Human Reproduction Update 2000, Vol. 6 No. 2 pp. 139–148© European Society of Human Reproduction and Embryology
Comparison between different routes of progesterone
administration as luteal phase support in infertility
A.Tavaniotou1, J.Smitz1, C.Bourgain2and P.Devroey1,*
1Centre for Reproductive Medicine and2Department of Pathology, Dutch-Speaking Free University of Brussels, Brussels, Belgium
Received on July 20, 1999; accepted on January 12, 2000
Different routes of natural progesterone supplementation have been tried as luteal phase support in infertility
treatments. Orally administered progesterone is rapidly metabolized in the gastrointestinal tract and its use has
proved to be inferior toi.m. and vaginal routes.Progesterone i.m. achievesserum progesterone values that are within
the range of luteal phase and results in sufficient secretory transformation of the endometrium and satisfactory
pregnancy rates. The comparison between i.m. and vaginal progesterone has led to controversial results as regards
the superiority of one or the other in inducing secretory endometrial transformation. However, there is increasing
evidence in the literature to favour the use of vaginal progesterone. Vaginally administered progesterone achieves
adequate endometrial secretory transformation but its pharmacokinetic properties are greatly dependent on the
formulation used. After vaginal progesterone application, discrepancies have been detected between serum
progesterone values and histological endometrial features. Vaginally administered progesterone results in adequate
secretory endometrial transformation, despite serum progesterone values lower than those observed after i.m.
administration, even if they are lower than those observed during the luteal phase of the natural cycle. This
discrepancy is indicative of the first uterine pass effect and therefore of a better bioavailability of progesterone in the
uterus, with minimal systematic undesirable effects.
Key words: In-vitro fertilization/luteal phase/oocyte donation/progesterone supplementation
TABLE OF CONTENTS
Different routes of progesterone support in IVF
Different routes of progesterone support in
First uterine pass effect
Adequate secretory transformation of the endometrium is essential
for embryonic implantation during the so-called ‘implantation
window’. Synchronization between embryonic development and
endometrial receptivity is of main concern in infertility treatments,
namely in IVF, in oocyte donation programmes and in frozen–
thawed cycles. Although it has been several years since the first
report of a delivery after IVF (Steptoe and Edwards, 1978) and
oocyte donation (Lutjen et al., 1984), the mechanisms that govern
endometrial receptivity and embryo implantation have not yet been
receptivity depend solely on the duration of exposure to adequate
progesterone concentrations, provided that sufficient oestrogen
priming has already occurred during the follicular phase (de Ziegler
et al., 1992).
Human chorionic gonadotrophin (HCG) and progesterone are
ordinarily used as luteal phase support in IVF. It has been suggested
that HCG might be superior to progesterone in gonadotrophin-
releasing hormone (GnRH) agonist cycles for IVF (Soliman et al.,
1994), but its application has also been associated with ovarian
hyperstimulation syndrome (OHSS) (Herman et al., 1990; Smitz
et al.,1990;Araujoetal.,1994).Sincenatural progesteroneis rapidly
metabolized after oral administration, synthetic progestins have been
designed which resist enzymatic degradation. However, synthetic
progesterone derivatives have been associated with a number of
undesirableeffects, notablyonlipids (Hirvonenetal.,1981;Ottosson
et al., 1985) or with psychological effects that may be severe enough
to limit their use (Dennerstein et al., 1979; Sherwin and Gelfand,
1989). In addition, synthetic progestogens, mainly those with
androgenic properties, have been connected with an increased risk of
fetal congenital malformations (Revesz et al., 1960; Wilkins, 1960;
Nora and Nora, 1975; Aarskog, 1979). Natural progesterone has no
*To whom correspondence should be addressed at: AZ-VUB, Centre for Reproductive Medicine, Laarbeeklaan 101, 1090 Brussels, Belgium.
Tel: +32 2 477 6501; fax: +32 2 4774 6549.
140 A.Tavaniotou et al.
adverse effects on high density lipoproteins (HDL) (Ottosson et al.,
1985), no known teratogenicity (Chez, 1978; Rock et al., 1985;
Check et al., 1986) and is more effective in inducing secretory
dehydrogesterone (Pelliceret al., 1989).
Different routes of progesterone administration have been
analysed, such as the intranasal (Steege et al., 1986; Cicinelli et al.,
1993; Cicinelli et al., 1994), sublingual (Chakmakjian and
Zacharian, 1987; Stovall et al., 1996) and rectal routes (Nillius and
Johansson, 1971; Johansson 1972; Chakmakjian and Zacharian,
1987). However, oral (Whitehead et al., 1980; Maxson and
Hargrove, 1985; Simon et al., 1993), i.m. (Nillius and Johansson,
1971; Johansson 1972; Devroey et al., 1989; Bourgain et al., 1990)
and vaginal (Nillius and Johansson, 1971; Villanueva et al., 1981;
Devroey et al., 1989; Archer et al., 1995; Fanchin et al., 1997)
routes have been the most frequently investigated.
