Hysteroscopy and female infertility a fresh look to a busy corner

Trang 1 Full Terms & Conditions of access and use can be found athttps://www.tandfonline.com/action/journalInformation?journalCode=ihuf20Georgi Stamenov Stamenov, Salvatore Giovanni Vita

Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ihuf20

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

To link to this article: https://doi.org/10.1080/14647273.2020.1851399

Published online: 02 Dec 2020

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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 Ganevaaand Sergio Haimovichf

a

Nadezhda Women’s Health Hospital, Sofia, Bulgaria;b

Obstetrics 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;f

Hillel Yaffe Medical Center/Technion - Israel Technology Institute, Hadera, Israel

ABSTRACT

Hysteroscopy has evolved from the traditional art of examining the uterine cavity for diagnostic

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

This article reviews the literature on the most common cervical, endometrial, uterine and tubal

pathologies such as chronic endometritis, endometrial polyps, adenomyosis, endometriosis,

endometrial atrophy, adhesions, endometrial hyperplasia, cancer, and uterine malformations

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

ARTICLE HISTORY

Received 30 March 2020 Accepted 28 September 2020

KEYWORDS

Diagnosis; female infertility; hysteroscopy; intrauterine pathologies; treatment

Introduction

Infertility is estimated to affect 9% of all

reproductive-aged couples, and female factors are responsible for

20 –35% of all infertility cases (Boivin et al., 2007 ).

Hysteroscopy is a valuable tool and is currently

consid-ered the “gold standard” approach in assessing the

uterine cavity for diagnosis and treatment of female

infertility (Bettocchi et al., 2004 ) Pathologies identified

during hysteroscopy in infertile women include

chronic endometritis, endometrial polyps, submucosal

myomas, intrauterine adhesions, adenomyosis, thin

endometrium, endometrial hyperplasia and/or cancer

and uterine malformations such as the uterine septum,

T-shaped uterus, arcuate uterus and unicornuate

ute-rus (Practice Committee of American Society for

Reproductive Medicine, 2012a ).

Many health care providers advocate that

undertak-ing diagnostic hysteroscopy before assisted

reproduc-tion treatment increases the chances of pregnancy

significantly (Bosteels et al., 2010 ) In addition to its

diagnostic value, hysteroscopy has also been shown

to treat successfully intrauterine abnormalities result-ing in significant enhancement of fertility and repro-ductive outcomes (Bosteels et al., 2015 ) This review summarises the available evidence on the role of hys-teroscopy in both the diagnosis and treatment of common uterine and tubal pathologies associated with female fertility and adverse reproduct-ive outcomes.

Materials and methods

The literature search was conducted using MEDLINE, EMBASE, Web of Sciences, Scopus, OVID, and Cochrane Library as electronic databases Papers were identified with the use of a combination of the follow-ing text words: “hysteroscopy,” “female infertility,”

“endometritis,” “endometrial polyps,” “adenomyosis,”

“intrauterine adhesions,” “myoma,” “endometrial can-cer, ” “uterine malformations,” “tubal endometriosis” and “endometrial atrophy” from 1970 to September

CONTACT Salvatore Giovanni Vitale sgvitale@unict.it 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

https://doi.org/10.1080/14647273.2020.1851399

and subheadings.

Intracavitary pathologies

Chronic endometritis

Two studies reported that chronic endometritis is

associated with female infertility, and significantly

increased the frequency of implantation failure and

spontaneous abortions (Cicinelli et al., 2015 ;

Kitaya, 2011 ).

The prevalence of chronic endometritis in infertile

women has been reported to range between 2.8 and

39%, and it may be more than 60% in women

diag-nosed with repeated implantation failure and

recur-rent miscarriages (Kasius et al., 2011 ) The diagnostic

gold standard for chronic endometritis is endometrial

sampling and histological detection of increased

stro-mal edoema accompanied by plasmacyte infiltration

within the endometrial stroma (Crum et al., 1983 ).

Immunohistochemistry (IHC) for detection of the

plasma cell marker CD138 (also known as syndecan-1)

is necessary to improve the detection rate of CE (Chen

et al., 2016 ; Crum et al., 1983 ).

