Keywords

17.1 Introduction

Infertility is a disease of the male or female reproductive system defined by the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse [1].

This condition affects millions of people worldwide with subsequent impact on their families and communities. Estimates suggest that between 48 million couples and 186 million individuals live with infertility globally [2].

Management of infertility is a difficult challenge, and the couple should be aware that delaying pregnancy increases the rates of infertility and complicated pregnancies. In the era of artificial intelligence, different functional in vitro fertilization prediction models for tailoring personalized treatment of infertile couples have been proposed. [3].

Practically, evaluation of the couple should begin after 12 months in a woman under 35 years, and after 6 in a woman over 35 and should be initiated even earlier in a woman older than 40 years, as age seems to play a role in the quality of oocytes, which appears to be a central point not only for infertility, but also in order to reach a viable pregnancy.

The assessment of infertility should be carried out by experienced physicians trained in the field of both diagnostics and surgery in a context of a multidisciplinary team.

The first step is a complete personal and familiar interview, in order to customize the following steps. In particular, it is essentially a complete obstetric, sexual, and menstrual history.

Moreover, it is important to assess any previous pelvic surgery or any possible symptom of endometriosis (dysmenorrhea, dyspareunia, dischezia), previous chemotherapy or irradiation, and also lifestyle habits that can interfere with conception such as alcohol or tobacco abuse.

BMI should be assessed at first visit as both obesity and underweight can reduce fertility.

Also, a complete physical examination should be performed looking for signs of discrinia, congenital Mullerian anomalies, and secondary sexual characteristics.

17.2 Laboratory Tests in Infertility

Some couples deserve laboratory tests in order to assess causes of infertility. Among others:

  1. 1.

    Semen analysis to exclude male factor.

  2. 2.

    Assessment of ovarian reserve: it can be either performed with ultrasound or biochemical tests. All women with infertility should perform:

    1. (a)

      a dosage of Anti Mullerian hormone (AMH). AMH is produced by the granulosa cells of early follicles and it is a good marker of ovarian reserve. It is also gonadotropin-independent, so it can be measured in all phases of the menstrual cycle. Moreover, AMH is a good predictor of success in IVF (in vitro fertilization);

    2. (b)

      an early-follicular-phase dosage of inhibin b, produced by preantral follicles. In advanced age, both AMH and early-follicular phase inhibin b tend to decline, reducing negative feedback on pituitary gland, and therefore on FSH secretion;

    3. (c)

      Follicle-stimulating hormone (FSH) is therefore an indirect marker of ovarian reserve. It should be dosed like inhibin b on the third day of the menstrual cycle. FSH stimulates the selection of a new pool of oocytes and therefore is higher in women with low ovarian reserve;

    4. (d)

      Clomiphene Citrate Challenge Test (CCCT): it is performed with measurements of FSH on the third day of the menstrual cycle and on day 10, after treatment with clomiphene citrate (100 mg from day 5 to 9). Women with a high level of FSH after CCCT have a lower ovarian reserve.

      However, CCCT is not superior as a marker of ovarian reserve than basal FSH combined with antral follicle count.

  3. 3.

    Assessment of ovulation: women who refer regular menses are likely to ovulate. In order to confirm it, a dosage of progesterone during mid-luteal phase can be useful (around day 21): a value >3 ng/mL confirms ovulation.

It is also possible to confirm ovulation with serial ultrasound transvaginal scans from the appearance of follicles to the selection of the dominant one till it disappears at ovulation.

Irregularity in menses should be checked for the most common causes of anovulation, such as thyroid dysfunction, PCOS, and PRL function. All these tests are not mandatory in evaluation of infertile women, but become necessary in case of suspicion of anovulation.

17.3 Imaging in Infertility

First of all, we must ask ourselves: is this enough to assess tubal patency and at the same time neglecting functional aspects of the tubal epithelium?

17.3.1 Hysterosalpingography

Even if hysterosalpingography (HSG) is still widely considered as the second step in the diagnostic approach to infertile women, it grants very low sensitivity in diagnosis of proximal (51%) and distal (42%) tubal occlusion [4].

Hysterosalpingography is performed with no analgesia as an outpatient procedure even if it is proven to be quite painful; van Welie et al. (2022) [5] showed that the mean pain score for HSG on the 1–10 Visual Analogue Scale (VAS) was 5.4 (SD 2.5), significantly high especially when compared to less expensive or less invasive techniques without leading to substantial differences in pregnancy rates. On the other hand, sonohysterography (HyFoSy) is associated with significantly less pain [6].

