Hysteroscopy and female infertility a fresh look to a busy corner

Human Fertility

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Hysteroscopy and female infertility: a fresh look to
a busy corner

Georgi Stamenov Stamenov, Salvatore Giovanni Vitale, Luigi Della Corte,
George Angelos Vilos, Dimitar Angelov Parvanov, Dragomira Nikolaeva
Nikolova, Rumiana Rumenova Ganeva & Sergio Haimovich

To cite this article: Georgi Stamenov Stamenov, Salvatore Giovanni Vitale, Luigi Della Corte,
George Angelos Vilos, Dimitar Angelov Parvanov, Dragomira Nikolaeva Nikolova, Rumiana
Rumenova Ganeva & Sergio Haimovich (2022) Hysteroscopy and female infertility: a fresh look
to a busy corner, Human Fertility, 25:3, 430-446, DOI: 10.1080/14647273.2020.1851399
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HUMAN FERTILITY
2022, VOL. 25, NO. 3, 430–446
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REVIEW ARTICLE

Hysteroscopy and female infertility: a fresh look to a busy corner

Georgi Stamenov Stamenova , Salvatore Giovanni Vitaleb , Luigi Della Cortec ,
George Angelos Vilosd , Dimitar Angelov Parvanova , Dragomira Nikolaeva Nikolovae,
Rumiana Rumenova Ganevaa and Sergio Haimovichf

aNadezhda Women’s Health Hospital, Sofia, Bulgaria; bObstetrics and Gynecology Unit, Department of General Surgery and Medical
Surgical Specialties, University of Catania, Catania, Italy; cDepartment of Neuroscience, Reproductive Sciences and Dentistry, School of
Medicine, University of Naples "Federico II", Naples, Italy; dDepartment of Obstetrics and Gynecology, Division of Reproductive
Endocrinology and Infertility, Western University, London, Canada; eDepartment of Medical Genetics, Medical Faculty, Medical
University – Sofia, Sofia, Bulgaria; fHillel Yaffe Medical Center/Technion - Israel Technology Institute, Hadera, Israel

ABSTRACT ARTICLE HISTORY
Received 30 March 2020
Hysteroscopy has evolved from the traditional art of examining the uterine cavity for diagnostic Accepted 28 September 2020
purposes to an invaluable modality to concomitantly diagnose and (see and) treat a multitude
of intrauterine pathologies, especially in the field and clinics specialising in female reproduction. KEYWORDS
This article reviews the literature on the most common cervical, endometrial, uterine and tubal Diagnosis; female infertility;
pathologies such as chronic endometritis, endometrial polyps, adenomyosis, endometriosis, hysteroscopy; intrauterine
endometrial atrophy, adhesions, endometrial hyperplasia, cancer, and uterine malformations. pathologies; treatment
The aim is to determine the efficiency of hysteroscopy compared with other available techni-
ques as a diagnostic and treatment tool and its association with the success of in vitro fertilisa-
tion procedures. Although hysteroscopy requires an experienced operator for optimal results

and is still an invasive procedure, it has the unique advantage of combining great diagnostic
and treatment opportunities before and after ART procedures. In conclusion, hysteroscopy
should be recommended as a first-line procedure in all cases with female infertility, and a spe-
cial effort should be made for its implementation in the development of new high-tech proce-
dures for identification and treatment infertility-associated conditions.

Introduction diagnostic value, hysteroscopy has also been shown
to treat successfully intrauterine abnormalities result-
Infertility is estimated to affect 9% of all reproductive- ing in significant enhancement of fertility and repro-
aged couples, and female factors are responsible for ductive outcomes (Bosteels et al., 2015). This review
20–35% of all infertility cases (Boivin et al., 2007). summarises the available evidence on the role of hys-
Hysteroscopy is a valuable tool and is currently consid- teroscopy in both the diagnosis and treatment of
ered the “gold standard” approach in assessing the common uterine and tubal pathologies associated
uterine cavity for diagnosis and treatment of female with female fertility and adverse reproduct-
infertility (Bettocchi et al., 2004). Pathologies identified ive outcomes.
during hysteroscopy in infertile women include
chronic endometritis, endometrial polyps, submucosal Materials and methods
myomas, intrauterine adhesions, adenomyosis, thin
endometrium, endometrial hyperplasia and/or cancer The literature search was conducted using MEDLINE,
and uterine malformations such as the uterine septum, EMBASE, Web of Sciences, Scopus, OVID, and
T-shaped uterus, arcuate uterus and unicornuate ute- Cochrane Library as electronic databases. Papers were
rus (Practice Committee of American Society for identified with the use of a combination of the follow-
Reproductive Medicine, 2012a). ing text words: “hysteroscopy,” “female infertility,”
“endometritis,” “endometrial polyps,” “adenomyosis,”
Many health care providers advocate that undertak- “intrauterine adhesions,” “myoma,” “endometrial can-
ing diagnostic hysteroscopy before assisted reproduc- cer,” “uterine malformations,” “tubal endometriosis”
tion treatment increases the chances of pregnancy and “endometrial atrophy” from 1970 to September
significantly (Bosteels et al., 2010). In addition to its

CONTACT Salvatore Giovanni Vitale Obstetrics and Gynecology Unit, Department of General Surgery and Medical Surgical

Specialties, University of Catania, Via Santa Sofia 78, Catania, 95123, Italy.

ß 2020 The British Fertility Society

HUMAN FERTILITY 431

2019. A review of articles also included the abstracts the absence of hysteroscopic features does not rule
of all references retrieved from the search. No restric- out CE’s diagnosis (Song et al., 2019). The most appro-
tions for language or geographic location were priate time for hysteroscopic identification of chronic
applied. The electronic search and the eligibility of endometritis is immediately after menstruation or in
studies were independently assessed by two authors the mid-luteal phase of the cycle.
(LDC and DAP).
Treatment with broad-spectrum antibiotics such as
Results doxycycline, ofloxacin, and metronidazole has been
proven relatively effective leading to the elimination
Based on the results identified in the search, the path- of the source of infection, restoration of normal endo-
ologies were grouped under the following headings metrial histology and receptivity and improvement of
and subheadings. IVF outcome in patients suffering from repeated
implantation failure (RIF) (Vitagliano et al., 2018). The
Intracavitary pathologies observed clearance rate of CD138ỵ plasma cells after
antibiotics treatment was up to 96% (Kitaya et al.,
Chronic endometritis 2012) and a recent review by Kimura et al. (2019) sug-
Two studies reported that chronic endometritis is gested that the administration of oral antibiotics is a
associated with female infertility, and significantly promising therapeutic option in infertile women with
increased the frequency of implantation failure and RIF due to CE.
spontaneous abortions (Cicinelli et al., 2015;
Kitaya, 2011). Therefore, chronic endometritis could be regarded
as one of the potential causes of both primary and
The prevalence of chronic endometritis in infertile secondary infertility, and all women with confirmed
women has been reported to range between 2.8 and infertility should be investigated for chronic endomet-

39%, and it may be more than 60% in women diag- ritis and treated accordingly.
nosed with repeated implantation failure and recur-
rent miscarriages (Kasius et al., 2011). The diagnostic Endometrial polyps
gold standard for chronic endometritis is endometrial Endometrial polyps are common in infertile women
sampling and histological detection of increased stro- with a prevalence of up to 45% (Fatemi et al., 2010;
mal edoema accompanied by plasmacyte infiltration Makrakis et al., 2009). It is also suggested that polyps
within the endometrial stroma (Crum et al., 1983). are present at a higher incidence in women with other
Immunohistochemistry (IHC) for detection of the coexisting pathologies such as endometriosis (Kim
plasma cell marker CD138 (also known as syndecan-1) et al., 2003). A potential mechanism by which polyps
is necessary to improve the detection rate of CE (Chen may cause infertility include irregular endometrial
et al., 2016; Crum et al., 1983). bleeding and inflammation, spatial inhibition of sperm
transport, impaired endocrine function, uterine recep-
Diagnostic hysteroscopy may also be utilised to tivity, and embryo-endometrium contact and cross-
confirm the histologic findings (Cicinelli et al., 2005; talk, and inhibition of sperm binding to the zona pel-
Oliveira et al., 2003; Polisseni et al., 2003). In several lucida through increased glycodelin levels (Oehninger
studies, the endometrial sample collected under hys- et al., 1995; Richlin et al., 2002).
teroscopy has shown higher specificity and positive
and negative predictive values than other methods of The most common symptom of polyps is abnormal
sample collection (Cicinelli et al., 2009; Moreno et al., uterine bleeding (Bakour et al., 2002; Elfayomy et al.,
2018; Song et al., 2019). Hysteroscopically, endometrial 2012). Hysteroscopy remains the gold standard in the
inflammation (endometritis) is characterised by hyper- management of endometrial polyps allowing simultan-
aemia (accentuated blood vessel accumulation at the eous diagnosis and polypectomy (American
periglandular level), stromal edoema (pale and thick- Association of Gynaecologic Laparoscopists, 2012).
ened endometrium in the proliferative phase) as well Usually, this procedure is performed in the early prolif-
as micropolyps (small pedunculated, vascularised pro- erative phase of the menstrual cycle (Figure 1) (Clark
trusions of the uterine mucosa measuring <1 mm) et al., 2002, 2015; Timmermans et al., 2007).
(Cicinelli et al., 2005, 2008). Identification of these hys-
teroscopic features should alert the observer of the The impact of polypectomy on infertile women is
presence of the CE, and endometrial biopsy should be controversial. Some studies reported no improvements
obtained to confirm or refute the diagnosis. However, in implantation, clinical pregnancy or live birth rates

after hysteroscopic polypectomy in patients with
newly diagnosed endometrial polyps subjected to IVF

432 G. S. STAMENOV ET AL.

Figure 1. Presence of multiple polyps involvng the whole Figure 2. Hysteroscopic view of adenomyosis.
endometrial cavity.
Hysteroscopy, histological examination of biopsies,
cycles (Isikoglu et al., 2006; Lass et al., 1999), in con- magnetic resonance (MR), transvaginal ultrasound
trast to other studies that have shown an increase of (TUV), and hysterosalpingography are valuable techni-
pregnancy rate (44.4% more than expected) (Batioglu ques in the determination and characterisation of
& Kaymak, 2005; Ghaffari et al., 2016). Therefore, well- adenomyosis (Garcia & Isaacson, 2011; Gordts et al.,
designed RCTs are needed to assess whether hystero- 2008; Popovic et al., 2011).
scopic removal of endometrial polyps is likely to bene-
fit women with otherwise unexplained subfertility, Hysteroscopy has the benefit of enabling direct
especially the effectiveness of polypectomy before visualisation of the uterine cavity and offers an oppor-
ART treatment (Bosteels et al., 2015). Sufficient evi- tunity for endomyometrial sampling collection under
dence is not available regarding the optimal time visual control (Di Spiezio Sardo et al., 2008; Molinas &
interval between hysteroscopic polypectomy and initi- Campo, 2006) (Figure 2). The principal limitation of
ation of a fresh IVF-ET cycle. The time interval this technique is that the field of vision is restricted to
between hysteroscopic polypectomy and the subse- the surface layer of the endometrium. However, some
quent IVF cycle does not seem to impact the success features are indicative of adenomyosis such as irregu-
rates of the IVF cycle (Eryilmaz et al., 2012; Pereira lar endometrium with small openings on the surface
et al., 2016). during the proliferative and secretory phase, pro-
nounced hypervascularization, a “strawberry” appear-
Adenomyosis ance of the endometrium, fibrous cystic intrauterine
Adenomyosis has been found in 22% of infertile lesions and cystic lesions of dark blue or chocolate
women less than 40 years old, with an estimated brown colour (Di Spiezio Sardo et al., 2017).
prevalence ranging from 20 to 25% in women under-
going IVF-ET (Younes & Tulandi, 2017). One study Surgical options for treatment of adenomyosis