Diagnostic hysteroscopy may also be utilised to

confirm the histologic findings (Cicinelli et al., 2005 ;

Oliveira et al., 2003 ; Polisseni et al., 2003 ) In several

studies, the endometrial sample collected under

hys-teroscopy has shown higher specificity and positive

and negative predictive values than other methods of

sample collection (Cicinelli et al., 2009 ; Moreno et al.,

2018 ; Song et al., 2019 ) Hysteroscopically, endometrial

inflammation (endometritis) is characterised by

hyper-aemia (accentuated blood vessel accumulation at the

periglandular level), stromal edoema (pale and

thick-ened endometrium in the proliferative phase) as well

as micropolyps (small pedunculated, vascularised

pro-trusions of the uterine mucosa measuring <1 mm)

(Cicinelli et al., 2005 , 2008 ) Identification of these

hys-teroscopic features should alert the observer of the

presence of the CE, and endometrial biopsy should be

obtained to confirm or refute the diagnosis However,

implantation failure (RIF) (Vitagliano et al., 2018 ) The observed clearance rate of CD138 þ plasma cells after antibiotics treatment was up to 96% (Kitaya et al.,

2012 ) and a recent review by Kimura et al ( 2019 ) sug-gested that the administration of oral antibiotics is a promising therapeutic option in infertile women with RIF due to CE.

Therefore, chronic endometritis could be regarded

as one of the potential causes of both primary and secondary infertility, and all women with confirmed infertility should be investigated for chronic endomet-ritis and treated accordingly.

Endometrial polyps

Endometrial polyps are common in infertile women with a prevalence of up to 45% (Fatemi et al., 2010 ; Makrakis et al., 2009 ) It is also suggested that polyps are present at a higher incidence in women with other coexisting pathologies such as endometriosis (Kim

et al., 2003 ) A potential mechanism by which polyps may cause infertility include irregular endometrial bleeding and inflammation, spatial inhibition of sperm transport, impaired endocrine function, uterine recep-tivity, and embryo-endometrium contact and cross-talk, and inhibition of sperm binding to the zona pel-lucida through increased glycodelin levels (Oehninger

et al., 1995 ; Richlin et al., 2002 ).

The most common symptom of polyps is abnormal uterine bleeding (Bakour et al., 2002 ; Elfayomy et al.,

2012 ) Hysteroscopy remains the gold standard in the management of endometrial polyps allowing simultan-eous diagnosis and polypectomy (American Association of Gynaecologic Laparoscopists, 2012) Usually, this procedure is performed in the early prolif-erative phase of the menstrual cycle ( Figure 1 ) (Clark

et al., 2002 , 2015 ; Timmermans et al., 2007 ).

The impact of polypectomy on infertile women is controversial Some studies reported no improvements

in implantation, clinical pregnancy or live birth rates after hysteroscopic polypectomy in patients with newly diagnosed endometrial polyps subjected to IVF

cycles (Isikoglu et al., 2006 ; Lass et al., 1999 ), in

con-trast to other studies that have shown an increase of

pregnancy rate (44.4% more than expected) (Batioglu

& Kaymak, 2005 ; Ghaffari et al., 2016 ) Therefore,

well-designed RCTs are needed to assess whether

hystero-scopic removal of endometrial polyps is likely to

bene-fit women with otherwise unexplained subfertility,

especially the effectiveness of polypectomy before

ART treatment (Bosteels et al., 2015 ) Sufficient

evi-dence is not available regarding the optimal time

interval between hysteroscopic polypectomy and

initi-ation of a fresh IVF-ET cycle The time interval

between hysteroscopic polypectomy and the

subse-quent IVF cycle does not seem to impact the success

rates of the IVF cycle (Eryilmaz et al., 2012 ; Pereira

et al., 2016 ).

Adenomyosis

Adenomyosis has been found in 22% of infertile

women less than 40 years old, with an estimated

prevalence ranging from 20 to 25% in women

under-going IVF-ET (Younes & Tulandi, 2017 ) One study

reported that adenomyosis significantly increased the

miscarriage risk (Stanekova et al., 2018 ) while another

reported no significant impact of adenomyosis on

embryo transfer outcomes (Benaglia et al., 2014 ) The

main factors associated with adenomyosis that may

contribute to infertility are changes in uterine tissue

architecture and function that negatively affect

endo-metrial receptivity, sperm transport, and embryo

implantation (Munro, 2019 ).

