Horm Mol Biol Clin Invest 2016; 27(1): 35–48

Gian Carlo Di Renzo*, Irene Giardina, Graziano Clerici, Eleonora Brillo and Sandro Gerli

Progesterone in normal and pathological

pregnancy
DOI 10.1515/hmbci-2016-0038 a tocolytic agent and also in the maintenance of uterine
Received July 21, 2016; accepted August 4, 2016 quiescence).

Abstract: Progesterone is an essential hormone in the Keywords: pathological pregnancy; pregnancy; preterm
process of reproduction. It is involved in the menstrual birth; progesterone; tocolysis.
cycle, implantation and is essential for pregnancy main-
tenance. It has been proposed and extensively used in the
treatment of different gynecological pathologies as well
as in assisted reproductive technologies and in the main-
Introduction
tenance of pregnancy. Called “the pregnancy hormone”,
Progesterone is an essential hormone in the process
natural progesterone is essential before pregnancy and
of reproduction. It is involved in the menstrual cycle,
has a crucial role in its maintenance based on different
implantation and is essential for pregnancy mainte-
mechanisms such as: modulation of maternal immune
nance. It has been proposed and extensively used in the
response and suppression of inflammatory response (the
treatment of different gynecological pathologies, such as
presence of progesterone and its interaction with pro-
endometrial hyperplasia, dysfunctional uterine bleeding,
gesterone receptors at the decidua level appears to play
amenorrhoea, luteal phase deficiency and premenstrual
a major role in the maternal defense strategy), reduction
syndrome, as well as in assisted reproductive technologies
of uterine contractility (adequate progesterone concentra-
and in the maintenance of pregnancy, alone or in combi-
tions in myometrium are able to counteract prostaglandin
nation with estrogens or to prevent endometrial hyper-
stimulatory activity as well as oxytocin), improvement of
plasia from unopposed estrogen in hormone replacement
utero-placental circulation and luteal phase support (it
therapy [1]. A clear distinction should be made with so
has been demonstrated that progesterone may promote
named progestins which are synthetic progestogens that
the invasion of extravillous trophoblasts to the decidua by
have progestogenic effects similar to those of natural pro-
inhibiting apoptosis of extravillous trophoblasts). Once
gesterone and are commonly used for hormonal contra-
the therapeutic need of progesterone is established, the
ception (either alone or with an estrogen).
key factor is the decision of the best route to administer
Moreover, progesterone is also efficacious when con-
the hormone and the optimal dosage determination. Pro-
tinuation of pregnancy is hampered by immunological
gesterone can be administered by many different routes,
factors, luteinic and neuroendocrine deficiencies and
but the most utilized are oral, the vaginal and intramus-
myometrial hypercontractility.
cular administration. The main uses of progesterone are
represented by: threatened miscarriage, recurrent mis-
carriage and preterm birth (in the prevention strategy, as

*Corresponding author: Gian Carlo Di Renzo, MD, PhD, FRCOG (hon),
FACOG (hon), FICOG (hon), Professor and Chairman, Department of
Obstetrics and Gynaecology, Centre for Perinatal and Reproductive
Medicine, Santa Maria della Misericordia University Hospital,
06132 San Sisto, Perugia, Italy, Phone: +39 075 5783829,
+39 075 5783231, Fax: +39 075 5783829,
E-mail: giancarlo.direnzo@unipg.it
Irene Giardina, Graziano Clerici, Eleonora Brillo and Sandro Gerli:
Department of Obstetrics and Gynaecology and Centre for Perinatal
and Reproductive Medicine, University of Perugia, Perugia, Italy
Role of progesterone
Called “the pregnancy hormone”, natural progester-
one is essential before pregnancy and has a crucial role
in its maintenance based on different mechanisms such
as: modulation of maternal immune response [1–3] and
suppression of inflammatory response [4], reduction of
uterine contractility [5–7], improvement of utero-placen-
tal circulation and luteal phase support [8, 9].
Hence, the therapeutic application of progester-
one during pregnancy, is targeted to the prevention and