reported that adenomyosis significantly increased the include uterine sparing therapies such as endometrial
miscarriage risk (Stanekova et al., 2018) while another ablation, hysteroscopic or laparoscopic resection, MR
reported no significant impact of adenomyosis on guided high-intensity focussed ultrasonography
embryo transfer outcomes (Benaglia et al., 2014). The (MRgHIFU), uterine artery embolization/occlusion
main factors associated with adenomyosis that may (UAE) and hysterectomy which is considered the
contribute to infertility are changes in uterine tissue definitive surgical treatment of symptomatic adeno-
architecture and function that negatively affect endo- myosis when fertility is not desired (Dueholm, 2018).
metrial receptivity, sperm transport, and embryo
implantation (Munro, 2019). Medical hormonal and non-hormonal treatments
are also used to manage pain and bleeding and to
Alteration of progesterone and oestrogen metabol- possibly improve fertility and reproductive outcomes
ism and down-regulation of progesterone receptors (Vannuccini & Petraglia, 2019). A variety of new drugs,
are known molecular mechanisms that cause the epi- such as selective progesterone (SPRMs) and oestrogen
genetic dysregulation of the genes involved in endo- receptor modulators (SERMs), aromatase inhibitors,
metrial receptivity and decidualization (Jiang et al., gonadotropin-releasing hormone agonist (GnRHa), val-
2016; Kitawaki et al., 2000; Nie et al., 2010). proic acid, and anti-platelet therapy, have been used
for the treatment of adenomyosis (Vannuccini et al.,

HUMAN FERTILITY 433

Figure 3. Hysteroscopic view of intrauterine adhesions. endometrial surface area, and uterine cavity volume or
mechanical obstruction of the cervical canal and/or
2018). However, the impact of these drugs on fertility uterine cavity (Figure 3). Besides, adhesions may be
and pregnancy outcomes remains speculative. associate with recurrent pregnancy loss
(Schenker, 1996).
Hysteroscopy is not a first-line treatment option for
women with adenomyosis but may be considered a Hysteroscopic adhesiolysis is the gold standard
reasonable choice for patients with childbearing desire approach for symptomatic IUAs. By restoring the nor-
(Grimbizis et al., 2014). Office hysteroscopy can be per- mal volume and shape of the uterine cavity, which
formed in selected cases of focal or diffuse superficial may allow normal menstrual flow, sperm transporta-

subtypes. However, for women who desire future tion for fertilisation, and embryo implantation
pregnancy, hysteroscopy can be a valid treatment (Hanstede et al., 2015). The pregnancy rate after adhe-
option only in the case of focal adenomyosis. Indeed, siolysis in women with secondary infertility is esti-
when an adenomyoma is small (<1.5 cm), it can be mated to be 48%, while the miscarriage rate is
removed by hysteroscopy (Di Spiezio Sardo et al., reduced from 86.5 to 42.8% (Goldenberg et al., 1995).
2017). The procedure requires particular attention for A recent study has confirmed these results and has
adequate identification of healthy myometrial tissue found an overall conception rate of 48.2%. However,
due to the lack of a distinct cleavage plane (Molinas & the extent of uterine adhesions can influence preg-
Campo, 2006). Pre-treatment with GnRH agonists can nancy outcomes, with a rate in case of severe IUAs
help reduce the vascularity and bleeding during the lower than in moderate and mild IUAs (Chen
operation. Sometimes, it may also help move the et al., 2017).
adenomyoma into the uterine cavity due to reduced
uterine volume (Li et al., 2018). Although it seems that Although hysteroscopic adhesiolysis is quite effect-
pregnancy rate may improve after conservative surgi- ive in restoring an adequate intrauterine cavity in the
cal treatment of adenomyosis, further research is majority cases, a crucial concern remains the preven-
required to definitively evaluate the benefits of con- tion of adhesion reformation, which could occur in
servative surgery, including hysteroscopic resection of 76% of the patients after the procedure (Aghajanova
adenomyosis for the treatment of fertility (Younes & et al., 2018; Yang et al., 2013). ff multicentre, pro-
Tulandi, 2018). spective randomised controlled trial showed that the
intrauterine instillation of auto-crosslinked hyaluronic
Adhesions acid (ACP) gel after dilatation and curettage (D&C) for
The reproductive outcomes of women with intrauter- miscarriage in women with at least one previous D&C
ine adhesions (IUA) are generally poor due to obstruc- seems to reduce the incidence and severity of IUAs
tion of the tubal ostia, insufficient or an inadequate

434 G. S. STAMENOV ET AL.

but does not eliminate the process of adhesion forma- Lewis & Gargiulo, 2016). Several retrospective cohort
tion (Hooker et al., 2017). Two case reports (34-year studies, focussed on assisted reproduction, support
old and 40 year old patients with IUA) reported a the conclusion that clinical pregnancy rates are higher

beneficial effect of autologous platelet-rich plasma in women who underwent hysteroscopic myomec-
(PRP) infused into the uterine cavity with potential tomy (Surrey et al., 2005).
positive influence not only on endometrial thickness,
but also the functional properties of the uterus There has been significant controversy regarding
(Aghajanova et al., 2018). Another promising therapy the impact of intramural myomas and their removal
for the treatment of severe cases of Asherman syn- on fertility and pregnancy outcomes. Therefore, given
drome is autologous cell transplantation with men- the paucity of contemporary RCTs examining the
strual blood-derived stromal cells (Tan et al., 2016) impact of myomectomy on fertility in women under-
and CD133ỵ bone marrow-derived stem cells going IVF, it would be prudent to perform studies
(Santamaria et al., 2016). with consistent patient selection and primary end-
points. Nevertheless, according to the Practice
Myomas Committee of the American Society for Reproductive
A meta-analysis by Pritts et al. (2009) reported that Medicine (2017) and the updated French guidelines
submucous myomas are associated with lower (Marret et al., 2012), in asymptomatic women with
implantation rates and increased risk for pregnancy cavity-distorting myomas (intramural with a submuco-
loss, while intramural myomas have a questionable sal component or submucosal) and desire of preg-
impact on fertility (Christopoulos et al., 2017; Styer nancy, myomectomy may be considered to improve
et al., 2017). Women with submucous myomas have pregnancy rates and reproductive outcomes.
recurrent pregnancy losses and implantation failures
and one of the possible reasons is the reduced Tubal endometriosis
amount of IL-2 (Hasegawa et al., 2012) and/or impair- Tubal endometriosis is another major cause of tubal
ment of uterine receptivity. infertility, found in 25% of ART patients (Impey et al.,
2008). Furthermore, it has been shown that patients
In conjunction with or in the absence of MRI, hys- with endometriosis experience lower implantation
teroscopy is a method of crucial importance to diag- rates (Budak et al., 2007) and gamete transport, fertil-
nose and characterise the types of submucosal isation, and embryo implantation are impaired due to
leiomyomas (Figure 4) following the International the inflammatory environment by the endometriotic
Federation of Gynaecology and Obstetrics (FIGO) lesions (Harada et al., 2001). The secreted inflamma-
Classification system (Munro et al., 2011, 2018). tory cytokines and the oxidative stress caused by
Hysteroscopy, performed by experienced surgeons, these lesions affect sperm motility (Eisermann et al.,

enables the removal of submucous myomas (types 0, 1989), and this inflammatory environment also induces
1, and 2) up to 4–5 cm diameter, whereas larger and apoptotic events in the embryos (Ding et al., 2010;
multiple myomas are best removed abdominally Rajani et al., 2012).
(American Association of Gynaecologic Laparoscopists:
Advancing Minimally Invasive Gynaecology, 2012; Endometriotic lesions on the Fallopian tube serosa
are usually not visualised at ultrasonographic,

Figure 4. Hysteroscopic view of myomas: (a) Intracavitary sessile myoma of the fundus; (b) Submucous myoma of posterior uter-
ine wall; (c) Intracavitary-submucous myoma of left uterine wall involving almost the entire cavity.

HUMAN FERTILITY 435

Figure 5. Hysteroscopic view of: (a) endometrial hyperplasia; and (b) endometrial carcinoma.

computed tomographic or magnetic resonance imag- cannot provide the embryo with the necessary envir-
ing and the tubes seem patent (Aznaurova et al., onment for implantation. Besides, atrophy is associ-
2014; Practice Committee of the American Society for ated with impaired hormonal regulation (Cavallini
Reproductive, 2012b). Diagnosis of endometriosis et al., 2011; Zhang et al., 2015), which in turn alters
includes direct visualisation histopathological confirm- the “behaviour” of the endometrial tissue and pre-
ation through biopsy (Ballard et al., 2008; Bazot et al., vents implantation (Vannuccini et al., 2016).
2009; Dunselman et al., 2014). A less invasive diagnos-
tic tool for tubal endometriosis may be hysteroscopy Atrophic endometrium is usually diagnosed by histo-
observing a brown liquid coming from the tubal ost- pathological examination of biopsy, where reduced
ium when the pressure of the incoming flow endometrial glands and dense compact stromal cells
is decreased. (Gupta, 2017) can be observed. During hysteroscopy, the
atrophic endometrium appears smooth and thin with
Many options for the treatment of endometriosis- direct visualisation of the deep endometrial vessels,
associated infertility are discussed in the literature. which are not seen in healthy endometrium.
Some authors report improved pregnancy rates after Hysteroscopy has been shown to have high sensitivity in
controlled ovarian stimulation and intrauterine insem- diagnosing atrophic endometrium (Trojano et al., 2018).

ination in patients with endometriosis (Vercellini et al.,
2006). Other authors propose non-hormonal treatment Many therapies have been proposed to treat infer-
such as ICON, VEGF antagonists, and stem cells, which tility thought to be due to endometrial atrophy such
may also prove to increase pregnancy rates by as vaginal insertion of sildenafil (Sher & Fisch, 2002) or
decreasing the extent of the endometriosis lesions treatment with pentoxifylline and alphatocopherol
(Petracco et al., 2012; Taylor et al., 2011). (Okusami et al., 2007). Some experimental studies sug-
gest using autologous CD 133ỵ bone marrow-derived
The highest pregnancy rates among endometriotic stem cells (BMDSCs) infused into the spiral arterioles
patients after several IVF failures were obtained after resulting in positive pregnancies after ART (Santamaria
the surgical removal of the endometriotic lesions et al., 2016). Also, a recent paper reported the effect
(Bulletti et al., 2008). Operative laparoscopy is a better of granulocyte macrophage colony-stimulating factor
option than diagnostic laparoscopy for spontaneous (GM-CSF) on unresponsive thin (<7 mm) endometrium
pregnancies in particularly in mild endometriosis cases. in patients undergoing frozen-thawed embryo transfer,
showed a significantly higher chemical pregnancy rate
Endometrial atrophy (35.3 vs. 20.0%; p ¼ 0.009) and clinical pregnancy rate
At least two publications have reported that up to 9% (28.6 vs. 13.3%; p ¼ 0.005) compared with patients in
of ART patients had a thin atrophic endometrium the control group (Mao et al., 2020).
(Miwa et al., 2009; Mouhayar et al., 2019). Additional
studies reported that a thin endometrium is associated Endometrial hyperplasia and endomet-
with implantation failure (Abdalla et al., 1994; Richter rial carcinoma
et al., 2007). Because atrophic endometrium lacks the The prevalence of endometrial hyperplasia and carcin-
structures characteristic of a receptive endometrium, it oma in women of reproductive age showed a

