Therapeutic Intervention of Endometrial Pathology Before Ovarian Stimulation




© Springer India 2015
Surveen Ghumman (ed.)Principles and Practice of Controlled Ovarian Stimulation in ART10.1007/978-81-322-1686-5_3


3. Therapeutic Intervention of Endometrial Pathology Before Ovarian Stimulation



Lakhbir K. Dhaliwal1 and Shalini Gainder 


(1)
Department of Obstetrics and Gynecology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India

 



 

Shalini Gainder



Abstract

Successful pregnancy occurs only if the development of oocytes is accompanied by parallel development of endometrium which is receptive once the fertilized embryo reaches the endometrial cavity and further synchronizes with the development of the embryo by undergoing complex series of decidualization. This forms a chain of complex events taking place in the endometrium. Knowledge about endometrial receptivity is still limited, and where needed, interventions can improve infertility outcome. This may be in the form of removing endometrial polyps, resection of sub-mucous fibroids, treatment of endometritis, resection of uterine septum and uterine adhesions and hormonal manipulation of the endometrial milieu using estrogen therapy, sildenafil, aspirin, pentoxifyline and vitamin E. Women with polycystic ovaries also need treatment of endometrium, which may be hostile under the influence of high androgens or due to excessive stimulation under estrogen therapy and harbour hyperplasia or endometrial carcinoma. Similarly, women with endometriosis have luteal phase deficit and therefore may have irregular bleeding. Stem cell therapy is emerging as a new hope for women with damaged endometrium as a result of Asherman syndrome.


Keywords
EndometriumPolypsSubmucous fibroidsAsherman syndromeStem cell



3.1 Introduction


Embryo implantation is dependent on multiple interactions that take place in the endometrium which are regulated by complex endocrine and paracrine–autocrine interactions; endometrial receptivity may undergo inter-cycle and inter-individual variations. Over the previous decades, a lot of research has benefited in improving the ovarian stimulation protocols, but pregnancy is difficult to achieve if a good receptive endometrium does not parallel the oocyte maturation. Various pathologies can affect the endometrium directly, and different infertility causes can have indirect effect on the endometrium. Therefore before ovulation induction, one needs to ascertain that the endometrium would be receptive for the embryo. Drugs being used for induction of ovulation also may influence the endometrium, therefore an infertility expert has to balance the hormonal milieu to obtain optimal endometrial lining in various stimulation protocols for controlled stimulation as well as when stimulation is for fresh IVF cycles or endometrium is prepared for frozen IVF cycles.


3.2 Various Endometrial Pathologies Affecting the Endometrium



3.2.1 Infections


Chronic endometritis may be found in infertile patients and would require a course of antibiotics. Besides that in India, tuberculosis forms an important cause of infertility, and endometrium is often involved. Clamydia may also be present.


3.2.2 Anatomical Malformations


Intrauterine synechia due to old infections, fibrosis and adhesions may cause a distorted endometrial cavity with decreased blood flow. Mullerian anomalies like uterine septum or bicornuate uterus may be present.


3.2.3 Fibroids


Fibroid in uterus or endometrial polyps may be present. It can cause an impaired blood flow to endometrium if it is a sub-mucous fibroid.


3.2.4 Foreign Body


Foreign bodies like bone fragments, old products of conception or intrauterine devices may be present.


3.2.5 Pathologies That Indirectly Affect the Endometrium



3.2.5.1 Polycystic Ovarian Syndrome


Oestrogenic effect leads to thick endometrium, endometrial hyperplasia and endometrial carcinoma. Androgenic effect leads to thin endometrium.


3.2.5.2 Luteal Phase Defect


Luteal phase defect may be seen in endometriosis or women with prolactin disorders, thyroid disorders and ovarian ageing. Irregular shedding leading to premenstrual spotting may occur.


3.2.5.3 Poor Hormonal Environment


Insufficient oestrogen, progesterone or high androgens could be responsible for poor endometrial development.


3.2.6 Iatrogenic


Excessive curettage could damage endometrium and lead to intrauterine adhesions. Use of clomiphene citrate in some cases leads to anti-oestrogenic effects on endometrium preventing its development in mid-cycle.


3.3 Evaluation of Endometrium Prior to Controlled Ovarian Stimulation



3.3.1 Clinical History


Knowledge of the menstrual cycle, amount of bleeding, number of days for which the woman bleeds and cycle length is vital as it gives an insight of the endometrium. Women may complain of premenstrual spotting in presence of luteal phase defect, especially if the oocyte is of poor quality, which may occur in endometriosis, prolactin disorders or in ageing women. Periods of amenorrhoea followed by excessive bleeding should make the physician consider anovulation-associated endometrial hyperplasia, which can be present in young women with PCOS. Scanty menstruation may be present in women having genital tuberculosis or Asherman syndrome or because of clomiphene therapy.