As natural progesterone is rapidly metabolized after oral
ingestion, a number of techniques have been developed in order to
improve its pharmacokinetic properties (Kincl et al., 1978).
Micronization of progesterone reduces particle size and increases
1985; Kimzey et al., 1991). Furthermore the combination of
micronized progesterone with polycarbophil gel results in a
sustained-release vaginal formulation (Casanas-Roux et al., 1996;
Ross et al., 1997; Fanchin et al., 1997; Gibbons et al., 1998).
Many studies have reported on the different effects that different
natural progesterone formulations exert on endometrial secretory
transformation. Orally administered natural progesterone has been
shown to be ineffective in inducing an in-phase secretory
endometrium (Lane et al., 1983; Dehou et al., 1987; Devroey et al.,
1988; Bourgain et al., 1990; Moyer et al., 1993). Progesterone i.m.
results in high serum progesterone concentrations, adequate
endometrial secretory features (Navot et al., 1986; Devroey et al.,
1989; Davies et al., 1990; Sauer et al., 1991) and satisfactory
pregnancy rates (Navot et al., 1986; Younis et al., 1992; Smitz
et al., 1992; Pados et al., 1992; Artini et al., 1995). However, daily
injections may be uncomfortable, especially for long-term
treatments, and endometrial histological characteristics may be
inferior to those observed after vaginal progesterone application
(Devroey et al., 1989; Bourgain et al., 1990). Vaginal progesterone
results in adequate endometrial secretory transformation, despite
serum progesterone concentrations that may be lower than those
observed during the luteal phase (Salat-Baroux et al., 1988;
Cicinelli et al., 1996; Fanchin et al., 1997). These discrepancies
between serum progesterone values and histological findings after
vaginal progesterone administration are indicative of the so-called
first uterine pass effect, i.e. the direct effect that might be generated
on the endometrium after vaginal progesterone application (Miles
et al., 1994; Balasch et al., 1996; Fanchin et al., 1997).
The aim of this paper is to provide a review of published data
regarding the different routes of progesterone supplementation as
luteal phase support in infertility treatments, mainly in ovulation
Pharmacokinetic properties and histological findings after different
routes of progesterone supplementation are reviewed. Particular
emphasis is placed on the existing evidence from the literature for
the so-called first uterine pass effect after vaginal progesterone
Although the convenience of orally administered progesterone is
indisputable, its use has been associated with systematic adverse
effects, e.g. drowsiness, flushing and nausea (Maxson and
Hargrove, 1985; Kimzey et al., 1991; Pouly et al., 1996). Sedative
and hypnotic effects or fluid retention have also been attributed to
progesterone or its metabolites after oral ingestion (Arafat et al.,
progesterone are further influenced by food uptake (Simon et al.,
1993) or by the characteristics of progesterone preparation such as
vehicle and particle size (Hargrove et al., 1989).
After oral digestion, progesterone is rapidly absorbed, rapidly
metabolized from the intestines and, during the first hepatic pass,
cleared from the circulation (Whitehead et al., 1980; Nahoul et al.,
1993). Maximal plasma progesterone concentrations are reached
(Whitehead et al., 1980; Padwick et al., 1986). Micronization of
natural progesterone improves its absorption and bioavailability
(Chakmakjian and Zacharian, 1987; Norman et al., 1991). After
ingestion of 200 mg of micronized progesterone, mean serum
progesterone concentrations (within the range of luteal phase) are
attained in 2–4 h and remain significantly elevated for the next 6–7 h
(Maxson and Hargrove, 1985; Padwick et al., 1986; Norman et al.,
1991). Nevertheless, even higher doses of oral micronized
progesterone (200 or 300 mg/day) have failed to induce uniform
secretory endometrial features in menopausal women (Lane et al.,
1983; Moyer et al., 1993). It has been indicated that interference
from high concentrations of progesterone metabolites produced
during the first liver pass, might provide serum progesterone
concentrations that are erroneously high, thus accounting for
concentrations (Nahoul et al., 1987; Nahoul and de Ziegler, 1994).
These falsely elevated progesterone values are caused by cross-
reaction of metabolites with the anti-progesterone polyclonal
antibodies in the direct immunoassays used in routine laboratories.
However, part of this interference can be eliminated by sample
pretreatments such as extraction with organic solvents followed by
chromatography or by using selected specific monoclonal
antibodies (Nahoul et al., 1987; Nahoul and de Ziegler, 1994).
The i.m. application of progesterone is uncomfortable, as it requires
daily injections to maintain appropriate serum concentrations. This
may be of main concern for patients with ovarian failure in oocyte
donation programmes, who are in need of a long-term treatment for
pregnancy support. Furthermore, i.m. progesterone administration
may lead to marked inflammation at the injection site, resulting in
redness, pain and even sterile abscess formation.