436 G. S. STAMENOV ET AL.

dramatic increase during the last few decades (Duska been shown that approximately 30% of patients expe-
et al., 2001; Matsuda et al., 2014). The observed rienced recurrence after the achievement of complete
changes in the architecture and function of endomet- response (Gallos et al., 2012; Ushijima et al., 2007) indi-
rium caused by hyperplasia could potentially lead to cating that once reproduction is completed, hysterec-
decreased implantation and an increased chance of tomy should be offered given the high risk of disease

miscarriage, but there are no data to support this relapse (Armstrong et al., 2012).
notion. Besides, this pathological condition is associ-
ated with other pathologies that may have a signifi- A meta-analysis has shown that the live birth rate is
cant impact on female fertility, including chronic different among women who underwent ART and
endometritis, which has been found to coexist with women who conceived spontaneously: a higher live
endometrial neoplasia in up to 50% of patients (Song birth rate was found in women subjected to ART (39 vs.
et al., 2018). 15%) (Gallos et al., 2012; Ushijima et al., 2007). Indeed,
the European Society of Gynaecological Oncology guide-
The hysteroscopic appearance of endometrial lines recommends a prior consultation with a fertility
hyperplasia and carcinoma is typical and relatively expert since a significant number of young patients with
easy for detection (Figure 5). The main hysteroscopic endometrial cancer have a history of infertility, polycystic
morphological parameters that may be used as hys- ovarian syndrome, or obesity (Gonthier et al., 2014;
teroscopic indicators of EH are local or diffuse endo- Jadoul & Donnez, 2003). There is no consistent evidence
metrial thickening with papillary or polypoid aspect, about which kinds of fertility treatments are most advan-
abnormal vascular patterns, presence of glandular tageous after conservative treatment for atypical endo-
cysts and glandular outlets demonstrating abnormal metrial hyperplasia and endometrial cancer, although it
architectural features (Garuti et al., 2005, 2006). has been suggested that ART is especially beneficial for
such patients (Matsuzaki et al., 2018). Therefore, prompt
The visual diagnosis of endometrial cancer is based and effective fertility treatment should be initiated just
on the presence of a gross distortion of the endomet- after conservative treatment in patients with these types
rial cavity, as a result of a nodular, polypoid, papillary, of pathologies who wish to get pregnant immediately.
or mixed pattern of neoplastic growth. Focal necrosis, This strategy usually leads to significantly better preg-
microcalcification, friable consistency, and atypical ves- nancy outcomes (Gonthier et al., 2014; Jadoul &
sels are other characteristics associated with endomet- Donnez, 2003).
rial cancer that could be easily detected by
hysteroscopic inspection (Koutlaki et al., 2010). Uterine malformations
However, the definitive diagnosis of both endometrial
cancer and hyperplasia remains a core competence of The diagnosis of uterine malformations is based on hys-
the histopathologist, and so it requires histological terosalpingography (HSG), transvaginal sonography (TVS),
analysis of endometrial tissue specimens (Armstrong three-dimensional ultrasound imaging (3 D US) and mag-

et al., 2012; Committee on Gynecologic Practice & netic resonance imaging (MRI), but the gold standard
Society of Gynecologic Oncology, 2015). method for visualisation of the cervix and uterine cavity
is hysteroscopy since it allows concomitant treatment
The standard treatment for atypical endometrial (Berger et al., 2014; Practice Committee of the American
hyperplasia and endometrial cancer is hysterectomy Society for Reproductive Medicine, 2016).
with bilateral oophorectomy (Morice et al., 2016).
However, a fertility-sparing therapy can be offered to T-shaped (dysmorphic) uterus
women who desire to retain fertility in cases of endo- Several studies in the past have shown very poor repro-
metrial hyperplasia or endometrioid cancer stage IA ductive performance when a T-shaped uterine malfor-
(without myometrial invasion) grade 1 (Koh et al., mation, also referred to as a dysmorphic uterus, was
2014; Rodolakis et al., 2015). Fertility-sparing treat- noted and not treated (Berger & Goldstein, 1980;
ments can be hormonal, hysteroscopic partial resec- Herbst et al., 1981). In addition, higher prevalence of
tion or combined. Medical treatment includes ectopic pregnancies (Fernandez et al., 2011) and
progestins and GnRH agonists (Grimbizis et al., 1999; increased frequency of miscarriages (Rongieres, 2007)
Perez-Medina et al., 1999). A meta-analysis reported were also reported. However, a stringent association
superiority of the combined treatment with partial between dysmorphic uterus and infertility remains
hysteroscopic resection (HR) and progesterone. The unclear. A possible explanation of reproductive failures
regression rates reported for hormones only, surgery may be associated with the observed change of
only, and hormones and surgery combined are 49.6,
75, and 100% (Erkanli & Ayhan, 2010). However, it has

HUMAN FERTILITY 437

Figure 6. Hysteroscopic view of uterine malformations: (a) T-shaped uterus; and (b–c) Uterine septum (incomplete and complete).

endometrial structure (excess of myometrium in the uterine septa in infertile women has been reported to
uterine walls) and increased uterine contractility in be significantly higher than in the general population,
women with uterine malformations (Haydardedeoglu suggesting a direct link with infertility (Shuiqing et al.,
et al., 2018; Meier & Campo, 2015). 2002; Tomazevic et al., 2010). Non-randomised pro-
spective trials have shown that uterine septum is asso-

Commonly applied diagnostic techniques for a dys- ciated with 47% lower implantation rate and a 67%
morphic uterus are hysteroscopy (Figure 6), laparos- chance of miscarriage (Mollo et al., 2009; Rikken et al.,
copy, magnetic resonance imaging (MRI), 2 D or 3 D 2018). A meta-analysis evaluating the effect of differ-
ultrasonography and hysterosalpingography (HSG). ent types of uterine anomalies on reproductive out-
comes reported that septate uterus was the only
Hysteroscopic metroplasty is the most commonly anomaly that was significantly associated with a
used surgical procedure that significantly improves the decrease in the probability of natural conception
total uterine cavity volume and live birth rate in (Venetis et al., 2014). Other studies also confirmed sev-
patients with a T-shaped uterus and a history of pri- eral-fold increase of miscarriage rate, late abortions
mary infertility and recurrent miscarriage. The enlarge- and preterm labour (Kupesic et al., 2002; Tomazevic
ment of the uterine cavity, using hysteroscopic et al., 2010).
metroplasty, could also improve endometrial vascular
perfusion and decrease uterine contractility and, as a The American Society for Reproductive Medicine
consequence, could make the embryo implantation guidelines recommended hysteroscopy for the diagno-
more probable (Haydardedeoglu et al., 2018). sis of uterine septum (Practice Committee of the
American Society for Reproductive Medicine, 2016)
Several studies have found an increase in delivery (Figure 6). Imaging with saline infusion/gel instillation
rate after the hysteroscopic treatment with a range sonography (SIS/GIS), magnetic resonance imaging
between 63.2 and 65% (Barranger et al., 2002; Di (MRI) and ultrasonography (US) are additional alterna-
Spiezio Sardo et al., 2015; Giacomucci et al., 2011). tives for screening and evaluation of uterine septum
However, the studies reporting anatomical and repro- (Ludwin et al., 2013; Mueller et al., 2007). Three-dimen-
ductive outcomes are few, with small sample size and a sional ultrasound and magnetic resonance imaging
retrospective design (Ducellier-Azzola et al., 2018). The are typically used in confirming the serosal fundal con-
study with the largest cohort, including 97 patients tour distinguishing a bicornuate from septate uteri,
with T-shaped uterus treated by hysteroscopic metro- whereas office hysteroscopy gives a rapid sense of the
plasty, reported an increase of live birth rate from 0 to depth of the internal indentation (Parry &
73%, and a decrease of miscarriage rate from 78 to Isaacson, 2019).
27% (Fernandez et al., 2011). Only a well-designed
randomised study may properly address the question Hysteroscopic division is currently the gold stand-
of whether hysteroscopic metroplasty is beneficial in ard for the treatment of uterine septa (Practice

patients with a T shaped uterus (Boza et al., 2019). Committee of the American Society for Reproductive
Medicine, 2016). Risk of subsequent pregnancy-related
Uterine septum uterine rupture could be caused by excessive septal
The uterine septum is associated with structural altera- excision, incidental deep penetration of the myome-
tions in the endometrium that affect embryo implant- trium, uterine wall perforation, and excessive use of
ation (Kormanyos et al., 2006). The incidence of

438 G. S. STAMENOV ET AL.

radiofrequency (RF) or laser energy during the initial approach is laparotomy or laparoscopy with complete
septum incision (Valle & Ekpo, 2013). removal of the rudimentary horn.

Multiple observational studies indicate that hystero- Transcervical uterine incision (TCUI) is an alternative
scopic septum incision is associated with improved procedure that could lead to a significant increase in
clinical pregnancy rates in women with infertility, pregnancy outcomes (Xia et al., 2017). These opera-
decreased subsequent miscarriage rates and improve- tions can lead to adverse effects on the reproductive
ment in live-birth rates in patients with infertility or prognosis of patients due to a small volume of the
recurrent pregnancy loss (Tomazevic et al., 2010; Valle residual uterine hemicavity (Pados et al., 2014;
& Ekpo, 2013; Venetis et al., 2014). In addition, hystero- So€nmezer et al., 2006). Nappi and Di Spiezio Sardo
scopic septum incision seems to improve IVF out- (2014) stated that the hysteroscopic approach is a less
comes when performed before the embryo transfer, invasive option with a more favourable impact on
by improving embryo implantation rates (Corroenne reproductive prognosis with the added advantage of
et al., 2018). The uterine cavity is healed by approxi- being able to distinguish a non communicating horn
mately 8 weeks after hysteroscopic septum incision with unicornuate uterus from a septate uterus.
and this period seems to be appropriate for a woman
to wait to conceive (Berkkanoglu et al., 2008; Yang Conclusion
et al., 2013).
Most of the discussed endometrial and tubal patholo-
Arcuate and unicornuate uteri gies are relatively common and have an essential dir-
The arcuate uterus usually is considered to be a vari- ect or indirect impact on female infertility.

