Adenomyosis and its impact on fertility

November 16, 2018
Anthony N. Imudia, MD
Anthony N. Imudia, MD

,
Rachel G. Sprague, MD
Rachel G. Sprague, MD

Comorbidities such as endometriosis can confound the picture in patients with adenomyosis, a condition that may lead to poor IVF outcomes.

Introduction

Adenomyosis is a common gynecologic disorder, yet its etiology and association with infertility remains unclear. It is a benign disorder previously associated with multiparity. Recently, however, an association with infertility has emerged. Adenomyosis can be asymptomatic or present with menorrhagia, dysmenorrhea, and metrorrhagia with these symptoms usually occurring in patients aged 35 to 50. 

Approximately 20% of cases of adenomyosis involve women younger than 40 and 80% are aged 40 to 50. On histological analysis, adenomyosis is defined by ectopic location of endometrial and stromal tissue distal to the endometrial-myometrial junction with associated myometrial smooth muscle hypertrophy.Histologic diagnostic criteria for adenomyosis have been debated and inconsistently applied, making studies unreliable and often incompatible. 

The most accepted hypothesis for the etiology of adenomyosis stems from the invagination of the endometrial basalis layer into the myometrium.2,3 Adenomyosis can have a diffuse, haphazard distribution or more focal regions known as adenomyomas. Women with the condition, therefore, present with enlarged, boggy uteri. 

How is adenomyosis diagnosed?

Traditionally, the diagnosis was made by means of histopathologic examination, usually on a hysterectomy specimen as the treatment of choice for the disease was hysterectomy.With the evolution of magnetic resonance imaging (MRI) and high-quality transvaginal ultrasound (TVS), today the diagnosis can be made with a level of accuracy of 80% to 90% without the need for excisional surgery (Figures 1a and 1b).5-7

Criteria used to define adenomyosis on ultrasound include focal areas with diffuse hyperechogeneity and loss of a normal endo-myometrial interface; increased or decreased areas of echogenicity; or cystic structures within myometrium with increased color Doppler flow. On MRI, assessment of the thickness of the junctional zone (the subendometrial myometrium) is the mainstay of diagnosis. The consensus for diagnosis of adenomyosis is when the junctional zone is greater than 12 mm but the disorder can be suspected when the thickness is between 8 and 12 mm.The advantage of MRI over TVS is that MRI has a greater specificity and can differentiate adenomyomata from leiomyoma.When noninvasive diagnosis with MRI and TVS imaging became available, the role of adenomyosis in infertility and early pregnancy was better recognized.10

How is the condition linked with infertility?

Most evidence that links adenomyosis to infertility is limited to case reports and small case series. There is also the potential for confounding in these studies as adenomyosis commonly coexists along with other pathologic processes linked to infertility, such as endometriosis, polyps, or leiomyoma.11 There is a significant association between pelvic endometriosis and adenomyosis, with estimates indicating that it occurs in 54% to 90% of cases.12,13 Because endometriosis is well-known to cause infertility, there is concern that findings of infertility were due to concurrent endometriosis rather than adenomyosis.14 However, a study in baboons showed a strong association between histological adenomyosis and lifelong infertility (20-fold increased odds) even in cases where coexisting endometriosis was excluded.15 In a study of women who received embryos created through oocyte donation rates of miscarriage were significantly higher in those who had adenomyosis alone versus those with co-existing endometriosis or controls.16 

A recent meta-analysis concluded that adenomyosis has a detrimental effect on clinical outcomes of in vitro fertilization (IVF). In women undergoing IVF, rates of implantation, clinical pregnancy per cycle, clinical pregnancy per embryo transfer, ongoing pregnancy, and live birth among women with adenomyosis were significantly lower than in those without adenomyosis.17 The miscarriage rate in women with adenomyosis was also higher than in those without adenomyosis.17One of the confounding variables in this study was age, given that women with adenomyosis were older; however, even after controlling for these confounders using regression analysis, the significant difference still existed.17

 

How does adenomyosis impact infertility?