Progesterone is rapidly absorbed after i.m. administration. High
plasma concentrations are achieved within 2 h and peak
concentrations are reached within 8 h (Nillius and Johansson, 1971;
Johansson, 1972; Simon et al., 1993). Serum concentrations
equivalent to those seen during the luteal phase have been attained
after the injection of 25 mg progesterone (Nillius and Johansson,
1971; Johansson, 1972). It has been also indicated that the i.m. site
of injection might function as a depot, by progesterone
accumulation within fat tissue, thus resulting in more sustained
Comparison of different routes of progesterone administration 141
serum progesterone concentrations after i.m. injection than after
vaginal or rectal application (Nillius and Johansson, 1971).
However, this was not confirmed by other studies using different
progesterone formulations, where better steady-state concentrations
were detected with the vaginal route (Devroey et al., 1989; Artini
et al., 1995). Ina randomizedstudy(Simon etal., 1993),comparing
oral micronized progesterone (200 mg) with i.m. progesterone
(50 mg), it was found that maximum serum progesterone
concentrations (Cmax) were higher (14.3 versus 4.3 ng/ml) and the
time (Tmax) taken to achieve these concentrations was longer (8.7
versus 2.5 h) after i.m. progesterone administration. Furthermore,
the relative bioavailability of oral progesterone was significantly
lower, only 10% of that observed after i.m. progesterone indicating,
according to the authors, a delayed rate of progesterone absorption
after i.m. administration, but with a greater availability of this
Vaginal mucosa epithelium readily absorbs proteins and lipids
(Hafez, 1977; Forsberg, 1995). It has been indicated that the vagina
might have a reservoir effect and vaginal mucosa might function as
a rate-limiting membrane allowing only a finite amount of
progesterone to be absorbed (Archer et al., 1995). Transvaginal
application of progesterone has been correlated with some side-
effects, e.g. discharge, irritation or local warmth (Kimzey et al.,
1991; Archer et al., 1995; Pouly et al., 1996). Progesterone
absorption from the vaginal epithelium is enhanced after vaginal
oestrogenization (Villanueva et al., 1981). Progesterone absorption
is further influenced by the formulation used, whether tablets,
suppositories, creams, oil-based solutions or the recently released
polycarbophil gel (Price et al., 1983; Fulper et al., 1987; Kimzey
et al., 1991; Cicinelli et al., 1996; Fanchin et al., 1997).
Vaginal application results in avoidance of first-pass metabolism
in the gastrointestinal tract and liver, and in sustained plasma
concentrations (Nillius and Johansson, 1971; Norman et al., 1991;
Kimzey et al., 1991; Archer et al., 1995). After vaginal
administration of progesterone, plasma progesterone levels reach
maximalconcentrations within3–8h, dependingon theformulation
used (Nillius and Johansson, 1971; Norman et al., 1991; Archer
et al., 1995; Artini et al., 1995) and gradually fall during the next
8 h (Nillius and Johansson, 1971). Vaginally administered
progesterone disappears more rapidly from the circulation than the
i.m.. Furthermore, higher doses are necessary of vaginal
progesterone (100 mg) than of i.m. progesterone (25 mg), in order
to achieve serum progesterone concentrations of the luteal phase
range (Nillius and Johansson, 1971; Johansson, 1972). The
comparison of thesamedoses (300 mg) of micronized progesterone
in a non-liquefying cream vaginally and capsules of micronized
progesterone orally favoured the use of the vaginal formulation,
since all the patients achieved luteal
concentrations in the vaginal group compared with only two out of
five patients in the oral group (Kimzey et al., 1991). The number of
daily doses necessary to achieve sustained serum progesterone
concentrations is dependent on the formulation used. Most
frequently, 300–600 mg of progesterone is administered daily,
spread over two or three dosages (Devroey et al., 1989; Critchley
et al., 1990;deZiegler et al., 1992). However, it has been suggested
that lower doses (45–90 mg) applied once a day or even once every
other day, might be effective with sustained-release formulations
(Pouly et al., 1996; Fanchin et al., 1997; Ross et al., 1997; Warren
et al., 1999).
Different routes of progesterone support in IVF
The introduction of GnRH analogues has led to fewer cycle
cancellations in IVF, by the prevention of a premature LH surge. In
cycles using GnRH agonists, a luteal phase defect has been
described, thus making luteal phase support necessary (Wildt et al.,
1986; Smitz et al., 1987). However, the need for luteal phase
supplementation was not confirmed in other ovarian stimulation
protocols not using GnRH analogues (Daya, 1988). HCG (i.m.) and
progesterone (in various routes) are used as luteal phase support in
ovulation induction, but the superiority of one form over the other
has not yet been established. In ameta-analysis of randomized trials
comparing different types of luteal support, it was suggested that
HCG might be superior to progesterone in GnRH agonist cycles
(Soliman et al., 1994).
