Lakhbir K. Dhaliwal1 and Shalini Gainder1
(1)
Department of Obstetrics and Gynecology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
Shalini Gainder
Email: sgainder@gmail.com
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].
3.4.6 Hypogonadotropic Hypogonadism
Women having diagnosis of hypogonadotropic hypogonadism should receive cyclical oestrogen followed by progesterone which helps in priming the endometrium for the future when controlled ovarian stimulation would be done. These women may not respond to combined oestrogen progesterone pills and therefore should receive oestrogen followed by progesterone in a more physiological pattern.
3.4.7 Polycystic Ovarian Syndrome
PCOS women have oligo or anovulatory cycles, and therefore there is suboptimal long-standing unopposed oestrogen leading to periods of amenorrhoea followed by heavy bleeding [16]. The regulatory role of progesterone is suboptimal or absent. The endometrial growth and differentiation in women with PCOS is influenced by androgens and insulin also. Under this hormonal milieu, the endometrium does not undergo a secretory transformation, and there continues a constant mitogenic effect of estradiol which may lead to endometrial overgrowth, unpredictable bleeding patterns, hyperplasia and endometrial carcinoma. The endometrium of women with PCOS is considered a model of dysfunctional endometrium, demonstrating over-expression of androgen receptors and failing to regulate oestrogen receptors (ERs), when compared to normal women. Studies carried out in PCOS have shown differences in complements of steroid receptors and co-activators, when compared to fertile women. The endometrium, in this case, over-expresses androgen receptors and fails to regulate the ER-α (oestrogen receptor, α) in the window of implantation [17–19]. Women with simple hyperplasia should be treated with progesterone cyclical for 3 months and then ovulation induction where luteal phase support with dihydroprogesterone 10 mgs is given for 10–12 days. Women with complex hyperplasia or diagnosis of early-stage carcinoma should be treated as per guidelines prior to ovulation induction. Giving high dose of megesterol (80–120 mgs/day) or medroxy progesterone acetate (200 mg/day) with or without levonorgestral containing intrauterine device, hysteroscopic resection of growth and re-evaluation after 3 months have been suggested. After 6 months of treatment, IVF can be advised in such women when regression is documented.
3.4.8 Hydrosalpinx
Women having hydrosalpinx have poor implantation which may be due to the toxic effect of the inflammatory fluid or due to the backflow of the fluid into the endometrial cavity effecting the implantation. Meta-analyses have shown that women with hydrosalpinx have lower implantation rates [20]. This can be treated prior to stimulation for IVF by removing the damaged tubes or by clipping the tubes or by hysteroscopic closure of hydrosalpinx using the Essure device.
3.4.9 Asherman Syndrome and Uterine Synechia
Any form of uterine infection causes endometritis leading to inflammation and destruction of the endometrium, its basal layer and myometrium and leads to adhesion formation called synechia which can sometimes follow the iatrogenic injury like excessive endometrial curettage. In Asherman syndrome, there is complete obliteration of the uterine cavity with adhesions resulting in amenorrhoea and infertility. The endometrial cavity may be replaced by adhesion and fibrosis. Symptoms relate to the degree and location of adhesions and include irregular bleeding ranging from hypomenorrhoea to amenorrhoea, infertility and pregnancy loss [10].
Treatment usually involves hysteroscopic resection of adhesions followed by oestrogen progesterone therapy. The management of moderate to severe disease still poses a challenge, and the prognosis of severe disease remains poor. Repeat surgery may be necessary in some cases but may not always produce the desired outcome. Stem cell therapy as described in the following section is an emerging treatment option. Future research should focus on the cellular and molecular aspects of endometrial tissue regeneration as well as the prevention of postsurgical adhesion formation and reformation.
3.4.10 Thin Endometrium
A thin endometrium is one of the most difficult problems encountered in assisted reproduction everyday practice. It is the single factor which has a significant impact on the pregnancy rate. Usually, there is no pregnancy when the endometrium remains below 7 mm, although pregnancy has been reported at endometrial thickness of 3.7 mm also, but these pregnancies can have poor outcome resulting in missed abortion and preterm labour [21]. Various interventions have been tried to improve the endometrial lining, still most are ineffective.