ation of normal uterine anatomy and has not been
associated with adverse reproductive outcomes (Chan This review has shown that hysteroscopy is an
et al., 2011; Gubbini et al., 2009) and no treatment is appropriate technique for accurate intrauterine evalu-
indicated (Mucowski et al., 2010). A recent study has ation before any therapy for infertility. The use of
shown that an arcuate uterus has no impact on ART office vaginoscopic hysteroscopy without a speculum
outcomes after embryo transfer subsequent to com- and cervical tenaculum allows examination without
prehensive chromosomal screening (Surrey et al., the need for anaesthesia and premedication. It is a
2018). Tomazevic et al. (2010) conducted a retrospect- successful procedure that significantly reduces anxiety
ive matched-control study in women with septate, and pain experienced by patients during the proced-
subseptate and arcuate uterus and they reported that ure, compared with traditional techniques using a
after hysteroscopic metroplasty the pregnancy rate vaginal speculum.
and live birth rate of women with arcuate uterus was
comparable to that of women with normal uterine Vaginoscopic hysteroscopy is associated not only
cavity (36.8 vs 39%; OR 1.1) while before metroplasty, with minimal patient discomfort, but also with excel-
the pregnancy rate was lower in women with arcuate lent visualisation, and very low complication and fail-
uterus compared to control group (20.9 vs 35.6%; OR ure rates. For this reason, office hysteroscopy should
2.1; p < 0.03). Similar results were found for live birth be recommended as the first diagnostic tool for the
rate (3 vs 30.4% before metroplasty, 28 vs 32.2% after evaluation of infertility.
hysteroscopic metroplasty) (Kupesic et al., 2002;
Tomazevic et al., 2010). There are several reasons why hysteroscopy, and in
particular the outpatient hysteroscopy, should be rec-
Unicornuate uterus ommended as a first-line procedure in all or almost all
Unicornuate uterus is associated with lower clinical cases with female infertility. The distinction between
pregnancy rate, increased risk of miscarriage and diagnostic and operative procedure has been reduced
ectopic pregnancy (Chen et al., 2018; Reichman et al., with the introduction of the so-called “see & treat hys-
2009; Venetis et al., 2014) and is more prevalent in teroscopy,” with the possibility to perform a single
women with infertility (0.5%), miscarriage (0.5%) or procedure in which the operative part is perfectly inte-
both (3.1%) (Chan et al., 2011). Several studies have grated within the diagnostic work-up: this is very
shown poorer outcomes of assisted reproductive tech- important considering how important the “time” is for
nology (ART) treatments in women with unicornuate an infertile couple. The improvement in technology

uterus compared to those with normal anatomy (Li and techniques made hysteroscopy less painful and
et al., 2017; Liu et al., 2017). The traditional surgical invasive allowing it to be performed in an ambulatory
setting with more accurate diagnosis and greater man-
agement options for intrauterine pathology with direct
access and a real-time view of the endometrial cavity

HUMAN FERTILITY 439

(Campo et al., 2018). On the whole, if we take into become a promising tool for fallopian tubes examin-
account the case of infertility due to intrauterine adhe- ation and treatment. In conclusion, hysteroscopy as a
sions or mild Asherman syndrome, office hysteroscopy diagnostic and therapeutic method of female infertility
without general anaesthesia can be safely carried out will become even more widely used and tightly linked
to allow the restoration of a normal uterine cavity by with ART.
breaking the adhesions using only the uterine disten-
sion pressure and the tip of the hysteroscope (Di Disclosure statement
Guardo et al., 2020). Its application has shown clinical
significance and economic benefits (Grade II evidence, No potential conflict of interest was reported by
Grade A recommendation). Nevertheless, outpatient the author(s).
hysteroscopy practitioners should have the proper
skills and expertise, mandatory to perform hystero- ORCID
scopy (Level VI, Recommended Intensity A). All
patients must sign an informed consent, receiving the Georgi Stamenov Stamenov />proper information before surgery (Level VI, 4583-2711
Recommended Intensity A). Finally, we must not for- Salvatore Giovanni Vitale />get that diagnostic hysteroscopy and, if necessary, 6871-6097
biopsy or even surgery should be performed in a well- Luigi Della Corte />equipped, well-staffed informal operating room to George Angelos Vilos />ensure patient safety and privacy (Level of evidence II, 2007-8791
Recommended Intensity B) (Italian Society of Dimitar Angelov Parvanov />Gynecological Endoscopy (SEGI), 2013). Improvements 4992-002X
in operative hysteroscopy, such as the availability of Sergio Haimovich />high-resolution mini-endoscopes, the application of
saline solution as distension medium, the miniaturisa- References
tion and insertion of atraumatic instruments, have led
to rapid acceptance and adaptation of this modality in Abdalla, H. I., Brooks, A. A., Johnson, M. R., Kirkland, A.,
the diagnosis and treatment of intrauterine patholo- Thomas, A., & Studd, J. W. (1994). Endometrial thickness:

gies associated with infertility. A predictor of implantation in ovum recipients? Human
Reproduction (Oxford, England), 9(2), 363–365. https://doi.
All the evidence on the efficacy of operative hys- org/10.1093/oxfordjournals.humrep.a138509
teroscopy on reproductive outcome in infertile women
with uterine pathologies are based on observational Aghajanova, L., Cedars, M. I., & Huddleston, H. G. (2018).
studies. Therefore, more well-designed RCTs are Platelet-rich plasma in the management of Asherman syn-
needed to assess whether the hysteroscopic treatment drome: Case report. Journal of Assisted Reproduction and
of uterine pathologies is likely to increase reproductive Genetics, 35(5), 771–775. />outcome compared to a control intervention, in 018-1135-3
women with unexplained infertility or recurrent
implantation failure. Robust and high-quality RCTs are American Association of Gynecologic Laparoscopists (AAGL):
also needed before hysteroscopy can be regarded as a Advancing Minimally Invasive Gynecology Worldwide
first-line procedure in infertile women, especially dur- (2012). AAGL practice report: practice guidelines for the
ing the initial clinical assessment of a couple, in order diagnosis and management of submucous leiomyomas.
to reduce the time-to-pregnancy and the need Journal of Minimally Invasive Gynecology, 19(2), 152–171.
for ART. />
Hysteroscopy is not only the gold standard for American Association of Gynecologic Laparoscopists (2012).
diagnostics and treatment of intrauterine conditions AAGL practice report: practice guidelines for the diagnosis
but also it is evolving as an integral part with the lat- and management of endometrial polyps. Journal of
est trends and developments in the field of reproduct- Minimally Invasive Gynecology, 19(1), 3–10. />ive medicine. In combination with other techniques, 10.1016/j.jmig.2011.09.003
such as hysterosalpingography, MRI and ultrasound
techniques, hysteroscopy provides opportunities for Armstrong, A. J., Hurd, W. W., Elguero, S., Barker, N. M., &
IVF clinics to increase clinical and life-birth rates. Zanotti, K. M. (2012). Diagnosis and management of endo-
Advances in hysteroscopic technologies also will metrial hyperplasia. Journal of Minimally Invasive
Gynecology, 19(5), 562–571. /> 2012.05.009

Aznaurova, Y. B., Zhumataev, M. B., Roberts, T. K., Aliper,
A. M., & Zhavoronkov, A. A. (2014). Molecular aspects of
development and regulation of endometriosis.
Reproductive Biology and Endocrinology : RB&E, 12(1), 50.
/>

Bakour, S. H., Khan, K. S., & Gupta, J. K. (2002). The risk of
premalignant and malignant pathology in endometrial

440 G. S. STAMENOV ET AL.

polyps. Acta obstetricia et gynecologica Scandinavica, 81(2), Bosteels, J., Weyers, S., Puttemans, P., Panayotidis, C., Van
182–183. Herendael, B., Gomel, V., Mol, B. W., Mathieu, C., &
Ballard, K. D., Seaman, H. E., de Vries, C. S., & Wright, J. T. D’Hooghe, T. (2010). The effectiveness of hysteroscopy in
(2008). Can symptomatology help in the diagnosis of improving pregnancy rates in subfertile women without
endometriosis? Findings from a national case-control other gynaecological symptoms: A systematic review.
study-Part 1. BJOG : An International Journal of Obstetrics Human Reproduction Update, 16(1), 1–11. /> and Gynaecology, 115(11), 1382–1391. 10.1093/humupd/dmp033
1111/j.1471-0528.2008.01878.x
Barranger, E., Gervaise, A., Doumerc, S., & Fernandez, H. Boza, A., Akin, O. D., Oguz, S. Y., Misirlioglu, S., & Urman, B.
(2002). Reproductive performance after hysteroscopic met- (2019). Surgical correction of T-shaped uteri in women
roplasty in the hypoplastic uterus: A study of 29 cases. with reproductive failure: Long term anatomical and
BJOG : An International Journal of Obstetrics and reproductive outcomes. Journal of Gynecology Obstetrics
Gynaecology, 109(12), 1331–1334. and Human Reproduction, 48(1), 39–44. /> 1471-0528.2002.01448.x 1016/j.jogoh.2018.10.013
Batioglu, S., & Kaymak, O. (2005). Does hysteroscopic poly-
pectomy without cycle cancellation affect IVF? Budak, E., Garrido, N., Soares, S. R., Melo, M. A., Meseguer,
Reproductive Biomedicine Online, 10(6), 767–769. https:// M., Pellicer, A., & Remohi, J. (2007). Improvements
doi.org/10.1016/S1472-6483(10)61121-2 achieved in an oocyte donation program over a 10-year
Bazot, M., Lafont, C., Rouzier, R., Roseau, G., Thomassin- period: sequential increase in implantation and pregnancy
Naggara, I., & Darai, E. (2009). Diagnostic accuracy of phys- rates and decrease in high-order multiple pregnancies.
ical examination, transvaginal sonography, rectal endo- Fertility and Sterility, 88(2), 342–349. /> scopic sonography, and magnetic resonance imaging to 1016/j.fertnstert.2006.11.118
diagnose deep infiltrating endometriosis. Fertility and
Sterility, 92(6), 1825–1833. Bulletti, C., Panzini, I., Borini, A., Coccia, E., Setti, P. L., &
stert.2008.09.005 Palagiano, A. (2008). Pelvic factor infertility: Diagnosis and
Benaglia, L., Cardellicchio, L., Leonardi, M., Faulisi, S., prognosis of various procedures. Annals of the New York
Vercellini, P., Paffoni, A., Somigliana, E., & Fedele, L. (2014). Academy of Sciences, 1127, 73–82. /> Asymptomatic adenomyosis and embryo implantation in annals.1434.020
IVF cycles. Reproductive Biomedicine Online, 29(5), 606–611.