Oral, vaginal and i.m. routes of progesterone administration have
IVF. Orally administered progesterone has proved to be inefficient
incomparisonwith i.m.HCG(Buvat etal.,1990a). Thecomparison
of i.m. HCG with i.m. or intravaginal progesterone has provided
controversial results. Some of the studies have found no difference
in pregnancy rates between i.m. progesterone and i.m. HCG (Smitz
et al., 1988; Claman et al., 1992; Araujo et al., 1994; Artini et al.,
1995) or between vaginal progesterone and i.m. HCG (Buvat et al.,
1990b; Artini et al., 1995) and others have indicated the superiority
of i.m. HCG to i.m. progesterone (Golan et al., 1993).
There are few prospective randomized studies in the literature
supplementation as luteal phase support in IVF cycles (Table I). No
differences in pregnancy rates were detected in a prospective
randomized comparison of i.m. HCG, i.m. progesterone and
micronized progesterone vaginally as luteal phase supplementation
in GnRH agonist cycles. However, better steady-state serum
progesterone concentrations were achieved with the vaginal
progesterone to i.m. progesterone supported the use of the latter, as
it resulted in significantly higher implantation rates (18.1% oral
versus 40.9% i.m.) (Licciardi et al., 1999). In addition, significantly
higher implantation rates were detected in GnRH agonist cycles
using vaginal micronized progesterone as luteal phase support
compared with cycles using the same dose (400 mg/day) of
micronized progesterone orally (Buvat et al., 1990b). On the other
hand, no difference in pregnancy rates was detected between oral
micronizedprogesteroneandmicronized progesterone in sustained-
release carbophilic gel as luteal phase support in GnRH agonist
cycles (Pouly et al., 1996).
In another prospective randomized study comparing i.m. natural
progesterone (50 mg/day) with vaginal micronized progesterone
(600 mg/day), in GnRH agonist cycles for IVF, significantly lower
earlymiscarriagerateas well as atrend towards higher implantation
rates, despite lower serum progesterone concentrations, was
detected in the vaginal group (Smitz et al., 1992). This might be
correlated with improved endometrial features after vaginal, rather
than after i.m. progesterone application, despite lower plasma
concentrations, thus suggesting a better local progesterone
routes of progesterone
142 A.Tavaniotou et al.
bioavailability in the uterus (Bourgain et al., 1992; Bourgain et al.,
1994). Endometrial biopsies obtained in the mid-luteal phase in
GnRH/human menopausal gonadotrophin (HMG) cycles for IVF
revealed a higher proportion of increased dissociated maturation in
the i.m. group, while most endometria were in phase after
supplementation with vaginal micronized progesterone (Bourgain
et al., 1994). Maturation delay with a mean value of 2.3 days was
also detected inmid-luteal biopsies after similar ovarianstimulation
and luteal phase supplementation with i.m. progesterone (50 mg/
day) and oestradiol valerate (6 mg/day) (Van Steirteghem et al.,
1988). On other hand, 18 of 22 mid-luteal biopsies performed in
GnRH/HMG cycles were in phase after supplementation with
vaginal micronized progesterone (600 mg/day) (Smitz et al., 1993).
Different routes of progesterone support in oocyte
Adequate secretory endometrial transformation and therefore
endometrial receptivity is the goal in oocyte donation programmes.
Oocyte donation protocols provide a useful tool in studying
endometrial receptivity. Progesterone supplementation must induce
secretory endometrial transformation and lead to endometrial
features that permit embryo implantation during the so-called
‘implantation window’. Furthermore, the need for long-term
progesterone treatment in women with deprived ovarian function
points to the importance of detecting the optimal progesterone
formulation. Many studies have therefore been performed in order
to investigate the various effects that different routes and doses of
progesterone supplementation exert on the endometrium.
The majority of oocyte donation programmes in the last decade
have used the i.m. (Navot et al., 1986; Younis et al., 1992; Pados
et al., 1992; Potter et al., 1998) or the vaginal route (Lutjen et al.,
1986; Salat-Baroux et al., 1988; Frydman et al., 1990; Pados et al.,
1992) and both of these have succeeded in providing favourable
pregnancy results. Different studies have analysed the hormonal
and histological parameters after various routes and doses of
progesterone supplementation in oocyte donation programmes
(Table II). Devroey et al. (1989) studied women with missing
ovaries for oocyte donation. The authors compared the histological
endometrial features in four groups of patients. After endometrial
priming with oestrogen, the patients received either 100 mg of
natural progesterone i.m. or 300 mg of micronized progesterone
orally or micronized progesterone vaginally in two different doses
(300 or 600 mg/day).Progesterone
commenced on day 14 and endometrial biopsies were performed on
day 21. Serum progesterone concentrations five times higher in the
i.m. group than in the intravaginal group were detected, although
better steady-state concentrations with fewer fluctuations in serum
Table I. Summary of prospective randomized studies comparing different routes of progesterone support in GnRH agonist cycles for IVF
Utrogestan = natural micronized progesterone capsules; Crinone = natural progesterone in vaginal gel.
aNo HCG was given as luteal phase support if the concentration of oestradiol was >2700 pg/ml.
bP < 0.01 versus oral;cP < 0.01 versus oral.