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36      Di Renzo et al.: Progesterone in normal and pathological pregnancy
treatment of threatened miscarriage, recurrent miscar-
riage and preterm birth.
Immunological factors and role in
implantation
For the maternal immune system, the fetus is recognized
as a semi-allograft. Maternal immune response, in fact,
has a key role not only during the implantation process
but also in the maintenance of early pregnancy. The
maternal immune cells do not attack and reject a fetus
during the pregnancy period. The immune tolerance is
established in the maternal decidua in a specific area
defined as the feto-maternal interface. On the contrary,
if there is an alteration of the complex local immune
network and maternal immune cells recognize the fetus
as not-self, the maternal immune cells will reject the
embryo fetus leading to implantation failure and miscar-
riage will occur [10].
The association between pro-inflammatory cytokines
and recurrent miscarriages may be due to an increase
in cell-mediated immunoresponse with a low antibody
Pregnancy outcome
Fetus/trophoblast
50% paternal/50% maternal
PIF - Preimplantation factor
Progesterone induced blocking factor (PIBF) at the decidual (CD56+) and PBMC level
Progesterone level sufficient to
form PIBF
Asymmetric antibodies Th2
bias’ NK cells
Fetus protection
Delivery
Figure 1: The pivotal role of progesterone receptor-mediated immunomodulation in successful pregnancy.
LAK cells, Lymphokine activated killer cell; NK, natural killer cells; PBMC, peripheral blood mononuclear cells.
production. On the one hand, Th1-type cytokines (IFN γ,
IL-2, TFN α) promote allograft rejection and compromise
pregnancy; on the other hand, Th2-type cytokines (IL-3,
IL-4, IL-5, IL-10, TGF β2), by inhibiting Th1 response,
promote allograft tolerance and therefore may improve
fetal survival. On the basis of this mechanism, the aim of
the therapy is to find ways to downregulate pro-inflam-
matory cytokines and/or to upregulate anti-inflammatory
cytokines [10]. Several immunological effects of proges-
terone are mediated by an immunomodulatory molecule
secreted by pregnancy lymphocytes so-called progester-
one-induced blocking factor (PIBF), a protein with inhibi-
tory effects on cell-mediated immune reactions [11, 12].
In this perspective, natural micronized progesterone and
dydrogesterone are interesting therapeutic agents for the
modulation of the effects that pro-inflammatory and anti-
inflammatory cytokines have on the fetus and placenta
[13]. The presence of progesterone and its interaction
with progesterone receptors at the decidua level appears
to play a major role in the maternal defense strategy [2].
It induces an important suppression of T-cell reactions,
inhibits NK cells and exerts a synergistic action with Pg E2
[14, 15] (Figure 1).
Progesterone level insufficient to
form PIBF
Symmetric antibodies Th1 bias
LAK cells
Cytotoxic, inflammatory
abortogenic reaction
Abortion
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 Di Renzo et al.: Progesterone in normal and pathological pregnancy      37
Luteal deficiency
A defect in corpus luteum function is associated both with
implantation failure and miscarriage. Before the placenta
starts producing progesterone, in fact, the corpus luteum
production has to support the early pregnancy [16].
It has been demonstrated that progesterone may
promote the invasion of extravillous trophoblasts to the
decidua by inhibiting apoptosis of extravillous tropho-
blasts [8], confirming its rational use for luteal-phase
support. In assisted reproductive cycles progesterone sup-
plementation is recommended after ovum pick up when it
is not sufficiently produced in early implantation [17, 18].
Role in myometrial contractility
Regarding the myometrial effect, progesterone has been
shown to possess tocolytic action on the myometrium
both in vitro and in vivo during pregnancy [19, 20].
It has been demonstrated that adequate progester-
one concentrations in myometrium are able to counteract
prostaglandin stimulatory activity as well as oxytocin.
Progesterone decreases the concentration of myometrial
oxytocin receptors, which counteract the effect of estro-
gens. The same is true with respect to the number and
properties of gap junctions [21]. Moreover, progesterone
and its metabolites induce uterine quiescence through
interactions between nuclear and membrane progester-
one receptors [6, 22, 23].
Progesterone has also been shown in vivo to be con-
centration dependent. Only high-dosage progesterone
exerts a tocolytic action in early pregnancy. This dosage
has also proven effective in the maintenance of uterine
quiescence during cervical cerclage (during the first tri-
mester of pregnancy) and/or following abdominal surgery
(e.g. appendectomy) [21].
It has been demonstrated, instead, that 17
α-hydroxyprogesterone caproate (17 OHP-C) does not
directly inhibit human myometrial contractions in vitro.
Ruddock et al., in fact, showed that surprisingly 17 OHP-C
dose dependently is able to stimulate contractility [24].
Since the 1990s, progesterone has been studied
for its possible role in preterm birth. Keirse in his meta-
analysis of placebo-controlled trials, investigated the
possible prophylactic use of a synthetic progestogen (17
OHP-C) in women at high risk. This analysis demonstrated
that this kind of progesterone offered no support against
miscarriage, but it demonstrated the reduction of the
occurrence of preterm birth and of the rate of low birth
weight babies [25]. Although the pharmacokinetics and
pharmacodynamics of natural progesterone have been
well studied since 1935 when it has been synthesized,
its use in the pathophysiology of pregnancy remains
­controversial. One of these concerns is the route of admin-
istration [26].
Key differences in the route
of administration
Once the therapeutic need of progesterone is established,
the key factor is the decision for the best route to admin-
ister the hormone and the optimal dosage determination.
The modality of absorption derives from: the pharma-
ceutical form used, the blood flow existing in the site of
administration, the solubility in tissues in which the drug
is placed.
Progesterone can be administered by many different
routes, but the most utilized are oral, vaginal and intra-
muscular administration (Table 1).
Even if oral administration guarantees optimal com-
pliance by patients, it may show several disadvantages,
depending the targeted indication, the main being its poor
bioavailability and rapid metabolism with high variability
in the plasma concentration mainly due to inter-individual
variability in gastric filling and enteropathic circulation. The
oral administration also shows major shortcoming when
used during pregnancy: i.e. metabolites produced during
liver passage that could interfere with specific progesterone
action and discrepancy between progesterone blood levels
and endometrial histology in controled stimulated cycles in
assisted reproductive technology (ART) [27, 28].
A number of synthetic oral progestogens including
dydrogesterone have been developed to overcome pro-
gesterone’s variability in bioavailability. Their biological
activities and receptor-binding affinities, however, differ
from natural micronized progesterone and may result
in different pharmacodynamics and pharmacological
effects, such as increased androgenic effects, fluid reten-
tion, alterations in high density lipoproteins, acne, weight
gain, headaches, mood disturbances, and possible muta-
genicity or teratogenicity (Table 2).
The oral route for progesterone may also result in
unwanted side effects such as nausea, headache and
sleepiness. To improve the characteristics of oral admin-
istration, micronization of progesterone manufactured
by hemi-synthesis from a plant source (i.e. Mexican wild
yams, Dioscorea barbasco), has been formulated in an
oil substrate yet the molecular structure of progester-
one is exactly “body-identical” to endogenous human
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38      Di Renzo et al.: Progesterone in normal and pathological pregnancy
Table 1: Routes of administration of progesterone.
Different routes of administration
Different pharmacokinetics and dynamics
Intramuscular
Supraphysiological plasma concentrations
– Peaks and valleys
– Possible allergic reactions
Oral
– High interindividual variability in plasma concentrations
– Rapid increase in plasma concentration followed by a gradual decrease
– First liver pass effect with several biological active metabolites
– Specific activity on different target organs (uterus, brain...)
Vaginal
– Stable plasma concentrations and consistent tissue levels
– First uterine pass effect with targeted delivery into the endometrium
– Mimics more physiological form of endometrium transformation
– Minimal adverse effects
Table 2: Biological activities of natural progesterone versus syn-
thetic progestins.
  PR  Anti-E  ER  AR  Anti-A  Anti-mineral   GABAA
Progesterone   +   +   −   −   +   +   +
Drospirenone   +   +   −   −   +   +   −
Dydrogesterone  +   +   −   −   −   ±   −
MPA   +   +   −   ±   −   −   −
LNG   +   +   −   +   −   −   − level was reached after intramuascular administration,
Adapted from Schindler et al., Kuhl, Barentsen et al. [29–31].
progesterone [32]. Micronization of progesterone in par-
ticle sizes of <10 μm extensively increases the available
surface area of the drug and enhances the aqueous dis-
solution rate and intestinal absorption of progesterone.
Suspension in oil packaged in a gelatin soft capsule has
been shown to further enhance the intestinal absorption
of micronized progesterone [33].
The vaginal route results in higher concentrations
in the uterus [21, 26]. Bulletti et  al. documented the
hypothesis of a “first uterine pass effect”, suggested by
the evidence of higher than expected uterine tissue con-
centrations after vaginal administration of progesterone.
Three different hypotheses have been reported to explain
the first uterine pass: direct diffusion through or between
cells from the vagina to the uterus, portal-like arrange-
ments of lymphatics linking the upper vagina to the
uterus, a counter occurrence circulation system, much
like a portal system, with vein to artery diffusion between
the upper vagina and the uterus. They demonstrated that
a “first uterine pass effect” occurs when a drug is deliv-
ered vaginally, confirming that the vaginal route permits
targeted drug delivery to the uterus, maximizing the
 
