Adenomyosis: new knowledge is generating new treatment strategies

Giuseppe Benagiano; Ivo Brosens; Sabina Carrara

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

Stem Cells and the Junctional Zone

The uterus has a remarkable capacity for vascular regeneration, not only after each menstrual cycle, but also, and to a greater extent, after delivery. The fact that JZ spiral arteries are capable of complete involution in the puerperium and that those with atherosclerotic lesions return to normal, has important implications in the field of vascular pathology.

Recent studies have provided evidence for the existence of human endometrial stem/progenitor cells. Chan et al. demonstrated clonogenicity of endometrial-derived cells by generating single-cell suspensions of epithelial and stromal cells from hysterectomy samples.^[61] In addition, Schwab et al. demonstrated that the frequency of clonogenic epithelial and stromal cells did not differ between phases of the menstrual cycle; also, there was no significant change in the number of clonogenic cells isolated from inactive endometrium.^[62] Since inactive endometrium contains only a basal layer, while the functional layer is absent, these data suggest that putative endometrial stem/progenitor cells reside along the endometrial–myometrial border.^[63]

Obviously, these preliminary findings open up new research avenues and, in light of this, Sasson and Taylor^[64] have posed a series of questions awaiting a response:

Which cell lineages – epithelial, stromal or myometrial – are generated by endometrial stem cells?
What is the physiological role of endometrial stem cells and what are their niches in pathologic processes?
Do endometriotic implant locations differ in their proclivity to originate from bone marrow-derived stem cells versus uterine-derived stem cells?
Does retrograde menstruation of endometrial stem cells seed the pelvis, whereas hematologic dissemination can seed both the pelvis and distant sites that are not directly accessible to menstrual flow?
Does the primary defect in the endometriosis pathway lie in the stem cell, or does disregulation within the niche permit aberrant biological processes to function in the stem cell?
Does ectopic stem cell differentiation have a function in the pathogenesis of other gynecological diseases, such as adenomyosis, chronic pelvic pain and gynecological cancers?

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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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