Alteration of progesterone and oestrogen

metabol-ism and down-regulation of progesterone receptors

are known molecular mechanisms that cause the

epi-genetic dysregulation of the genes involved in

endo-metrial receptivity and decidualization (Jiang et al.,

2016 ; Kitawaki et al., 2000 ; Nie et al., 2010 ).

Hysteroscopy, histological examination of biopsies, magnetic resonance (MR), transvaginal ultrasound (TUV), and hysterosalpingography are valuable techni-ques in the determination and characterisation of adenomyosis (Garcia & Isaacson, 2011 ; Gordts et al.,

2008 ; Popovic et al., 2011 ).

Hysteroscopy has the benefit of enabling direct visualisation of the uterine cavity and offers an oppor-tunity for endomyometrial sampling collection under visual control (Di Spiezio Sardo et al., 2008 ; Molinas & Campo, 2006 ) ( Figure 2 ) The principal limitation of this technique is that the field of vision is restricted to the surface layer of the endometrium However, some features are indicative of adenomyosis such as irregu-lar endometrium with small openings on the surface during the proliferative and secretory phase, pro-nounced hypervascularization, a “strawberry” appear-ance of the endometrium, fibrous cystic intrauterine lesions and cystic lesions of dark blue or chocolate brown colour (Di Spiezio Sardo et al., 2017 ).

Surgical options for treatment of adenomyosis include uterine sparing therapies such as endometrial ablation, hysteroscopic or laparoscopic resection, MR guided high-intensity focussed ultrasonography (MRgHIFU), uterine artery embolization/occlusion (UAE) and hysterectomy which is considered the definitive surgical treatment of symptomatic adeno-myosis when fertility is not desired (Dueholm, 2018 ) Medical hormonal and non-hormonal treatments are also used to manage pain and bleeding and to possibly improve fertility and reproductive outcomes (Vannuccini & Petraglia, 2019 ) A variety of new drugs, such as selective progesterone (SPRMs) and oestrogen receptor modulators (SERMs), aromatase inhibitors, gonadotropin-releasing hormone agonist (GnRHa), val-proic acid, and anti-platelet therapy, have been used for the treatment of adenomyosis (Vannuccini et al.,

Figure 2 Hysteroscopic view of adenomyosis

Figure 1 Presence of multiple polyps involvng the whole

endometrial cavity

2018 ) However, the impact of these drugs on fertility

and pregnancy outcomes remains speculative.

Hysteroscopy is not a first-line treatment option for

women with adenomyosis but may be considered a

reasonable choice for patients with childbearing desire

(Grimbizis et al., 2014 ) Office hysteroscopy can be

per-formed in selected cases of focal or diffuse superficial

subtypes However, for women who desire future

pregnancy, hysteroscopy can be a valid treatment

option only in the case of focal adenomyosis Indeed,

when an adenomyoma is small ( <1.5 cm), it can be

removed by hysteroscopy (Di Spiezio Sardo et al.,

2017 ) The procedure requires particular attention for

adequate identification of healthy myometrial tissue

due to the lack of a distinct cleavage plane (Molinas &

Campo, 2006 ) Pre-treatment with GnRH agonists can

help reduce the vascularity and bleeding during the

operation Sometimes, it may also help move the

adenomyoma into the uterine cavity due to reduced

uterine volume (Li et al., 2018 ) Although it seems that

pregnancy rate may improve after conservative

surgi-cal treatment of adenomyosis, further research is

required to definitively evaluate the benefits of

con-servative surgery, including hysteroscopic resection of

adenomyosis for the treatment of fertility (Younes &

Tulandi, 2018 ).

Adhesions

The reproductive outcomes of women with

intrauter-ine adhesions (IUA) are generally poor due to

obstruc-tion of the tubal ostia, insufficient or an inadequate

endometrial surface area, and uterine cavity volume or mechanical obstruction of the cervical canal and/or uterine cavity ( Figure 3 ) Besides, adhesions may be associate with recurrent pregnancy loss (Schenker, 1996 ).