 
  Metabolization
  – in the gut (bacteria with 5b-reductase activity)
– in the intestinal wall (5a-reductase activity)
– in the liver (5b-reductase, 3a- and 20a-hydrodylase
activities)
  Metabolization
  – normal vaginal bacteria and mucosa seem devoid od 5a-
and 5b-reductases
– after vaginal, only a small increase in 5a-pregnanolone
observed and 5b-pregnanolone levels were not affected
desired effects while minimizing the potential for adverse
systemic effects [34, 35] (Figure 2).
Endometrial progesterone concentrations were higher
with vaginally administered progesterone than endome-
trial concentrations observed in women with normal ovu-
lation exceeding by more than 10-folds the levels achieved
by systemic administration; but supraphysiologic plasma
about seven times higher than after vaginal administra-
tion. The time to peak concentration is generally slightly
lower than after administration of the oral micronized
preparation. Moreover, after vaginal administration,
plasma concentrations display a plateau-like profile, with
a more constant concentration over time. Peak plasma
levels of progesterone obtained appear to be variable
and not consistently greater or less than corresponding
peak plasma values obtained after oral administration
of micronized progesterone [33]. Cicinelli et  al. demon-
strated in a randomized open study the direct transport of
progesterone from vagina to uterus comparing progester-
one concentrations in serum and endometrial tissue from
hysterectomy specimens after vaginal or intramuscular
administration of progesterone. The ratios of endome-
trial to serum progesterone concentrations were markedly
higher in women who received vaginal progesterone [36].
Historically, the most common delivery method of
progesterone has been through the intramuscular route
[33]. However, progesterone administered intramuscularly
cannot be applied by the patient herself (it requires assis-
tance from a nurse), can provide local discomfort (painful
injection, redness, non-septic abscesses at the injection
site) and may rarely induce acute eosinophilic pneumo-
nia [37] but it is the route that results in the highest blood
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Pharmacokinetics data: vaginal route vs. IM
Plasma progesterone concentrations
in steady state
80
70
60
ng Pg/mg protein
50
ng/mL
40
30
20
10
0 0
4 × 200 mg/day 2 × 50 mg/day
vaginal Pg IM Pg
Figure 2: Comparison between vaginal and intramuscular route of administration.
Adapted from Miles et al. [35].
levels, that can be administered to a patient with vaginal
bleeding and needs only one single daily dose [21, 26].
Others routes of administration have been suggested
[38]. Several formulations of transdermal progesterone
including patches, gels and creams that can effectively
penetrate the skin have been proposed but there is insuf-
ficient evidence from scientific studies to substantiate
the transdermal application of progesterone when sys-
temic luteal phase blood levels are mandatory such as in
pregnancy maintenance. Even if those preparations are
not known to pose any risks to health, it is noteworthy,
in fact, that progesterone is rapidly metabolized by the
5-α-reductase enzyme present in the skin, which converts
it to 5-α-dihydro-progesterone, thereby lowering plasma
progesterone levels. Lastly, the use of rectal administra-
tion, provides wide variability absorption and moreover
there is insufficient scientific clinical evidence concerning
this route of administration and its effects on the endome-
trium [39]. Moreover the prevalence of tenesmus (35.1 vs.
21.1%) and rectal itching (26.7 vs. 2.8%) were more signifi-
cant in the rectal route compared to the vaginal route of
­administration [40].
Main uses of progesterone
Threatened miscarriage
The various causes of spontaneous abortion make it dif-
ficult to prevent and manage the condition. A high per-
centage of the so-called “threatened miscarriages” settle
spontaneously as a result of bed rest or no treatment, and
Di Renzo et al.: Progesterone in normal and pathological pregnancy      39
Progesterone concentrations in uterine
tissue in steady state
12
10
8
6
4
2
4 × 200 mg/day 2 × 50 mg/day
vaginal Pg IM Pg
vaginal bleeding in early pregnancy is not synonymous
with threatened miscarriage [26].
In many cases of miscarriage a causative factor may
be an insufficient secretion of progesterone; consequently
in these cases progestogens have been used, beginning
from the first trimester of pregnancy, in order to prevent
spontaneous miscarriage. Haas and Ramsey demon-
strated that there is no evidence to support the routine
use of progestogen to prevent miscarriage in early to mid-
pregnancy; however, there seems to be evidence of benefit
of this therapy in women with a history of recurrent mis-
carriage [41].
Sotiriadis et  al. demonstrated in a review that,
although bed rest and progesterone supplements are
often advised, they do not seem to improve the outcome of
women with a threatened abortion [42].
The lack of evidence regarding the use of progester-
one, however, probably does not correspond to its lack of
efficacy taking into consideration some convincing bio-
logical plausibility.
Through a randomized, parallel group, double-
blind, double-dummy, controlled study, Czajkowski et al.
studied the effect of progesterone on uteroplacental cir-
culation in threatened abortions comparing a micronized
vaginal progesterone formulation with oral dydrogester-
one tablets. It showed that micronized vaginal progester-
one, but not dydrogesterone, significantly decreased the
spiral artery PI and RI, both markers of adequate uteropla-
cental ­circulation [9] (Figure 3).
Siew et al. in a recent parallel-group, open-label, ran-
domized controlled trial, compared the change in serum
progesterone and progesterone-induced blocking factor
pretreatment and posttreatment (at day 4–6 of treatment)
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40      Di Renzo et al.: Progesterone in normal and pathological pregnancy

