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Adenomyosis and Infertility
- 1. 15/03/2015/1
- 2. Adenomyosis Fertility Enhancing Treatments AGES ASM 2015 March 11, 2015 Anusch Yazdani MBBS (Hons) FRANZCOG CREI
- 3. 15/03/2015/3 Declaration of Interest • Appointments • Director, Eve Health Australia • Clinical Director of Research and Education, QFG • Clinical Director, Reproductive Endocrinology and Infertility, RBWH • Program Director, Reproductive Endocrinology and Infertility (CREI) • Vice President, Australasian Gynaecological Endoscopy & Surgery Society (AGES) • Councillor, RANZCOG • Associate Professor, University of Queensland • Consultant, AHPRA • Educational Third Party Funding • MSD • Merck-Serono • Ferring • AGES Society Research Foundation • Financial Disclosure • Minority shareholder Virtus Health
- 4. 15/03/2015/4 Adenomyosis • ectopic location of endometrial tissue deep to the endometrial-myometrial junction Bird. Am J Obstet Gynecol. 1972; 112: 583
- 5. 15/03/2015/5 Pathology • big boggy uterus • epithelial and stromal elements situated deep to the endometrial–myometrial junction • the ectopic endometrium must be located past the deepest glands of the basalis • ‘collars’ of hypertrophic bundle smooth muscle surround these foci • glands and stroma are usually in the proliferative phase, but may contain secretory to menstrual changes • stromal fibroblasts differ cytologically from adjacent smooth muscle • distribution • diffuse • adenomyosis has a haphazard distribution within the myometrium • depth of penetration has been variably defined as • 2 mm or deeper in the myometrium • >1 microscopic field at 10 x magnification from the endomyometrial junction • more than 25% of the myometial thickness • focal • a localised distribution: adenomyoma Bergeron. Best Pract Res Clin Obstet Gynaecol. 2006; 20: 511
- 6. 15/03/2015/6 The Junctional Zone • the myometrial layers deep to the endometrium • thickening may be a common pathway to both endometriosis and adenomyosis • related to abnormal angiogenesis • histologically • myocyte hyperplasia and angiogenensis Benagiano. Womens Health. 2009; 5: 297 • functionally, though not histologically, distinct from the remaining myometrium • thickness of the junction zone • increases with age from 5 to 8mm • combined oral contraceptive pill appears to be protective • increased with endometriosis or fibroids, the junctional zone increases significantly beyond this • a junctional zone of more than 12mm on MRI is associated with a histological diagnosis of adenomyosis Reinhold. Radiology. 1996; 199: 151
- 7. 15/03/2015/7 Prevalence • based on histology: 9 to 88% of hysterectomy specimen • based on MRI: junctional zone thickening has been demonstrated in 79% of patients with endometriosis, 52% patients with pelvic pain Benagiano. Womens Health (Lond Engl). 2009; 5: 297 Kunz. Hum Reprod. 2005; 20: 2309 • not only dependent on patient factors and presenting symptoms, but also the stipulated criteria for the diagnosis of adenomyosis, such as the depth of penetration and methodological differences, such as the number of sections per specimen Bergeron. Best Pract Res Clin Obstet Gynaecol. 2006; 20: 511 Gordts. Reprod Biomed Online. 2008; 17: 244 • Maryland Women’s Health Study: the prevalence of adenomyosis varied from 10% to 88% among histopathologists in the study group Seidman JD. Int J Gynecol Pathol. 1996; 15: 217
- 8. 15/03/2015/8 Diagnosis: Histology • uterine biopsy • 102 premenopausal women scheduled for hysterectomy for menorrhagia and/or pelvic pain underwent preoperative transvaginal ultrasonography. • single full-thickness 14 G needle myometrial biopsy was taken from the posterior uterine wall • approach has been adapted to make a definitive diagnosis at the time of laparoscopy Vercellini. Hum Reprod. 1998; 13: 2884 • hysterectomy • gold standard • hysterectomy specimen provide the most reliable diagnostic opportunity, but , by necessity, limited conception opportunities sensitivity specificity TVUSS 82.7 67.1 Biopsy 44.8 95.9
- 9. 15/03/2015/9 Diagnosis: Imaging • ultrasound • TVUSS sensitivity 50% to 87% • better than TAUSS • reduced with large uterus and fibroids Levgur M. J Reprod Med. 2007; 52: 177 • MRI • sensitivity 73 to 96% • typical MR features include • diffuse or focal thickening of the junctional zone • junctional zone of greater than 12 mm is predictive of histological adenomyosis • a diffuse, homogeneous, low-signal-intensity thickening of the junctional zone • ill-defined low signal intensity in the myometrium on T2-weighted MRI images • islands of ectopic endometrial tissue may be identified as punctate foci of high signal intensity Fusi . Best Pract Res Clin Obstet Gynaecol. 2006; 20: 479 • furthermore, MRI differentiates adenomyomata from fibroids
- 10. 15/03/2015/10 Associations • increased risk • pain • menorrhagia • multiparity • endometriosis • endometrial hyperplasia • uterine trauma (C/Section and abortion) • decreased risk • prolapse • nuliparity • reduced number of histological sections • non-specialised pathologist infertility?