Campo, R., Santangelo, F., Gordts, S., Di Cesare, C., Van
Berger, A., Batzer, F., Lev-Toaff, A., & Berry-Roberts, C. (2014). Kerrebroeck, H., De Angelis, M. C., & Di Spiezio Sardo, A.
Diagnostic imaging modalities for Mu€llerian anomalies: (2018). Outpatient hysteroscopy. Facts, Views & Vision in
The case for a new gold standard. Journal of Minimally Obgyn, 10(3), 115–122. /> Invasive Gynecology, 21(3), 335–345. ume-10/number-3/editorial/outpatient-hysteroscopy/
1016/j.jmig.2013.10.014
Berger, M. J., & Goldstein, D. P. (1980). Impaired reproductive Cavallini, A., Resta, L., Caringella, A. M., Dinaro, E., Lippolis,
performance in DES-exposed women. Obstetrics and C., & Loverro, G. (2011). Involvement of estrogen receptor-
Gynecology, 55(1), 25–27. related receptors in human ovarian endometriosis. Fertility
journal/Abstract/1980/01000/Impaired_Reproductive_ and Sterility, 96(1), 102–106. /> Performance_in_DES_Exposed.6.aspx stert.2011.04.032
Berkkanoglu, M., Isikoglu, M., Arici, F., & Ozgur, K. (2008).
What is the best time to perform intracytoplasmic sperm Chan, Y. Y., Jayaprakasan, K., Zamora, J., Thornton, J. G.,
injection/embryo transfer cycle after hysteroscopic surgery Raine-Fenning, N., & Coomarasamy, A. (2011). The preva-
for an incomplete uterine septum? Fertility and Sterility, lence of congenital uterine anomalies in unselected and
90(6), 2112–2115. high-risk populations: A systematic review. Human
10.018 Reproduction Update, 17(6), 761–771. />Bettocchi, S., Nappi, L., Ceci, O., & Selvaggi, L. (2004). Office 1093/humupd/dmr028
hysteroscopy. Obstetrics and Gynecology Clinics of North
America, 31(3), 641–654, xi. Chen, Y. Q., Fang, R. L., Luo, Y. N., & Luo, C. Q. (2016).
2004.05.007 Analysis of the diagnostic value of CD138 for chronic
Boivin, J., Bunting, L., Collins, J. A., & Nygren, K. G. (2007). endometritis, the risk factors for the pathogenesis of
International estimates of infertility prevalence and treat- chronic endometritis and the effect of chronic endometri-
ment-seeking: Potential need and demand for infertility tis on pregnancy: A cohort study. BMC Womens Health,
medical care. Human Reproduction (Oxford, England), 22(6), 16(1), 60. /> 1506–1512. />Bosteels, J., Kasius, J., Weyers, S., Broekmans, F. J., Mol, B. W., Chen, Y., Nisenblat, V., Yang, P., Zhang, X., & Ma, C. (2018).
& D’Hooghe, T. M. (2015). Hysteroscopy for treating sub- Reproductive outcomes in women with unicornuate ute-
fertility associated with suspected major uterine cavity rus undergoing in vitro fertilization: A nested case-control
abnormalities. Cochrane Database of Systematic Reviews, 2, retrospective study. Reproductive Biology and
CD009461. Endocrinology, 16(1), 64. /> pub3 018-0382-6

Chen, L., Zhang, H., Wang, Q., Xie, F., Gao, S., Song, Y., Dong,
J., Feng, H., Xie, K., & Sui, L. (2017). Reproductive out-
comes in patients with intrauterine adhesions following

hysteroscopic adhesiolysis: Experience from the largest
women’s hospital in China. Journal of Minimally Invasive
Gynecology, 24(2), 299–304. /> 2016.10.018

Christopoulos, G., Vlismas, A., Salim, R., Islam, R., Trew, G., &
Lavery, S. (2017). Fibroids that do not distort the uterine

HUMAN FERTILITY 441

cavity and IVF success rates: An observational study using (2020). Evaluation and treatment of infertile women with
extensive matching criteria. BJOG: An International Journal
of Obstetrics & Gynaecology, 124(4), 615–621. https://doi. Asherman syndrome: An updated review focusing on the
org/10.1111/1471-0528.14362
Cicinelli, E., De Ziegler, D., Nicoletti, R., Colafiglio, G., Saliani, role of hysteroscopy. Reproductive Biomedicine Online,
N., Resta, L., Rizzi, D., & De Vito, D. (2008). Chronic endo-
metritis: Correlation among hysteroscopic, histologic, and 41(1), 55–61. /> bacteriologic findings in a prospective trial with 2190 con-
secutive office hysteroscopies. Fertility and Sterility, 89(3), Di Spiezio Sardo, A., Calagna, G., Santangelo, F., Zizolfi, B.,
677–684. />Cicinelli, E., De Ziegler, D., Nicoletti, R., Tinelli, R., Saliani, N., Tanos, V., Perino, A., & De Wilde, R. L. (2017). The role of
Resta, L., Bellavia, M., & De Vito, D. (2009). Poor reliability
of vaginal and endocervical cultures for evaluating micro- hysteroscopy in the diagnosis and treatment of adeno-
biology of endometrial cavity in women with chronic
endometritis. Gynecologic and Obstetric Investigation, 68(2), myosis. BioMed Research International, 2017, 2518396.
108–115. />Cicinelli, E., Matteo, M., Tinelli, R., Lepera, A., Alfonso, R., /> Indraccolo, U., Marrocchella, S., Greco, P., & Resta, L.
(2015). Prevalence of chronic endometritis in repeated Di Spiezio Sardo, A., Florio, P., Nazzaro, G., Spinelli, M.,
unexplained implantation failure and the IVF success rate
after antibiotic therapy. Human Reproduction (Oxford, Paladini, D., Di Carlo, C., & Nappi, C. (2015). Hysteroscopic
England), 30(2), 323–330. /> deu292 outpatient metroplasty to expand dysmorphic uteri
Cicinelli, E., Resta, L., Nicoletti, R., Tartagni, M., Marinaccio,
M., Bulletti, C., & Colafiglio, G. (2005). Detection of chronic (HOME-DU technique): A pilot study. Reproductive
endometritis at fluid hysteroscopy. Journal of Minimally

Invasive Gynecology, 12(6), 514–518. Biomedicine Online, 30(2), 166–174. /> 1016/j.jmig.2005.07.394
Clark, T. J., Khan, K. S., & Gupta, J. K. (2002). Current practice 1016/j.rbmo.2014.10.016
for the treatment of benign intrauterine polyps: A
national questionnaire survey of consultant gynaecologists Di Spiezio Sardo, A., Guida, M., Bettocchi, S., Nappi, L.,
in UK. European Journal of Obstetrics, Gynecology, and
Reproductive Biology, 103(1), 65–67. Sorrentino, F., Bifulco, G., & Nappi, C. (2008). Role of hys-
1016/S0301-2115(02)00011-8
Clark, T. J., Middleton, L. J., Cooper, N. A., Diwakar, L., Denny, teroscopy in evaluating chronic pelvic pain. Fertility and
E., Smith, P., Gennard, L., Stobert, L., Roberts, T. E., Cheed,
V., Bingham, T., Jowett, S., Brettell, E., Connor, M., Jones, Sterility, 90(4), 1191–1196. /> S. E., & Daniels, J. P. (2015). A randomised controlled trial
of Outpatient versus inpatient Polyp Treatment (OPT) for stert.2007.07.1351
abnormal uterine bleeding. Health Technology Assessment
(Winchester, England), 19(61), 1–194. Ding, G. L., Chen, X. J., Luo, Q., Dong, M. Y., Wang, N., &
3310/hta19610
Committee on Gynecologic Practice, Society of Gynecologic Huang, H. F. (2010). Attenuated oocyte fertilization and
Oncology. (2015). The American College of Obstetricians
and Gynecologists Committee Opinion no. 631. embryo development associated with altered growth fac-
Endometrial intraepithelial neoplasia. Obstetrics and
Gynecology, 125(5), 1272–1278. tor/signal transduction induced by endometriotic periton-
AOG.0000465189.50026.20
Corroenne, R., Legendre, G., May-Panloup, P., El Hachem, H., eal fluid. Fertility and Sterility, 93(8), 2538–2544. https://
Dreux, C., Jeanneteau, P., Boucret, L., Ferre-L’Hotellier, V.,
Descamps, P., & Bouet, P.-E. (2018). Surgical treatment of doi.org/10.1016/j.fertnstert.2009.11.011
septate uterus in cases of primary infertility and before
assisted reproductive technologies. Journal of Gynecology Ducellier-Azzola, G., Lecointre, L., Hummel, M., Pontvianne,
Obstetrics and Human Reproduction, 47(9), 413–418.
M., & Garbin, O. (2018). Hysteroscopic enlargement metro-
Crum, C. P., Egawa, K., Fenoglio, C. M., & Richart, R. M.
(1983). Chronic endometritis: the role of immunohisto- plasty for T-shaped uterus: 24 years’ experience at the
chemistry in the detection of plasma cells. American

Journal of Obstetrics and Gynecology, 147(7), 812–815. Strasbourg Medico-Surgical and Obstetrical Centre
/>Di Guardo, F., Della Corte, L., Vilos, G. A., Carugno, J., (CMCO). European Journal of Obstetrics & Gynecology and
To€ro€k, P., Giampaolino, P., Manchanda, R., & Vitale, S. G.
Reproductive Biology, 226, 30–34. />
ejogrb.2018.04.036

Dueholm, M. (2018). Minimally invasive treatment of adeno-

myosis. Best Practice & Research. Clinical Obstetrics &

Gynaecology, 51, 119–137. />
gyn.2018.01.016

Dunselman, G. A., Vermeulen, N., Becker, C., Calhaz-Jorge, C.,

D’Hooghe, T., De Bie, B., Heikinheimo, O., Horne, A. W.,

Kiesel, L., Nap, A., Prentice, A., Saridogan, E., Soriano, D., &

Nelen, W., & European Society of Human Reproduction

and Embryology. (2014). ESHRE guideline: Management of

women with endometriosis. Human Reproduction (Oxford,

England), 29(3), 400–412. />
det457

Duska, L. R., Garrett, A., Rueda, B. R., Haas, J., Chang, Y., &

Fuller, A. F. (2001). Endometrial cancer in women 40 years

old or younger. Gynecologic Oncology, 83(2), 388–393.

/>
Eisermann, J., Register, K. B., Strickler, R. C., & Collins, J. L.

(1989). The effect of tumor necrosis factor on human

sperm motility in vitro. Journal of Andrology, 10(4),

270–274. />
tb00100.x

Elfayomy, A. K., Habib, F. A., Elkablawy, M. A., & Alkabalawy,

M. A. (2012). Role of hysteroscopy in the detection of

endometrial pathologies in women presenting with post-

menopausal bleeding and thickened endometrium.

Archives of Gynecology and Obstetrics, 285(3), 839–843.

/>
Erkanli, S., & Ayhan, A. (2010). Fertility-sparing therapy in

young women with endometrial cancer: 2010 update.

442 G. S. STAMENOV ET AL.

International Journal of Gynecological Cancer : Official Journal Gordts, S., Brosens, J. J., Fusi, L., Benagiano, G., & Brosens, I.
of the International Gynecological Cancer Society, 20(7), (2008). Uterine adenomyosis: A need for uniform termin-
1170–1187. ology and consensus classification. Reproductive
Eryilmaz, O. G., Gulerman, C., Sarikaya, E., Yesilyurt, H., Karsli, Biomedicine Online, 17(2), 244–248. /> F., & Cicek, N. (2012). Appropriate interval between endo- 1016/S1472-6483(10)60201-5
metrial polyp resection and the proceeding IVF start.
Archives of Gynecology and Obstetrics, 285(6), 1753–1757. Grimbizis, G. F., Mikos, T., & Tarlatzis, B. (2014). Uterus-spar-
ing operative treatment for adenomyosis. Fertility and
Fatemi, H. M., Kasius, J. C., Timmermans, A., van Disseldorp, Sterility, 101(2), 472–487.e478. /> J., Fauser, B. C., Devroey, P., & Broekmans, F. J. (2010). fertnstert.2013.10.025
Prevalence of unsuspected uterine cavity abnormalities
diagnosed by office hysteroscopy prior to in vitro fertiliza- Grimbizis, G., Tsalikis, T., Tzioufa, V., Kasapis, M., &
tion. Human Reproduction (Reproduction), 25(8), Mantalenakis, S. (1999). Regression of endometrial hyper-
1959–1965. plasia after treatment with the gonadotrophin-releasing
Fernandez, H., Garbin, O., Castaigne, V., Gervaise, A., & hormone analogue triptorelin: A prospective study.
Levaillant, J. M. (2011). Surgical approach to and repro- Human Reproduction (Oxford, England), 14(2), 479–484.
ductive outcome after surgical correction of a T-shaped /> uterus. Human Reproduction (Reproduction), 26(7),
1730–1734. Gubbini, G., Di Spiezio Sardo, A., Nascetti, D., Marra, E.,
Gallos, I. D., Yap, J., Rajkhowa, M., Luesley, D. M., Spinelli, M., Greco, E., Casadio, P., & Nappi, C. (2009). New
Coomarasamy, A., & Gupta, J. K. (2012). Regression, outpatient subclassification system for American Fertility
relapse, and live birth rates with fertility-sparing therapy Society Classes V and VI uterine anomalies. Journal of
for endometrial cancer and atypical complex endometrial Minimally Invasive Gynecology, 16(5), 554–561. https://doi.
hyperplasia: A systematic review and metaanalysis. org/10.1016/j.jmig.2009.06.002
American Journal of Obstetrics and Gynecology, 207(4),
266.e1–266.e12. Gupta, R. C. (Ed.). (2017). Reproductive and developmental
Garcia, L., & Isaacson, K. (2011). Adenomyosis: Review of the toxicology (2nd ed.). Elsevier.
literature. Journal of Minimally Invasive Gynecology, 18(4),
428–437. Hanstede, M. M., van der Meij, E., Goedemans, L., & Emanuel,
Garuti, G., Cellani, F., Garzia, D., Colonnelli, M., & Luerti, M. M. H. (2015). Results of centralized Asherman surgery,
(2005). Accuracy of hysteroscopic diagnosis of endometrial 2003–2013. Fertility and Sterility, 104(6), 1561–1568.e1561.
hyperplasia: A retrospective study of 323 patients. Journal /> of Minimally Invasive Gynecology, 12(3), 247–253. https://

