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Clinical Opinion ajog.

org

GYNECOLOGY
Menstrual preconditioning for the prevention
of major obstetrical syndromes in polycystic
ovary syndrome
Ivo Brosens, MD; Giuseppe Benagiano, MD

is evidence that infertility in women with


The presence of multiple ovarian cysts, anovulation, and endometrial progesterone PCOS cannot be attributed to anov-
resistance in the neonate seems remarkably similar to ovarian and endometrial features ulation only but also to endometrial
of the polycystic ovary syndrome (PCOS) of adolescent and adult women. In fact, in the dysfunction. A recent endometrial
absence of cyclic menstruations after menarche, the neonatal progesterone resistance is biopsy study by Lopes et al4 showed
likely to persist and adversely affect young women with PCOS at the time of pregnancy that conventional doses of proges-
after induction of ovulation, because any persisting defect in progesterone response can terone may not be enough to correct
interfere with the process of decidualization and trophoblast invasion. The primigravid PCOS-associated changes in the endo-
woman with PCOS therefore is likely to be at risk of defective deep placentation as metrial histomorphologic condition and
manifested by the increased risk of major obstetric syndromes. A recent, large epide- the receptivity markers. It is a fact that,
miologic study has demonstrated that the risk of preeclampsia and preterm delivery is despite the ability to correct ovulatory
elevated in the 13- to 15-year old group, although it does not persist in the 16- to 17-year disorders in PCOS, pregnancy rates
old group. It is proposed therefore that induction of ovulation in the infertile nulligravid remain paradoxically low, and sponta-
woman with PCOS should be preceded by a period of progesterone withdrawal bleedings neous pregnancy loss rates are high.5
to achieve full endometrial progesterone response by the time of pregnancy. The cyclic Once a woman with PCOS has
administration of clomiphene citrate for a period to be determined by vascular response conceived, her problems are not over
may be an appropriate tool to reduce the risk of major obstetric syndromes by menstrual because she will be at a higher risk of
preconditioning. miscarriage, both after spontaneous or
assisted conception (ART).6 A recent
Key words: clomiphene citrate, endometrium, metformin, polycystic ovary syndrome, Cochrane-based data review7 on the use
preeclampsia, preterm birth, progesterone resistance of metformin (an oral antidiabetic drug
used to reduce insulin resistance) evi-

T he polycystic ovary syndrome


(PCOS) is among the most com-
mon female endocrine disorders, which
of hyperandrogenemia, insulin resis-
tance, obesity, infertility, and obstetric
complications. As a consequence, it may
denced that (1) there is no conclusive
evidence that metformin treatment
before or during ART cycles improves
occurs in 4-18% of reproductive-age have signicant implications for the the live birth rates in women with PCOS
women worldwide.1 The syndrome is a long-term physical and reproductive who undergo ovulation induction or
complex metabolic and endocrine dis- health of affected women. In view of the in vitro fertilization and (2) its use
order that is associated with the presence heterogeneity of the syndrome and the increases clinical pregnancy rates and
lack of understanding of its pathogenesis decreases the risk of ovarian hyperstim-
and mechanisms of action, it is not sur- ulation syndromes.
From Catholic University Leuven, Leuven prising that, even after 3 consensus In this clinical opinion, we focus on a
Institute for Fertility and Embryology, Leuven, meetings, the criteria to diagnose PCOS new theory of the pathogenesis of major
Belgium (Dr Brosens); and the Department of obstetric complications that have been
Gynecology, Obstetrics and Urology, Sapienza
remain unsettled. Currently, PCOS is
University, Rome, Italy (Dr Benagiano). diagnosed by the presence of 2 of the associated with PCOS to improve our
following features: chronic oligo- or understanding and potentially the man-
Received May 19, 2015; revised July 10, 2015;
accepted July 17, 2015. anovulation, clinical or biochemical ev- agement of these obstetric complications
idence of androgen excess, and the in women who are affected by PCOS.
The authors report no conict of interest.
Corresponding author: Ivo Brosens, MD. presence of polycystic ovaries on sono-
ivo.brosens@med.kuleuven.be graphic examination.2 Methods
0002-9378 Generally, the belief is that, in most The literature was searched via Scopus
2015 The Authors. Published by Elsevier Inc. on cases of PCOS, infertility results from and PubMed for the following key words:
behalf of ASCRS and ESCRS. This is an open access the absence of ovulation; at the same polycystic ovary syndrome, progesterone
article under the CC BY-NC-ND license (http://
time, it has also been recognized that resistance, and metformin in combi-
creativecommons.org/licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.ajog.2015.07.021 anovulation may not be the only reason nation with endometrium, menstrual
for the failure to conceive.3 Indeed, there preconditioning, pregnancy, trophoblast,