Hysteroscopic adhesiolysis is the gold standard approach for symptomatic IUAs By restoring the nor-mal volume and shape of the uterine cavity, which may allow normal menstrual flow, sperm transporta-tion for fertilisation, and embryo implantation (Hanstede et al., 2015 ) The pregnancy rate after adhe-siolysis in women with secondary infertility is esti-mated to be 48%, while the miscarriage rate is reduced from 86.5 to 42.8% (Goldenberg et al., 1995 ).

A recent study has confirmed these results and has found an overall conception rate of 48.2% However, the extent of uterine adhesions can influence preg-nancy outcomes, with a rate in case of severe IUAs lower than in moderate and mild IUAs (Chen

et al., 2017 ).

Although hysteroscopic adhesiolysis is quite effect-ive in restoring an adequate intrauterine cavity in the majority cases, a crucial concern remains the preven-tion of adhesion reformapreven-tion, which could occur in 76% of the patients after the procedure (Aghajanova

et al., 2018 ; Yang et al., 2013 ) ff multicentre, pro-spective randomised controlled trial showed that the intrauterine instillation of auto-crosslinked hyaluronic acid (ACP) gel after dilatation and curettage (D&C) for miscarriage in women with at least one previous D&C seems to reduce the incidence and severity of IUAs

Figure 3 Hysteroscopic view of intrauterine adhesions

but does not eliminate the process of adhesion

forma-tion (Hooker et al., 2017 ) Two case reports (34-year

old and 40 year old patients with IUA) reported a

beneficial effect of autologous platelet-rich plasma

(PRP) infused into the uterine cavity with potential

positive influence not only on endometrial thickness,

but also the functional properties of the uterus

(Aghajanova et al., 2018 ) Another promising therapy

for the treatment of severe cases of Asherman

syn-drome is autologous cell transplantation with

men-strual blood-derived stromal cells (Tan et al., 2016 )

and CD133 þ bone marrow-derived stem cells

(Santamaria et al., 2016 ).

Myomas

A meta-analysis by Pritts et al ( 2009 ) reported that

submucous myomas are associated with lower

implantation rates and increased risk for pregnancy

loss, while intramural myomas have a questionable

impact on fertility (Christopoulos et al., 2017 ; Styer

et al., 2017 ) Women with submucous myomas have

recurrent pregnancy losses and implantation failures

and one of the possible reasons is the reduced

amount of IL-2 (Hasegawa et al., 2012 ) and/or

impair-ment of uterine receptivity.

In conjunction with or in the absence of MRI,

hys-teroscopy is a method of crucial importance to

diag-nose and characterise the types of submucosal

leiomyomas ( Figure 4 ) following the International

Federation of Gynaecology and Obstetrics (FIGO)

Classification system (Munro et al., 2011, 2018).

Hysteroscopy, performed by experienced surgeons,

enables the removal of submucous myomas (types 0,

1, and 2) up to 4 –5 cm diameter, whereas larger and

multiple myomas are best removed abdominally

(American Association of Gynaecologic Laparoscopists:

Advancing Minimally Invasive Gynaecology, 2012;

Lewis & Gargiulo, 2016 ) Several retrospective cohort studies, focussed on assisted reproduction, support the conclusion that clinical pregnancy rates are higher

in women who underwent hysteroscopic myomec-tomy (Surrey et al., 2005 ).

There has been significant controversy regarding the impact of intramural myomas and their removal

on fertility and pregnancy outcomes Therefore, given the paucity of contemporary RCTs examining the impact of myomectomy on fertility in women under-going IVF, it would be prudent to perform studies with consistent patient selection and primary end-points Nevertheless, according to the Practice Committee of the American Society for Reproductive Medicine ( 2017 ) and the updated French guidelines (Marret et al., 2012 ), in asymptomatic women with cavity-distorting myomas (intramural with a submuco-sal component or submucosubmuco-sal) and desire of preg-nancy, myomectomy may be considered to improve pregnancy rates and reproductive outcomes.