Proposed mechanisms of infertility in patients with adenomyosis focus on derangements of three putative pathways: uterotubal transport, endometrial receptivity, and implantation.18In patients with adenomyosis, uterotubal transport is impaired due to intrauterine anatomical distortion that blocks the tubal ostia and potentially blocks sperm migration and embryo transport.19 Uterine hyperperistalsis has been seen on ultrasound in patients with adenomyosis due to destruction of normal myometrial architecture.20,21 These abnormal myometrial contraction waves lead to abnormal sperm transport through the uterine cavity and may also lead to increased intrauterine pressure.22

Endometrial receptivity and function becomes altered via increased production of estrogens from aromatization of androgens and altered estrogen receptor/progesterone receptor expression.23,24 The inflammatory response in women with adenomyosis has also been shown to be increased.25 Patients with severe adenomyosis in whom implantation failed were found to have higher density of macrophages.26 This increased macrophage density subsequently increases intrauterine inflammatory response and release of reactive oxygen species that are thought to be embryotoxic.27

Lastly, impaired implantation results from a lack of adequate expression of adhesion molecules, reduced expression of implantation markers, and altered function of the gene for embryonic development (HOXA10).28

In contrast to women with endometriosis, adenomyosis has not yet been shown to have an adverse influence on oocyte function or folliculogenesis.29 In patients with endometriosis, levels of activated macrophages, prostaglandins, interleukin (IL)-1β, tumor necrosis factor (TNF)α, and proteases were increased in peritoneal fluid and their high concentrations may adversely affect oocyte function.30 As of yet, there no association has been found between adenomyosis and oocyte quality or function. 

Possible treatments for adenomyosis in infertility

Based on limited available evidence, patients with adenomyosis could be treated with medical and/or surgical therapies to improve pregnancy and live birth outcomes. Treatment with gonadotrophin-releasing hormone agonist (GnRH-a) serves to down-regulate the pituitary, exert an anti-proliferative effect, promote apoptosis, and reduce the anti-inflammatory and angiogenesis effect.31 Multiple case reports show conception and live birth in women with infertility and adenomyosis after pretreatment with GnRH-a for 3 to 5 months.32,33 In other retrospective studies, pretreatment with GnRH-a prior to fresh- or frozen-embryo transfer appears to increase pregnancy rates.34,35 Further prospective studies with larger sample size are needed to validate these findings.

In retrospective studies, conservative surgery or combination surgery with GnRH-a has shown to be more effective in controlling symptoms and also in increasing pregnancy and live birth rates when compared with GnRH-a alone in patients with extensive adenomyosis.36 In case reports and case series, multiple methods of fertility-sparing surgery for adenomyosis have been performed, with subsequent pregnancies. These techniques include classical adenomyomectomy, H-incision, triple-flap method, and laparoscopic cytoreductive surgery.37,38 No evidence as of yet points to superiority of one technique over another (Video). Surgical management of adenomyomas and adenomyosis can present an operative challenge, especially compared with myomectomy.39 Adenomyomas are less distinct given absence of well-defined borders and given protrusion into the myometrium. During dissection, the plane is identified mainly by recognizing healthy myometrium rather than simple enucleation as in myomectomies. This can lead to increased risk of intraoperative bleeding and weakening of the myometrium, which can increase risk of uterine rupture or abnormal placentation in future pregnancies. Uterine-preserving surgeries have shown benefit for women who have previously experienced IVF treatment failures, especially patients ≤ 39 years old.40

A large prospective study showed that combination conservative surgery and medical treatment with GnRH-a for patients with severe symptomatic adenomyoma lowers symptom relapse rates and yields a trend toward improved reproductive outcomes.36 Therefore, for patients with presumed severe adenomyosis who want to retain fertility, surgical cytoreduction and GnRH-a combined may be desirable.