HSG only assesses tubal and cavity patency; the injection of contrast allows the evaluation of various genital tract anomalies using X-rays, but it needs further instrumental examinations to confirm diagnosis in several situations:

  1. (a)

    Filling defects, such as polyps, myomas, and synechiae, are indistinguishable in hysterosalpingograms and always require further evaluations;

  2. (b)

    Uterine contour anomalies, such as adenomyosis, and Mullerian anomalies, (single horn uterus, arcuate uterus, didelphys uterus, or uterine septa). However, for differential diagnosis, it is often mandatory to evaluate the diagnosis with magnetic resonance, 3D ultrasound, hysteroscopy, and/or laparoscopy.

So we may conclude that HSG is an obsolete technique with very poor performance.

Given those evidences since 2013, the National Institute for Care and Health Excellence (NICE) proposes sonohysterography (HyFoSy) as an effective alternative to HSG [7].

This imaging does not require contrast media, reducing the risk for allergic reactions, or adverse events such as Wolff-Chaikoff effect or thyrotoxicosis.

HyFoSy should be scheduled, like HSG, during mid-luteal phase, when the endometrium is very thin in order to avoid false positives. Using a small catheter, saline water-based infusion media is injected in utero. Uterine cavity is then studied both in longitudinal axis and coronal planes. If fluid passes in the Douglas, at least one of the two tubes is patent.

Maheux-Lacroix et al. in 2014 demonstrated that HyFoSy, performed alternatively to HSG in the evaluation of tubal patency, grants best performances for the evaluation of uterine cavity and gives the benefit of simultaneous evaluation of both ovaries and myometrium [8].

17.3.2 Ultrasounds

Together with HyFoSy, a Three-Dimensional ultrasound (3D) scan is nowadays an essential tool to optimize the infertility treatment outcomes [9]. It allows to see several renderings that wouldn’t be possible with a 2D technique.

An ultrasound assessment is an essential searching for infertility causes in several conditions:

  1. 1.

    Congenital uterine anomalies: Since Congenital Uterine anomalies are mostly asymptomatic, it is difficult to determine the exact prevalence.

    1. (a)

      Arcuate uterus, a milder abnormality, consists in a midline indentation, sometimes associated with a fundal cavity indentation. It is not associated with pregnancy adverse outcomes in literature. Ultrasound scan shows a <1 cm depth from the interstitial line to the apex of the fundal indentation and an indentation angle greater than 90°;

    2. (b)

      Septate or subseptate uterus, the most common Mullerian anomaly. A 3D US coronal view allows diagnosing a septate uterus using the following criteria: the depth from the interstitial line to the apex of the indentation is >1 cm, and the angle of indentation is less than 90°. MRI could be an option, especially if expertise in 3D-US is not available. Septate uterus is strongly associated with preterm birth, breech presentation, and abruption and has been associated with several pregnancy adverse outcomes;

    3. (c)

      Bicornuate uterus: A 3D-US scan will show two separate endometrial cavities and an indentured uterine contour. Pregnancy adverse outcomes are quite common;

    4. (d)

      Didelphys uterus comes from the failure of Mullerian ducts fusion. US shows two separate horns with a wide fundal indentation. In this case, MRI is the gold standard for definitive diagnosis. High rates of abortion and premature delivery have been reported, 32% and 28%, respectively. Surgical treatment (metroplasty) must be considered in case of RPL or pelvic pain.

    5. (e)

      Unicornuate uterus, only one Mullerian duct evolves correctly, so one normal emicavity is associated with a rudimentary horn which can communicate with the uterus or may not. A noncommunicant horn exposes the patient to higher risk of ectopic pregnancies, chronic pelvic pain, first and second-trimester abortion, preterm birth.

    In 2013, the CONUTA scientific committee proposed a new classification system for Mullerian abnormalities (the ESGE/ESHRE 2013 CONUTA classification System). The main classes are designed to focus on the embryological origin of the uterine malformation, while each subclass is designed focusing on the different degree of uterine deformity and its clinical significance [10].

  2. 2.

    Fibroids and Polyps: A recent meta-analysis conducted by Somigliana et al. showed insufficient evidence to confirm a cause-effect relationship between fibroids and infertility. Nevertheless, fibroids affect up to 27% of women looking for pregnancy. Fibroids distort the cavity with subsequent alteration of endometrial receptivity, and sometimes sexual discomfort. Ultrasonography is the preferred initial imaging modality for diagnosis of fibroids. Based on the position in the myometrium, fibroids are defined as intramural, subserous, and submucosal.