Tubal endometriosis

Tubal endometriosis is another major cause of tubal infertility, found in 25% of ART patients (Impey et al.,

2008 ) Furthermore, it has been shown that patients with endometriosis experience lower implantation rates (Budak et al., 2007 ) and gamete transport, fertil-isation, and embryo implantation are impaired due to the inflammatory environment by the endometriotic lesions (Harada et al., 2001 ) The secreted inflamma-tory cytokines and the oxidative stress caused by these lesions affect sperm motility (Eisermann et al.,

1989 ), and this inflammatory environment also induces apoptotic events in the embryos (Ding et al., 2010 ; Rajani et al., 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 uteruter-ine wall involving almost the entire cavity

computed tomographic or magnetic resonance

imag-ing and the tubes seem patent (Aznaurova et al.,

2014 ; Practice Committee of the American Society for

Reproductive, 2012b ) Diagnosis of endometriosis

includes direct visualisation histopathological

confirm-ation through biopsy (Ballard et al., 2008 ; Bazot et al.,

2009 ; Dunselman et al., 2014 ) A less invasive

diagnos-tic tool for tubal endometriosis may be hysteroscopy

observing a brown liquid coming from the tubal

ost-ium when the pressure of the incoming flow

is decreased.

Many options for the treatment of

endometriosis-associated infertility are discussed in the literature.

Some authors report improved pregnancy rates after

controlled ovarian stimulation and intrauterine

insem-ination in patients with endometriosis (Vercellini et al.,

2006 ) Other authors propose non-hormonal treatment

such as ICON, VEGF antagonists, and stem cells, which

may also prove to increase pregnancy rates by

decreasing the extent of the endometriosis lesions

(Petracco et al., 2012 ; Taylor et al., 2011 ).

The highest pregnancy rates among endometriotic

patients after several IVF failures were obtained after

the surgical removal of the endometriotic lesions

(Bulletti et al., 2008 ) Operative laparoscopy is a better

option than diagnostic laparoscopy for spontaneous

pregnancies in particularly in mild endometriosis cases.

Endometrial atrophy

At least two publications have reported that up to 9%

of ART patients had a thin atrophic endometrium

(Miwa et al., 2009 ; Mouhayar et al., 2019 ) Additional

studies reported that a thin endometrium is associated

with implantation failure (Abdalla et al., 1994 ; Richter

et al., 2007 ) Because atrophic endometrium lacks the

structures characteristic of a receptive endometrium, it

cannot provide the embryo with the necessary envir-onment for implantation Besides, atrophy is associ-ated with impaired hormonal regulation (Cavallini

et al., 2011 ; Zhang et al., 2015 ), which in turn alters the “behaviour” of the endometrial tissue and pre-vents implantation (Vannuccini et al., 2016 ).

Atrophic endometrium is usually diagnosed by histo-pathological examination of biopsy, where reduced endometrial glands and dense compact stromal cells (Gupta, 2017 ) can be observed During hysteroscopy, the atrophic endometrium appears smooth and thin with direct visualisation of the deep endometrial vessels, which are not seen in healthy endometrium Hysteroscopy has been shown to have high sensitivity in diagnosing atrophic endometrium (Trojano et al., 2018 ) Many therapies have been proposed to treat infer-tility thought to be due to endometrial atrophy such

as vaginal insertion of sildenafil (Sher & Fisch, 2002 ) or treatment with pentoxifylline and alphatocopherol (Okusami et al., 2007 ) Some experimental studies sug-gest using autologous CD 133 þ bone marrow-derived stem cells (BMDSCs) infused into the spiral arterioles resulting in positive pregnancies after ART (Santamaria

et al., 2016 ) Also, a recent paper reported the effect

of granulocyte macrophage colony-stimulating factor (GM-CSF) on unresponsive thin ( <7 mm) endometrium

in patients undergoing frozen-thawed embryo transfer, showed a significantly higher chemical pregnancy rate (35.3 vs 20.0%; p ¼ 0.009) and clinical pregnancy rate (28.6 vs 13.3%; p ¼ 0.005) compared with patients in the control group (Mao et al., 2020 ).

endomet-rial carcinoma

The prevalence of endometrial hyperplasia and carcin-oma in women of reproductive age showed a

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

dramatic increase during the last few decades (Duska

et al., 2001 ; Matsuda et al., 2014 ) The observed

changes in the architecture and function of

endomet-rium caused by hyperplasia could potentially lead to

decreased implantation and an increased chance of

miscarriage, but there are no data to support this

notion Besides, this pathological condition is

associ-ated with other pathologies that may have a

signifi-cant impact on female fertility, including chronic

endometritis, which has been found to coexist with

endometrial neoplasia in up to 50% of patients (Song

et al., 2018 ).