488 American Journal of Obstetrics & Gynecology OCTOBER 2015


ajog.org Gynecology Clinical Opinion
preeclampsia, or preterm delivery. In
addition, the references were examined TABLE 1
in published papers on related topics. Major obstetric syndrome in women with polycystic ovary syndrome
Syndrome Odds ratio 95% confidence interval
Pregnancy complications in PCOS Pregnancy-induced hypertension 3.67 1.98e6.81
Several studies have documented an
Preeclampsia 3.47 1.16e2.62
association between PCOS and major
obstetric complications, particularly Preterm birth 1.75 1.16e2.62
preeclampsia and preterm birth. A Gestational diabetes mellitus 2.94 1.70e5.08
metaanalysis of pregnancy outcomes in Perinatal death 3.07 1.03e9.21
women with PCOS demonstrated a 8
Boomsma et al.
signicantly higher risk of the develop-
Brosens. Menstrual preconditioning in polycystic ovary syndrome. Am J Obstet Gynecol 2015.
ment of gestational diabetes mellitus,
pregnancy-induced hypertension, pre-
eclampsia, and preterm birth (Table 1).8 wall stiffness has also been observed in investigated particularly in women with
An exhaustive review of the literature these patients. The risk of preeclampsia, endometriosis.17 There is increasing ev-
that assessed pregnancy outcomes and which is the most severe of all compli- idence that an impaired progesterone
the effect of metformin treatment cations, is also 4 times higher in those response can be found in the endome-
among women with PCOS by Ghazeeri who experience PCOS.13 trium of women with PCOS. Gregory
et al9 concluded that the weight of A MEDLINE search on relevant trials et al18 demonstrated that the expression
available evidence suggests that pregnant by Zheng et al14 found that, in pregnant of the p160 steroid receptor coactivators,
women with PCOS are at increased risk women with PCOS, the pooled odds which serve as transcriptional coac-
of the development of preterm birth and ratio was 0.32 (95% CI, 0.19e0.55) for tivators for a number of nuclear and
hypertensive disorders of pregnancy, early pregnancy loss, 0.37 (95% CI, nonnuclear receptors, is regulated in the
with a prevalence of 6-15% for preterm 0.25e0.56) for gestational diabetes endometrium during the menstrual cy-
birth, 10-30% for gestational hyperten- mellitus, 0.53 (95% CI, 0.30e0.95) for cle in normal fertile women but is
sion, and 8-15% for preeclampsia. The preeclampsia, and 0.30 (95% CI, over-expressed in the endometrium of
authors concluded that metformin has 0.13e0.68) for preterm delivery. The women with PCOS. Cermik et al19
proved to be effective in improving authors concluded that metformin investigated the up-regulation of the
ovulation and pregnancy rates among therapy throughout pregnancy could homeobox gene HOXA10 that is neces-
patients who receive fertility-enhancing decrease pregnancy-related complica- sary for the receptivity to embryo im-
agents and supports its use among tions in pregnant women with PCOS plantation. In vitro ndings and
anovulatory women with PCOS. with no serious detrimental side-effects. endometrial biopsy specimens that
However, the continuation of metfor- An epianalysis of 2 randomized, were obtained from women with
min throughout pregnancy remains controlled trials that included 313 PCOS show that testosterone decreases
controversial. women with PCOS who were 18-42 HOXA10-messenger RNA, which leads
A population-based cohort study of years old and who had singleton preg- to the conclusion that diminished uter-
the risk of adverse pregnancy outcomes nancies performed by Vanky et al15 ine HOXA10 expression may contribute
in women with PCOS found that, in showed that the metformin-treated pa- to the diminished reproduction poten-
singleton births, PCOS was associated tients had fewer late miscarriages/pre- tial of women with PCOS. A review of
strongly with preeclampsia (adjusted term deliveries. At the same time, there endometrial aspects of the window of
odds ratio, 1.45; 95% condence interval was no difference in the prevalence implantation in women with PCOS that
[CI], 1.24e1.69) and very preterm birth of gestational diabetes mellitus and focused mainly on adhesion molecules
(adjusted odds ratio, 2.21; 95% CI, preeclampsia between the metformin suggested that endometrial receptivity
1.69e2.90).10 A systematic review that and the placebo groups. The authors seems to be the major limiting factor for
involved 2544 patients with at least 2 suggested that further randomized the establishment of pregnancy.4
features of the 2003 Rotterdam criteria studies should be performed before rm Savaris et al,20 who compared gene
for PCOS11 and 89,848 patients without conclusions can be drawn. expression between endometrial samples
PCOS conrmed that women with of normal fertile control subjects and
the syndrome had signicantly higher Endometrial progesterone resistance women with PCOS, concluded that
rates of gestational diabetes mellitus, in PCOS existing differences in gene expression
pregnancy-induced hypertension, pre- The concept of progesterone resistance provide evidence of progesterone resis-
eclampsia, preterm delivery, and small- implies that, in certain individuals, there tance in midsecretory PCOS endome-
for-gestational-age infants.12 A 4-fold is a decreased responsiveness of target trium, independent of clomiphene
increase in the risk of pregnancy- tissues to bioavailable progesterone.16 In citrate (CC). It can also explain differ-
induced hypertension linked to arterial recent years, the concept has been ences that were observed in this group of