Blood flow indices in the spiral arteries

p = 0.009 Resistance index progesterone
8 Pulsatile index progesterone
7 Systolic/diastolic ratio progesterone
6 p = 0.0059
Resistance index dydrogesterone
5 Pulsatile index dydrogesterone
Systolic/diastolic ratio dydrogesterone
4
3
p = 0.007
2
1
Visit 1: 12 ± 2 days of gestation
0 Visit 2: 24 ± 2 days of gestation
Visit 1 Visit 2 Visit 3 Visit 1 Visit 2 Visit 3
Visit 3: 23 weeks of gestation

Figure 3: Effect of micronized vaginal progesterone versus dydrogesterone on uteroplacental circulation in threatened abortion.
Adapted from Czajkowski et al. [9].

in women with threatened miscarriage, who were ran-
domized to receive micronized vaginal progesterone or
oral dydrogesterone tablets. Micronized progesterone
treatment led to a greater increase in serum progesterone
and progesterone-induced blocking factor levels post-
treatment. However, there was no significant difference
in their clinical efficacy and the extent of bleeding at day
4–6 and subsequent miscarriage rates were comparable.
Those results could be useful in early prognostication of
treatment outcome [43].
An optimal strategy to face this situation is to encour-
age an appropriate diagnosis in order to apply a treatment
aimed to the pathology. One possible way is to decrease or
to stop uterine contraction. Progesterone has been shown
to possess, only at high dosage, a tocolytic action in early
pregnancy [21].
A recent meta-analysis of cohort studies suggested
that a single progesterone measurement for women in
early pregnancy presenting with bleeding or pain and
inconclusive ultrasound assessments can rule out a viable
pregnancy [44].
Finally, the authors of a recent Cochrane Database of
Systematic Reviews suggested that progestogens are effec-
tive in the treatment of threatened miscarriage with no
evidence of increased rates of pregnancy-induced hyper-
tension or antepartum hemorrhage as harmful effects
to the mother, nor increased occurrence of congenital
abnormalities in the newborn. However, the analysis was
limited by the small number and the poor methodologi-
cal quality of eligible studies (four studies) and the small
number of the participants (421), which limited the power
of the meta-analysis and hence of this conclusion [45].
Moreover, a recent NICE guideline stated that a very large
multicenter randomized controlled trial of women treated
with either progesterone or placebo should be conducted.
In this perspective, the on-going PRISM study in the UK,
a large prospective double-blind placebo randomized
clinical trial sufficiently powered will determine the effi-
cacy of vaginal micronized progesterone 400  mg BID
supplementation in 4150 women presenting with vaginal
bleeding and pain in the first 12 weeks of pregnancy in the
prevention of threatened miscarriage.
Recurrent miscarriage
Recurrent miscarriage is defined as three consecutive
pregnancy losses. Extensive investigation of the women
involved will fail to find a recognizable cause in up to half
of cases [21, 26].
The pathophysiology of recurrent miscarriage is
complex and it includes anatomical, genetic and molecu-
lar abnormalities, endocrine disorders, thrombophilias
and anti-pospholipid syndrome.
Luteal phase defects and immunotolerance derange-
ments are the most common recognizable causes [21, 26].
Considerable evidence indicates that women with idi-
opathic recurrent miscarriage may benefit from proges-
terone treatment, as it has been shown to be an essential
immunomodulatory agent in early pregnancy.
Walch et al. demonstrated that dydrogesterone given
orally during the first trimester of pregnancy in women
suffering from recurrent miscarriage can induce immu-
nomodulation and improve pregnancy outcome [46].
Also other studies have shown that the progestogen
supplementation can potentially provide a treatment
option for those patients. The progesterone role is prob-
ably exerted in the expression, modulation and inhibition
of various growth factors, cytokines, cell adhesion mol-
ecules decidual proteins [47].
We tested the role of micronized progesterone in
recurrent miscarriages (women with 2 or >2 abortions)
comparing women with positive or negative anamnesis for
autoimmunity (for different types of autoantibodies but

