- Email: [email protected]
Asherman syndrome and insufficient endometrial thickness: A hypothesis of integrated approach to restore the endometrium
Journal Pre-proofs Asherman Syndrome and insufficient endometrial thickness: a hypothesis of integrated approach to restore the endometrium Federica Di Guardo, Marco Palumbo PII: DOI: Reference:
S0306-9877(19)31272-1 https://doi.org/10.1016/j.mehy.2019.109521 YMEHY 109521
To appear in:
Medical Hypotheses
Received Date: Revised Date: Accepted Date:
11 November 2019 3 December 2019 7 December 2019
Please cite this article as: F. Di Guardo, M. Palumbo, Asherman Syndrome and insufficient endometrial thickness: a hypothesis of integrated approach to restore the endometrium, Medical Hypotheses (2019), doi: https://doi.org/ 10.1016/j.mehy.2019.109521
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.
Asherman Syndrome and insufficient endometrial thickness: a hypothesis of integrated approach to restore the endometrium.
Federica Di Guardo1, Marco Palumbo1
Department of Medical Surgical Specialties, University of Catania, Viale Carlo Azeglio Ciampi, 95121 Catania CT, Italy 1
Corresponding Author
Federica Di Guardo, MD Department of Medical Surgical Specialties, Gynecology and Obstetrics Section, University of Catania, Via Tindaro 2, 95124 Catania, Italy. tel: +39 3493696016 - fax: +39 0957435518 e-mail: [email protected]
Funding: this work was not supported by any grant or other form of funding.
Abstract Asherman syndrome consists in an acquired condition characterized from the development of fibrous intrauterine adhesions involving until two-thirds of the uterine cavity. Common signs of Asherman syndrome are represented by alterations of regular menses, hypomenorrhea and amenorrhea. Moreover, women affected by Asherman syndrome, often struggle with fertility problems such as difficulty in spontaneous conceiving as well as complications including recurrent pregnancy loss and invasive placentation. The abnormality of the endometrial line consisting in insufficient thickness and/or endometrial trauma damaging the decidua basalis, are characteristic elements of Asherman syndrome. Several studies have been conducted during the last ten years to find a solution restoring the regular endometrial line solving the fertility issue in Asherman women. Hormonal therapy as well as the use of stem cells seem to represent valid options to regenerate the endometrium opening a new scenario in the fertility treatment of these women. In this context, the presented study proposes an integrated approach to reach an adequate endometrial reconstitution and consequentially optimal fertility outcomes.
Introduction Asherman syndrome represents an acquired condition showing the development of fibrous intrauterine adhesions involving two-thirds of the uterine cavity. Women affected by Asherman syndrome report alterations of regular menses from hypomenorrhea to amenorrhea. Moreover, they often struggle with difficulty in spontaneous conceiving as well as fertility complications such as recurrent pregnancy loss and invasive placentation related to the endometrial line insufficient thickness and its trauma leading to defects or absence of decidua basalis [1-2].
The establishment of the syndrome prognosis is challenging: in this context, several imaging modalities may help the clinicians, especially determining the extent of the intrauterine adhesions. Preoperative assessment is based on transvaginal ultrasonography, hysterosalpingography (HSG), saline infusion sonohysterography and/or hysteroscopy [3-4]. Once a prognosis is defined, an integrated approach involving preoperative, intraoperative and postoperative measures as well as procedures aimed to prevent the adhesions’ recurrence may be used in order to achieve optimal fertility outcomes. Interventions such as ultrasound-directed hysteroscopic adhesions lisis, mechanical separation of the endometrium and estrogen administration to induce endometrial proliferation [5–6], may result necessary. The advantage of using an integrated approach helps the clinicians either to assess a preoperative prognosis as well as to prepare the uterine cavity to a hypothetic pregnancy, especially with reference to those interventions aimed to promote the endometrial healing.
The hypothesis The alteration of the normal endometrial line such as insufficient thickness and trauma damaging the decidua basalis, are characteristic elements of Asherman syndrome. Several studies have been conducted during the last ten years focusing on restoration of regular endometrium in order to solve the fertility issue in Asherman women. Hormonal therapy as well as use of stem cells seem to represent valid options to regenerate the endometrium opening a new scenario in the fertility treatment of these women. In this context, the presented study proposes an integrated approach to reach an adequate endometrial reconstitution and consequentially optimal fertility outcomes.