Other methods of fertility-sparing treatment for adenomyosis have recently generated interest. High-intensity focused ultrasound ablation (HIFU) has been used for leiomyoma and is now being used for patients with adenomyosis who want fertility.41 HIFU is a noninvasive thermal ablation technique in which high-intensity ultrasound energy is focused on a small focal region to increase tissue temperature sufficient to cause irreparable cell damage in the target at a certain depth within the body.42 Selection criteria for using HIFU ablation for adenomyosis vary depending on the center, but very strict selection criteria are required to improve efficacy and decrease risk of thermal injury.43,44 Patients typically must be age 18 or older, premenopausal, have no history of pelvic inflammatory disease or severe pelvic endometriosis, and have symptomatic adenomyosis with junctional zone thickness > 3 cm for diffuse adenomyosis or a lesion diameter between 3 and 10 cm for focal adenomyosis.45A recent retrospective study showed high rates of conception and live birth in HIFU-treated patients with adenomyosis, suggesting that it is a promising noninvasive fertility-sparing treatment option.44 In another study, pregnancies after HIFU resulted in 2 miscarriages and delivery of 4 healthy babies. One delivery was complicated by a major placenta previa and hemorrhage.45

Conclusion

Although adenomyosis is a common gynecologic disorder, its role in infertility is unclear. It previously was believed to be a symptomatic disease in older women but it is now being seen in an asymptomatic and younger population undergoing evaluation for infertility. Limited studies have found an association between adenomyosis and poor reproductive outcomes. However, other coexisting pathologies, such as endometriosis, may be 
significant confounders. 

 

Proposed mechanisms of adenomyosis and infertility point toward derangements in uterotubal transport, endometrial receptivity, and intrauterine inflammation impairing implantation. No association with oocyte function has yet to be identified. Women with severe adenomyosis and in whom IVF previously failed who want fertility can be treated with GnRH-a and/or surgical resection. The strategy has produced promising outcomes in pregnancy and live birth along with symptom improvement. While definitive treatment with hysterectomy was previously the gold standard for adenomyosis, emerging conservative surgical interventions are gaining momentum. Alternatively, HIFU thermal ablation has been presented as another potential noninvasive option for fertility preservation. Large prospective trials are needed to confirm the clinical efficacy of these new fertility-sparing treatment modalities and to better understand their risk and safety profiles.  

Disclosures:

The authors report no potential conflicts of interest with regard to this article.

References:

