Adenomyosis: new knowledge is generating new treatment strategies

Giuseppe Benagiano; Ivo Brosens; Sabina Carrara

Women's Health. 2009;5(3):297-311.

Treatment of Adenomyosis

In a recent review, Yang et al. list 12 different medical or surgical techniques for the treatment of adenomyosis; by and large these modalities are identical to those utilized in cases of endometriosis.^[65]

It is beyond the scope of this review to discuss classic treatments of adenomyosis; however, the few novel approaches to the treatment, medical or surgical, of this condition will be summarized below.

Surgical Approaches

In a recent paper, Rabinovici and Stewart reviewed new interventional techniques that have been introduced over the last few years in order to find an adequate noninvasive therapy for adenomyosis.^[66] They warn that there are no evidence-based data to guide us in using minimally invasive therapy, since most data regarding these evolving therapies come from the inadvertent treatment of adenomyosis in studies designed to treat uterine leiomyomata. For this reason, all data are from case reports or small case series. An additional problem is represented by the lack of an agreed imaging definition of adenomyosis, and so therapies that do not excise the uterus have no 'gold standard' for comparison.

Nonetheless, some reports suggest that there may be efficacy in techniques such as uterine artery embolization and MRI-guided focused ultrasound surgery (MRIgFUS).

Uterine Artery Embolization

In 2001, Siskin et al. retrospectively evaluated the MRI appearance and clinical response of patients undergoing uterine artery embolization (UAE) for the treatment of menorrhagia due to adenomyosis.^[67] Of the 15 patients in the study, five had diffuse adenomyosis without evidence of uterine fibroids, one had focal adenomyosis without evidence of uterine fibroids and the remaining nine had adenomyosis with one or more fibroids. At 12 months follow-up, 92.3% patients reported significant improvement in symptomatology and quality of life. Postoperative MRI revealed significant reductions in median uterine and fibroid volume and mean JZ. Larger, prospective studies are needed to establish the safety and efficacy of this procedure in women with adenomyosis.

Several reports followed, mostly from the Far East, which confirmed that UAE is an effective therapy for adenomyosis.

Worth mentioning is a South Korean study that investigated UAE in women with adenomyosis, but no fibroids.^[68] They observed significant improvements in dysmenorrhea and menorrhagia with a decrease in uterine size in most patients. In addition, MRI evaluation produced results suggestive of coagulation necrosis of adenomyosis in the majority of patients.

Another important study was conducted in South Korea to evaluate the return of fertility; unfortunately, of the initial series of 94 patients, only six desired to become pregnant; five of them succeeded with one case of premature rupture of the membrane.^[69]

Larger studies specifically applying surgical techniques to the conservative management of adenomyosis are needed, provided that adequate solutions are found for the diagnosis and improved technical parameters are determined.

MRI-guided Focused Ultrasound Surgery

Recently, Fukunishi et al. evaluated the thermal ablative effects of MRIgFUS on adenomyosis in improving clinical parameters in 20 premenopausal women; since adenomyosis symptoms are similar to those of uterine myomata, they used the symptom severity score questionnaire available for evaluating the effect of MRIgFUS on myoma.^[70] They reported that most adenomyotic lesions could be satisfactorily ablated close to the serosal surface or the endometrium and, at 6 months, the mean uterine volume had decreased by 12.7%. Symptom severity score improved significantly during the 6 months of follow-up and no serious complications were observed.

Therefore, it seems that MRIgFUS represents a new, safe and effective method for the ablation of adenomyotic tissue.

Medical Approaches

As previously stated, a constant feature of medical therapy for adenomyosis is that, over the years, it has mimicked that which has been applied to endometriosis. At present, medical therapy of adenomyosis can be attempted for symptomatic relief, especially in premenopausal women and in women who wish to become pregnant.

Two novel approaches discussed below are either already available or will soon be ready for large-scale trials.