    In 1993, Wamsteker suggested the following fibroid classification based on myometrial penetration assessed by ultrasound and hysteroscopic findings; this classification is still recommended by the European Society of Gynecological Endoscopy (ESGE).

    1. (a)

      G0 Myoma’s development is completely inside the uterine cavity.

    2. (b)

      G1 The myoma is inside the uterine cavity for more than 50%.

    3. (c)

      G2 The myoma is inside myometrial thickness for more than 50%.

    Moreover, in 2011, FIGO classification system (PALM COEIN), for causes of abnormal uterine bleeding in women of reproductive age, added 6 more classes [11]:

    1. (a)

      Type 3, entirely submucosal myoma.

    2. (b)

      Type 4, entirely intramural myoma.

    3. (c)

      Type 5 subserosal, at least 50% intramural.

    4. (d)

      Type 6 subserosal, less than 50% intramural.

    5. (e)

      Type 7 subserosal, attached to the serosal by a stalk.

  3. 3.

    Pelvic inflammatory disease: Pelvic inflammatory disease is a polymicrobial infection-induced inflammation that involves upper female genital tract, sometimes including endometrium, fallopian tubes, ovaries, and peritoneum. It primarily affects sexually active young women.

    Organisms most commonly isolated are Neisseria Gonorrhoeae and Chlamydia Trachomatis.

    Sonographic markers of acute salpingitis are [12]:

    1. (a)

      Tubal wall thickness >5 mm.

    2. (b)

      Sausage-like structure.

    3. (c)

      “Cogwheel” sign

    4. (d)

      Incomplete septa.

    5. (e)

      Fluid in the Pouch of Douglas.

    6. (f)

      Tubo-ovarian complex.

17.3.3 Laparoscopy

Unluckily, both HSG and ultrasound can evaluate less more than patency and cannot assess tubal mucosa nor permit direct vision of the pelvis.

On the other hand, laparoscopy (LPS) offers a direct vision of the entire abdomen and allows diagnosis and eventually treatment of other pathologies such as endometriosis, pelvic adhesions, and some Mullerian anomalies.

Laparoscopy with chromo-pertubation allows direct vision of the tubes and it is possible to inject a dye through a catheter directly in utero and then it flows through fallopian tubes [13].

However, laparoscopy requires general anesthesia and it is an invasive procedure and consequently it is not usually performed in the beginning of the workup of an infertile woman; as a matter of fact, the National Institute for Care and Health Excellence (NICE) recommends laparoscopy only in women suspected for comorbidities such as endometriosis which can be cured at the same time [14].

Laparoscopy with cromo-salpingoscopy provides direct vision of the external surface of fallopian tubes and its patency as HSG and HyFoSy, respectively.

In the early 80s, in order to overcome these limits, salpingoscopy was proposed as a new endoscopic technique, useful for direct vision of tubal mucosa other than the presence or absence of anatomical distortions [15].

Salpingoscopy was done in infertile women who underwent diagnostic laparoscopy and showed at least one patent tube on chromo-pertubation test, during postmenstrual phase (day 5–day 9) under general anesthesia.

Laparoscopy was done through a standard 3-trocar access (5-mm ports for ancillary instruments) and salpingoscope. Laparoscopic external tubal morphology can be assessed, but at the same time for salpingoscopy, a 2-mm, 30 rigid salpingoscope (Karl Storz, Germany Hopkins II) with an outer sheath of 2.8 mm diameter is used.

Salpingoscopic mucosal appearance can also be graded according to Brosens and Puttemans classification (1989) as follows:

  • Grade I: normal mucosal folds (both major and minor).

  • Grade II: the major folds are separated and flattened, but otherwise normal/dye staining of mucosa/minimal flattening.

  • Grade III: focal adhesions between mucosal folds and variable flattening.

  • Grade IV: extensive adhesions between mucosal folds and disseminated flat areas.

  • Grade V: complete loss of mucosal fold pattern.

Other classifications have been proposed by Kerin et al. [16] and Hershlag et al. [17].

With salpingoscopy, lesions of the infundibulum and ampullary region can also be detected in patients for whom HSG has shown apparently normal tubes [18].

According to previous studies, laparoscopy and salpingoscopy probably complement; unfortunately, this technique is no longer performed and disappeared maybe for complexity of instrumentation and consequent lack of investments.

17.3.4 Hysteroscopy

In infertile women, a complete assessment of the uterine cavity is essential, and among several modalities, hysteroscopy is considered the gold standard.

Since the early 90s, our group advisedly decided to abandon previous dogmas and look at the uterine cavity from a completely different perspective.

