
test. The questionnaire addressed issues such as: ease of
use, hygiene, interference with coitus, itching, burning,
pain, leakage, time to administer the drug, and overall im-
pression. Responses were recorded on a scale of 1 to 10 with
1 being very convenient and 10 being very inconvenient.
The respondents’ overall impression significantly favored
the vaginal gel formulation (2.9 [2.7–3.0] vs 4.8 [4.7–5.0],
gel vs tablet; P < 0.0001).
A second prospective, randomized trial of vaginal gel
(8%, 90 mg daily; n = 130) and vaginal capsule (3 × 2 100 mg;
n = 136) formulations of progesterone reported similar ef-
ficacy, defined as clinical pregnancy rates for the two
progesterone formulations, but the gel formulation was bet-
ter tolerated and more acceptable (Simunic et al., 2007).
Patients completed a questionnaire with yes/no responses
on the day of embryo transfer. Significant (P < 0.05) findings
included that the gel formulation was more acceptable, less
messy, easier to administer, and more convenient with its
once daily use compared with the capsule formulation.
Vaginal gel (8%; n = 403)) and inserts (100 mg 2 or 3
times daily; n = 404 for each frequency) were compared
in a prospective, randomized, open-label trial (Doody et
al., 2009). Clinical outcome measures and tolerability were
similar for all groups. Adverse events that might be related
to the use of vaginal progesterone formulations (e.g., vagi-
nal irritation, discharge, bleeding, difficulty with insertion)
were not commonly reported and did not differ among the
groups.
Bleeding
The significance of luteal phase bleeding with progesterone
supplementation (8% gel, 90 mg daily, n = 206; intramuscu-
lar, 50 mg daily, n = 201) was evaluated in a prospective
randomized study in which women were contacted by tele-
phone 3 to 16 weeks after oocyte retrieval/randomization
and asked if they had experienced any bleeding (spotting,
moderate, heavy) before their scheduled pregnancy test
(Yanushpolsky et al., 2011). Any bleeding was considered
important and recorded. The overall incidence of luteal
phase bleeding was not statistically different between the
progesterone administration groups (33.2% vs 25.7%, gel vs
intramuscular). Among those who experienced luteal phase
bleeding, there were no significant differences between
the groups for either ongoing/delivered pregnancy rates
S11
(12.8% vs 17.7%, gel vs intramuscular) or pregnancy rates
(44.4% vs 46.7%). Luteal phase bleeding occurred with equal
frequency among pregnant patients in both progesterone
administration groups; only among non-pregnant patients
who received progesterone gel was there a higher rate of
luteal phase bleeding. The findings from this study show
that luteal phase bleeding does not affect ongoing preg-
nancy rates or outcomes. In addition, it is not a valuable
prognostic sign regardless of the form of progesterone
supplementation used. The lower numerical rate of luteal
phase bleeding with intramuscular progesterone likely is
due to its delaying the expected onset of menses in non-
pregnant cycles without having any positive effect on the
cycle outcome.
Estrogen supplementation in the luteal phase can reduce
bleeding in non-pregnant cycles, but does not affect cycle
outcome (Yanushpolsky et al., 2011). Patient counseling by
physicians and nurses regarding why luteal phase bleeding
occurs and that it does not adversely affect pregnancy
outcome is an important management tool. Counseling pati-
ents before undergoing IVF about the various progesterone
formulations and their pros and cons will assist the decision-
making process and may increase patient acceptance. Route
of administration, ease of administration, number of daily
doses, cost, FDA approval status, and whether a given pro-
duct is commercially available or a compounded formulation
are all factors to consider when counseling patients.
In summary, published data demonstrate higher patient
satisfaction and tolerability with daily administration of a
vaginal gel formulation than for either intramuscular or va-
ginal tablet and capsule formulations. Although tolerability
with both vaginal gel and insert formulations is similar,
convenience of administration may be a factor for some
patients as the inserts require administration two or three
times daily compared with once daily for the gel formula-
tion. Although luteal phase bleeding may be more common
following vaginal gel administration when compared with
intramuscular progesterone, it does not affect pregnancy
outcome and may be mitigated with concomitant estrogen
use.
Factors such as ease of administration, convenience,
tolerability, and patient satisfaction may have an effect on
patient compliance. If overall satisfaction with treatment is
low, it may translate to extra patient and clinic burden to
resolve issues related to satisfaction. A collaborative effort
among physicians, nurses, and patients to select the best
progesterone formulation will help to maximize the success
of the cycle as well as patient satisfaction.
Consensus statements
Following their presentations and discussion of progeste-
rone administration in IVF-embryo transfer cycles, Summit
faculty finalized statements based on the available evi-
dence, assessed the quality of the evidence supporting
the statement (Table 5), and ranked their level of agree-
ment with the statement (Table 6). The statements and
the assessments of the supporting data and their level of
agreement follow.
S12 D. Shapiro et al.

Table 5 Categories of evidence to support Summit consensus Patient satisfaction with treatment
statements.
• Patient preference and satisfaction are important fac-
• Category I Evidence obtained from at least 1 well- tors in the choice of treatment; selection of a vaginal
designed randomized, controlled clinical trial progesterone formulation can significantly affect patient
• Category II Evidence obtained from well-designed cohort satisfaction.
or case-controlled studies
• Category III Evidence obtained from case series, case Evidence Category: I Agreement Level: 1
reports, or flawed clinical trials
• Category IV Evidence obtained from opinions of respected
authorities based on clinical experience, Conflict of interest
descriptive studies, or reports of expert
committees Dan Shapiro is a consultant/advisor to Merck, Merck-Serono
• Category V Evidence is insufficient to form an opinion and OvaScience. He is on the speakers’ bureau of Actavis,
Merck and Merck-Serono and received a research grant from
Actavis.
Table 6 Categories for Summit faculty level of agreement with Robert Boostanfar is a consultant/advisor to Actavis,
consensus statements. Merck and Ferring. He is on the speakers’ bureau of Actavis,
Merck and Ferring, and received a research grant from
• Level 1 Accept completely Activis and Merck.
• Level 2 Accept with some reservations Kaylen Silverberg is on the speakers’ bureau of Actavis
• Level 3 Accept with major reservations and received a research grant from Actavis.
• Level 4 Reject with reservations Elena H. Yanushpolsky has nothing to disclose.
• Level 5 Reject completely

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