3.3.2 Ultrasound


A baseline trans-vaginal ultrasonography helps in imaging of the endometrium to rule out the presence of any endometrial polyps or fibroid which may be polypoidal projecting into the cavity or sub-endometrial in location. Any collection inside the endometrial cavity can be seen, or thick echogenic endometrium may suggest endometrial proliferation or hyperplasia. Endometrial adhesions may be suggested by thin irregular endometrium with areas of echogenicity. Sometimes, uterine septa or other anatomical malformations can be suspected on performing USG.


3.3.3 Colour Doppler


In recent years, the role of colour Doppler to assess endometrial vascularity has been introduced. Endometrial and sub-endometrial blood flows can assess the angiogenesis that takes place during the cyclical growth of endometrium.


3.3.4 3D Ultrasonography


A 3D sonography may at times give insight into the shape of the endometrial cavity in cases of malformations and help to distinguish between septate and bicornuate uterus. Endometrial polyps and fibroid location can be more defined; however, if a patient is anyway planned for hysteroscopy, then this test may only add to the cost of patient treatment.


3.3.5 Endometrial Biopsy/Aspiration


Endometrial biopsy/aspiration for endometrial sampling is not a mandatory evaluation in the developed countries; however, its importance is unmatched to any other investigation as it helps to pick up about 8–15 % of cases of genital tuberculosis either by the microscopic examination of simple concentrated smear by Ziehl-Neilsen stain to identify the acid-fast bacilli or by identification from various short-term cultures like BACTEC, MGIT 460 or by conventional culture. Histopathology also aids in diagnosing granulomas, or features of chronic inflammation along with detailed dating of the endometrium. Cases of hyperplasia both simple and complex as well as early cases of endometrial carcinoma have been diagnosed while evaluating endometrium for infertility at our centre, which thereby changes the management of these women.

Endometrial aspiration is usually performed in the premenstrual phase, and the aspirate is divided; a part of it is taken in saline and forwarded for smear, culture and PCR for tuberculosis, whereas a part of the sample is forwarded in formalin for histopathology examination.


3.3.6 Hysterosalpingography


This is a simple outpatient procedure used mainly for demonstrating the tubal patency; however, it gives a real insight into the shape of the endometrial cavity and can document any anatomical distortion either due to anomaly or due to presence of polyps, synechia or adhesions.


3.3.7 Saline Infusion Sono-Hysterography


It is done by instilling saline in the uterine cavity and distending the cavity, which helps in identifying the presence of any polyps in the cavity and distinguishing them from sessile fibroids. This helps in deciding whether they can be adequately managed by hysteroscopy. This technique is safe, low cost, well tolerated and feasible in most outpatient infertility clinics. Saline infusion sono-hysterography has been demonstrated to be superior to TVS and/or HSG also for the diagnosis of uterine malformations. Soares et al. [1] found that SIS had a higher sensitivity (77.8 %) compared with TVS and HSG (44.4 %). Alborzi et al. [2] showed in a study of 20 patients with a history of recurrent pregnancy loss and an HSG diagnosis of septate/bicornuate uterus that SIS was better than HSG for differentiating a septate from a bicornuate uterus [3].


3.3.8 Hysteroscopy


If any endometrial pathology is suspected, then a hysteroscopy becomes mandatory, as a directed intervention is possible along with confirmation of the diagnosis. When a polyp is seen, then a polyp removal or resection of sub-mucous myoma is possible. Operative hysteroscopy can be used to remove adhesions and perform septum resection thereby improving the uterine capacity. In all women where any endometrial pathology is suspected, hysteroscopy can help diagnose and treat and thereby improve the subsequent implantation and pregnancies. In women with unexplained infertility, hysteroscopy can at times help in finding small adhesions which can be resected simultaneously and visualize areas of endometritis, calcifications or granulomas. It is not rare to find women having remnant bone chips in the endometrial cavity from a previous abortion which prevent implantation and pregnancy thereby warranting removal. A hysteroscopic visualization and removal of all the bone fragments improve the likelihood of having pregnancy in future.

Hysteroscopy along with laparoscopy also help in diagnosing the Mullerian anomaly present and distinguish presence of septum in the cavity from bicornuate or didelphus uterus. A metroplasty or septum resection may improve the chances of pregnancy after surgery.