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Clinical Opinion Gynecology ajog.org

women in phenotypes of hyperplasia, high circulating progesterone levels and complex than previously appreciated.
cancer, and poor reproductive outcomes. classied this response as null (prolifer- Progesterone resistance, as manifested
In an in vitro experiment, Kajihara et al21 ative or inactive) in 68% of their cases, in conditions such as endometriosis, is
investigated the effect of androgens on partial or early response (subnuclear not only a consequence of perturbed
the expression of genes that are involved vacuolization) in 27%, and full (decidu- progesterone signal transduction caused
in oxidative stress resistance in decid- alization or menstrual-like shedding) in by chronic inammation but also is
ualized human endometrial stromal only 5%. Thus, remarkably, at birth most associated with long-lasting epigenetic
cells. These cells that were isolated from neonates satisfy the current criteria for reprogramming of steroid hormone
hysterectomy specimens were decid- the diagnosis of PCOS by the presence responses in the endometrium and
ualized with 8-bromo cyclic adenosine of polycystic ovaries, anovulation, and beyond. In this context, it is assumed
monophosphate and progesterone in the progesterone-resistant endometrium.26 that cyclic endometrial decidualization
presence or absence of dihydrotestoster- It can be speculated that the type of followed by menstrual shedding is an
one at various concentrations. The au- progesterone resistance that is present in example of physiologic preconditioning
thors concluded that androgens might the endometrium at birth is likely to that prepares uterine tissue for the dra-
play a critical role in the decidualization persist until the onset of puberty when matic vascular remodeling that is asso-
process at the time of embryo implan- endogenous estrogens begin to stimulate ciated with deep placentation. Indeed,
tation and trophoblast invasion by pro- endometrial cells.26,27 Although full deep placentation involves the rem-
moting resistance to oxidative stress. progesterone response with neonatal odeling of the spiral arteries in the
Recently, in the endometrium of patients menstruation has been linked to placentation zone, which includes the
with PCOS, Yan et al22 showed differ- pelvic endometriosis in premenarche endometrial and, most critically, the
ences in FADD (a gene that plays a role in and adolescence,26,27 a persisting degree myometrial segments. It is well accepted
cell proliferation, cycle regulation, and of progesterone resistance of the endo- that the pathogenesis of late onset pre-
development) and BCL-2 (a gene that metrium after menarche can be linked to eclampsia in the primigravid woman is
encodes a protein that blocks the defective deep placentation and major linked with defective deep placentation,
apoptotic death of some cells such as obstetric disorders, which include pre- which is dened by a restricted remod-
lymphocytes) expression during the eclampsia, fetal growth restriction, and eling of the myometrial segments of the
window of implantation. They suggested preterm birth.28,29 spiral arteries in the placental bed.32
that the decrease in cell apoptosis during
the implantation window in patients Menstrual preconditioning reduces Defective decidualization and
with PCOS may be 1 of the causes of progesterone resistance trophoblast invasion in PCOS
reduced endometrial receptivity. The concepts of ontogenetic proges- Decidualization is described as the
Finally, a recent review of endometrial terone resistance and of menstrual postovulatory process of endometrial
progesterone resistance in women with preconditioning infer that the human remodeling in preparation for preg-
PCOS concluded that progesterone- uterus may start out as a relatively nancy, which includes secretory trans-
mediated signaling pathways of expres- immature organ that acquires the formation of the uterine glands, inux
sion, regulation, and signaling in the competence for deep placentation in of specialized uterine natural killer
nucleus are involved.23 response to dynamic remodeling events cells, and vascular remodeling. A more
triggered by menstruations, miscarri- restricted denition of the decidual
Neonatal progesterone response age, or parturition.30 Menstrual pre- process denotes the morphologic and
resistance conditioning implies that progesterone biochemical reprogramming of the
Throughout pregnancy, the fetus is withdrawal bleedings or menstruations endometrial stromal compartment. This
exposed to high plasma concentrations evolved in the human because of the differentiation process is dependent
of unbound estrogens and progesterone. need to initiate decidualization in the entirely on the convergence of cyclic
Progesterone in the fetal circulation rises absence of pregnancy and protect uter- adenosine monophosphate and proges-
to reach much higher values than in the ine tissues from the profound hyper- terone signaling pathways that drives
maternal circulation because of the de- inammation and oxidative stress that integrated changes at both the tran-
hydrogenase activity of the endothelial are associated with deep placentation. scriptome and the proteome level.33
cells of the placental circulation.24 Ober It is conceivable that, in most young Decidualization of stromal cells pre-
and Bernstein25 carefully investigated girls, ontogenetic progesterone resis- cedes and regulates trophoblast invasion
neonatal ovaries and uteri in a series of tance may persist until menarche and to resist inammatory and oxidative
169 autopsies and observed that, in that full progesterone-responsiveness is insults and to dampen local maternal
newborn infants, ovaries are frequently achieved only gradually after the onset immune responses. Jindal et al34 sug-
polycystic, but failed to show any sign of of cyclic menstruations. Al-Sabbagh gested that the spectrum of maternal and
ovulation or corpus luteum formation. et al31 conjectured that steroid hor- fetal complications that are associated
In the uteri, they described in detail the mone responses in the endometrium are with PCOS may be related to impaired
response of the fetal endometrium to the likely to be much more dynamic and trophoblast invasion in the placental bed.