Inhibitors of Angiogenesis

New knowledge of a modified angiogenesis in heterotopic uterine mucosa in case of endometriosis and adenomyosis is opening the way for a new treatment line. Starting from the observation that dopamine and its agonists, such as cabergoline (Cb2), promote endocytosis of VEGF receptor (VEGFR)-2 in endothelial cells, thereby preventing VEGF–VEGFR-2 binding and reducing neoangiogenesis, the group of Pellicer et al. has now evaluated in an animal model the antiangiogenic properties of Cb2 on the growth of established endometriosis lesions.^[71] After treatment with Cb2, they found a significant decrease in the percentage of active endometriotic lesions and of cellular proliferation index, associated to a reduced neoangiogenesis, and a significant modification of gene expression.

In women with suspected (nonhistological) diagnosis of adenomyosis, after insertion of a levonorgestrel-releasing intrauterine system, VEGF expression is substantially reduced in eutopic endometrial glands and stroma; however, it is not known whether the same occurs in the heterotopic glands.^[72]

Another approach aimed at inhibiting angiogenesis has been studied by the group of Creatsas using pentoxiphylline, a phosphodiesterase inhibitor.^[73] In an animal model, they evaluated changes in morphology and in the expression of VEGF-C and of the receptor for tyrosine kinase, Flk-1 (a VEGF receptor) and observed a significant reduction in the mean volume of the endometriotic implants per animal when compared with the control group. Their conclusion was that pentoxiphylline may cause suppression of endometriotic lesions by suppressing angiogenesis through VEGF-C and Flk-1 expression.

A preliminary clinical confirmation of the usefulness of pentoxiphilline in the treatment of endometriosis-associated infertility comes from Creus et al.^[74] In a prospective, randomized, controlled, blind trial, a group of patients was randomly assigned, immediately after laparoscopic surgery, to treatment with either oral pentoxiphylline (800 mg/day) or an oral placebo. These women were then observed for the occurrence of pregnancy for 6 months. In the approximate 100 patients who completed the study, the 6-month overall pregnancy rates were 28 and 14% in the pentoxiphylline and placebo groups, respectively (p = 0.1). These findings provide preliminary clinical evidence to suggest that new experimental treatment approaches toward endometriosis, that are based on immunomodulation deserve further attention. Well-designed multicenter trials are warranted to confirm or refute these results.

For completeness, it must be mentioned that almost 20 years ago, Steinleitner et al. used an animal model for endometriosis (the golden hamster) to determine the effect of pentoxiphylline on early reproductive performance.^[75] At laparotomy, they subjected groups of animals to either excision of the right uterine horn, or excision of the right uterine horn with explantation of four 2-cm² uterine fragments onto the left uterine mesentery. Surgically treated hamsters and nonsurgically treated controls were subjected to ovulation induction 6 weeks later; subsequently, the animals were divided into groups for periovulatory treatment with either pentoxiphylline (2.5 mg/kg) or placebo. Fertilization rates in surgical and nonsurgical control groups exceeded 90%. Fertilization was significantly impaired in saline-treated animals bearing uterine explants (mean of 2.3 ± 1.9%). Administration of pentoxiphylline dramatically reversed this effect (99.0 ± 0.7% mean fertilization rate). Thus, an important role for immunomodulators in eliminating the adverse influence of endometrial explants on fertilization was evidenced; Steinleitner even suggested that, "the periovulatory administration of nonteratogenic immunomodulatory agents may provide an alternative to conventional treatment for endometriosis."

Levonorgestrel-releasing intrauterine system

In 1997, Fedele et al. utilized the levonorgestrel-releasing intrauterine system (LNG-IUS) for relief from adenomyosis-associated menorrhagia.^[76] In 23 women with recurrent menorrhagia and adenomyosis diagnosed with TVS, the insertion of the system induced amenorrhea in two, oligomenorrhea in three, spotting in two and regular flows in the remaining 16 women after 1 year. Significant increases in hemoglobin, hematocrit and serum ferritin were also observed. This small trial documented that the LNG-IUS produces the same positive effects on excessive bleeding also when adenomyosis is present.