A systematic review and meta-analysis investigated the use of routine hysteroscopy prior to starting the first IVF cycle on treatment outcome in asymptomatic women. One randomized and five non-randomized controlled studies including a total of 3179 participants were included comparing hysteroscopy with no intervention in the cycle proceeding the first IVF cycle. There was a significantly higher clinical pregnancy rate (relative risk, RR, 1.44, 95 % CI 1.08–1.92, P = 0.01) and LBR (RR 1.30, 95 % CI 1.00–1.67, P = 0.05) in the subsequent IVF cycle in the hysteroscopy group. Hysteroscopy in asymptomatic women prior to their first IVF cycle could improve treatment outcome when performed just before commencing the IVF cycle [4]. Recommendations regarding the efficacy of routine use of hysteroscopy prior to starting the first IVF treatment cycle are lacking.


3.4 Endometrial Pathology



3.4.1 Endometrial Polyps


Polyps diagnosed prior to commencement of controlled ovarian stimulation (COS) for in vitro fertilization (IVF) should be removed. The management of polyps seen during the course of COS for IVF should be individualized given the number of embryos created, the previous reproductive history of the patient and the individual clinics’ success rates for their frozen embryo programme. Polyps when present especially near the cornua may inhibit the transport of sperms and thereby interfere with fertility [5].


3.4.2 Fibroids


Submucosal myomas and intramural myomas that distort the endometrial cavity are associated with lower pregnancy, implantation and delivery rates in women undergoing IVF compared with infertile women without myomas [6, 7]. Reproductive outcomes improve after myomectomy for a submucosal myoma, and the difference is more pronounced if the myoma was the only identifiable aetiology. Recent studies demonstrate that leiomyomas may adversely affect the overlying endometrium and impair endometrial receptivity by altered expression of HOXA-10 in endometrial stromal cells during the window of implantation in 69 % of patients with uterine leiomyomas [8].


3.4.3 Mullerian Anomaly/Septate Uterus


The septum in the uterus has poor vascular supply and therefore lowers fecundity. The role of metroplasty or hysteroscopic septum resection in patients with primary infertility remains controversial especially done prophylactically during infertility treatment when it is only proposed to hinder fertility, and its impact on pregnancy is unknown. Hysteroscopic incision of the septum has been shown to be a safe, simple, and efficient method of treating septate uteri [9]. Many IVF centres recommend removal of incomplete uterine septa before IVF to reduce the possibility of miscarriage and improve the pregnancy outcome [9, 10].


3.4.4 Genital Tuberculosis


The definitive diagnosis of genital tuberculosis is in most cases based on the microbiology report or the histopathology of the endometrial sampling done prior to treatment of infertility. Once a diagnosis of tuberculosis is established, then it is mandatory to treat them for the disease else it progresses to damage the endometrium to the extent when treatment is impossible or the scarring is produced. The treatment is in the form of anti-tubercular drugs given for duration of 12 months. It is advisable to repeat the biopsy at 6 months after treatment and confirm treatment. However if the bacilli still persist, then she may be a candidate having multidrug-resistant form of tuberculosis where second-line therapy or category II drugs are needed [11].

Once the treatment is completed, then a hysteroscopy and laparoscopy should be done to see the effect of tuberculosis on the genital tract. If any adhesions or synechia are seen, they should be cut, and the anatomical correction may benefit in achieving conception.


3.4.5 Endometriosis


The decrease in implantation rates in endometriotic patients is still a matter of debate. The meta-analysis of Barnhart [12, 13], which evaluated the impact of endometriosis on IVF outcome, showed a lower pregnancy rate, with a particular impact of endometriosis on implantation (OR = 0.86 IC = 0.85–0.87). The sub-group analysis according to the stage of endometriosis highlighted a weaker implantation in the event of severe endometriosis. This effect is mediated through a decrease in embryo quality, probably consequent to a decrease in the number of embryos available. More recent studies with long GnRH agonist protocols of stimulation did not find these results: Hickman studied 149 cycles, comparing patients with endometriosis with those having a tubal infertility; the rate of implantation was comparable between groups (of 28.0 % versus 29.8 %, respectively), thereby suggesting that suppression of endometriosis by GnRH analogues does seem to have an overall benefit in treatment of endometriosis [14]. The decreased expression of biomarkers of implantation such as glycodelin A (GdA), osteopontin (OPN), lysophosphatidic acid receptor 3 (LPA3) and HOXA10 may indicate impaired endometrial receptivity in patients with endometriosis [15].

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Jun 8, 2017 | Posted by in GYNECOLOGY | Comments Off on Therapeutic Intervention of Endometrial Pathology Before Ovarian Stimulation

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