The hysteroscopic appearance of endometrial

hyperplasia and carcinoma is typical and relatively

easy for detection ( Figure 5 ) The main hysteroscopic

morphological parameters that may be used as

hys-teroscopic indicators of EH are local or diffuse

endo-metrial thickening with papillary or polypoid aspect,

abnormal vascular patterns, presence of glandular

cysts and glandular outlets demonstrating abnormal

architectural features (Garuti et al., 2005 , 2006 ).

The visual diagnosis of endometrial cancer is based

on the presence of a gross distortion of the

endomet-rial cavity, as a result of a nodular, polypoid, papillary,

or mixed pattern of neoplastic growth Focal necrosis,

microcalcification, friable consistency, and atypical

ves-sels are other characteristics associated with

endomet-rial cancer that could be easily detected by

hysteroscopic inspection (Koutlaki et al., 2010 ).

However, the definitive diagnosis of both endometrial

cancer and hyperplasia remains a core competence of

the histopathologist, and so it requires histological

analysis of endometrial tissue specimens (Armstrong

et al., 2012 ; Committee on Gynecologic Practice &

Society of Gynecologic Oncology, 2015 ).

The standard treatment for atypical endometrial

hyperplasia and endometrial cancer is hysterectomy

with bilateral oophorectomy (Morice et al., 2016 ).

However, a fertility-sparing therapy can be offered to

women who desire to retain fertility in cases of

endo-metrial hyperplasia or endometrioid cancer stage IA

(without myometrial invasion) grade 1 (Koh et al.,

2014 ; Rodolakis et al., 2015 ) Fertility-sparing

treat-ments can be hormonal, hysteroscopic partial

resec-tion or combined Medical treatment includes

progestins and GnRH agonists (Grimbizis et al., 1999 ;

Perez-Medina et al., 1999 ) A meta-analysis reported

superiority of the combined treatment with partial

hysteroscopic resection (HR) and progesterone The

regression rates reported for hormones only, surgery

only, and hormones and surgery combined are 49.6,

75, and 100% (Erkanli & Ayhan, 2010 ) However, it has

been shown that approximately 30% of patients expe-rienced recurrence after the achievement of complete response (Gallos et al., 2012 ; Ushijima et al., 2007 ) indi-cating that once reproduction is completed, hysterec-tomy should be offered given the high risk of disease relapse (Armstrong et al., 2012 ).

A meta-analysis has shown that the live birth rate is different among women who underwent ART and women who conceived spontaneously: a higher live birth rate was found in women subjected to ART (39 vs 15%) (Gallos et al., 2012 ; Ushijima et al., 2007 ) Indeed, the European Society of Gynaecological Oncology guide-lines recommends a prior consultation with a fertility expert since a significant number of young patients with endometrial cancer have a history of infertility, polycystic ovarian syndrome, or obesity (Gonthier et al., 2014 ; Jadoul & Donnez, 2003 ) There is no consistent evidence about which kinds of fertility treatments are most advan-tageous after conservative treatment for atypical endo-metrial hyperplasia and endoendo-metrial cancer, although it has been suggested that ART is especially beneficial for such patients (Matsuzaki et al., 2018 ) Therefore, prompt and effective fertility treatment should be initiated just after conservative treatment in patients with these types

of pathologies who wish to get pregnant immediately This strategy usually leads to significantly better preg-nancy outcomes (Gonthier et al., 2014 ; Jadoul & Donnez, 2003 ).

Uterine malformations

The diagnosis of uterine malformations is based on hys-terosalpingography (HSG), transvaginal sonography (TVS), three-dimensional ultrasound imaging (3 D US) and mag-netic resonance imaging (MRI), but the gold standard method for visualisation of the cervix and uterine cavity

is hysteroscopy since it allows concomitant treatment (Berger et al., 2014 ; Practice Committee of the American Society for Reproductive Medicine, 2016 ).