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In a case-control study, Rabaglino et al35
used a bioinformatics approach and TABLE 2
found evidence for impaired endome- Comparison of preeclampsia and preterm delivery in polycystic ovary
trial maturation in early pregnancy in syndrome and teenager groups
women who subsequently experienced Polycystic ovary
preeclampsia. Palomba et al36 in an Variable syndromea 13-15 years oldb 16-17 years oldb
experimental case-control study colle- Preeclampsia 3.5 (1.9e6.2) 2.5 (1.1e5.8) 0.7 (0.5e1.0)
cted trophoblastic and decidual tissue Preterm delivery 1.8 (1.2e2.7) 3.0 (1.6e5.7) 1.1 (0.9e1.5)
after pregnancy termination during the
Data presented as odds ratio (95% confidence interval).
week 12 of gestation in women with and a
Boomsma et al8; b Leppalathi et al.40
without PCOS. The rate of implantation
Brosens. Menstrual preconditioning in polycystic ovary syndrome. Am J Obstet Gynecol 2015.
site vessels with endovascular tropho-
blast invasion and the extent of endo-
vascular trophoblast invasion were basal plate of the placenta, which repre- progesterone resistance in women with
signicantly lower in patients with sents the battleeld between decidua and anovulatory PCOS.36,37 Therefore, it
PCOS, compared with healthy non- trophoblast, and, as such, is rather a poor seems plausible that, in young women
PCOS subjects. area for assessing deep invasion, and with PCOS, the presence of ontogenetic
In a macroscopic and microscopic (2) biopsy specimens from the center of progesterone resistance, combined with
study, Palomba et al37 investigated the the placenta may not be representative the absence of menstrual precondition-
placenta from women with PCOS, for deep invasion because decreased in- ing constitutes a risk factor for pre-
excluding obese patients who achieved a vasion is not observed in the central but eclampsia and preterm delivery. A recent
pregnancy after the use of ovulation in- in the paracentral region.39 large epidemiologic study demonstrated
duction or ART. They showed that that the risk of preeclampsia and preterm
placental weight, thickness, density, and Menstrual preconditioning to improve delivery is high in 13- to 15-year-old
volume were signicantly inferior in pregnancy outcome pregnant teenagers and is normalized in
women with PCOS, compared with As stated, preeclampsia and preterm the 16- to 17-year-old pregnant teen-
those without PCOS. Also, the percent- birth are major obstetric risks in women ager40 (Table 2). This is in agreement
age of patients with placental lesions and with PCOS and are characterized by with the gradual increase of ovulatory
the mean number of these lesions were defective deep placentation.39 It has been cycles from 49% at 1 year to 86% at
higher in the PCOS group than in the shown that insufcient or defective 5 years after the menarche.41 Therefore,
control group. maturation of endometrium and de- the high risk of preeclampsia and pre-
A third study by the same group cidual natural killer cells during the term birth in PCOS after induction of
attempted a matched-control evaluation secretory phase and early pregnancy ovulation in young subjects can be
of the type of phenotype of PCOS that is precede the development of preeclamp- explained by the absence of menstrual
associated with placentation disorder, sia35; in addition, the defective or preconditioning and the persistence of
again excluding obese patients who ach- restrictive trophoblast invasion of the ontogenetic progesterone resistance at
ieved a pregnancy after the use of ovula- spiral arteries can be explained by the the time of ovulation induction.
tion induction or ART.38 They found that
placental weight, thickness, density, and
fetoplacental weight ratio were signi- TABLE 3
cantly different in the full-blown PCOS Prospective trials of clomiphene citrate vs metformin
and nonpolycystic ovary phenotypes vs Authors Trial Medication Ovulation, % Recommendationa
the ovulatory and nonhyperandrogenic Palomba et al43 PnRT MF CC vs CC 62.9 vs 67.0 Both first-line options
phenotypes. The incidence of macro-
Moll et al44 RT MF CC vs CC 64 vs 72 Both effective; higher
scopic placental lesions was only signi- incidence of side-effects
cantly different between control subjects with MF
and the full-blown and nonpolycystic
Legro et al3 RT CC vs MF 49 vs 29 CC superior to MF
phenotypes. The overall incidence
of microscopic placental lesions was MF CC 60.4
45
signicantly different among PCOS Zain et al RT CC vs MF 59 vs 23.7 CC the first-line treatment for
phenotypes and was signicantly higher induction of ovulation
in the full-blown and nonpolycystic MF CC 68.1
phenotypes than in the ovulatory and CC, clomiphene citrate; MF, metformin; PnRT, prospective non-randomized trial; RT, randomized trial.
nonhyperandrogenic phenotypes. a
As first choice for the induction of ovulation in women with anovulatory polycystic ovary syndrome.
A major limitation of these placental Brosens. Menstrual preconditioning in polycystic ovary syndrome. Am J Obstet Gynecol 2015.
studies is that (1) they are based on the