Discussion of the hypothesis The clinicians goal after hysteroscopic surgery is represented by the prevention of adhesions recurrence, restoring of the regular menses and normal endometrial layer especially in presence of fertility desire. Experience in frozen embryo transfer, demonstrated that the hormonal endometrium preparation using sequential treatment with oestrogen and progesterone, is effective in endometrial growth also by excluding the ovarian functionality. This result can be reach recurring to protocols that prevent ovulation and corpus luteum formation [7]. Considering the previous evidence, the endometrial line restoration in patients affected by Asherman syndrome, may benefit of the use of high dosage hormonal therapy. This issue has been widely analyzed during the last ten years, however a strong consensus about when the hormonal therapy should be started, type of regimen and duration has not yet been established. Postoperative oestrogen administration is used after intrauterine adhesiolysis to improve the fertility outcomes: several studies, in fact, reported the effectiveness of postoperative oestrogen therapy in preventing the adhesions’ recurrence, restoring the regular menses as well as the endometrium thickness. Latest evidences showed encouraging results comparing the use of low dosage (4 mg) and higher dosage (10 mg) of oestradiol valerate daily administration in the postoperative period. Although the higher dosage seems to be more effective in restoration of the menstrual pattern, the same positive outcome was not demonstrated in limiting the recurrence of the intrauterine adhesions. In this context, the findings of the study suggested that both higher and lower dosages are as effective in preventing the adhesion reformation. In considering the fertility outcomes, the overall conception rate of the study was 29% (36/125), appearing lower than the rates reported in other series. The main explanation for this fact, is the inclusion in the study of only women belonging to moderate or severe category of Asherman [8]. The association of prolonged preoperative and a postoperative treatment with estrogens represents another strategy to treat Asherman patients with severe amenorrhea. Oral E2 4-6 mg were administered daily 4-8 weeks before the hysteroscopic adhesiolysis and continued for 4-10 weeks
after surgery. All women resumed a normal menstrual pattern and 50% of them became pregnant [9]. A recent study suggested a role for combination of oestradiolvalerate 4 mg (daily 4 weeks administration) and medroxyprogesterone acetate 10 mg (daily 2 weeks administration) as postoperative therapy in Asherman syndrome [1]. Satisfying results were also reported using the association of oestrogen and progestin after adhesiolysis. More in deep, after 21 days of treatment, transvaginal ultrasound showed an endometrium augmented in thickness, width and volume compared to the women who have not received the treatment [5]. In addition, Tsui et al. proposed an oestrogen long treatment (oestradiol acetate 2mg twice a day for 8-10 weeks) after hysteroscopic adhesiolysis, removal of baloon and second look hysteroscopy. Transvaginal ultrasound was used to assess the endometrial thickness: the endometrium was significantly thicker than at baseline (median endometrial thickness, 7.5 mm versus 3.0 mm, p < 0.05) and all the women conceived successfully (spontaneously of after embryo transfer) [10]. Finally, several studies investigating the role of stem cells have been conducted during the last ten years opening a new scenario in treatment of AS [11]. Literature has recently suggested the role of human endometrial Side Population (a heterogeneous population) in possibly regenereting the endometrial stem cells [12]. However, more studies are necessary to prove the stem cells effectiveness in restoring an appropriate endometrial line. Although the role of hormonal therapy in Asherman patients has never been confirmed with adequately randomized controlled trials, considering the evidences aforementioned, we would like to propose a hypothetic approach to reestablish the endometrial thickness preventing the adhesions recurrence and restoring the regular menses. In this context, we encourage the long postoperative supplementation with oestrogen (8-10 weeks) after cautious hysteroscopic adhesiolys eventually followed by apposition of dispositives limiting the recurrence of adhesions (Hyalobarrier or IUIBallon). Second look hysteroscopy may be performed after 2 months from the previous intervention to assess the eventual recurrence of adhesions and before starting the hormonal therapy. Transvaginal ultrasound might be always
assessed to evaluate the endometrial thickness. Active assisted reproductive techniques/embryo transfer must be performed when the measurement of endometrium reaches >5mm, as already documented in literature [10]. Finally, the treatment with stem cells can be considered a valid option to be combined with the oestrogen supplementation or as alternative in case of hormonal therapy failure.