*P = 0.07; **P = 0.004.
AuthorStimulation protocolNo of
Luteal phase support Pregnancy rates (%)
(implantation rates) (%)
Buvat et al. (1990)
Triptorelin/HMG (short)32 HCG 3 × 1500 IUa
19Utrogestan 400 mg/day orally5
20Utrogestan 400 mg/day vaginally 55c
Triptorelin/HMG (long)47 HCG 3 × 1500 IUa
41 Utrogestan 400 mg/day orally27
35Utrogestan 400 mg/day vaginally 40
Smitz et al. (1992)
Buserelin/HMG (long)131Progesterone 50 mg i.m. + oestradiol
valerate 6 mg/day
131Utrogestan 600 mg vaginally + oestradiol
valerate 6 mg/day
Artini et al. (1995)
Buserelin/pFSH + HMG (long) 44 HCG 3 × 2000 IU 13.6
44Progesterone 50 mg i.m./day 13.6
44 Micronized progesterone in vaginal cream
44 No support9.1
Pouly et al. (1996)
Decapeptyl/HMG (long) 139Crinone 90 mg/day vaginally28.8 (35.3)
144Utrogestan 300 mg/day orally 25 (29.9)
Licciardi et al. (1999) GnRH/FSH/HMG (long)
19 Progesterone 50 mg i.m. 57.9 (40.9)**
24 Micronized progesterone 600 mg/day orally 45.8 (18.1)**
Comparison of different routes of progesterone administration 143
progesterone concentrations were observed in the vaginal group.
Among the four groups, serum progesterone values were lowest
after oral progesterone administration. Additionally, none of the
biopsies obtained from this group provided evidence of adequate
progesteroneeffect. Onthecontrary,classicalendometrial secretory
morphology was induced both in i.m. and intravaginal groups but
better endometrial maturation was achieved in the vaginal group.
The insufficiency of orally administered progesterone to induce
adequate endometrial secretory transformation in oocyte donation
programmes has been confirmed by other studies (Dehou et al.,
1987; Bourgain et al., 1990; Critchley et al., 1990). Dehou et al.
(1987) reported on endometrial maturation delays and abnormal
endometrial features, as assessed both with light and electron
microscopy, in biopsies from artificial cycles replaced during the
secretory phase with 300–600 mg oral micronized progesterone/
day. The control group that was composed of women treated with
50–100 i.m. natural progesterone/day revealed normal glandular
maturation. In another study, it was demonstrated that only one out
of five mid-luteal biopsies during mock cycles in patients with
premature ovarian failure were in phase after daily ingestion of 300
mg oral micronized progesterone. In contrast, five out of six
biopsies obtained after daily treatment with 300 mg vaginal
micronized progesterone were in phase (Critchley et al., 1990).
The ability of natural vaginal progesterone to induce secretory
transformation ofthe endometrium
demonstrated in the literature (Salat-Baroux et al., 1988; Hung
et al., 1989; Devroey et al., 1989; Bourgain et al., 1990; de Ziegler
et al., 1992; Cicinelli et al., 1996). De Ziegler et al. (1992)
performed endometrial biopsies on days 20 and 24 of the cycle in
women with deprived ovarian function after application of 300 mg
micronized progesterone vaginally/day and prior endometrial
priming with oestrogen for 14 days. In most of the cases, the
endometrium was in phase and the distribution of oestrogen and
progesterone receptors was typical of that expected for this day of
the cycle. Similarly, all late luteal phase biopsies were in phase in
artificial cycles after substitution with vaginal progesterone (Hung
et al., 1989).
Progesterone administered i.m. induces adequate endometrial
transformation and satisfactory pregnancy rates in oocyte donation
protocols. Of late luteal endometrial biopsies, 14% were out of
phase after i.m. progesterone (50–100 mg), but this was limited to
patients aged >40 years and was corrected by higher progesterone
dosages (Potter et al., 1998). Furthermore, endometrial biopsy
specimens obtained on days 18 and 22 of artificial cycles
supplemented with 25–50 mg i.m. progesterone/day corresponded
to the expected days of the cycle (17 ± 0.57 and 21 ± 1.4
respectively) (Navot et al., 1986).