- 11. 15/03/2015/11 Adenomyosis and Infertility • adenomyosis = infertility • studies are inconsistent and variable • limited by • diagnostic difficulties • study design • association with confounders • effect on natural and assisted conception has not been established • no large scale baseline studies for natural conception • secondary evidence from infertile populations in ART /
- 12. The likelihood of clinical pregnancy in infertile women with or without adenomyosis undergoing IVF/ICSI. Paolo Vercellini et al. Hum. Reprod. 2014;29:964-977
- 13. The risk of miscarriage in clinical pregnancies obtained at IVF/ICSI in women with or without adenomyosis. Paolo Vercellini et al. Hum. Reprod. 2014;29:964-977
- 14. 15/03/2015/14 Pathophysiology puberty reproductive menopause dysmenorrhoea infertility miscarriage pelvic pain dyspareunia menorrhagia dysmenorrhoea
- 15. 15/03/2015/15 Treatment: Medical • natural conception • aromatase inhibitors • tissue specific reduction in oestrogen • randomized non-blind trial compared 3-months of goserelin (3.6 mg/month) with letrozole (2.5 mg/day) in women with adenomyosis diagnosed by TV-US • equal reduction in uterine (56.0 vs 46.5%) and adenomyoma (49.1 vs 40.9%) volumes • GnRHa group: 86% of women hot flashes and none pregnant • letrozole group: no hot flashes and two pregnant Vercilini. Expert Opin Pharmacother. 2014, 16: 2347
- 16. 15/03/2015/16 Treatment: Medical • ART: GnRH agonist • pituitary downregulation • GnRH agonists modify inflammatory endometrial response Khan. Hum Reprod 2010;25:642 • GnRh agonists reduce junctional thickness based MRI assessment Imaoka. J Magn Reson Imaging 2002;15:2850
- 17. 15/03/2015/17 Treatment: Medical • ART: GnRH agonist • case series suggest GnRh agonist effective in improving pregnancy rates in women with endometriosis Tremellen. Aust N Z J Obstet Gynaecol 2011;51: 280 • analysis of observational data Vercilini. Human Reproduction 2014, 29: 964
- 18. The likelihood of clinical pregnancy in infertile women with or without adenomyosis undergoing IVF/ICSI after a short or long protocol down-regulation.
- 19. 15/03/2015/19 Treatment: Medical • ART: GnRH agonist • long term pituitary downregulation prior to frozen embryo transfer may increase pregnancy rates • retrospective study of 339 patients with endometriosis • long downregulation + HRT significantly improved pregnancy rate (51 vs 25%) Niu Z1. Gynecol Endocrinol. 2013, 29:1026 .