  • Bird CC, McElin TW, Manalo-Estrella P. The elusive adenomyosis of the uterus-revisited. Am J Obstet Gynecol. 1972; 112(5):583-593.
  • García-Solares J, Donnez J, Donnez O, Dolmans MM. Pathogenesis of uterine adenomyosis: invagination or metaplasia? Fertil Steril. 2018;109:371–9. 
  • Gordts S, Grimbizis I, Campo R. Symptoms and classification of uterine adenomyosis. Fertil Steril. 2018;109:380–8. 
  • L. Fedele, S. Bianchi, G. Frontino. Hormonal treatments for adenomyosis. Best Pract Res Clin Obstet Gynaecol, 22 (2008), pp. 333-339.
  • Luciano DE, Exacoustos C, Albrecht L, et al. Three-dimensional ultrasound in diagnosis of adenomyosis: histologic correlation with ultrasound targeted biopsies of the uterus. J Minim Invasive Gynecol. 2013;20:803–810.
  • Champaneria, R., Abedin, P., Daniels, J., Balogun, M., and Khan, K.S. Ultrasound scan and magnetic resonance imaging for the diagnosis of adenomyosis: systematic review comparing test accuracy. Acta Obstet Gynecol Scand. 2010; 89: 1374–1384.
  • Novellas S, Chassang M, Delotte J, et al. MRI characteristics of the uterine junctional zone: from normal to the diagnosis of adenomyosis. AJR Am J Roentgenol. 2011;196:1206–1213.
  • Gordts S, Brosens J J, Fusi L, et al. Uterine adenomyosis:a need for uniform terminology and consensus classification. Reprod Biomed Online. 2008;17:244–8.
  • Dueholm M, Lundorf E, Hansen ES, et al. Magnetic resonance imaging and transvaginal ultrasonography for the diagnosis of adenomyosis. Fertil Steril. 2001;76:588–594.
  • Devlieger R, D’Hooghe T, Timmerman D. Uterine adenomyosis in the infertility clinic. Hum Reprod Update. 2003;9:139–147.
  • Pervez SN, Javed K. Adenomyosis among samples from hysterectomy due to abnormal uterine bleeding. J Ayub Med Coll Abbottabad. 2013;25(1-2):68-70.
  • De Souza NM, Brosens JJ, Schwieso JE, Paraschos T, Winston RM. The potential value of magnetic resonance imaging in infertility. Clin Radiol. 1995; 50(2):75-9.
  • Kunz G, Beil D, Huppert P, Noe M, Kissler S, Leyendecker G. Adenomyosis in endometriosis – prevalence and impact on fertility. Evidence from magnetic resonance imaging. Hum Reprod. 2005; 20(8):2309-16.
  • Tomassetti C, Meuleman C, Timmerman D, D’Hooghe T. Adenomyosis and Subfertility: Evidence of Association and Causation. Semin Reprod Med. 2013; 31(02):101-108.
  • Barrier BF, Malinowski MJ, Dick EJ Jr, et al. Adenomyosis in the baboon is associated with primary infertility. Fertil Steril. 2004; 82 Suppl 3:1091.
  • Martínez-Conejero JA, Morgan M, Montesinos M, et al. Adenomyosis does not affect implantation, but is associated with miscarriage in patients undergoing oocyte donation. Fertil Steril. 2011;96:943–950.
  • Younes G, Tulandi T. Effects of adenomyosis on in vitro fertilization treatment outcomes: a meta-analysis. Fertil Steril. 2017;108(3):483.e3–490.e3.
  • Harada T, Khine YM, Kaponis A, et al. The Impact of Adenomyosis on Women’s Fertility. Obst and Gyn Survey. 2016; 71(9):557-568.
  • Kissler S, Hamscho N, Zangos S, Wiegratz I, Schlichter S, Menzel C, et al. Uterotubal transport disorder in adenomyosis and endometriosis- a cause for infertility. BJOG. 2006;113:902–908.
  • Birnholz JC. Ultrasonic visualization of endometrial movements. Fertil Steril. 1984;41:157–158. 
  • Mehasseb MK, Bell SC, Pringle JH, et al. Uterine adenomyosis is associated with ultrastructural features of altered contractility in the inner myometrium. Fertil Steril. 2010;93:2130–2136.
  • Kunz G, Beil D, Deininger H, et al. The dynamics of rapid sperm transport through the female genital tract: evidence from vaginal sonography of uterine peristalsis and hysterosalpingoscintigraphy. Hum Reprod. 1996;11:627–632.
  • Fang Z, Yang S, Lydon JP, et al. Intact progesterone receptors are essential to counteract the proliferative effect of estradiol in a genetically engineered mouse model of endometriosis. Fertil Steril. 2004;82:673–678. 