3.5 Therapeutic Interventions to Improve Endometrium and Implantation
3.5.1 Extended Oestrogen Therapy
Women with thin endometrium either due to previous iatrogenic causes like excessive curettage or endometritis having secondary amenorrhoea which fail to respond to cyclical oestrogen progesterones. Vaginal E2 gives maximum levels at uterus. Endometrium may still be irresponsive to oestrogen therapy when there is receptor defect in women where the receptors are depleted due to damaged endometrium or there may be a genetic defect rarely [22].
Women who have amenorrhoea due to end-organ damage not responding to cyclical oestrogen therapy may be put on continuous high oestrogen therapy either orally or vaginally to cause regeneration of endometrium given for 4–6 weeks before progesterone is supplemented. Tourgeman et al. [23] compared vaginal administration of E2 with oral E2 administration in recipients of donor oocytes. They observed an increase in endometrial thickness to 7 mm and an ongoing pregnancy rate of 70 % with vaginal E2 administration extended to 4–6 weeks before the addition of progesterone.
3.5.2 Role of Aspirin
Numerous pharmacological interventions have been studied as adjuvant therapy over the years [24, 25]. Aspirin (acetylsalicylic acid) is a widely used vasoactive substance that exerts its effects by inhibiting the enzyme cyclo-oxygenase in platelets. In low doses, it inhibits synthesis of thromboxane A2 (a vasoconstrictor and promoter of platelet aggregation) more than that of prostacyclin (a vasodilator). Due to these antithrombotic and vasodilatory effects, aspirin has been one of the agents studied in several trials to evaluate its potential role in increasing IVF success rate through improving either ovarian blood flow, foliculo-genesis and ovarian responsiveness or uterine vascularity and receptiveness, or both [26, 27]. Some authors have recommended starting low-dose aspirin in the preceding cycle or on day 15 or 21 continuing till pregnancy is achieved whereas others have considered aspirin from day 2 of the cycle. Till date, only conflicting results are available, and it is not recommended but can be considered under clinical trials only [28].
3.5.3 Sildenafil
Nitric oxide (NO) relaxes vascular smooth muscle through a cGMP-mediated pathway, and NO synthase isoforms have been identified in the uterus. Sildenafil citrate (Viagra), a type-5-specific phosphodiesterase inhibitor, augments the vasodilatory effects of NO by preventing the degradation of cGMP. The use of vaginal sildenafil helps in improving uterine artery blood flow and sonographic endometrial appearance, and women with prior failed assisted reproductive cycles due to poor endometrial response have conceived following its use [29].
3.5.4 Endometrial Injury to Improve Endometrial Receptivity
Implantation is a process of embryonic attachment to the endometrium and subsequent invasion into the stroma of the uterine wall. It is a multistage process involving several cytokines and growth factors. One of the most promising methods of improving implantation is local injury to the endometrium. In 2003, Barash et al. [30] reported that endometrial injury before in vitro fertilization (IVF) among women with repeated implantation failure was associated with increased rates of implantation, clinical pregnancy and live birth. The findings were supported by two other studies [31, 32]. Endometrial injury results in decidualization. Massive release of cytokines and growth factors from injured endometrium has been suggested as an underlying process [33].
Friedler et al. [34] reported patients with repeated implantation failure who were treated by a special protocol including hysteroscopy, dilation and curettage, triple antibiotics and oestrogen. Six of fourteen patients conceived (pregnancy rate 43 %) in the subsequent IVF-ET cycle with implantation rate of 24 %. The authors postulated that implantation failure could have been caused by endometritis that was treated with antibiotics. In addition, the endometrial flow was improved by oestrogen administration. Because dilation and curettage was part of this protocol, it is also possible that endometrial injury by curettage plays a role in their improved results.