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Several randomized studies have preliminary studies have demonstrated to be exposed to ontogenetic endometrial
demonstrated the efciency of CC in that metformin has the potential to progesterone resistance with increased
comparison with metformin for the reduce the risk of adverse pregnancy risk of miscarriage, preeclampsia, and
induction of ovulation in oligo- or outcomes in women with PCOS.15,49 preterm delivery.
anovulatory women (Table 3). Based on Third, the question arises how to best It is suggested that a period of induced
the results of a randomized, double-blind monitor the use of CC or metformin to cyclic progesterone withdrawal bleedings
clinical trial, Moll et al44 proposed to use induce ovulatory cycles in achieving full by CC, rather than metformin, may
CC as a primary method for the induc- maturation of progesterone response in mature the endometrial progesterone
tion of ovulation rather than metformin the spiral arteries before attempting response.
or to add metformin to CC. Zain et al45 pregnancy. The most direct method at Therefore, it should be investigated by
conrmed in an Asian randomized- present is the estimation of blood ow in prospective studies whether uterine pro-
controlled study that CC is superior to the spiral arteries at their origin in the gesterone response can be matured by a
metformin in inducing ovulation in myometrial junctional zone and in the period of cyclic menstruations before an
anovulatory women with PCOS. endometrium. Yang et al42 were the rst attempt of the induction of ovulation for
When deciding on the best method to group to use a modied color Doppler the treatment of infertility. -
induce ovulatory cycles in young patients technique to determine the outcome
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