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 Di Renzo et al.: Progesterone in normal and pathological pregnancy      41

Women with
Delivery women with unexplained recurrent miscarriage. The
Abortion
2 abortions
treatment consisted in vaginal micronized progesterone
No therapy (n = 5) 2 (40%) 3 (60%) 400  mg twice-daily or placebo, from a time soon after a
Autoimmunity
negative (n = 10) ASA: low dose aspirin 5 (100%) 0 positive urinary pregnancy test, no later than 6 weeks
Autoimmunity
100 mg/day (n = 5) of gestation, through 12 week of gestation. They dem-
positive (n = 30)
ASA 100 mg/day and
progesterone (n = 30)
28 (93%) 2 (7%) onstrated that in women with a history of unexplained
recurrent miscarriages, progesterone therapy in the first
Women with No therapy
3 (50%) 3 (50%)
trimester of pregnancy does not result in a significantly
>2 abortions (n = 6)
high rate of births beyond 24 weeks. However, a second-
Autoimmunity
ASA 100 mg/day 18 (85%) 3 (15%) ary outcome demonstrated that vaginal progesterone was
negative (n = 27)
(21)
safe for the mother and the fetus, due to no statistical sig-
ASA 100 mg/day
and
nificant difference in frequency of adverse events between
Autoimmunity 29 (85%) 5 (15%)
positive (n = 34) progesterone treatment and placebo [48] (Tables 3 and 4).
(n = 34)
As the authors mention in the discussion of the publi-
Figure 4: Use of progesterone in recurrent miscarriages. cation, there are some limitations in this study. Progester-
one treatment was initiated only after a urinary pregnancy
test was confirmed, for a duration limited to 12 weeks of
especially thyroid autoantibodies) treated with no drugs, pregnancy, and for some patients taking the progester-
acetyl-salicylic acid (ASA) 100  mg/day alone or in asso- one treatment for a very short period of time and thus this
ciation with micronized progesterone 200 mg/day. Results study result cannot address, as to whether progesterone
showed that the group of women with proven autoim- supplementation should be more effective in reducing
munity treated with ASA and progesterone had the same the risk of miscarriage if administered during the luteal
outcomes (live birth rate at term) as the group with auto- phase of the cycle, before confirmation of pregnancy and/
immunity not proven treated only with aspirin (Figure 4). or after week 12 of pregnancy. However, this the first well-
In a recent multicenter, double-blind, placebo-­ designed randomized controlled trial with live birth rate
controlled, randomized trial, it was discussed whether as the primary outcome, different from relative risk of mis-
progesterone supplementation in the first trimester of carriage outcome in previous studies with progesterone
pregnancy could increase the rate of live births among [49] or dydrogesterone [50].

Table 3: Primary outcome and secondary outcomes.

Outcome   No./total no. (%)   Relative risk (95% CI)   p-Value

 
Progesterone   Placebo

Pregnancy outcomes
 Clinical pregnancy at 6–8 weeks   326/398 (81.9)   334/428 (78.0)   1.05 (0.98–1.12)   0.16
 Ongoing pregnancy at 12 weeks   267/398 (67.1)   277/428 (64.7)   1.04 (0.94–1.14)   0.47
 Ectopic pregnancy   6/398 (1.5)   7/428 (1.6)   0.92 (0.31–2.72)   0.88
 Miscarriagea   128/398 (32.2)   143/428 (33.4)   0.96 (0.79–1.17)   0.70
 Stillbirth   1/398 (0.3)   2/428 (0.5)   0.54 (0.05–5.92)   0.61
 Live birth after 24 weeks 0 days of gestationb   262/398 (65.8)   271/428 (63.3)   1.04 (0.94–1.15)   0.45
 Twin live births after 24 weeks 0 days of gestationb   4/398 (1.0)   5/428 (1.2)   0.86 (0.23–3.18)   0.82
Gestation outcomes among women with live births
 Live birth before 28 weeks 0 days of gestation   1/262 (0.4)   1/271 (0.4)   1.03 (0.06–16.49)   0.98
 Live birth before 34 weeks 0 days of gestation   10/262 (3.8)   10/271 (3.7)   1.03 (0.44–2.45)   0.94
 Live birth before 37 weeks 0 days of gestation   27/262 (10.3)   25/271 (9.2)   1.12 (0.67–1.87)   0.68
Neonatal outcomesc
 Any congenital anomaly   8/266 (3.0)   11/276 (4.0)   0.75 (0.31–1.85)   0.54
 Genital congential anomaly   1/266 (0.4)   1/276 (0.4)   1.04 (0.07–16.50)   0.98
Newborn survival to 28 daysb   260/261 (99.6)   269/269 (100)   1.00 (0.99–1.00)   0.32
a
The median gestational age at miscarriage was 7.3 weeks (interquartile range, 6.0–8.7) in the progesterone group and 7.1 weeks (interquar-
tile range, 6.0–8.5) in the placebo group (relative risk, 0.0; 95% CI, –0.6 to 0.4; p = 0.87). bThe end point is listed per trial participant. cThe
end point is listed per neonate. From Coomarasamy et al. [48].