Basic scientific studies regarding the pathophysiology of local injury and improved implantation are lacking. Endometrium in IVF cycles is ahead of that of natural cycles by 2–4 days. It is possible that repeated IVF-ET implantation failure is related to asynchrony of the endometrium with the embryo stage [35–37]. Zhou et al. [32] postulated that local endometrial injury in stimulated cycle delays the endometrial development because of wound repair processes correcting the asynchrony between endometrial and embryo stages.
3.5.5 Prolonged Use of Pentoxifyline and Vitamin E
A combination of pentoxyfylline and tocopherol may improve endometrial growth in resistant cases by reducing fibro-atrophic uterine lesions. It thus improves the uterine response to HRTs that are unresponsive to conventional therapy. Endometrial thickness, myometrial dimensions and diastolic uterine artery flow improved significantly. A study by Acharya et al. where women were given 800 mg of PTX and 1,000 IU of Vit E daily for up to 8 months showed improvement in endometrial thickness. The mean thickness of endometrium before and after treatment was 4.37 and 6.05 mm, respectively. Pregnancy occurred in 40 % of the cases [38].
3.5.6 Stem Cell Therapy
Human endometrium is a highly regenerative tissue, undergoing more than 400 cycles of growth, differentiation and shedding during a woman’s reproductive years. Adult stem cells are identified in the endometrium which can reconstruct endometrial tissue in vivo suggesting their possible use in treating disorders associated with inadequate endometrium. In scarred endometrium or endometrium obliterated with adhesions, functional endometrial stem/progenitor cells likely are lacking, as scant functional endometrium is present in the uterine cavity.
From adult autologous stem cells, endometrial angiogenic stem cells can be separated. These cells are placed in the endometrial cavity under ultrasound guidance after curettage. Patients can then be given cyclical hormonal therapy. On development of endometrium with a thickness of 8 mm and good vascularity, in vitro fertilization and embryo transfer was done. This has resulted in pregnancy. The bone marrow cells act by production of trophic factors promoting angiogenesis and tissue growth to regenerate endometrial tissue. Various other adult cells like endometrial epithelial progenitor, menstrual, bone marrow or embryonic stem cells can be used for generation of endometrium stem cells [39].
3.5.7 Granulocyte Colony-Stimulating Factor
Recently, the use of granulocyte colony-stimulating factor in women with inadequate endometrial growth has been tried, but its use is during stimulation cycles at the time of receiving HCG.
3.6 Scope for Research
The understanding of endometrial receptivity still needs a clear understanding, and the research in stem cell therapy and gene therapy gives hope of treating damaged endometrium. To summarize, various interventions for the endometrium may help in achieving pregnancy when the defect lies in it, although this is the most difficult at times when endometrium fails to respond to all treatment options.
References
1.
Soares SR, Barbosa dos Reis MM, Camargos AF. Diagnostic accuracy of sonohysterography, transvaginal sonography, and hysterosalpingography in patients with uterine cavity diseases. Fertil Steril. 2000;73(2):406–11.CrossRefPubMed
2.
Alborzi S, Dehbashi S, Parsanezhad ME. Differential diagnosis of septate and bicornuate uterus by sonohysterography eliminates the need for laparoscopy. Fertil Steril. 2002;78(1):176–8.CrossRefPubMed
3.
Tur-Kaspa I, Michael Gal M, Hartman M, Hartman J, Hartman A. A prospective evaluation of uterine abnormalities by saline infusion sonohysterography in 1,009 women with infertility or abnormal uterine bleeding. Fertil Steril. 2006;86(6):1731–5.CrossRefPubMed
4.
Pundir J, Pundir V, Omanwa K, Khalaf Y, El-Toukhy T. Hysteroscopy prior to the first IVF cycle: a systematic review and meta-analysis. Reprod Biomed Online. 2014;28(2):151–61.CrossRefPubMed
5.