- 20. 15/03/2015/20 Treatment: Medical • ART: steroids • inflammatory endometrial response in adenomyosis Khan. Hum Reprod 2010;25: 642 • case series suggest GnRh agonist effective in improving pregnancy rates in women with endometriosis Tremellen. Aust N Z J Obstet Gynaecol 2011; 51: 280
- 21. 15/03/2015/21 Treatment: Surgical • surgical approaches • submucous • adenomyomatous polyp hysteroscopic excision • superficial adenomyosis endometrial ablation • intramural • deep (>2.5 cm) adenomyosis hysterectomy • focal adenomyoma excision/reduction, hysterectomy • subserous or subperitoneal • superficial excision/excision • retrocervical, rectovaginal laparoscopic excision Best Practice & Research Clinical Obstetrics and Gynaecology 2006; 20: 603
- 22. 15/03/2015/22 Treatment: Surgical • pregnancy J ObstetGynaecol Res. 2009 35: 495 • conservative surgery or combination therapy provides more effective and longer durable symptom control in symptomatic women with extensive adenomyosis, compared to GnRH agonist • reproductive performance was also better in patients treated with conservative surgery with/without GnRH agonist Surgery GnRH clinical pregnancy 46.4% 10.8% live birth 32.1% 8.1%
- 23. 15/03/2015/23 Treatment: Radiology • uterine artery embolization has been evaluated by a number of authors in both randomised and non randomised trials • other groups have assessed the role of MR guided focussed ultrasound Kim. J Vasc Interv Radiol. 2011; 22: 497 Siskin. AJR Am J Roentgenol. 2001; 177: 297 • at present there is insufficient data to support the management of the infertile couple outside of a clinical trial
- 24. 15/03/2015/24 Management Plan • full assessment • maximise lifestyle factors • manage any coexisting pathology • endometriosis • fibroids • spontaneous conception • limited evidence to support aromatase inhibitors in women with infertility • resection of adenomyosis may increase spontaneous conception rates • assisted reproduction • limited evidence to support the use of GnRH agonists in patients undergoing assisted reproduction • no evidence on the effect of surgical therapy on assisted reproduction • insufficient evidence that steroid therapy improves assisted reproduction success • interventional radiology limited to trials male ovulatorypelvic
- 25. 15/03/2015/25
Editor's Notes
- 10 November 1977, Lesley Brown underwent a procedure developed by Patrick Steptoe and Robert Edwards, later to become known as IVF. Edwards was awarded the 2010 Nobel Prize in Medicine for this work Brown was born 25 July 1978 at 11:47 p.m. at Oldham General Hospital, Oldham, via planned Caesarean section delivered by registrar John Webster. She weighed 5 pounds, 12 ounces (2.608 kg) at birth. Her younger sister, Natalie Brown, was also conceived through IVF, four years later, and became the world's fortieth IVF baby, and the first one to give birth herself—naturally—in 1999.
- based on mrijunctional zone thickening has been demonstrated in 79% of patients with endometriosis2
- Vercellini. Transvaginal ultrasonography vs uterine needle biopsy in the diagnosis of diffuse adenomyosis. Hum Reprod. 1998; 13: 2884
- Levgur M. Diagnosis of adenomyosis: a review. J Reprod Med. 2007; 52: 177-93. normal JZ ing 5 mm in thickness. A junctional zone of greater than 12 mm is predictive of histological adenomyosis. Adenomyosis is seen on MR imaging as a diffuse, homogeneous, low-signal-intensity thickening of the junctional zone. Thickening of the junctional zone on MR imaging is correlated with inner myocyte proliferation (uterine junctional-zone hyperplasia). In contrast, adenomyosis is a histological diagnosis based on the detection of endometrial glands and stroma, often surrounded by hyperplastic bundles of smooth muscle cells that are tightly packed and poorly orientated, some distance away from the endometrio-myometrial junction
- Forest plot showing individual and combined effect size estimates and 95% confidence intervals (CIs) in studies that evaluated the likelihood of clinical pregnancy in infertile women with or without adenomyosis undergoing IVF/ICSI. Horizontal lines indicate 95% CIs; boxes show the study-specific weight; diamond represents combined effect size; dashed line indicates the overall estimate.
- Forest plot showing individual and combined effect size estimates and 95% confidence intervals (CIs) in studies that evaluated the risk of miscarriage in clinical pregnancies obtained at IVF/ICSI in women with or without adenomyosis. Horizontal lines indicate 95% CIs; boxes show the study-specific weight; diamond represents combined effect size; dashed line indicates the overall estimate.