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42      Di Renzo et al.: Progesterone in normal and pathological pregnancy

Table 4: Vaginal progesterone in women with an asymptomatic short cervix in the midtrimester ultrasound decreases PTD and improves
neonatal outcome.

Outcome   No. of  No. of events/total no.  Pooled RR (95% CI)  NNT (95% CI)
trials 
Vaginal progesterone     Placebo

Preterm birth <37 week   5  144/388     165/387  0.89 (0.75–1.06)  –

Preterm birth <36 week   5  108/388     136/387  0.82 (0.67–1.00)  –
Preterm birth <35 week   5  79/388     118/387  0.69 (0.55–0.88)  11 (7–27)
Preterm birth <34 week   5  62/388     105/387  0.61 (0.47–0.81)  9 (7–19)
Preterm birth <30 week   5  29/388     51/387  0.58 (0.38–0.89)  18 (12–69)
Preterm birth <28 week   5  21/388     43/387  0.50 (0.30–0.81)  18 (13–47)
Spontaneous preterm birth <33 week  5  39/388     71/387  0.57 (0.40–0.81)  13 (9–29)
Spontaneous preterm birth <34 week  5  51/388     87/387  0.62 (0.46–0.84)  12 (8–28)
Respiratory distress syndrome   5  25/411     52/416  0.48 (0.30–0.76)  15 (11–33)
Neonatal death   5  8/411     15/416  0.55 (0.26–1.19)  –
Admission to NICU   5  85/411     121/416  0.75 (0.59–0.94)  14 (8–57)
Mechanical ventilation   5  35/411     51/416  0.66 (0.44–0.98)  24 (15–408)
Congenital anomaly   7  30/1967     34/1954  0.89 (0.55–1.44)  –
Any maternal adverse event   3  86/624     80/595  1.04 (0.79–1.38)  –
Intraventricular hemorrhage   5  6/411     9/416  0.74 (0.27–2.05)  –

Adapted from Romero et al. [59].

Preterm birth they became irreversible and to find effective intervention

Preterm birth is the leading cause of perinatal mortality
and morbidity. Its incidence has not declined (12% of all
births) and, due to its long-term neuro-developmental
sequelae, it is one of the major expenses on health and
educational resources [51–53]. The mechanism of human
parturition is the expression of anatomic, biochemical,
physiologic and clinical events that occur in the mother
and in the fetus in both term and preterm labor. This
pathway consists of:
–– decidual/fetal membrane activation
–– increased uterine contractility
–– cervical ripening (dilatation and effacement).
of arresting the process of preterm labor to enhance the
effectiveness of current available interventions.
Regarding the management of threatened preterm
labor, tocolysis and administration of corticosteroids to
induce lung maturation are the first therapeutic tools;
also bed rest and hydration are usually recommended in
the management of these patients, although not proven to
have a clear efficacy.
The tocolytic effect of oral micronized progesterone
was already suggested in1985 as reported by Erny et  al.

Preterm labor is the consequence of the pathologic activa-

tion of one or more of those elements (Figure 5).
The apparent loss of progesterone sensitivity at term
could be a consequence of several different mechanisms
including: alterations in progesterone receptors (PR)
isoform ratios anti-inflammatory function of progester-
one, the catabolism of progesterone in the uterus into
inactive compounds, changes in cofactor protein levels
affecting PR transactivation and inflammation-induced
trans-repression of PR [21].
Before undertaking any therapeutic strategy, careful
identification is needed, so as to detect manageable con-
Figure 5: Labor, term and preterm, is characterized by increased
ditions and fetal and/or maternal contraindications. myometrial contractility, cervical dilatation and rupture of the chori-
The real challenge is to develop sensitive and specific onamniotic membranes.
tests that reliably detect these pregnancy’s changes before Adapted from Romero et al. [54].