The comparison of i.m. and vaginal routes has produced
conflicting results. Bourgain et al. (1990) performed mid-luteal
biopsies during trial cycles in patients undergoing oocyte donation
because of primary ovarian failure. A range of abnormal
endometrial features in the group of patients receiving adoseof 100
mg i.m. progesterone/day were detected,
maturation delay in 43.5% of patients and asynchrony between
endometrial glands and stroma in 9%, with the maturation delay
observed in the glandular endometrial compartment. On the other
hand, all endometrial features studied both with electron and light
microscopy, were markedly improved in the vaginal groups which
has been repeatedly
were supplemented with300 or 600 mg of micronized progesterone
daily. Asynchronous maturation between endometrial glands and
stroma with the stroma being fibrocystic or dense in the first
replacement cycle have also been reported after i.m. progesterone
endometrial glands compared with stroma, have been detected after
i.m. progesterone treatment (Miles et al., 1994) and, although not
statistically significant, such dissociated maturation was not found
after supplementation with vaginal progesterone. As clinical
pregnancies were achieved only in patients with synchronous
endometrial maturation and no maturation delay of >2 days
(Bourgain et al., 1990), improved and synchronous endometrial
development might provide a better chance of implantation.
Although overall endometrial delay was improved in the vaginal
groups, significantly higher serum progesterone concentrations
were observed in the i.m. group and no difference was detected
between the two vaginal groups (progesterone dose of 300 or
600 mg) with respectto morphology
concentrations (Bourgain et al., 1990).The observation that,despite
significantly lower serum progesterone concentrations, vaginally
transformation and satisfactory pregnancy and implantation rates
was also confirmed by a recent randomized study comparing i.m.
progesterone with vaginal micronized progesterone in a sustained-
release polycarbophil gel, in trial cycles for oocyte donation
(Gibbons et al., 1998). Endometrial histology assessed with late
endometrial biopsies (days 25–27), showed normal endometrial
development in both groups, although serum progesterone values
were significantly higher in the group receiving i.m. progesterone.
However, steady-state progesterone concentrations were attained
earlier after vaginal progesterone application.
On the other hand, different results have been obtained in other
studies comparing i.m. with vaginal routes of progesterone
(1991) reported on better histological
supplementation (100 mg/day), than after vaginal progesterone
suppositories (200 mg) in ovarian failure patients. Since better
endometrial scoring with less discrepancy with the chronological
date expectations (–1.5 days versus –2.9 days) and higher serum
progesterone concentrations have been reported after daily i.m.
progesterone administration than after vaginal administration in
patients with primary ovarian failure (Davies et al., 1990), it has
been suggestedthat higher
concentrations might be correlated with improved endometrial
histology. It was also found that five-fold higher i.m. progesterone
dosage than the standard had no effect on endometrial glandular
maturation in artificial cycles; however, according to the authors, it
mighthavesomeeffect onthestroma (Li et al., 1992).Furthermore,
luteal phase progesterone concentrations were not detected to be a
significant factor affecting pregnancy or implantation rates in a
retrospective analysis in an oocyte donation programme (Younis
et al., 1992).
There is increasing evidence in the literature that serum
progesterone concentrations after vaginal progesterone application
are not indicative of the effect that vaginally administered
progesterone has on the endometrium. The daily application of
micronized progesterone in an oil-based solution (100 mg) to
144A.Tavaniotou et al.
Table II. Summary of studies comparing hormonal and histological parameters between different routes of progesterone administration as luteal phase support in artificial cycles for oocyte
donation and after pretreatment with various types of oestrogen during the follicular phase
Utrogestan = natural micronized progesterone capsules; Crinone = natural progesterone in vaginal gel; Cyclogest = natural progesterone pessaries; p.o. = orally; p.v. = vaginally
aP < 0.01;bP = 0.014;cP < 0.0001;dP = 0.03;eP < 0.05;fP < 0.00001.
Daily progesterone dose
Luteal progesterone values
Day of biopsy
Dehou et al. (1987)
Primary ovarian failure
Utrogestan 300–600 mg p.o
Progesterone 50–100 mg i.m.
Normal glandular maturation.
Fibrocystic stroma in first cycle,
improved in next cycles
Devroey et al. (1989)
Utrogestan 300 mg p.o. (100 mg
on day 14)
Lowest serum progesteronebetween all four groups
100% out of phase
Progesterone 100 mg i.m. (50 mg
on day 14)
Serum progesterone five times
higher than the vaginal groups
2/31 out of phase
Utrogestan 300 mg p.v (100 mg
on day 14)
18/18 in phase
Utrogestan 600 mg p.v. (200 mg
on day 14)
10/10 in phase
Critchley et al. (1990)
Premature ovarian failure
Micronized progesterone 300 mg p.o.
14 ± 2 (mean ± SE) nmol/la
100 mg micronized progesterone
30 ± 16 (mean ± SE) nmol/la
300 mg micronized progesterone p.v.
45 ± 5 (mean ± SE) nmol/la
Bourgain et al. (1990)
Primary ovarian failure
Utrogestan 300 mg p.o.
2.79 ± 0.6 (mean ± SEM) µg/l
1/12 in phase
Progesterone 100 mg i.m.