Afif K, Anand S, Nallapeta S, Gelbaya TA. Management of endometrial polyps in subfertile women: a systematic review. Eur J Obstet Gynecol Reprod Biol. 2010;151(2):117–21.CrossRef
6.
Donnez J, Jadoul P. What are the implications of myomas on fertility? A need for a debate? Hum Reprod. 2002;17(6):1424–30.CrossRefPubMed
7.
Goldenberg M, Sivan E, Sharabi Z, Bider D, Rabinovici J, Seidman DS. Outcome of hysteroscopic resection of submucous myomas for infertility. Fertil Steril. 1995;64(4):714–6.PubMed
8.
Matsuzaki S, Canis M, Darcha C, Pouly JL, Mage G. HOXA-10 expression in the mid-secretory endometrium of infertile patients with either endometriosis, uterine fibromas or unexplained infertility. Hum Reprod. 2009;24(12):3180–7.CrossRefPubMed
9.
Ozgur K, Isikoglu M, Donmez L, Oehninger S. Is hysteroscopic correction of an incomplete uterine septum justified prior to IVF? Reprod Biomed Online. 2007;14(3):335–40.CrossRefPubMed
10.
Revel A. Defective endometrial receptivity. Fertil Steril. 2012;97(5):1028–32.CrossRefPubMed
11.
Gupta N, Sharma JB, Mittal S, Singh N, Misra R, Kukreja M. Genital tuberculosis in Indian infertility patients. Int J Gynecol Obstet. 2007;97(2):135–8.CrossRef
12.
Gauche-Cazalis C, Koskas M, Scali SC, Luton D, Chadi Yazbeck C. Endometriosis and implantation: myths and facts. Middle East Fertil Soc J. 2012;17(2):79–81.CrossRef
13.
Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002;77(6):1148–55.CrossRefPubMed
14.
Hickman TN. Impact of endometriosis on implantation. Data from the Wilford Hall Medical Center IVF-ET Program. J Reprod Med. 2002;47(10):801–8.PubMed
15.
Wei Q, St Clair JB, Fu T, Stratton P, Nieman LK. Reduced expression of biomarkers associated with the implantation window in women with endometriosis. Fertil Steril. 2009;91(5):1686–91.PubMedCentralCrossRefPubMed
16.
Cakmak H, Taylor HS. Human implantation failure: molecular mechanisms and clinical treatment. Hum Reprod Update. 2011;17(2):242–53.PubMedCentralCrossRefPubMed
17.
Gregory CW, Wilson EM, Apparao KB, Lininger RA, Meyer WR, Kowalik A, et al. Steroid receptor coactivator expression throughout the menstrual cycle in normal and abnormal endometrium. J Clin Endocrinol Metab. 2002;87(6):2960–6.CrossRefPubMed
18.
Apparao KB, Lovely LP, Gui Y, Lininger RA, Lessey BA. Elevated endometrial androgen receptor expression in women with polycystic ovarian syndrome. Biol Reprod. 2002;66(2):297–304.CrossRefPubMed
19.
Wang A, Ji L, Shang W, Li M, Chen L, White RE, et al. Expression of GPR30, ERα and ERβ in endometrium during window of implantation in patients with polycystic ovary syndrome: a pilot study. Gynecol Endocrinol. 2011;27(4):251–5.CrossRefPubMed
20.
Camus E, Poncelet C, Goffinet F, Wainer B, Merlet F, Nisand I, et al. Pregnancy rates after in-vitro fertilization in cases of tubal infertility with and without hydrosalpinx: a meta-analysis of published comparative studies. Hum Reprod. 1999;14(5):1243–9.CrossRefPubMed
21.
Check JH, Cohen R. Live fetus following embryo transfer in a woman with diminished egg reserve whose maximal endometrial thickness was less than 4 mm. Clin Exp Obstet Gynecol. 2011;38(4):330–2.PubMed
22.
Chen MJ, Yang JH, Peng FH, Chen SU, Ho HN, Yang YS. Extended estrogen administration for women with thin endometrium in frozen-thawed in-vitro fertilization programs. J Assist Reprod Genet. 2006;23(7–8):337–42.CrossRefPubMed
23.