  • Franco HL, Jeong JW, Tsai SY, et al. In vivo analysis of progesterone receptor action in the uterus during embryo implantation. Semin Cell Dev Biol. 2008;19:178–186.
  • Wang F, Li H, Yang Z, et al. Expression of Interleukin-10 in patients with adenomyosis. Fertil Steril. 2009;91:1681–1685.
  • Tremellen KP, Russell P. The distribution of immune cells and macrophages in the endometrium of women with recurrent reproductive failure. II: adenomyosis and macrophages. J Reprod Immunol. 2012;93:58–63.
  • Noda Y, Matsumoto H, Umaoka Y, et al. Involvement of superoxide radicals in the mouse two-cell block. Mol Reprod Dev. 1991;28:356–360.
  • Fischer CP, Kayisili U, Taylor HS. HOXA10 expression is decreased in endometrium of women with adenomyosis. Fertil Steril. 2011;95:1133–1136.
  • Sanchez AM, Vanni VS, Bartiromo L, et al. Is the oocyte quality affected by endometriosis? A review of the literature. J Ovarian Res. 2017; 10:43.
  • Cheong YC, Shelton JB, Laird SM, et al. IL-1, IL-6 and TNF-alpha concentrations in the peritoneal fluid of women with pelvic adhesions. Hum Reprod. 2002; 17(1):69-75.
  • Khan, K.N., Kitajima, M., Hiraki, K., Fujishita, A., Nakashima, M., Ishimaru, T. et al. Cell proliferation effect of GnRH agonist on pathological lesions of women with endometriosis, adenomyosis and uterine myoma. Hum Reprod. 2010; 25: 2878–2890.
  • Nelson JR, Corson SL. Long-term management of adenomyosis with a gonadotropin-releasing hormone agonist. Fertil Steril. 1993;59:441–443. 
  • Silva PD, Perkins HE, Schauberger CW. Live birth after treatment of severe adenomyosis with a gonadotropin-releasing hormone agonist. Fertil Steril. 1994;61:171–172. 
  • Huang FJ, Kung FT, Chang SY, et al. Effects of short-course buserelin therapy on adenomyosis. A report of two cases. J Reprod Med. 1999;44:741–744. 
  • Strizhakov AN, Davydov AI. Myometrectomy-a method of choice for the therapy of adenomyosis patients in the reproductive period [In Russian]. Akush Ginekol (Mosk). 1995;5:31–33. 
  • Ozaki T, Takahashi K, Okada M, et al. Live birth after conservative surgery for severe adenomyosis following magnetic resonance imaging and gonadotropin-releasing hormone agonist therapy. Int J Fertil Womens Med. 1999;44:260–264. 
  • Osada H, Silber S, Kakinuma T, et al. Surgical procedure to conserve the uterus for future pregnancy in patients suffering from massive adenomyosis. Reprod Biomed Online. 2011;22:94–99.
  • Wang PH, Fuh JL, Chao HT, et al. Is the surgical approach beneficial to subfertile women with symptomatic extensive adenomyosis? J Obstet Gynaecol Res. 2009;35:495–502.
  • Grimbizis GF, Mikos T, Tarlatzis B. Uterus-sparing operative treatment for adenomyosis. Fertil Steril. 2014; 101(2):474-487. 
  • Grimbizis GF, Mikos T, Zepiridis L, et al. Laparoscopic excision of uterine adenomyomas. Fertil Steril. 2008;89(4):953–961.
  • Kishi Y, Yabuta M, Taniguchi F. Who will benefit from uterus-sparing surgery in adenomyosis-associated subfertility? Fertil Steril. 2014;102(3):802–807.
  • Zhang L, Rao F, Setzen R. High intensity focused ultrasound for the treatment of adenomyosis: selection criteria, efficacy, safety and fertility. Acta Obstet Gynecol Scand. 2017 Jun;96(6):707-714.
  • Lynn JG, Zwenmer RL, Chick AJ. A new method for generation and use of focused ultrasound in experimental biology. J Gen Physiol. 1942;26:179–93.
  • Xiong Y, Yue Y, Shui L, Orsi F, He J, Zhang L. Ultrasound guided high intensity focused ultrasound (USgHIFU) ablation for the treatment of patients with adenomyosis and prior abdominal surgical scars: a retrospective study. Int J Hyperthermia. 2015;31:777–83.
  • Zhang L, Zhang W, Orsi F, Chen W, Wang Z. Ultrasound guided high intensity focused ultrasound for the treatment of gynaecological conditions: a review of safety and efficacy. Int J Hyperthermia. 2015;22:1–5.
  • Zhou M, Chen JY, Tang LD, Chen WZ, Wang ZB. Ultrasound-guided high-intensity focused ultrasound ablation for adenomyosis: the clinical experience of a single center. Fertil Steril. 2011;95(3):900–905.