43.4 ± 0.60 (mean ±SEM) µg/lc
16/34 in phase
Utrogestan 300 mg p.v
6.79 ± 1.28 (mean ±SEM) µg/lc
16/21 in phase.
Utrogestan 600 mg p.v.
8.09 ± 1.74 (mean ±SEM) µg/lc
6/8 in phase
Davies et al. (1990)
Premature ovarian failure/
gonadal dysgenesis/failureof IVF stimulation
Progesterone 25–50 mg i.m.
60 ± 8 nmol/lb
Mean endometrial score: –1.5
Cyclogest 200–400 mg p.v.
29.8 ± 5.4 nmol/lb
Mean endometrial score: – 2.9
Sauer et al. (1991)
Idiopathic ovarian failure/
Progesterone 100 mg i.m. (50 mg
on day 15)
48.8 ± 10.4 ng/ml
Progesterone suppositories 200 mg p.v.
(100 mg on day 15)
29.4 ± 4.8 ng/ml
7/19 excessive oestrogen effect
Miles et al. (1994)
Progesterone 100 mg i.m.
69.8 ± 5.9 (mean ± SE) ng/mle
Mean dating of glands: 18.9 ± 0.1
Micronized progesterone capsules
800 mg p.v.
11.9 ± 1.2 (mean ± SE) ng/mle.
Mean dating of glands: 20.5 ± 1
Gibbons et al. (1998)
Primary ovarian failure/
diminished ovarian reserve
Progesterone 100 mg i.m.
Crinone 180 mg p.v.
Comparison of different routes of progesterone administration 145
post-menopausal women after previous oestrogen priming, was
able to induce endometrial secretory changes, despite maximal
serum hormonal concentrations lower than those observed during
theluteal phase(5.4± 0.92 ng/ml) (Cicinelli et al., 1996). Similarly,
16 of 18 mid-luteal biopsies performed in trial cycles for oocyte
donation, were in phase after endometrial preparation with
oestrogen and vaginal micronized progesterone (100–200 mg),
resulting in pregnancy rates of 31%, despite serum progesterone
concentrations lower than those observed during the luteal phase of
the natural cycle (Salat-Baroux et al., 1988). Low mid-luteal
progesteroneconcentrations but arateof 75%in-phaselate(day 28)
endometrial biopsies were also reported by Balasch et al. (1996) in
infertilepatients undergoingartificialcycles andsupplementedwith
vaginal micronized progesterone.
Successful secretory endometrial transformation was also
observed in post-menopausal women or women with secondary
amenorrhoea after application of micronized progesterone in
carbophilic gel, with low doses ranging from 45 to 90 mg every
other day (Casanas-Roux et al., 1996; Ross et al., 1997; Fanchin
et al., 1997; Warren et al., 1999), despite low mean serum
progesterone concentrations (3.6 ± 0.2 ng/ml) (Fanchin et al.,
1997). The fact that serum progesterone concentrations are not
indicative of the local bioavailability that vaginally administered
progesterone exerts on the endometrium was further confirmed by
Miles et al. (1994). After 6 days of progesterone replacement in 20
functionally agonadal women who were candidates for oocyte
donation, serum progesterone concentrations were almost seven
times lower as a result of the vaginal route (800 mg/day) than as a
result of the i.m. route (100 mg/day), whereas endometrial
progesterone concentrations were almost 10 times higher after
vaginal progesterone than after i.m. progesterone.
First uterine pass effect
Vaginal progesterone administered as luteal phase supplementation
in oocyte donation programmes and in stimulated cycles results in
adequate endometrial secretory transformation and satisfactory
pregnancy rates (Lutjen et al., 1986; Salat-Baroux et al., 1988;
Devroey et al., 1989; Smitz et al., 1992; Smitz et al., 1993; Artini
et al., 1995; Gibbons et al., 1998). In the majority of the studies,
orally administered progesteronewas foundto beinferior tovaginal
(Devroey et al., 1989; Bourgain et al., 1990; Critchley et al., 1990)
or to i.m. administration (Dehou et al., 1987; Devroey et al., 1988;
Licciardi et al., 1999) and it has beensuggested that its usemight be
limited to preparatory cycles (Devroey et al., 1989; Pados et al.,
The comparison between vaginal and i.m. progesterone provided
contradictory results. Some of the studies advocated the superiority
of the vaginal route due to higher implantation and lower early
miscarriage rates (Smitz et al., 1992) or due to better histological
findings (Bourgain et al., 1990, 1994) or because of better steady-
state progesterone concentrations (Artini et al., 1995; Gibbons
et al., 1998) and other trials supported the superiority of the i.m.
route (Davies et al., 1990; Sauer et al., 1991).