- Hum Reprod. 2010 Mar;25(3):642-53. doi: 10.1093/humrep/dep437. Epub 2009 Dec 15. Changes in tissue inflammation, angiogenesis and apoptosis in endometriosis, adenomyosis and uterine myoma after GnRH agonist therapy. Khan KN1, Kitajima M, Hiraki K, Fujishita A, Sekine I, Ishimaru T, Masuzaki H. BACKGROUND: Information is limited regarding the multifunctional role of GnRH agonist (GnRHa) therapy in reproductive diseases. We investigated the pattern of changes in inflammatory reaction, micro-vessel density and apoptosis in the tissues collected from women with endometriosis, adenomyosis and uterine myoma who were treated with or without GnRHa therapy. METHODS: Biopsy specimens were collected from lesions, myometria and corresponding endometria of 45 women with ovarian endometrioma, 35 women with adenomyosis and 56 women with uterine myoma. A fraction of these women were treated with GnRHa therapy for a variable period of 3-6 months before surgery. We performed immunohistochemical analysis of CD68, a macrophage (Mvarphi) marker and von Willebrand factor (VWF), a vessel marker, using respective antibodies. Changes in apoptosis were examined using TdT-mediated dUTP-biotin nick end-labeling assay and by the immunoexpression of activated caspase-3 in tissues after GnRHa therapy. RESULTS: The infiltration of CD68-positive Mvarphi and VWF-positive micro-vessel density were significantly decreased in the endometria of women with endometriosis, adenomyosis and uterine myoma in the GnRHa-treated group when compared with that in the non-treated group. Marked decreases in inflammatory and angiogenic responses were observed in lesions and myometria of these diseases. When compared with the non-treated group, a significant increase in apoptotic index (apoptotic cells per 10 mm(2) area) and quantitative-histogram scores of activated caspase-3 after GnRHa therapy were observed in the eutopic endometria, lesions and myometria of these diseases. CONCLUSIONS: GnRHa was able to markedly reduce the inflammatory reaction and angiogenesis and to significantly induce apoptosis in tissues derived from women with endometriosis, adenomyosis and uterine myoma. These multiple biological effects at the tissue level may be involved in the regression of these reproductive diseases.
- case series of 4; co treatment with steroids
- Forest plot showing individual and combined effect size estimates and 95% confidence intervals (CIs) in studies that evaluated the likelihood of clinical pregnancy in infertile women with or without adenomyosis undergoing IVF/ICSI after a short or long protocol down-regulation. Horizontal lines indicate 95% CIs; boxes show the study-specific weight; diamonds represent combined effect sizes; dashed line indicates the overall estimate.
- Gynecol Endocrinol. 2013 Dec;29(12):1026-30. doi: 10.3109/09513590.2013.824960. Epub 2013 Sep 5. Long-term pituitary downregulation before frozen embryo transfer could improve pregnancy outcomes in women with adenomyosis. Niu Z1, Chen Q, Sun Y, Feng Y. Author information Abstract Some studies have shown that long-term gonadotropin-releasing hormone (GnRH) agonist administration before in vitro fertilization/intracytoplasmic sperm in infertile women with endometriosis or adenomyosis significantly increases the chances of pregnancy. We were interested in whether long-term GnRH agonist pretreatment could improve pregnancy outcomes in adenomyosis patients undergoing frozen embryo transfer (FET) after preparation of the endometrium with hormone replacement therapy (HRT). Totally, 339 patients with adenomyosis were included in this retrospective study, 194 received long-term GnRH agonist plus HRT (down-regulation + HRT) and 145 received HRT. There were no differences between the groups in characteristic such as age, body mass index, duration or cause of infertility, serum CA-125 level and basal hormone levels. On the day of progesterone administration, mean endometrial thickness and serum progesterone level were significantly greater in HRT patients. Mean score and number of embryos transferred showed no differences. In down regulation + HRT group, clinical pregnancy, implantation and ongoing pregnancy rates were 51.35%, 32.56% and 48.91%, respectively, significantly higher than that of HRT group (24.83%, 16.07% and 21.38%, respectively). So, we concluded that in FET, long-term GnRH agonist pretreatment significantly improved pregnancy outcomes in patients with adenomyosis.