doi.org/10.1016/j.jmig.2005.03.006 Harada, T., Iwabe, T., & Terakawa, N. (2001). Role of cytokines
Garuti, G., Mirra, M., & Luerti, M. (2006). Hysteroscopic view in endometriosis. Fertility and Sterility, 76(1), 1–10. https://
in atypical endometrial hyperplasias: A correlation with doi.org/10.1016/S0015-0282(01)01816-7
pathologic findings on hysterectomy specimens. Journal
of Minimally Invasive Gynecology, 13(4), 325–330. https:// Hasegawa, E., Ito, H., Hasegawa, F., Hatano, K., Kazuka, M.,
doi.org/10.1016/j.jmig.2006.03.010 Usuda, S., & Isaka, K. (2012). Expression of leukemia inhibi-
Ghaffari, F., Arabipoor, A., Bagheri Lankarani, N., Hosseini, F., tory factor in the endometrium in abnormal uterine cav-
& Bahmanabadi, A. (2016). Hysteroscopic polypectomy ities during the implantation window. Fertility and Sterility,
without cycle cancellation in IVF/ICSI cycles: A cross-sec- 97(4), 953–958. /> tional study. European Journal of Obstetrics, Gynecology, 113
and Reproductive Biology, 205, 37–42. /> 1016/j.ejogrb.2016.08.019 Haydardedeoglu, B., Dogan Durdag, G., S¸ims¸ek, S., C¸aglar
Giacomucci, E., Bellavia, E., Sandri, F., Farina, A., & Scagliarini, Aytac¸, P., C¸ok, T., & Bulgan Kılıc¸dag, E. (2018).
G. (2011). Term delivery rate after hysteroscopic metro- Reproductive outcomes of office hysteroscopic metro-
plasty in patients with recurrent spontaneous abortion plasty in women with unexplained infertility with dys-
and T-shaped, arcuate and septate uterus. Gynecologic morphic uterus. Journal of Turkish Society of Obstetric and
and Obstetric Investigation, 71(3), 183–188. Gynecology, 15(3), 135–140. /> 10.1159/000317266 30111
Goldenberg, M., Sivan, E., Sharabi, Z., Mashiach, S., Lipitz, S.,
& Seidman, D. S. (1995). Reproductive outcome following Herbst, A. L., Hubby, M. M., Azizi, F., & Makii, M. M. (1981).
hysteroscopic management of intrauterine septum and Reproductive and gynecologic surgical experience in
adhesions. Human Reproduction (Oxford, England), 10(10), diethylstilbestrol-exposed daughters. American Journal of
2663–2665. Obstetrics and Gynecology, 141(8), 1019–1028. https://doi.
a135763 org/10.1016/S0002-9378(16)32693-X
Gonthier, C., Walker, F., Luton, D., Yazbeck, C., Madelenat, P.,
& Koskas, M. (2014). Impact of obesity on the results of Hooker, A. B., de Leeuw, R., van de Ven, P. M., Bakkum, E. A.,
fertility-sparing management for atypical hyperplasia and Thurkow, A. L., Vogel, N. E. A., van Vliet, H., Bongers, M. Y.,
grade 1 endometrial cancer. Gynecologic Oncology, 133(1), Emanuel, M. H., Verdonkschot, A. E. M., Brolmann,
33–37. H. A. M., & Huirne, J. A. F. (2017). Prevalence of intrauter-
ine adhesions after the application of hyaluronic acid gel
after dilatation and curettage in women with at least one
previous curettage: Short-term outcomes of a multicentre,
prospective randomized controlled trial. Fertility and

Sterility, 107(5), 1223–1231.e1223. /> fertnstert.2017.02.113

Impey, L. W., Greenwood, C. E., Black, R. S., Yeh, P. S., Sheil,
O., & Doyle, P. (2008). The relationship between intrapar-
tum maternal fever and neonatal acidosis as risk factors
for neonatal encephalopathy. American Journal of

HUMAN FERTILITY 443

Obstetrics and Gynecology, 198(1), 49.e1–46.e41. https:// Kormanyos, Z., Molnar, B. G., & Pal, A. (2006). Removal of a
doi.org/10.1016/j.ajog.2007.06.011 residual portion of a uterine septum in women of
Isikoglu, M., Berkkanoglu, M., Senturk, Z., Coetzee, K., & advanced reproductive age: obstetric outcome. Human
Ozgur, K. (2006). Endometrial polyps smaller than 1.5 cm Reproduction (Oxford, England), 21(4), 1047–1051. https://
do not affect ICSI outcome. Reproductive Biomedicine doi.org/10.1093/humrep/dei438
Online, 12(2), 199–204. /> 6483(10)60861-9 Koutlaki, N., Dimitraki, M., Zervoudis, S., Skafida, P., Nikas, I.,
Italian Society of Gynecological Endoscopy (SEGI). (2013). Mandratzi, J., Liberis, A., & Liberis, V. (2010). Hysteroscopy
Practical guideline in office hysteroscopy. o- and endometrial cancer. Diagnosis and influence on prog-
gynaeteam.com/wp-content/uploads/2013/10/Practical- nosis. Gynecological Surgery, 7(4), 335–341. /> guideline-in-office-hysteroscopy-SEGi.pdf 10.1007/s10397-010-0613-0
Jadoul, P., & Donnez, J. (2003). Conservative treatment may
be beneficial for young women with atypical endometrial Kupesic, S., Kurjak, A., Skenderovic, S., & Bjelos, D. (2002).
hyperplasia or endometrial adenocarcinoma. Fertility and Screening for uterine abnormalities by three-dimensional
Sterility, 80(6), 1315–1324. ultrasound improves perinatal outcome. Journal of
0282(03)01183-X Perinatal Medicine, 30(1), 9–17. />Jiang, J. F., Sun, A. J., Xue, W., Deng, Y., & Wang, Y. F. (2016). JPM.2002.002
Aberrantly expressed long noncoding RNAs in the eutopic
endometria of patients with uterine adenomyosis. Lass, A., Williams, G., Abusheikha, N., & Brinsden, P. (1999).
European Journal of Obstetrics, Gynecology, and The effect of endometrial polyps on outcomes of in vitro
Reproductive Biology, 199, 32–37. fertilization (IVF) cycles. Journal of Assisted Reproduction
ejogrb.2016.01.033 and Genetics, 16(8), 410–415. />Kasius, J. C., Fatemi, H. M., Bourgain, C., Sie-Go, D. M., a:1020513423948
Eijkemans, R. J., Fauser, B. C., Devroey, P., & Broekmans,
F. J. (2011). The impact of chronic endometritis on repro- Lewis, E. I., & Gargiulo, A. R. (2016). The role of hysteroscopic

ductive outcome. Fertility and Sterility, 96(6), 1451–1456. and robot-assisted laparoscopic myomectomy in the set-
ting of infertility. Clinical Obstetrics and Gynecology, 59(1),
Kim, M. R., Kim, Y. A., Jo, M. Y., Hwang, K. J., & Ryu, H. S. 53–65. /> (2003). High frequency of endometrial polyps in endomet-
riosis. The Journal of the American Association of Li, J. J., Chung, J. P. W., Wang, S., Li, T. C., & Duan, H. (2018).
Gynecologic Laparoscopists, 10(1), 46–48. The investigation and management of adenomyosis in
10.1016/S1074-3804(05)60233-2 women who wish to improve or preserve fertility. BioMed
Kimura, F., Takebayashi, A., Ishida, M., Nakamura, A., Research International, 2018, 6832685. /> Kitazawa, J., Morimune, A., Hirata, K., Takahashi, A., Tsuji, 1155/2018/6832685
S., Takashima, A., Amano, T., Tsuji, S., Ono, T., Kaku, S.,
Kasahara, K., Moritani, S., Kushima, R., & Murakami, T. Li, X., Ouyang, Y., Yi, Y., Lin, G., Lu, G., & Gong, F. (2017).
(2019). Review: Chronic endometritis and its effect on Pregnancy outcomes of women with a congenital uni-
reproduction. The Journal of Obstetrics and Gynaecology cornuate uterus after IVF-embryo transfer. Reproductive
Research, 45(5), 951–960. Biomedicine Online, 35(5), 583–591. />Kitawaki, J., Koshiba, H., Ishihara, H., Kusuki, I., Tsukamoto, K., 1016/j.rbmo.2017.07.015
& Honjo, H. (2000). Progesterone induction of 17beta-
hydroxysteroid dehydrogenase type 2 during the secre- Liu, J., Wu, Y., Xu, S., Su, D., Han, Y., & Wu, X. (2017).
tory phase occurs in the endometrium of estrogen- Retrospective evaluation of pregnancy outcomes and clin-
dependent benign diseases but not in normal endomet- ical implications of 34 Han Chinese women with unicornu-
rium. The Journal of Clinical Endocrinology and Metabolism, ate uterus who received IVF-ET or ICSI-ET treatment.
85(9), 3292–3296. Journal of Obstetrics and Gynaecology : The Journal of the
Kitaya, K. (2011). Prevalence of chronic endometritis in recur- Institute of Obstetrics and Gynaecology, 37(8), 1020–1024.
rent miscarriages. Fertility and Sterility, 95(3), 1156–1158. /> />Kitaya, K., Tada, Y., Taguchi, S., Funabiki, M., Hayashi, T., & Ludwin, A., Pitynski, K., Ludwin, I., Banas, T., & Knafel, A.
Nakamura, Y. (2012). Local mononuclear cell infiltrates in (2013). Two- and three-dimensional ultrasonography and
infertile patients with endometrial macropolyps versus sonohysterography versus hysteroscopy with laparoscopy
micropolyps. Human Reproduction (Oxford, England), in the differential diagnosis of septate, bicornuate, and
27(12), 3474–3480. arcuate uteri. Journal of Minimally Invasive Gynecology,
Koh, W.-J., Greer, B. E., Abu-Rustum, N. R., Apte, S. M., 20(1), 90–99. /> Campos, S. M., Chan, J., Cho, K. R., Cohn, D., Crispens,
M. A., Dupont, N., Eifel, P. J., Fader, A. N., Fisher, C. M., Makrakis, E., Hassiakos, D., Stathis, D., Vaxevanoglou, T.,
Gaffney, D. K., George, S., Han, E., Huh, W. K., Lurain, J. R., Orfanoudaki, E., & Pantos, K. (2009). Hysteroscopy in
Martin, L., … Hughes, M. (2014). Uterine neoplasms, ver- women with implantation failures after in vitro fertiliza-
sion 1.2014. Journal of the National Comprehensive Cancer tion: Findings and effect on subsequent pregnancy rates.
Network : JNCCN, 12(2), 248–280. Journal of Minimally Invasive Gynecology, 16(2), 181–187.