Methodically implementing some great intuitions time after time, we first put aside the traditional and outdated approach to hysteroscopy and nowadays clinicians performing office hysteroscopy worldwide use the vaginoscopic approach: quicker and less painful [19].

By not using the speculum and the tenaculum before hysteroscopic examination, we eliminated discomfort not related to the technique itself and reduced the number of instruments necessary. It is ideal for office hysteroscopy and in patients who otherwise might require general anesthesia.

Two recent randomized studies with several critical biases failed to demonstrate a real advantage of hysteroscopy before IVF in increasing live birth rates.

The inSIGHT study is a multicenter, randomized, comparative study. InSIGHT concerned women scheduled for IVF (in vitro fertilization) and a normal transvaginal ultrasound. Women were randomized for proceeding directly for IVF or performing an hysteroscopy before IVF. Routine hysteroscopy did not increase live birth rate, therefore is not recommended in case of normal US scan [20].

In 2016, a similar study (the TROPHY study) involved women with at least two failed IVF and a normal US scan, randomized for performing routine hysteroscopy or directly another IVF cycle. Hysteroscopy did not increase the live birth rate [21].

Otherwise, we must be aware that the real innovation constituted by hysteroscopy is the so-called see & treat’ approach, which introduced the concept of a single procedure in which the operative part is perfectly integrated in the diagnostic workup.

Despite the great advantages and cost savings of such philosophy, the number of gynecologists who prefer to perform operative procedures in an outpatient setting rather than in the operative theatre continues to be low.

Apart from this new perspective, our group proposed a contemporary approach to almost every concept in the field of hysteroscopy such as myomas and cervical stenosis, and on the other hand, we helped to develop increasingly less invasive and effective devices.

Absolute indications for hysteroscopy in infertile women include intracavitary abnormalities such as endometrial polyps, submucous fibroids, uterine septum, endometritis, and adhesions (Figs. 17.1, 17.2, 17.3, and 17.4).

Fig. 17.1
figure 1

Endometrial polyp. (Reproduced from Bettocchi et al. 2021)

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Fig. 17.2
figure 2

Cervical polyp. (Reproduced from Bettocchi et al. 2021)

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Fig. 17.3
figure 3

Sub-mucous myomas. (Reproduced from Bettocchi et al. 2021)

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Fig. 17.4
figure 4

Uterus with fibroids, Laparoscopy. (Reproduced from Bettocchi et al. 2021)

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Several intracavitary pathologies that may cause infertility can be diagnosed and at the same time treated with an outpatient hysteroscopy:

  • Endometrial Polyps can cause infertility with different mechanisms, including irregular endometrial bleeding, inflammatory response, interference in the interaction between embryo and endometrium, and interference with normal patterns of endocrine function. Moreover, polyps were commonly associated with chronic endometritis and the majority are positive for CD-138 staining, suggesting a link between chronic inflammation, a debated cause of infertility, and Eps [22]. Hysteroscopic polypectomy can be performed with cold instruments, such as miniaturized forceps or scissors, with bipolar instruments or with laser devices mostly in an outpatient modality;

  • Submucosal Fibroids: as polyps do, fibroids can cause infertility in different ways: distortion of the cavity, abnormal uterine contractility, obstruction of tubal ostia, abnormalities in uterine vascularization, impaired endometrial receptivity, and subsequent implantation failure. Only hysteroscopy allows a complete mapping of the localization of the myoma and depth of myometrial invasion. Vaginal approach for submucosal myomectomy is feasible, secure, and with low discomfort for the patient.

Nowadays, hysteroscopic myomectomy is the gold standard in order to improve cumulative pregnancy rate as well as live birth rate in selected women with submucosal myomas and history of reproductive failure.

The rate of live birth increases and the rate of abortion decreases after hysteroscopic myomectomy. Pregnancy rate is higher in women who underwent a hysteroscopic myomectomy compared with those with fibroids left in situ even if the evidence is still widely debated [23].

Myomectomy could be performed with several techniques apart from the classical slicing technique [24]. Sometimes this technique upfront could be somehow challenging, especially when facing some large G1 or G2 submucosal fibroids. OPPIuM technique has been proposed and seems to achieve the downgrading of these types of leiomyomas in approximately 93% of cases, without any significant surgical complications or the need of hormonal agents’ administration. In this way, the safer and quicker subsequent complete myomectomy is facilitated [25].