A single case was then published of a patient in whom a diagnosis of adenomyosis had been made, for whom conservative therapy initiated with mefenamic acid was unsatisfactory. The patient suffered from menorrhagia, dysmenorrhea and an enlarged uterus. A marked decrease in uterine size occurred within 12 months of insertion accompanied by resolution of the menorrhagia and dysmenorrhea. This is the first description of successful treatment of the full symptomatology of adenomyosis.^[77]

Very recently, a full-scale trial aimed at evaluating the efficacy of the LNG-IUS in the treatment of the full range of symptoms of adenomyosis, was conducted by Sheng et al.^[78]. In 94 women with moderate or severe dysmenorrhea, as diagnosed by TVS, improvements were documented for dysmenorrhea (using a visual analog scale [VAS]), uterine volume and serum CA125 levels, over a period of 36 months. They observed a continuous and significant drop in VAS from the baseline score (p < 001). The uterine volume decreased significantly from 113.8 ± 46.9 ml to 87.7 ± 35.8 ml (p < 001) at 12 months and serum CA125 levels were significantly reduced from 6 months onwards (p < 001). Given these encouraging results, additional studies are now warranted.

According to Farquhar and Brosens, there are several mechanisms that could explain the role of the LNG-IUS in adenomyosis.^[79] First of all, following insertion of the system there is a decidualization of the endometrium and this is followed by atrophic changes that produce a marked reduction in menstrual blood loss. Through absorption within the myometrium, the progestin also acts directly on the adenomyotic foci. In addition, downregulation of estrogen receptors, in both glandular and stromal endometrial layers, occurs shortly after placement of the device and persists for at least the first year of use. Adenomyotic deposits are then reduced in size, uterine contractility improves and the uterine size decreases. The LNG-IUS positive effect on dysmenorrhea is probably mediated through a reduction of prostaglandin production within the endometrium; reduction in the size and activity of adenomyotic tissue may also account for the improvement in dysmenorrhea.

Gonadotropin-releasing Hormone Analogues

In 2002, Imaoka et al. investigated a possible role of gonadotropin-releasing hormone analogues for the treatment of diffuse adenomyosis, as evidenced by MRI. They administered the analogue over a 6-month period to 31 patients with MRI features suggestive of diffuse adenomyosis and concluded that use of gonadotropin-releasing hormone analogues is associated with a decrease in myometrium JZ width. Furthermore, asymmetric adenomyosis with high-signal intensity foci appears to be the most sensitive to hormonal therapy.^[80]

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Executive Summary

Incidence of Adenomyosis & Endometriosis

Prevalence of adenomyosis is under discussion since different imaging criteria are used.
In different studies, the prevalence varies between 27 and 70% in women with endometriosis and has been estimated at 54% in young women with infertility, dysmenorrhea or menorrhagia, and 9% in healthy controls.

Clinical Diagnosis

Today, a clinical diagnosis of adenomyosis is considered almost impossible.
Although aspecific, pelvic pain is an important symptom in many affected women.
In candidates for hysterectomy, the presence of adenomyosis does not modify the incidence of fibroids, endometriosis, abnormal bleeding or chronic pelvic pain.

Endomyometrial Junctional Zone

Inner myometrial layers underlying the endometrium have been carefully evaluated, thanks to modern imaging techniques, both transvaginal sonography and MRI.
Named the junctional zone (JZ), inner myometrial layers appear to be a distinct anatomical structure, despite the lack of histological distinction on light optic microscopy.
This portion of the myometrium demonstrates functional similarities with the endometrium.
Its thickness (similar to that of the endometrium, but not that of the outer myometrium), increases with age between 20 and 50 years.
In women taking oral contraceptives or gonadotropin-releasing hormone analogues and in postmenopausal women, suppression of ovarian activity decreases the thickness of the JZ.
In normally menstruating women, uterine peristaltic activity originates exclusively from the JZ, while the outer myometrium remains quiescent.