jnccn.2014.0025 />
Mao, X., Zhang, J., Cai, R., Tao, Y., Gao, H., Kuang, Y., &
Zhang, S. (2020). Therapeutic role of granulocyte macro-
phage colony-stimulating factor (GM-CSF) in patients with
persistent thin endometrium: A prospective and random-
ized study. International Journal of Gynecology &
Obstetrics, 150(2), 194–199. /> 13152

Marret, H., Fritel, X., Ouldamer, L., Bendifallah, S., Brun, J. L.,
De Jesus, I., Derrien, J., Giraudet, G., Kahn, V., Koskas, M.,

444 G. S. STAMENOV ET AL.

Legendre, G., Lucot, J. P., Niro, J., Panel, P., Pelage, J. P., & Mueller, G. C., Hussain, H. K., Smith, Y. R., Quint, E. H., Carlos,
Fernandez, H., & CNGOF (French College of Gynecology R. C., Johnson, T. D., & DeLancey, J. O. (2007). Mu€llerian
and Obstetrics). (2012). Therapeutic management of uter- duct anomalies: Comparison of MRI diagnosis and clinical
ine fibroid tumors: Updated French guidelines. European diagnosis. AJR. American Journal of Roentgenology, 189(6),
Journal of Obstetrics, Gynecology, and Reproductive Biology, 1294–1302. /> 165(2), 156–164. /> 030 Munro, M. G. (2019). Uterine polyps, adenomyosis, leiomyo-
Matsuda, A., Matsuda, T., Shibata, A., Katanoda, K., Sobue, T., mas, and endometrial receptivity. Fertility and Sterility,
& Nishimoto, H., & Japan Cancer Surveillance Research 111(4), 629–640. /> Group. (2014). Cancer incidence and incidence rates in 02.008
Japan in 2008: A study of 25 population-based cancer
registries for the Monitoring of Cancer Incidence in Japan Munro, M. G., Critchley, H. O., Broder, M. S., & Fraser, I. S., &
(MCIJ) project. Japanese Journal of Clinical Oncology, 44(4), FIGO Working Group on Menstrual Disorders (2011). FIGO
388–396. classification system (PALM-COEIN) for causes of abnormal
Matsuzaki, T., Iwasa, T., Kawakita, T., Yamamoto, Y., Abe, A., uterine bleeding in nongravid women of reproductive
Hayashi, A., Yano, K., Nishimura, M., Kuwahara, A., & age. International Journal of Gynaecology and Obstetrics:
Irahara, M. (2018). Pregnancy outcomes of women who The Official Organ of the International Federation of
received conservative therapy for endometrial carcinoma Gynaecology and Obstetrics, 113(1), 3–13. /> or atypical endometrial hyperplasia. Reproductive Medicine 10.1016/j.ijgo.2010.11.011
and Biology, 17(3), 325–328. /> 12209 Munro, M. G., Critchley, H., & Fraser, I. S., & FIGO Menstrual
Meier, R., & Campo, R. (2015). T-shaped uterus. In C. R. Disorders Committee (2018). The two FIGO systems for

Grimbizis G., Tarlatzis B., Gordts S. (Eds.), Female genital normal and abnormal uterine bleeding symptoms and
tract congenital malformations (Vol. 106, pp. classification of causes of abnormal uterine bleeding in
261–270).Springer. the reproductive years: 2018 revisions. International
5146-3_25 Journal of Gynaecology and Obstetrics: The Official Organ
Miwa, I., Tamura, H., Takasaki, A., Yamagata, Y., Shimamura, of the International Federation of Gynaecology and
K., & Sugino, N. (2009). Pathophysiologic features of “thin” Obstetrics, 143(3), 393–408. /> endometrium. Fertility and Sterility, 91(4), 998–1004. 12666
/>Molinas, C. R., & Campo, R. (2006). Office hysteroscopy and Nappi, C., & Di Spiezio Sardo, A. (2014). State-of-the-art hys-
adenomyosis. Best Practice & Research. Clinical Obstetrics & teroscopic approaches to pathologies of the genital tract.
Gynaecology, 20(4), 557–567. Endo-Press.
bpobgyn.2006.01.019
Mollo, A., De Franciscis, P., Colacurci, N., Cobellis, L., Perino, Nie, J., Liu, X., & Guo, S. (2010). Promoter hypermethylation
A., Venezia, R., Alviggi, C., & De Placido, G. (2009). of progesterone receptor isoform B (PR-B) in adenomyosis
Hysteroscopic resection of the septum improves the preg- and its rectification by a histone deacetylase inhibitor and
nancy rate of women with unexplained infertility: A pro- a demethylation agent. Reproductive Sciences, 17(11),
spective controlled trial. Fertility and Sterility, 91(6), 995–1005. /> 2628–2631. />Moreno, I., Cicinelli, E., Garcia-Grau, I., Gonzalez-Monfort, M., Oehninger, S., Coddington, C. C., Hodgen, G. D., & Seppala,
Bau, D., Vilella, F., De Ziegler, D., Resta, L., Valbuena, D., & M. (1995). Factors affecting fertilization: endometrial pla-
Simon, C. (2018). The diagnosis of chronic endometritis in cental protein 14 reduces the capacity of human sperma-
infertile asymptomatic women: A comparative study of tozoa to bind to the human zona pellucida. Fertility and
histology, microbial cultures, hysteroscopy, and molecular Sterility, 63(2), 377–383. /> microbiology. American Journal of Obstetrics and 0282(16)57372-5
Gynecology, 218(6), 602.e1–602.e16. /> 1016/j.ajog.2018.02.012 Okusami, A. A., Moore, M. E., Hurwitz, J. M., Richlin, S. S., &
Morice, P., Leary, A., Creutzberg, C., Abu-Rustum, N., & Darai, Leondires, M. P. (2007). A case series of patients with
E. (2016). Endometrial cancer. Lancet (London, England), endometrial insufficiency treatment with pentoxifylline
387(10023), 1094–1108. and alphatocopherol. Fertility and Sterility, 88(Suppl1),
6736(15)00130-0 S200. />Mouhayar, Y., Franasiak, J. M., & Sharara, F. I. (2019).
Obstetrical complications of thin endometrium in assisted Oliveira, F. G., Abdelmassih, V. G., Diamond, M. P., Dozortsev,
reproductive technologies: A systematic review. Journal of D., Nagy, Z. P., & Abdelmassih, R. (2003). Uterine cavity
Assisted Reproduction and Genetics, 36(4), 607–611. https:// findings and hysteroscopic interventions in patients
doi.org/10.1007/s10815-019-01407-y undergoing in vitro fertilization-embryo transfer who
Mucowski, S. J., Herndon, C. N., & Rosen, M. P. (2010). The repeatedly cannot conceive. Fertility and Sterility, 80(6),
arcuate uterine anomaly: A critical appraisal of its diagnos- 1371–1375. /> tic and clinical relevance. Obstetrical & Gynecological

Survey, 65(7), 449–454. Pados, G., Tsolakidis, D., Athanatos, D., Almaloglou, K.,
0b013e3181efb0db Nikolaidis, N., & Tarlatzis, B. (2014). Reproductive and
obstetric outcome after laparoscopic excision of func-
tional, non-communicating broadly attached rudimentary
horn: A case series. European Journal of Obstetrics,
Gynecology, and Reproductive Biology, 182, 33–37. https://
doi.org/10.1016/j.ejogrb.2014.08.023

Parry, J. P., & Isaacson, K. B. (2019). Hysteroscopy and why
macroscopic uterine factors matter for fertility. Fertility
and Sterility, 112(2), 203–210. /> fertnstert.2019.06.031

HUMAN FERTILITY 445

Pereira, N., Amrane, S., Estes, J. L., Lekovich, J. P., Elias, R. T., (Oxford, England), 17(10), 2742–2747. /> Chung, P. H., & Rosenwaks, Z. (2016). Does the time inter- 1093/humrep/17.10.2742
val between hysteroscopic polypectomy and start of Richter, K. S., Bugge, K. R., Bromer, J. G., & Levy, M. J. (2007).
in vitro fertilization affect outcomes? Fertility and Sterility, Relationship between endometrial thickness and embryo
105(2), 539–544.e531. implantation, based on 1,294 cycles of in vitro fertilization
2015.10.028 with transfer of two blastocyst-stage embryos. Fertility and
Sterility, 87(1), 53–59. />Perez-Medina, T., Bajo, J., Folgueira, G., Haya, J., & Ortega, P. 2006.05.064
(1999). Atypical endometrial hyperplasia treatment with Rikken, J. F. W., Kowalik, C. R., Emanuel, M. H., Bongers,
progestogens and gonadotropin-releasing hormone ana- M. Y., Spinder, T., de Kruif, J. H., Bloemenkamp, K. W. M.,
logues: Long-term follow-up. Gynecologic Oncology, 73(2), Jansen, F. W., Veersema, S., Mulders, A. G. M. G. J.,
299–304. Thurkow, A. L., Hald, K., Mohazzab, A., Khalaf, Y., Clark,
T. J., Farrugia, M., van Vliet, H. A., Stephenson, M. S., van
Petracco, R. G., Kong, A., Grechukhina, O., Krikun, G., & Taylor, der Veen, F., … Goddijn, M. (2018). The randomised uter-
H. S. (2012). Global gene expression profiling of proliferative ine septum transsection trial (TRUST): design and protocol.
phase endometrium reveals distinct functional subdivisions. BMC Women’s Health, 18(1), 163. /> Reproductive Sciences (Thousand Oaks, Calif..), 19(10), s12905-018-0637-6
1138–1145. Rodolakis, A., Biliatis, I., Morice, P., Reed, N., Mangler, M., Kesic,
V., & Denschlag, D. (2015). European Society of Gynecological