T-shaped (dysmorphic) uterus

Several studies in the past have shown very poor repro-ductive performance when a T-shaped uterine malfor-mation, also referred to as a dysmorphic uterus, was noted and not treated (Berger & Goldstein, 1980 ; Herbst et al., 1981 ) In addition, higher prevalence of ectopic pregnancies (Fernandez et al., 2011 ) and increased frequency of miscarriages (Rongi
eres, 2007 ) were also reported However, a stringent association between dysmorphic uterus and infertility remains unclear A possible explanation of reproductive failures may be associated with the observed change of

endometrial structure (excess of myometrium in the

uterine walls) and increased uterine contractility in

women with uterine malformations (Haydardedeoglu

et al., 2018 ; Meier & Campo, 2015 ).

Commonly applied diagnostic techniques for a

dys-morphic uterus are hysteroscopy ( Figure 6 ),

laparos-copy, magnetic resonance imaging (MRI), 2 D or 3 D

ultrasonography and hysterosalpingography (HSG).

Hysteroscopic metroplasty is the most commonly

used surgical procedure that significantly improves the

total uterine cavity volume and live birth rate in

patients with a T-shaped uterus and a history of

pri-mary infertility and recurrent miscarriage The

enlarge-ment of the uterine cavity, using hysteroscopic

metroplasty, could also improve endometrial vascular

perfusion and decrease uterine contractility and, as a

consequence, could make the embryo implantation

more probable (Haydardedeo glu et al., 2018 ).

Several studies have found an increase in delivery

rate after the hysteroscopic treatment with a range

between 63.2 and 65% (Barranger et al., 2002 ; Di

Spiezio Sardo et al., 2015 ; Giacomucci et al., 2011 ).

However, the studies reporting anatomical and

repro-ductive outcomes are few, with small sample size and a

retrospective design (Ducellier-Azzola et al., 2018 ) The

study with the largest cohort, including 97 patients

with T-shaped uterus treated by hysteroscopic

metro-plasty, reported an increase of live birth rate from 0 to

73%, and a decrease of miscarriage rate from 78 to

27% (Fernandez et al., 2011 ) Only a well-designed

randomised study may properly address the question

of whether hysteroscopic metroplasty is beneficial in

patients with a T shaped uterus (Boza et al., 2019 ).

Uterine septum

The uterine septum is associated with structural

altera-tions in the endometrium that affect embryo

implant-ation (Kormanyos et al., 2006 ) The incidence of

uterine septa in infertile women has been reported to

be significantly higher than in the general population, suggesting a direct link with infertility (Shuiqing et al.,

2002 ; Tomazevic et al., 2010 ) Non-randomised pro-spective trials have shown that uterine septum is asso-ciated with 47% lower implantation rate and a 67% chance of miscarriage (Mollo et al., 2009 ; Rikken et al.,

2018 ) A meta-analysis evaluating the effect of differ-ent types of uterine anomalies on reproductive out-comes reported that septate uterus was the only anomaly that was significantly associated with a decrease in the probability of natural conception (Venetis et al., 2014 ) Other studies also confirmed sev-eral-fold increase of miscarriage rate, late abortions and preterm labour (Kupesi c et al., 2002 ; Tomazevic

et al., 2010 ).

The American Society for Reproductive Medicine guidelines recommended hysteroscopy for the diagno-sis of uterine septum (Practice Committee of the American Society for Reproductive Medicine, 2016 ) ( Figure 6 ) Imaging with saline infusion/gel instillation sonography (SIS/GIS), magnetic resonance imaging (MRI) and ultrasonography (US) are additional alterna-tives for screening and evaluation of uterine septum (Ludwin et al., 2013 ; Mueller et al., 2007 ) Three-dimen-sional ultrasound and magnetic resonance imaging are typically used in confirming the serosal fundal con-tour distinguishing a bicornuate from septate uteri, whereas office hysteroscopy gives a rapid sense of the depth of the internal indentation (Parry & Isaacson, 2019 ).

Hysteroscopic division is currently the gold stand-ard for the treatment of uterine septa (Practice Committee of the American Society for Reproductive Medicine, 2016 ) Risk of subsequent pregnancy-related uterine rupture could be caused by excessive septal excision, incidental deep penetration of the myome-trium, uterine wall perforation, and excessive use of

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

radiofrequency (RF) or laser energy during the initial

septum incision (Valle & Ekpo, 2013 ).