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 Di Renzo et al.: Progesterone in normal and pathological pregnancy      43
These investigators evaluated the effects of 400  mg of
orally absorbed micronized progesterone or placebo in
women at risk for premature labor; 88% of the patients
who were treated with oral micronized progesterone had
decreased uterine activity compared with 42% of the
patients who received placebo [33].
In a recent FIGO Committee Report it has been estab-
lished that the prevention of preterm birth should be
based on the use of cervical length and the progesterone.
It has been recommended, in fact to screen the sono-
graphic cervical length in all women at 19–23 6/7 weeks
using transvaginal ultrasound and treatment with daily
vaginal progesterone in cases of cervical length  ≤ 25 mm.
It has been studied as a cost-effective model for the pre-
vention of preterm birth [55].
Vaginal micronized progesterone and related syn-
thetic compounds such as 17 OHP-C injections, as well
as others progestogens, have been tested in clinical trials
for the prevention of preterm birth [56], especially on the
three main groups of patients considered at particularly
high risk:
–– patients with a history of spontaneous preterm birth,
–– patients with a short cervix,
–– patients with multiple pregnancies.
Studies using synthetic progesterone to reduce the rate of
preterm delivery have been reported with mixed results,
more especially with 17 OHP-C injections in women at risk
for preterm birth with a short cervix [57], while women
assuming natural progesterone demonstrated more con-
sistently benefits in view of efficacy, cost-effectiveness,
availability and biological safety in mothers and their
children [1, 57].
No other progestagens have been so far used in the
management of preterm labor and birth.
The vast majority of clinical trials were performed
with various formulations of either vaginal micronized
progesterone vaginally applied and 17 OHP-C weekly
intramuscular injections. The use of both vaginal micro-
nized progesterone and 17 OHP-C intramuscular injections
was advised in asymptomatic women at risk with prior
history of preterm birth as an early prophylaxis of preterm
birth, but only vaginal micronized progesterone was rec-
ommended in single pregnant, nulliparous women with a
silent cervical shortening (<25 mm) detected with trans-
vaginal ultrasound at midgestation.
Furthermore Istwan et al. demonstrated that in patients
with a history of one prior spontaneous preterm delivery
receiving prophylactic 17 OHP-C, but not in patients with
more than one prior spontaneous preterm delivery, a previ-
ous term delivery confers a reduction in risk [58].
One of the first well-designed study concerning the
prophylactic use of vaginal progesterone to decrease the
rate of preterm birth in patient at high risk (at least one
previous spontaneous preterm birth, prophylactic cervi-
cal cerclage, uterine malformation) has been performed
by Fonseca et  al. They demonstrated that the daily use
of 100 mg vaginal progesterone in these women is able to
reduce the frequency of uterine contractions and the rate
of preterm birth [59].
More recently it has also been demonstrated, based
on a systematic review of five randomized controlled trials
and a meta-analysis of individual patient data that the
use of vaginal micronized progesterone in asymptomatic
women with a sonographic short cervix not only reduces
the risk of preterm birth, but it is also able to reduce neo-
natal morbidity and mortality (Figure 6, Table 4) [60].
In nulliparous women with a midtrimester cervical
length <30 mm, the use of weekly intramuscular 17 OHP-C
was not shown to reduce the frequency of preterm birth [61].
Comparing the use of vaginal micronized proges-
terone with the the intramuscular administration of 17
OHP-C, it also demonstrated a statistically significant
decrease in severe side effects and the number of admis-
sions to the Neonatal Intensive Care Unit in the vaginal
progesterone group [62].
It has also been studied if maternal weight and body
mass index (BMI) modifies the effectiveness of 17 OHP-C
in preventing preterm birth. It resulted that both maternal
weight and BMI reduced the effectiveness of this treatment
due to subtherapeutic serum levels in those patients [63].
In either twins or triplets, neither vaginal micronized
progesterone nor 17 OHP-C are able to prevent preterm
birth [56]. Already in 1980, Hartikainen-Sorri et al. treated
77 twin pregnancies during the last trimester until the
37th gestational week with weekly injections of either 17
OHP-C or a placebo, showing no differences in the gesta-
tional length, birth weight and outcome of the neonates
[64]. Cooms et al. demonstrated that nowadays the pro-
phylactic administration of 17 OH-C to mother with twin
pregnancy does not reduce the rate of preterm delivery
or neonatal morbidity [65]. A recent individual partici-
pant data meta-analysis (IPDMA) of 13 eligible RCTs, in
unselected women with an uncomplicated twin gesta-
tion, treatment with progestogens (intramuscular 17Pc or
vaginal natural progesterone) did not improve the peri-
natal outcome. However, vaginal micronized progester-
one may be effective in the reduction of adverse perinatal
outcome in women with a cervical length of  ≤ 25 mm;
further research is warranted to confirm this finding [66].
It has recently been demonstrated that the possible
effect of vaginal progesterone, but not of 17 OHP-C, in the
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44      Di Renzo et al.: Progesterone in normal and pathological pregnancy

Vaginal
Relative risk (fixed) progesterone Placebo Weight Relative risk
Study (95% CI) n/N n/N (%) (95% CI)

Fonseca 2007 23/114 39/112 30.4 0.58 (0.37–0.90)

O'Brien 2007 4/12 6/19 3.6 1.06 (0.37–2.98)

Hassan 2011 26/235 43/223 34.1 0.57 (0.37–0.90)

Cetingoz 2011 1/4 1/4 0.8 1.00 (0.09–11.03)

OPPTIMUM 2016 33/133 38/118 31.1 0.77 (0.52–1.14)

Combined 87/498 127/476 100.0 0.66 (0.52–0.83)

0.1 0.2 0.3 0.5 1 2 3 5 10 Test for heterogeneity: I 2 = 0%

Favors vaginal progesterone Favors placebo Test for overall effect: Z = 3.44, p = 0.0006

Figure 6: Vaginal progesterone and reduction of preterm birth before 33 weeks of gestation.
From Romero et al. [59].