References [1] Yu D, Wong YM, Cheong Y, Xia E, Li TC. Asherman syndrome—one century later. Fertility and sterility. 2008 Apr 1;89(4):759-79. [2] Bajwa SK, Singh A, Bajwa SJ. Contemporary issues in the management of abnormal placentation during pregnancy in developing nations: An Indian perspective. International journal of critical illness and injury science. 2013 Jul;3(3):183. [3] Schlaff WD, Hurst BS. Preoperative sonographic measurement of endometrial pattern predicts outcome of surgical repair in patients with severe Asherman’s syndrome. Fertility and sterility. 1995 Feb 1;63(2):410-3. [4] Salle B, Gaucherand P, de Saint Hilaire P, Rudigoz RC. Transvaginal sonohysterographic evaluation of intrauterine adhesions. Journal of clinical ultrasound. 1999 Mar;27(3):131-4. [5] Farhi J, Bar-Hava I, Homburg R, Dicker D, Ben-Rafael Z. Induced regeneration of endometrium following curettage for abortion: a comparative study. Human Reproduction. 1993 Jul 1;8(7):11434. [6] Zikopoulos KA, Kolibianakis EM, Platteau P, de Munck L, Tournaye H, Devroey P, Camus M. Live delivery rates in subfertile women with Asherman's syndrome after hysteroscopic adhesiolysis using the resectoscope or the Versapoint system. Reproductive biomedicine online. 2004 Jan 1;8(6):720-5. [7] Young SL. Oestrogen and progesterone action on endometrium: a translational approach to understanding endometrial receptivity. Reproductive biomedicine online. 2013 Nov 1;27(5):497505. [8] Liu L, Huang X, Xia E, Zhang X, Li TC, Liu Y. A cohort study comparing 4 mg and 10 mg daily doses of postoperative oestradiol therapy to prevent adhesion reformation after hysteroscopic adhesiolysis. Human Fertility. 2019 Jul 3;22(3):191-7.
[9] Myers EM, Hurst BS. Comprehensive management of severe Asherman syndrome and amenorrhea. Fertility and sterility. 2012 Jan 1;97(1):160-4. [10] Tsui KH, Lin LT, Cheng JT, Teng SW, Wang PH. Comprehensive treatment for infertile women with severe Asherman syndrome. Taiwanese Journal of Obstetrics and Gynecology. 2014 Sep 1;53(3):372-5. [11] Nagori CB, Panchal SY, Patel H. Endometrial regeneration using autologous adult stem cells followed by conception by in vitro fertilization in a patient of severe Asherman's syndrome. Journal of human reproductive sciences. 2011 Jan;4(1):43. [12] López-Pérez N, Gil-Sanchis C, Ferrero H, Faus A, Díaz A, Pellicer A, Cervelló I, Simón C. Human Endometrial Reconstitution From Somatic Stem Cells: The Importance of Niche-Like Cells. Reproductive Sciences. 2019 Jan;26(1):77-87.
S0306-9877(19)31272-1 https://doi.org/10.1016/j.mehy.2019.109521 YMEHY 109521
To appear in:
Medical Hypotheses
Received Date: Revised Date: Accepted Date:
11 November 2019 3 December 2019 7 December 2019
Please cite this article as: F. Di Guardo, M. Palumbo, Asherman Syndrome and insufficient endometrial thickness: a hypothesis of integrated approach to restore the endometrium, Medical Hypotheses (2019), doi: https://doi.org/ 10.1016/j.mehy.2019.109521
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.
Asherman Syndrome and insufficient endometrial thickness: a hypothesis of integrated approach to restore the endometrium.
Federica Di Guardo1, Marco Palumbo1
Department of Medical Surgical Specialties, University of Catania, Viale Carlo Azeglio Ciampi, 95121 Catania CT, Italy 1
Corresponding Author
Federica Di Guardo, MD Department of Medical Surgical Specialties, Gynecology and Obstetrics Section, University of Catania, Via Tindaro 2, 95124 Catania, Italy. tel: +39 3493696016 - fax: +39 0957435518 e-mail: [email protected]
Funding: this work was not supported by any grant or other form of funding.
Abstract Asherman syndrome consists in an acquired condition characterized from the development of fibrous intrauterine adhesions involving until two-thirds of the uterine cavity. Common signs of Asherman syndrome are represented by alterations of regular menses, hypomenorrhea and amenorrhea. Moreover, women affected by Asherman syndrome, often struggle with fertility problems such as difficulty in spontaneous conceiving as well as complications including recurrent pregnancy loss and invasive placentation. The abnormality of the endometrial line consisting in insufficient thickness and/or endometrial trauma damaging the decidua basalis, are characteristic elements of Asherman syndrome. Several studies have been conducted during the last ten years to find a solution restoring the regular endometrial line solving the fertility issue in Asherman women. Hormonal therapy as well as the use of stem cells seem to represent valid options to regenerate the endometrium opening a new scenario in the fertility treatment of these women. In this context, the presented study proposes an integrated approach to reach an adequate endometrial reconstitution and consequentially optimal fertility outcomes.