Multiple observational studies indicate that

hystero-scopic septum incision is associated with improved

clinical pregnancy rates in women with infertility,

decreased subsequent miscarriage rates and

improve-ment in live-birth rates in patients with infertility or

recurrent pregnancy loss (Tomazevic et al., 2010 ; Valle

& Ekpo, 2013 ; Venetis et al., 2014 ) In addition,

hystero-scopic septum incision seems to improve IVF

out-comes when performed before the embryo transfer,

by improving embryo implantation rates (Corroenne

et al., 2018 ) The uterine cavity is healed by

approxi-mately 8 weeks after hysteroscopic septum incision

and this period seems to be appropriate for a woman

to wait to conceive (Berkkanoglu et al., 2008 ; Yang

et al., 2013 ).

Arcuate and unicornuate uteri

The arcuate uterus usually is considered to be a

vari-ation of normal uterine anatomy and has not been

associated with adverse reproductive outcomes (Chan

et al., 2011 ; Gubbini et al., 2009 ) and no treatment is

indicated (Mucowski et al., 2010 ) A recent study has

shown that an arcuate uterus has no impact on ART

outcomes after embryo transfer subsequent to

com-prehensive chromosomal screening (Surrey et al.,

2018 ) Tomazevic et al ( 2010 ) conducted a

retrospect-ive matched-control study in women with septate,

subseptate and arcuate uterus and they reported that

after hysteroscopic metroplasty the pregnancy rate

and live birth rate of women with arcuate uterus was

comparable to that of women with normal uterine

cavity (36.8 vs 39%; OR 1.1) while before metroplasty,

the pregnancy rate was lower in women with arcuate

uterus compared to control group (20.9 vs 35.6%; OR

2.1; p < 0.03) Similar results were found for live birth

rate (3 vs 30.4% before metroplasty, 28 vs 32.2% after

hysteroscopic metroplasty) (Kupesic et al., 2002;

Tomazevic et al., 2010 ).

Unicornuate uterus

Unicornuate uterus is associated with lower clinical

pregnancy rate, increased risk of miscarriage and

ectopic pregnancy (Chen et al., 2018 ; Reichman et al.,

2009 ; Venetis et al., 2014 ) and is more prevalent in

women with infertility (0.5%), miscarriage (0.5%) or

both (3.1%) (Chan et al., 2011 ) Several studies have

shown poorer outcomes of assisted reproductive

tech-nology (ART) treatments in women with unicornuate

uterus compared to those with normal anatomy (Li

et al., 2017 ; Liu et al., 2017 ) The traditional surgical

approach is laparotomy or laparoscopy with complete removal of the rudimentary horn.

Transcervical uterine incision (TCUI) is an alternative procedure that could lead to a significant increase in pregnancy outcomes (Xia et al., 2017 ) These opera-tions can lead to adverse effects on the reproductive prognosis of patients due to a small volume of the residual uterine hemicavity (Pados et al., 2014 ; S€onmezer et al., 2006 ) Nappi and Di Spiezio Sardo ( 2014 ) stated that the hysteroscopic approach is a less invasive option with a more favourable impact on reproductive prognosis with the added advantage of being able to distinguish a non communicating horn with unicornuate uterus from a septate uterus.

Conclusion

Most of the discussed endometrial and tubal patholo-gies are relatively common and have an essential dir-ect or indirdir-ect impact on female infertility.

This review has shown that hysteroscopy is an appropriate technique for accurate intrauterine evalu-ation before any therapy for infertility The use of office vaginoscopic hysteroscopy without a speculum and cervical tenaculum allows examination without the need for anaesthesia and premedication It is a successful procedure that significantly reduces anxiety and pain experienced by patients during the proced-ure, compared with traditional techniques using a vaginal speculum.

Vaginoscopic hysteroscopy is associated not only with minimal patient discomfort, but also with excel-lent visualisation, and very low complication and fail-ure rates For this reason, office hysteroscopy should

be recommended as the first diagnostic tool for the evaluation of infertility.

There are several reasons why hysteroscopy, and in particular the outpatient hysteroscopy, should be rec-ommended as a first-line procedure in all or almost all cases with female infertility The distinction between diagnostic and operative procedure has been reduced with the introduction of the so-called “see & treat hys-teroscopy, ” with the possibility to perform a single procedure in which the operative part is perfectly inte-grated within the diagnostic work-up: this is very important considering how important the “time” is for

an infertile couple The improvement in technology and techniques made hysteroscopy less painful and 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