Tourgeman DE, Slater CC, Stanczyk FZ, Paulson RJ. Endocrine and clinical effects of micronized estradiol administered vaginally or orally. Fertil Steril. 2001;75(1):200–2.CrossRefPubMed
24.
Weckstein LN, Jacobson A, Galen D, Hampton K, Hammel J. Low dose aspirin for oocyte donation recipients with a thin endometrium: prospective, randomized study. Fertil Steril. 1997;68(5):927–30.CrossRefPubMed
25.
Fanchin R, Righini C, Schonauer LM, Olivennes L, Cunha Filho JS, Frydman R. Vaginal versus oral E2 administration: effects on endometrial thickness, uterine perfusion, and contractility. Fertil Steril. 2001;76(5):994–8.CrossRefPubMed
26.
Sher G, Fisch JD. Effect of sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development. Fertil Steril. 2002;78(5):1073–6.CrossRefPubMed
27.
Rubinstein M, Marazzi A, Polak de Fried E. Low dose aspirin treatment improves ovarian responsiveness, uterine and ovarian blood flow velocity, implantation and pregnancy rates in patients undergoing in-vitro fertilization: a prospective, randomized, double-blind placebo-controlled assay. Fertil Steril. 1999;71(5):825–9.CrossRefPubMed
28.
Khair M, Banerjee K, El-Toukhy T, Coomarasamy A, Khalaf Y. Aspirin in women undergoing in vitro fertilization treatment: a systematic review and meta-analysis. Fertil Steril. 2007;88(4):822–31.CrossRef
29.
Sher G, Fisch JD. Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF. Hum Reprod. 2000;15(4):806–9.CrossRefPubMed
30.
Barash A, Dekel N, Fieldust S, Segal I, Schechtman E, Granot I. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization. Fertil Steril. 2003;79(6):1317–22.CrossRefPubMed
31.
Raziel A, Schachter M, Strassburger D, Bern O, Ron- El R, Friedler S. Favorable influence of local injury to the endometrium in intracytoplasmic sperm injection patients with high-order implantation failure. Fertil Steril. 2007;87(1):198–201.CrossRefPubMed
32.
Zhou L, Li R, Wang R, Huang H, Zhong K. Local injury to the endometrium in controlled ovarian hyperstimulation cycles improves implantation rates. Fertil Steril. 2008;89:1166–9.CrossRefPubMed
33.
Benjamin Almog B, Shalom-Paz E, Dufort D, Tulandi T. Promoting implantation by local injury to the endometrium. Fertil Steril. 2010;94(6):2026–9.CrossRefPubMed
34.
Friedler S, Margalioth E, Kafka I, Yaffe H. Treatable uterine cause for in-vitro fertilisation failures. Lancet. 1993;341(8854):1213.CrossRefPubMed
35.
Macklon N, Fauser B. Impact of ovarian hyperstimulation on the luteal phase. J Reprod Fertil Suppl. 2000;55:101–8. Review.PubMed
36.
Mirkin S, Nikas G, Hsiu J, Diaz J, Oehninger S. Gene expression profiles and structural/functional features of the peri-implantation endometrium in natural and gonadotropin-stimulated cycles. J Clin Endocrinol Metab. 2004;89(11):5742–52.CrossRefPubMed
37.
Li R, Hao G. Local injury to the endometrium: its effect on implantation. Curr Opin Obstet Gynecol. 2009;21(3):236–9.CrossRefPubMed
38.
Acharya S, Yasmin E, Balen AH. The use of a combination of pentoxifylline and tocopherol in women with a thin endometrium undergoing assisted conception therapies–a report of 20 cases. Hum Fertil (Camb). 2009;12(4):198–203.CrossRef
39.
Gargett CE, Ye L. Endometrial reconstruction from stem cells. Fertil Steril. 2012;98(1):11–20.CrossRefPubMed