Introduction Asherman syndrome represents an acquired condition showing the development of fibrous intrauterine adhesions involving two-thirds of the uterine cavity. Women affected by Asherman syndrome report alterations of regular menses from hypomenorrhea to amenorrhea. Moreover, they often struggle with difficulty in spontaneous conceiving as well as fertility complications such as recurrent pregnancy loss and invasive placentation related to the endometrial line insufficient thickness and its trauma leading to defects or absence of decidua basalis [1-2].
The establishment of the syndrome prognosis is challenging: in this context, several imaging modalities may help the clinicians, especially determining the extent of the intrauterine adhesions. Preoperative assessment is based on transvaginal ultrasonography, hysterosalpingography (HSG), saline infusion sonohysterography and/or hysteroscopy [3-4]. Once a prognosis is defined, an integrated approach involving preoperative, intraoperative and postoperative measures as well as procedures aimed to prevent the adhesions’ recurrence may be used in order to achieve optimal fertility outcomes. Interventions such as ultrasound-directed hysteroscopic adhesions lisis, mechanical separation of the endometrium and estrogen administration to induce endometrial proliferation [5–6], may result necessary. The advantage of using an integrated approach helps the clinicians either to assess a preoperative prognosis as well as to prepare the uterine cavity to a hypothetic pregnancy, especially with reference to those interventions aimed to promote the endometrial healing.
The hypothesis The alteration of the normal endometrial line such as insufficient thickness and trauma damaging the decidua basalis, are characteristic elements of Asherman syndrome. Several studies have been conducted during the last ten years focusing on restoration of regular endometrium in order to solve the fertility issue in Asherman women. Hormonal therapy as well as use of stem cells seem to represent valid options to regenerate the endometrium opening a new scenario in the fertility treatment of these women. In this context, the presented study proposes an integrated approach to reach an adequate endometrial reconstitution and consequentially optimal fertility outcomes.
Discussion of the hypothesis The clinicians goal after hysteroscopic surgery is represented by the prevention of adhesions recurrence, restoring of the regular menses and normal endometrial layer especially in presence of fertility desire. Experience in frozen embryo transfer, demonstrated that the hormonal endometrium preparation using sequential treatment with oestrogen and progesterone, is effective in endometrial growth also by excluding the ovarian functionality. This result can be reach recurring to protocols that prevent ovulation and corpus luteum formation [7]. Considering the previous evidence, the endometrial line restoration in patients affected by Asherman syndrome, may benefit of the use of high dosage hormonal therapy. This issue has been widely analyzed during the last ten years, however a strong consensus about when the hormonal therapy should be started, type of regimen and duration has not yet been established. Postoperative oestrogen administration is used after intrauterine adhesiolysis to improve the fertility outcomes: several studies, in fact, reported the effectiveness of postoperative oestrogen therapy in preventing the adhesions’ recurrence, restoring the regular menses as well as the endometrium thickness. Latest evidences showed encouraging results comparing the use of low dosage (4 mg) and higher dosage (10 mg) of oestradiol valerate daily administration in the postoperative period. Although the higher dosage seems to be more effective in restoration of the menstrual pattern, the same positive outcome was not demonstrated in limiting the recurrence of the intrauterine adhesions. In this context, the findings of the study suggested that both higher and lower dosages are as effective in preventing the adhesion reformation. In considering the fertility outcomes, the overall conception rate of the study was 29% (36/125), appearing lower than the rates reported in other series. The main explanation for this fact, is the inclusion in the study of only women belonging to moderate or severe category of Asherman [8]. The association of prolonged preoperative and a postoperative treatment with estrogens represents another strategy to treat Asherman patients with severe amenorrhea. Oral E2 4-6 mg were administered daily 4-8 weeks before the hysteroscopic adhesiolysis and continued for 4-10 weeks