Polisseni, F., Bambirra, E. A., & Camargos, A. F. (2003). Oncology Task Force for Fertility Preservation: Clinical recom-
Detection of chronic endometritis by diagnostic hystero- mendations for fertility-sparing management in young endo-
scopy in asymptomatic infertile patients. Gynecologic and metrial cancer patients. International Journal of Gynecological
Obstetric Investigation, 55(4), 205–210. Cancer : Official Journal of the International Gynecological
1159/000072075 Cancer Society, 25(7), 1258–1265. /> 0000000000000493
Popovic, M., Puchner, S., Berzaczy, D., Lammer, J., & Bucek, Rongieres, C. (2007). Uterus malforme et assistance medicale
R. A. (2011). Uterine artery embolization for the treatment a la procreation: prevention du defaut d’implantation?
of adenomyosis: A review. Journal of Vascular and [Uterine anomalies and assisted reproductive techniques:
Interventional Radiology : JVIR, 22(7), 901–909. https://doi. Preventing implantation failure?]. Gynecologie, obstetrique
org/10.1016/j.jvir.2011.03.013 & fertilite, 35(9), 842–847. /> 2007.07.027
Practice Committee of American Society for Reproductive Santamaria, X., Cabanillas, S., Cervello, I., Arbona, C., Raga, F.,
Medicine. (2012a). Diagnostic evaluation of the infertile Ferro, J., Palmero, J., Remohi, J., Pellicer, A., & Simon, C.
female: A committee opinion. Fertility and Sterility, 98(2), (2016). Autologous cell therapy with CD133ỵ bone mar-
302–307. row-derived stem cells for refractory Asherman’s syn-
drome and endometrial atrophy: A pilot cohort study.
Practice Committee of the American Society for Human Reproduction (Oxford, England), 31(5), 1087–1096.
Reproductive Medicine. (2012b). Endometriosis and infer- /> tility: A committee opinion. Fertility and Sterility, 98(3), Schenker, J. G. (1996). Etiology of and therapeutic approach
591–598. to synechia uteri. European Journal of Obstetrics,
Gynecology, and Reproductive Biology, 65(1), 109–113.
Practice Committee of the American Society for /> Reproductive Medicine. (2016). Uterine septum: A guide- Sher, G., & Fisch, J. D. (2002). Effect of vaginal sildenafil on
line. Fertility and Sterility, 106(3), 530–540. the outcome of in vitro fertilization (IVF) after multiple IVF
10.1016/j.fertnstert.2016.05.014 failures attributed to poor endometrial development.
Fertility and Sterility, 78(5), 1073–1076. />Practice Committee of the American Society for 1016/S0015-0282(02)03375-7
Reproductive Medicine. (2017). Removal of myomas in Shuiqing, M., Xuming, B., & Jinghe, L. (2002). Pregnancy and its
asymptomatic patients to improve fertility and/or reduce outcome in women with malformed uterus. Chinese Medical
miscarriage rate: A guideline. Fertility and Sterility, 108(3), Sciences Journal ¼ Chung-kuo i hsueh k’o hsueh tsa chih, 17(4),
416–425. 242–245. /> Song, D., Feng, X., Zhang, Q., Xia, E., Xiao, Y., Xie, W., & Li, T. C.
Pritts, E. A., Parker, W. H., & Olive, D. L. (2009). Fibroids and (2018). Prevalence and confounders of chronic endometritis
infertility: an updated systematic review of the evidence. in premenopausal women with abnormal bleeding or repro-
Fertility and Sterility, 91(4), 1215–1223. ductive failure. Reproductive Biomedicine Online, 36(1), 78–83.

1016/j.fertnstert.2008.01.051 /> Song, D., Li, T. C., Zhang, Y., Feng, X., Xia, E., Huang, X., &
Rajani, S., Chattopadhyay, R., Goswami, S. K., Ghosh, S., Xiao, Y. (2019). Correlation between hysteroscopy findings
Sharma, S., & Chakravarty, B. (2012). Assessment of oocyte and chronic endometritis. Fertility and Sterility, 111(4),
quality in polycystic ovarian syndrome and endometriosis 772–779. /> by spindle imaging and reactive oxygen species levels in So€nmezer, M., Taskin, S., Atabekoglu, C., Gu€ngo€r, M., & Unlu€, C.
follicular fluid and its relationship with IVF-ET outcome. (2006). Laparoscopic management of rudimentary uterine
Journal of Human Reproductive Sciences, 5(2), 187–193.
/>
Reichman, D., Laufer, M. R., & Robinson, B. K. (2009).
Pregnancy outcomes in unicornuate uteri: A review.
Fertility and Sterility, 91(5), 1886–1894. /> 1016/j.fertnstert.2008.02.163

Richlin, S. S., Ramachandran, S., Shanti, A., Murphy, A. A., &
Parthasarathy, S. (2002). Glycodelin levels in uterine flush-
ings and in plasma of patients with leiomyomas and pol-
yps: Implications for implantation. Human Reproduction

446 G. S. STAMENOV ET AL.

horn pregnancy: Case report and literature review. JSLS : the American Society of Clinical Oncology, 25(19),
Journal of the Society of Laparoendoscopic Surgeons, 10(3), 2798–2803. /> 396–399. Valle, R. F., & Ekpo, G. E. (2013). Hysteroscopic metroplasty
Stanekova, V., Woodman, R. J., & Tremellen, K. (2018). The for the septate uterus: Review and meta-analysis. Journal
rate of euploid miscarriage is increased in the setting of of Minimally Invasive Gynecology, 20(1), 22–42. https://doi.
adenomyosis. Human Reproduction Open, 2018(3), hoy011. org/10.1016/j.jmig.2012.09.010
Vannuccini, S., Clifton, V. L., Fraser, I. S., Taylor, H. S.,
Styer, A. K., Jin, S., Liu, D., Wang, B., Polotsky, A. J., Critchley, H., Giudice, L. C., & Petraglia, F. (2016). Infertility
Christianson, M. S., Vitek, W., Engmann, L., Hansen, K., and reproductive disorders: Impact of hormonal and
Wild, R., Legro, R. S., Coutifaris, C., Alvero, R., Robinson, inflammatory mechanisms on pregnancy outcome. Human
R. D., Casson, P., Christman, G. M., Christy, A., Diamond, Reproduction Update, 22(1), 104–115. /> M. P., Eisenberg, E., Zhang, H., Santoro, N., … National 1093/humupd/dmv044
Institute of Child Health and Human Development Vannuccini, S., Luisi, S., Tosti, C., Sorbi, F., & Petraglia, F.
Reproductive Medicine Network (2017). Association of (2018). Role of medical therapy in the management of

uterine fibroids and pregnancy outcomes after ovarian uterine adenomyosis. Fertility and Sterility, 109(3), 398–405.
stimulation-intrauterine insemination for unexplained /> infertility. Fertility and Sterility, 107(3), 756–762.e3. https:// Vannuccini, S., & Petraglia, F. (2019). Recent advances in under-
doi.org/10.1016/j.fertnstert.2016.12.012 standing and managing adenomyosis. F1000Research, 8, 283.
Surrey, E. S., Katz-Jaffe, M., Surrey, R. L., Small, A. S., /> Gustofson, R. L., & Schoolcraft, W. B. (2018). Arcuate ute- Venetis, C. A., Papadopoulos, S. P., Campo, R., Gordts, S.,
rus: Is there an impact on in vitro fertilization outcomes Tarlatzis, B. C., & Grimbizis, G. F. (2014). Clinical implica-
after euploid embryo transfer? Fertility and Sterility, 109(4), tions of congenital uterine anomalies: A meta-analysis of
638–643. comparative studies. Reproductive Biomedicine Online,
Surrey, E. S., Minjarez, D. A., Stevens, J. M., & Schoolcraft, W. B. 29(6), 665–683. /> (2005). Effect of myomectomy on the outcome of assisted Vercellini, P., Fedele, L., Aimi, G., De Giorgi, O., Consonni, D.,
reproductive technologies. Fertility and Sterility, 83(5), & Crosignani, P. G. (2006). Reproductive performance, pain
1473–1479. recurrence and disease relapse after conservative surgical
Tan, J., Li, P., Wang, Q., Li, Y., Li, X., Zhao, D., Xu, X., & Kong, treatment for endometriosis: The predictive value of the
L. (2016). Autologous menstrual blood-derived stromal current classification system. Human Reproduction (Oxford,
cells transplantation for severe Asherman’s syndrome. England), 21(10), 2679–2685. /> Human Reproduction (Oxford, England), 31(12), 2723–2729. rep/del230
Vitagliano, A., Saccardi, C., Noventa, M., Di Spiezio Sardo, A.,
Taylor, H. S., Osteen, K. G., Bruner-Tran, K. L., Lockwood, C. J., Saccone, G., Cicinelli, E., Pizzi, S., Andrisani, A., & Litta, P. S.
Krikun, G., Sokalska, A., & Duleba, A. J. (2011). Novel thera- (2018). Effects of chronic endometritis therapy on in vitro
pies targeting endometriosis. Reproductive Sciences fertilization outcome in women with repeated implant-
(Thousand Oaks, Calif..), 18(9), 814–823. ation failure: A systematic review and meta-analysis.
1177/1933719111410713 Fertility and Sterility, 110(1), 103–112.e101. />Timmermans, A., Opmeer, B. C., Veersema, S., & Mol, B. W. 10.1016/j.fertnstert.2018.03.017
(2007). Patients’ preferences in the evaluation of postme- Xia, E. L., Li, T. C., Choi, S. S., & Zhou, Q. Y. (2017). reproduct-
nopausal bleeding. BJOG : An International Journal of ive outcome of transcervical uterine incision in unicornu-
Obstetrics and Gynaecology, 114(9), 1146–1149. https://doi. ate uterus. Chinese Medical Journal, 130(3), 256–261.
org/10.1111/j.1471-0528.2007.01424.x />Tomazevic, T., Ban-Frangez, H., Virant-Klun, I., Verdenik, I., Yang, J. H., Chen, M. J., Chen, C. D., Chen, S. U., Ho, H. N., &
Pozlep, B., & Vrtacnik-Bokal, E. (2010). Septate, subseptate Yang, Y. S. (2013). Optimal waiting period for subsequent
and arcuate uterus decrease pregnancy and live birth fertility treatment after various hysteroscopic surgeries.
rates in IVF/ICSI. Reproductive Biomedicine Online, 21(5), Fertility and Sterility, 99(7), 2092–2096.e2093. https://doi.
700–705. org/10.1016/j.fertnstert.2013.01.137
Trojano, G., Damiani, G. R., Casavola, V. C., Loiacono, R., Malvasi, Younes, G., & Tulandi, T. (2017). Effects of adenomyosis on
A., Pellegrino, A., Siciliano, V., Cicinelli, E., Salerno, M. G., & in vitro fertilization treatment outcomes: A meta-analysis.
Battini, L. (2018). The role of hysteroscopy in evaluating post- Fertility and Sterility, 108(3), 483–490.e483. /> menopausal asymptomatic women with thickened endomet- 10.1016/j.fertnstert.2017.06.025

rium. Gynecology and Minimally Invasive Therapy, 7(1), 6–9. Younes, G., & Tulandi, T. (2018). Conservative surgery for
adenomyosis and results: A systematic review. Journal of
Ushijima, K., Yahata, H., Yoshikawa, H., Konishi, I., Yasugi, T., Minimally Invasive Gynecology, 25(2), 265–276. https://doi.
Saito, T., Nakanishi, T., Sasaki, H., Saji, F., Iwasaka, T., org/10.1016/j.jmig.2017.07.014
Hatae, M., Kodama, S., Saito, T., Terakawa, N., Yaegashi, N., Zhang, D., Li, J., Xu, G., Zhang, R., Zhou, C., Qian, Y., Liu, Y.,
Hiura, M., Sakamoto, A., Tsuda, H., Fukunaga, M., & Chen, L., Zhu, B., Ye, X., Qu, F., Liu, X., Shi, S., Yang, W.,
Kamura, T. (2007). Multicenter phase II study of fertility- Sheng, J., & Huang, H. (2015). Follicle-stimulating hormone
sparing treatment with medroxyprogesterone acetate for promotes age-related endometrial atrophy through cross-
endometrial carcinoma and atypical hyperplasia in young talk with transforming growth factor beta signal transduc-
women. Journal of Clinical Oncology : Official Journal of tion pathway. Aging Cell, 14(2), 284–287. /> 10.1111/acel.12278