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AdenomyosisFertility Enhancing Treatments

AGES ASM 2015

March 11, 2015

Anusch YazdaniMBBS (Hons) FRANZCOG CREI

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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

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Adenomyosis

• ectopic location of endometrial tissue deep to the endometrial-myometrial junction

Bird. Am J Obstet Gynecol. 1972; 112: 583

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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

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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

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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

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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 laparoscopyVercellini. 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

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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

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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 pathologistinfertility?

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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

/

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

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

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Pathophysiology

puberty reproductive menopause

dysmenorrhoeainfertility

miscarriage

pelvic paindyspareuniamenorrhagia

dysmenorrhoea

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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

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Treatment: Medical

• ART: GnRH agonist

• pituitary downregulation

• GnRH agonists modify inflammatory endometrial responseKhan. Hum Reprod 2010;25:642

• GnRh agonists reduce junctional thickness based MRI assessmentImaoka. J Magn Reson Imaging 2002;15:2850

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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

The likelihood of clinical pregnancy in infertile women with or without adenomyosis undergoing

IVF/ICSI after a short or long protocol down-regulation.

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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

.

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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

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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 excisionBest Practice & Research Clinical Obstetrics and Gynaecology 2006; 20: 603

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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%

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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

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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

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