Adenomyosis & the Junctional Zone

On MRI scans, adenomyosis is accompanied by either diffuse or focal thickening of the inner myometrium, or an ill-defined myometrial nodule of low-signal intensity.
It is characterized by a homogeneous thickening of the myometrium JZ and this feature has become the standard parameter for the diagnosis of even mild forms of the condition.
Thickening of the myometrium JZ observed in MRI scans is thought to be the consequence of inordinate inner myocyte proliferation and/or angiogenesis.
It seems that disruption of JZ architecture precedes and predisposes for the subsequent development of adenomyosis.

Adenomyosis & Endometriosis

Relationship between adenomyosis and endometriosis seems to have gone full circle: in the early days, only one pathological definition (adenomyoma) was utilized to describe both.
Following the identification of endometrial foci in the peritoneal cavity and ovaries, the two entities remained separated.
With the identification and characterization of the JZ of the myometrium, connections between them began to reappear and a high prevalence of diffuse and focal adenomyosis was found in patients with endometriosis.
It seems that JZ hyperplasia precedes adenomyosis and endometriosis and that both have a common predisposing factor: an alteration of spiral arterioles' angiogenesis.

Angiogenesis, Adenomyosis & Endometriosis

Menstrual cycles produce waves of active angiogenesis within the endometrium, with development of arterioles and a capillary network.
In women with adenomyosis, VEGF, hypoxia-inducible factor-1a expression and microvessel density are increased, particularly in epithelial cells, when comparing heterotopic versus normotopic endometrium in the same woman.
Eutopic endometrium in patients with endometriosis is abnormal and evidence is beginning to emerge that pre-eclampsia, fetal growth restriction and premature delivery are linked and they may also be related to the two menstrual disorders.

Menstruation Preconditioning Hypothesis

Menstruation and pregnancy are both inflammatory conditions that cause a degree of physiological ischemia/reperfusion tissue injury.
Spontaneous ovulatory menstrual cycles seem to have a functional role in priming the uterine vascular microenvironment to secure the rapid spiral artery remodeling and deep placentation before a first pregnancy.
Preconditioning the uterus for successful deep placentation, may represent the common predisposing factor linking, adenomyosis, endometriosis and pregnancy complications.
Decidualized cells are a major source of angiogenic growth factors and decidual angiogenesis may play a role in the initial spiral artery remodeling.
Endometriosis (and possibly adenomyosis) is associated with increased endometrial and JZ blood flow during the late secretory phase of the cycle.

Adenomyosis & Fertility

Adenomyosis is increasingly diagnosed in women with endometriosis, but the precise role of adenomyosis per se in infertility remains controversial.
Adenomyosis is strongly associated with primary infertility in baboons, even in the absence of coexisting endometriosis.
Excessive JZ contractions have been shown to reduce implantation rates in both spontaneous and stimulated cycles and this phenomenon is present in patients with adenomyosis.
Sperm transport in women with endometriosis and/or adenomyosis is also disrupted.

Stem cells & the Junctional Zone

There is increasing evidence of the existence of human endometrial stem/progenitor cells.
Endometrial-derived cells in single-cell suspensions of epithelial and stromal cells from hysterectomy samples show clonogenicity.
It is not known which cell lineages are generated by endometrial stem cells, or what is their physiological or pathological role.

Treatment of Adenomyosis

New knowledge on the genesis of adenomyosis is generating new treatment strategies.
On the surgical front, uterine artery embolization and focused ultrasound surgery seem promising even in women desiring pregnancy.
Several innovative medical approaches are also being attempted: use of angiogenesis inhibitors and of the levonorgestrel-releasing intrauterine system and treatment with gonadotropin-releasing hormone analogues.

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