Although some studies have demonstrated better steady-state
concentrations after vaginal formulation with less intra- and inter-
individual variations (Devroey et al., 1989; Artini et al., 1995),
lower serum progesterone values were constantly observed after
vaginal application thanafter i.m. application(Devroey et al., 1989;
Davies et al., 1990; Sauer et al., 1991; Smitz et al., 1992; Miles
et al., 1994). In some trials, although the observed serum
progesterone concentrations were lower than those observed during
the luteal phase of the natural cycle, adequate secretory endometrial
transformation was achieved (Balasch et al., 1996; Casanas-Roux
et al., 1996; Ross et al., 1997; Fanchin et al., 1997; Warren et al.,
progesterone concentrations and normal histological findings
suggests that vaginally administered progesterone exerts a
pronounced local effect on the endometrium, the so-called first
uterine pass effect; i.e. a fraction of the regimen might have on the
endometriumadirectimpact,without enteringatfirst thesystematic
circulation. Consequently, this better local bioavailability of
vaginally administered progesterone in the uterus might result in a
maximal local endometrial effect and minimal undesirable
There is increasing evidence in the literature from experimental
models that drugs administered vaginally have a preferential
distribution in the uterus. Miles et al. (1994) have elegantly shown
in their experiment that, despite lower serum progesterone
concentrations, endometrial progesterone concentrations are higher
after vaginal progesterone application than after i.m.. Significantly
higher progesterone concentrations were detected in the uterine
artery than in the radial artery in post-menopausal women
undergoing hysterectomy who received micronized progesterone in
an oil-based solution before the operation, providing further
evidence of the preferential drug distribution to the uterus after
vaginal application (Cicinelli et al., 1998). High endometrial
progesterone concentrations were detected in a ex-vivo uterine
perfusion model after application of radio-labelled progesterone in
the vaginal cuff after hysterectomy, suggesting that progesterone
migratesprogressively into the
concentrations in endometrium and myometrium (Bulletti et al.,
1997). Similar results have also been obtained after the vaginal
application of other compounds, e.g. terbutaline, misoprostol,
danazol (Kullander and Svanberg, 1985; El-Refaey et al., 1995;
Mizutani et al., 1995).
Parallel to thebenefit of achieving high endometrial progesterone
concentrations with the vaginal route, it has been suggested that
such high concentrations might exert an unfavourable effect by
influencing the secretion of endometrial progesterone-dependent
peptides such as insulin-like growth factor binding protein-1
(IGFBP-1). This was indicated by a prospective, randomized study
comparing orally (300 mg/day) and vaginally (300 mg/day)
administered progesterone in non-IVF, clomiphene citrate-induced
cycles, where lower pregnancy rates and higher serum IGFBP-1
concentrations were observed with the vaginal formulation (Wang
and Soong, 1996). Nevertheless, it has also been demonstrated that
clomiphene treatment increases serum concentrations of IGFBP-1
(Pekonen et al., 1992) and theneed of luteal phase support in cycles
using clomiphene citrate has not yet been confirmed (Daya, 1988;
Agarwal and Buyalos, 1995; Shalev et al., 1995; Deaton et al.,
1997). Furthermore, no difference in endometrial histological
features were detected between two (300 and 600 mg/day)
(Bourgain et al., 1990) and three (45, 90, 180 mg every other day)
(Fanchin et al., 1997) different vaginal progesterone dosages as
luteal phase support in patients with ovarian failure. However, it
uterusand reaches high
146 A.Tavaniotou et al.
could be intriguing to investigate the possible favourable or adverse
effects of high endometrial progesterone concentrations, on all the
possible paracrine or autocrine mechanisms that are involved in
embryo implantation and in all different forms of ovulation
induction and luteal phase support.
Although there is evidence for the first uterine pass effect after
vaginal drug application, the mechanism of this has not yet been
elucidated. Whether this is due to absorption into the rich venous or
lymphatic vaginal system and/or possibly countercurrent transfer
between uterovaginal lymph vessels or veins and arteries, or due to
direct drug diffusion through tissues or due to intraluminal transfer
from the uterus to vagina similar to sperm transport, has not yet
been clarified. Nevertheless, the vaginal route might, as a result of
thefirst uterinepass effect, be provedto bea valuable routefor drug
delivery, not only in infertility treatments but also in daily practice
in general obstetrics and gynaecology.
Thereis increasing evidence in the literature suggestingthat vaginal
progesterone might be superior to other routes, mainly due to the
postulated first uterine pass effect, which results in a better local
progesterone bioavailability in the uterus. However, large
prospective randomized studies are necessary in order to confirm
this superiority and to detect the optimal dose and formulation.
Furthermore, the development of experimental models is necessary
in order to investigate the importance and mechanism of the
postulated first uterine pass effect.
The authors wish to thank the clinical, paraclinical and laboratory
staff of the Centre for Reproductive Medicine, Brussels, Belgium.
The authors also thank Mr F.Winter of the Language Education
Centre for correcting the manuscript.
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Received on July 20, 1999; accepted on January 12, 2000