This technique developed by our group more than a decade ago consisted of an incision of the endometrial mucosa covering the myoma by means of cold scissors or bipolar Versapoint Twizzle electrode, along its reflection line on the uterine wall, up to the precise identification of the cleavage surface between the myoma and its pseudo-capsule. Such procedure was aimed at triggering the protrusion of the intramural portion of the myoma into the uterine cavity during the following menstrual cycles, thus facilitating the subsequent total removal of the lesion via resectoscopic surgery [26].

In the last few years, new other minimally invasive techniques have been developed for the treatment of uterine fibroids. There are some incisionless procedures that use various forms of energy to heat and ablate uterine fibroids like radiofrequency, focused ultrasound, and microwaves (Figs. 17.5 and 17.6).

Fig. 17.5
figure 5

Laparoscopic myomectomy. (Reproduced from Bettocchi et al. 2021)

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Fig. 17.6
figure 6

Endometriosis—kissing ovaries. (Reproduced from Bettocchi et al. 2021)

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Recently, MR-guided focused ultrasound (MRgFUS), another modality of hyperthermic ablation, has been approved by the US Food and Drug Administration as a validated treatment for fibroids in women seeking pregnancy.

Radiofrequency myolysis (RFM) is the latest uterine-conserving technique, generates thermal effects inside the myoma (60–80 °C), and it results in distinct histological changes: necrosis of tissue cells from coagulation, vascular thrombosis, and inactivation of hormonal receptors within the myoma that prevents tumor tissue from growing [27].

Other incisionless techniques include the use of surgical lasers (Argon, CO2, Yag, KTP, and others). Diode lasers have been used in hysteroscopic surgery with many advantages.

The main disadvantages for the clinical application of this technology might be the cost because laser equipment currently tend to be expensive and an adequate learning curve to better understand the instrumentation technical characteristics [28].

Recent literature strongly supports hysteroscopic approach even in the treatment of uterine septum, as it has proven to be simple, with minimal postoperative sequelae, improving reproductive outcomes.

These findings have been strong enough to lead to a more liberalized approach, which includes the treatment not only of patients with recurrent pregnancy loss or premature labor, but also the ones with infertility or with IVF plans [29, 30].

We usually perform each metroplasty during the early proliferative phase (day 4 to 9) under general anesthesia using a bipolar 15 Fr. Mini-Resectoscope (Karl Storz Co., Tuttlingen, Germany is connected to an advanced bipolar generator (Autocon III 400, Karl Storz Co., Tuttlingen, Germany). Intrauterine pressure is carefully kept stable (around 45 mmHg) using a dedicated pump (Endomat, Karl Storz Co, Tuttlingen, Germany).

Usually the septum is initially incised ‘‘in a classic fashion,” adopting an “L-shape” bipolar electrode (Karl Storz Co., Tuttlingen, Germany) up to the fundal area. The septum is then longitudinally transected into two parts, forming an anterior and a posterior triangle on each uterine wall, with the base on the fundus.

Thanks to a careful analysis, we are nowadays able to describe the fine anatomy of the muscle bundles taking part to the septum: this entity should no longer be considered as a fibrous notch in the middle of the cavity, but as a real three-dimensional structure with a ‘‘myoma-like” component.

Once we got rid of previous misconceptions, we developed and proposed a new surgical approach based on fine anatomy of the septum: first of all, we completely incise/resect those symmetric fibrous bundles at the base of the septum and then we resect the apex of the septum until the central muscular core is reached.

During this step and given the parallel arrangement of muscular fibers in this area, the fundal area spontaneously flattens and the central muscular core is finally resected [31].

Apart from adequate anatomical knowledge which is essential for successful clinical practice [30], our proposal in resectoscopic surgery should also persuade from a technical point of view as relies on the implementation in our clinical practice of the 15 Fr.

Mini-Resectoscope itself grants at least two more great advantages. First of all, it’s a native bipolar system and carries itself all the clear advantages of bipolar energy: the plasma effect of bipolar current allows better cut and coagulation. Moreover, it has minor risk of interference on other electronic equipment (electrocardiogram, pace makers, and others) simultaneously connected to the patient.

Incidence of overflow syndrome in gynecology and TUR syndrome in urology varies considerably in the literature, ranging from 0.18% to 10.9%.

The use of saline solution for distension media of the uterine cavity is the principal advantage of this technology avoiding hypotonic nonelectrolyte solution that can cause fluid overload during the surgical procedure.

Everything said up to now represents a new frontier in the modern hysteroscopic surgical approach to intrauterine pathology in order to increase fertility [32]; the relevance of this technique has been emphasized over during the recent pandemic [33]. Otherwise, large multicentric trials are needed in order to evaluate and reevaluate the endometrial function after surgery and its impact on fertility, of which we know relatively little or nothing.