after surgery. All women resumed a normal menstrual pattern and 50% of them became pregnant [9]. A recent study suggested a role for combination of oestradiolvalerate 4 mg (daily 4 weeks administration) and medroxyprogesterone acetate 10 mg (daily 2 weeks administration) as postoperative therapy in Asherman syndrome [1]. Satisfying results were also reported using the association of oestrogen and progestin after adhesiolysis. More in deep, after 21 days of treatment, transvaginal ultrasound showed an endometrium augmented in thickness, width and volume compared to the women who have not received the treatment [5]. In addition, Tsui et al. proposed an oestrogen long treatment (oestradiol acetate 2mg twice a day for 8-10 weeks) after hysteroscopic adhesiolysis, removal of baloon and second look hysteroscopy. Transvaginal ultrasound was used to assess the endometrial thickness: the endometrium was significantly thicker than at baseline (median endometrial thickness, 7.5 mm versus 3.0 mm, p < 0.05) and all the women conceived successfully (spontaneously of after embryo transfer) [10]. Finally, several studies investigating the role of stem cells have been conducted during the last ten years opening a new scenario in treatment of AS [11]. Literature has recently suggested the role of human endometrial Side Population (a heterogeneous population) in possibly regenereting the endometrial stem cells [12]. However, more studies are necessary to prove the stem cells effectiveness in restoring an appropriate endometrial line. Although the role of hormonal therapy in Asherman patients has never been confirmed with adequately randomized controlled trials, considering the evidences aforementioned, we would like to propose a hypothetic approach to reestablish the endometrial thickness preventing the adhesions recurrence and restoring the regular menses. In this context, we encourage the long postoperative supplementation with oestrogen (8-10 weeks) after cautious hysteroscopic adhesiolys eventually followed by apposition of dispositives limiting the recurrence of adhesions (Hyalobarrier or IUIBallon). Second look hysteroscopy may be performed after 2 months from the previous intervention to assess the eventual recurrence of adhesions and before starting the hormonal therapy. Transvaginal ultrasound might be always
assessed to evaluate the endometrial thickness. Active assisted reproductive techniques/embryo transfer must be performed when the measurement of endometrium reaches >5mm, as already documented in literature [10]. Finally, the treatment with stem cells can be considered a valid option to be combined with the oestrogen supplementation or as alternative in case of hormonal therapy failure.
References [1] Yu D, Wong YM, Cheong Y, Xia E, Li TC. Asherman syndrome—one century later. Fertility and sterility. 2008 Apr 1;89(4):759-79. [2] Bajwa SK, Singh A, Bajwa SJ. Contemporary issues in the management of abnormal placentation during pregnancy in developing nations: An Indian perspective. International journal of critical illness and injury science. 2013 Jul;3(3):183. [3] Schlaff WD, Hurst BS. Preoperative sonographic measurement of endometrial pattern predicts outcome of surgical repair in patients with severe Asherman’s syndrome. Fertility and sterility. 1995 Feb 1;63(2):410-3. [4] Salle B, Gaucherand P, de Saint Hilaire P, Rudigoz RC. Transvaginal sonohysterographic evaluation of intrauterine adhesions. Journal of clinical ultrasound. 1999 Mar;27(3):131-4. [5] Farhi J, Bar-Hava I, Homburg R, Dicker D, Ben-Rafael Z. Induced regeneration of endometrium following curettage for abortion: a comparative study. Human Reproduction. 1993 Jul 1;8(7):11434. [6] Zikopoulos KA, Kolibianakis EM, Platteau P, de Munck L, Tournaye H, Devroey P, Camus M. Live delivery rates in subfertile women with Asherman's syndrome after hysteroscopic adhesiolysis using the resectoscope or the Versapoint system. Reproductive biomedicine online. 2004 Jan 1;8(6):720-5. [7] Young SL. Oestrogen and progesterone action on endometrium: a translational approach to understanding endometrial receptivity. Reproductive biomedicine online. 2013 Nov 1;27(5):497505. [8] Liu L, Huang X, Xia E, Zhang X, Li TC, Liu Y. A cohort study comparing 4 mg and 10 mg daily doses of postoperative oestradiol therapy to prevent adhesion reformation after hysteroscopic adhesiolysis. Human Fertility. 2019 Jul 3;22(3):191-7.
[9] Myers EM, Hurst BS. Comprehensive management of severe Asherman syndrome and amenorrhea. Fertility and sterility. 2012 Jan 1;97(1):160-4. [10] Tsui KH, Lin LT, Cheng JT, Teng SW, Wang PH. Comprehensive treatment for infertile women with severe Asherman syndrome. Taiwanese Journal of Obstetrics and Gynecology. 2014 Sep 1;53(3):372-5. [11] Nagori CB, Panchal SY, Patel H. Endometrial regeneration using autologous adult stem cells followed by conception by in vitro fertilization in a patient of severe Asherman's syndrome. Journal of human reproductive sciences. 2011 Jan;4(1):43. [12] López-Pérez N, Gil-Sanchis C, Ferrero H, Faus A, Díaz A, Pellicer A, Cervelló I, Simón C. Human Endometrial Reconstitution From Somatic Stem Cells: The Importance of Niche-Like Cells. Reproductive Sciences. 2019 Jan;26(1):77-87.