- Hum Reprod. 2010 Mar;25(3):642-53. doi: 10.1093/humrep/dep437. Epub 2009 Dec 15. Changes in tissue inflammation, angiogenesis and apoptosis in endometriosis, adenomyosis and uterine myoma after GnRH agonist therapy. Khan KN1, Kitajima M, Hiraki K, Fujishita A, Sekine I, Ishimaru T, Masuzaki H. BACKGROUND: Information is limited regarding the multifunctional role of GnRH agonist (GnRHa) therapy in reproductive diseases. We investigated the pattern of changes in inflammatory reaction, micro-vessel density and apoptosis in the tissues collected from women with endometriosis, adenomyosis and uterine myoma who were treated with or without GnRHa therapy. METHODS: Biopsy specimens were collected from lesions, myometria and corresponding endometria of 45 women with ovarian endometrioma, 35 women with adenomyosis and 56 women with uterine myoma. A fraction of these women were treated with GnRHa therapy for a variable period of 3-6 months before surgery. We performed immunohistochemical analysis of CD68, a macrophage (Mvarphi) marker and von Willebrand factor (VWF), a vessel marker, using respective antibodies. Changes in apoptosis were examined using TdT-mediated dUTP-biotin nick end-labeling assay and by the immunoexpression of activated caspase-3 in tissues after GnRHa therapy. RESULTS: The infiltration of CD68-positive Mvarphi and VWF-positive micro-vessel density were significantly decreased in the endometria of women with endometriosis, adenomyosis and uterine myoma in the GnRHa-treated group when compared with that in the non-treated group. Marked decreases in inflammatory and angiogenic responses were observed in lesions and myometria of these diseases. When compared with the non-treated group, a significant increase in apoptotic index (apoptotic cells per 10 mm(2) area) and quantitative-histogram scores of activated caspase-3 after GnRHa therapy were observed in the eutopic endometria, lesions and myometria of these diseases. CONCLUSIONS: GnRHa was able to markedly reduce the inflammatory reaction and angiogenesis and to significantly induce apoptosis in tissues derived from women with endometriosis, adenomyosis and uterine myoma. These multiple biological effects at the tissue level may be involved in the regression of these reproductive diseases.
- Is the surgical approach beneficial to subfertile women with symptomatic extensive adenomyosis? Peng-Hui Wang1, Jong-Ling Fuh2, Hsiang-Tai Chao1, Wei-Min Liu3, Ming-Huei Cheng1 and Kuan-Chong Chao1 Taiwan J. Obstet. Gynaecol. Res. Vol. 35, No. 3: 495–502, June 2009 Abstract Aim: Our aim was to assess the role of surgical intervention for symptom control and reproductive performance improvement in the management of subfertile women with symptomatic extensive uterine adenomyosis. Methods: Sixty-five subfertile women with pathology-proven extensive uterine adenomyosis, who were treated with conservative surgery or medical treatment with 6-month gonadotrophin-releasing hormone (GnRH) agonist or combination therapy, were retrospectively reviewed and their data analyzed. Twenty-eight women received conservative surgery with/without GnRH agonist (group A), and 37 received 6-month GnRH agonist therapy only (group B). Follow-up evaluations, including subjective symptoms (a self-reported 6-point verbal numeric rating scale and an analgesic usage score for dysmenorrhea) and objective parameters (serum CA125 level, and uterine size), and clinical pregnancy and successful delivery rates were made semi-annually over the ensuing 3 or more years. Results: The women in groupA had higher serum CA125 levels, more infertile years, and a larger uterine size. Subjective symptom control and objective parameters were better in group A during the entire 36-month follow up compared with those in group B. Cumulative 3-year clinical pregnancy and successful delivery rates were significantly higher in group A, compared with those in group B (46.4% [13/28] versus 10.8% [4/37], P = 0.002, and 32.1% [9/28] versus 8.1% [3/37], P = 0.022, respectively). Conclusion: Conservative surgery or combination therapy provides more effective and longer durable symptom control in the management of symptomatic women with extensive uterine adenomyosis, compared with GnRH agonist alone. Reproductive performance was also better in patients treated with conservative surgery with/without GnRH agonist. Key words: adenomyosis, conservative surgery, gonadotrophin-releasing hormone agonist, subfertility.