prevention on preterm birth is related to its immunomod-
ulatory functions. Furcron et al. studied the local effects
of vaginal progesterone and 17 OHP-C on adaptive and
innate immune cells implicated in the process of parturi-
tion in the murine maternal-fetal interface. They showed
that only vaginal progesterone exerts local anti-inflamma-
tory effects at the maternal-fetal interface and the cervix
protecting against endotoxin-induced preterm birth [67].
The use of vaginal progesterone has also be proposed
in combination with cervical pessary; in a recent study,
Stricker et al. compared two groups of at-risk patients and
screening patients treated with a cervical pessary alone to
patients treated with a pessary plus vaginal micronized
progesterone.
Treatment of precocious cervical ripening with a cer-
vical pessary plus vaginal progesterone did not reduce
the rates of preterm delivery compared to a pessary alone.
However, the neonatal intensive care utilization was
shorter in patients who received additional vaginal pro-
gesterone although there was no difference in composite
poor neonatal outcome [68].
The administration of high-dosage progesterone has
been advocated as a possible tocolytic agent.
Natural progesterone has documented properties of
inhibiting uterine contractions, whereas 17 OHP-C seems
to have no effect on uterine contractions [56]. The action
of progesterone is slow and it can be used for acute toco-
lysis only in conjunction with acute tocolytic agents such
as β-agonists [69]. The combination of the two drugs has
shown synergistic effects by decreasing the need for high
concentrations of β-agonists, which have potentially dan-
gerous side effects [21, 26] (Table 5).
A recent study of Baumbach et al. demonstrates that
progesterone significantly inhibits uterine contractility
at relatively high concentration and its combination with
nifedipine and indomethacin increases this effect [70]
(Figure 7).
Also Chanrachakul et  al. recently demonstrated this
synergetic effect of progesterone with β-mimetics. They
concluded that natural progesterone is able to increase
the relaxant effect of ritodrine, most likely through non
genic action [51]. This was also suggested previously by
Noblot et al. [71].
Progesterone can be taken into consideration for the
maintenance of uterine quiescence in the case of patients
already treated for an episode of threatened preterm labor.
In comparison with nifedipine, progesterone has a signifi-
cantly higher role in prolonging pregnancies of women
with arrested preterm labor and, moreover, it results in a
better neonatal outcome with lesser side effects [52]. In a
recent meta-analysis of randomized controlled trials the
efficacy of maintenance tocolysis with vaginal micronized
progesterone compared to placebo or no treatment in sin-
gleton gestation with arrested preterm labor was e­ valuated.
Suhag et  al., suggested that maintenance tocolysis with
vaginal micronized progesterone is associated with preven-
tion of preterm birth, significant prolongation of pregnancy
and lower neonatal sepsis [72]. Borna et  al. also studied
the role of progesterone in the maintenance of tocolysis
after threatened preterm labor treated with intravenous

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 Di Renzo et al.: Progesterone in normal and pathological pregnancy      45

Table 5: Use of progesterone in association with tocolytic agents.

Patients   47   42
Gestational age   30.5 ws   30.3 ws
Treatment   –R itodrine (100 mg in saline   – Ritodrine (50 mg in saline 0.1–0.3 mg/min)
0.1–0.3 mg/min) – Progesterone (200 mg die)
Outcome   – Deliveries after 48 h: 87%   – Deliveries after 48 h: 85%
– Deliveries after 7 days: 65% – Deliveries after 7 days: 68%
Side effects   – Mat. tachicardia: 97%   – Mat tachicardia: 42%
– Nausea and vomiting: 28% – Nausea and vomiting: 6%
– Tremblings: 26% – Tremblings: 12%
– Palpitations: 32% – Palpitations: 12%
– Chest pain: 15% – Chest pain: 8%
– Hyperglycemia: 47% – Hyperglycemia: 28%
– Hypokaliemia: 92% – Hypokaliemia: 23%

Modified from Di Renzo et al. [26].

magnesium sulfate. They found a longer latency until
delivery and better gestational age at delivery and low birth
weight [73]. Moreover there is evidence that the only use of
micronized progesterone reduced the rate of preterm birth
in women successfully treated for a preterm labor episode,
despite some negative existing trials [56, 74]. In conclusion,
natural “body-identical” progesterone is a molecule exten-
sively and well-studied and nowadays more evaluated than
before. According to guidelines published in the recent
years by different societies [the International Federation
of Gynecology and Obstetrics (FIGO), The Royal College of
Obstetricians and Gynaecologists (RCOG), the American
Congress of Obstetricians and Gynecologists (ACOG), the
European Association of Perinatal Medicine (EAPM) and
the Society of Obstetricians and Gynaecologists of Canada
(SOGC)] concerning the management of preterm labor, the
use of progesterone can be recommended as follows:
–– early prophylaxis (from 12 to 36 weeks of gestation)
with either micronized P4 (200 mg vaginally daily) or
17 OHP-C (injection of 250 mg weekly) to prevent recur-
rence in the case of prior history of PTB [55, 74, 75];
–– vaginal micronized progesterone in singleton gesta-
tion, with and without history of prior PTB, with short
cervical length (<25 mm) at 18–23 weeks of gestation,
as it has been found to be associated with reduction in
the rate of PTB and perinatal morbidity and mortality
(200 mg vaginal daily) [54, 55, 75];
–– in nulliparous women in single pregnant women suc-
cessfully treated for a PTL as maintenance tocolysis,
(400  mg vaginal progesterone), but further studies
may be required to optimize the daily dosage [54, 55]
–– use of vaginal progesterone in acute tocolysis (400 mg
vaginal daily for 48 h) in association with drugs usu-
ally utilized for tocolysis.

20

a a a a a 0
0 a a
Vehicle a
a a a a a
a a a –5 a a a Vehicle
a a P4 (10 M) a a
–20
% Changes, AUC

a P4 (10–5 M)
% Changes, AUC

–20 a a
a a
b a
–40 b b b a
b b
b Ind (10–5 M)
–8 –40
c Nife (10 M) b
–60
c c c b
c c
Nife + P4 –60 b
–80 b b
Ind + P4
–100
–80
0 1 2 3 4 5 6 0 1 2 3 4 5 6 7
Hours Hours
Nifedipine Indomethacine

Figure 7: Effects of nifedipine (left) or indomethacin (right) with and without P4 on myometrial contractility.
AUC, Area under contractions curve; Nife, nifedipine; P4, progesterone. From Baumbach et al. [69].

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46      Di Renzo et al.: Progesterone in normal and pathological pregnancy
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