Infertility and Adenomyosis

INTRODUCTION

Adenomyosis or endometriosis genitalis interna is a condition in which epithelial cells of the endometrium and fibroblasts from stroma invade the uterine myometrium consequently resulting in hyperplasia, hypertrophy, and fibrosis of the myometrium.

Historically, the diagnosis of adenomyosis was made on the histopathology report of uterine specimen, for hysterectomy performed in older woman.^[1] However, presently adenomyosis has been demonstrated in younger females belonging to reproductive age group presenting with dysmenorrhea, abnormal uterine bleeding, dyspareunia, pelvic pain, or infertility. In one third of cases, adenomyosis has been an incidental diagnosis in asymptomatic patients.^[2] Additionally, adenomyosis coexisting with endometriosis and uterine fibroids has also been demonstrated.^[3]

Ultrasound can be used to visualize adenomyosis uteri in 20.9% of cases.^[4] Around 10 to 35% of histopathologic findings of posthysterectomy uterus specimen reveal adenomyosis.^[5] As per a study on infertile women, the prevalence of adenomyosis is 22% in women younger than 40 years age and 24.4% in women older than 40 years of age. Adenomyosis prevalence was calculated to be 38.2% in cases of recurrent pregnancy loss and 20 to 25% in women undergoing treatment via assisted reproductive technologies (ARTs) for infertility.^[6] Around 20 to 80% of women having adenomyosis have associated endometriosis also.^[7]

Association with infertility

Many theories have been proposed to explain how adenomyosis can lead to infertility. Patients suffering from adenomyosis have been shown to exhibit abnormal utero-tubal transport owing to the anatomical distortion of the uterine cavity by the pathology. Additionally, adenomyomas can also obstruct the tubal ostia thereby impeding migration of sperms as well as the transport of the embryo, resulting in infertility.

Hricak et al.^[8] was the first to elucidate the functional uterine zone, which signifies the junction between the endometrium and the inner myometrium. Based on magnetic resonance imaging (MRI) it is divided in to three distinct layers—a high signal intensity signifying the endometrial stripe, an inner low signal intensity in proximity to the basal endometrium correlating to the junctional zone (JZ) or subendometrial layer, and an outer medium signal intensity denoting the subserosal zone or outer myometrium. In patients affected by adenomyosis, invagination of the endometrial glands and stroma causes alteration of JZ and inner myometrium leading to the development of dysfunctional hyperperistalsis and increased intrauterine pressure. This in turn negatively impacts sperm transport and fertility in these patients. Increased uterine JZ activity just prior to embryonic transfer in in vitro fertilization (IVF) is also associated with a reduced pregnancy rate and increased frequency of ectopic pregnancy.^[9] A JZ >7 mm is associated with higher implantation failure.^[10] Studies have also proposed a positive relationship between spontaneous abortion and JZ function.^[11]

A plethora of molecular alterations have been seen in the endometrium of infertile women with adenomyosis which have caused development of altered receptivity.^[12] Dysfunctional expression of mRNA and aromatase cytochrome P450 protein have been observed in the endometrium of women with adenomyosis.^[13] There is evidence of increased inflammatory markers such as tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1) along with reactive oxygen species produced by macrophages which are toxic to embryos.^[14] Additionally, an abnormally high level of free radicals present in women with adenomyosis has detrimental effects on sperm transport, implantation, and decidualization.^[15]

Dysfunctional implantation has been attributed to a reduced expression of implantation markers like leukemia inhibitory factor, to a lack of expression of adhesion molecules such as integrin β-3, osteopontin, and to the altered function of the gene for embryonic development HOXA10.^[16]

Diagnosis

Ultrasound and MRI are common modalities used for the diagnosis of adenomyosis.

Effect on reproductive outcomes

There is limited data on the effect of adenomyosis on pregnancy, but several studies have described the impact of it on women undergoing infertility treatment.

Vercellini et al. in a meta-analysis reported a higher miscarriage rate in women with adenomyosis (31%) compared to those without the condition (14.1%).^[21] Another study found that the presence of definite morphological features of adenomyosis on ultrasound was associated with poor reproductive outcomes, including decreased clinical pregnancy rates. Clinical pregnancy rates decreased from 42.7% in women without it, to 22.9% in women with four ultrasound features and 13.0% in women with all the ultrasound features of adenomyosis.^[22]

Furthermore, a meta-analysis^[23] on IVF treatment outcomes in adenomyosis showed reduced rates of implantation, clinical pregnancy per cycle, clinical pregnancy per embryo transfer, ongoing pregnancy, and live-birth rate. The study also suggested that pre-IVF treatment with a gonadotropin-releasing hormone analogue (GnRHa) may be beneficial for pregnancy. Similar results was observed in women with endometriosis and adenomyosis.^[24]

Zang et al.^[25] studied the effect of adenomyosis on assisted reproductive techniques. They found a significantly higher early abortion rate in the adenomyosis group compared to the control group (13.3 vs 5.6%, respectively; P = 0.012).

Bourdon et al.^[26] examined the association of adenomyosis with infertility and found a clear association between focal adenomyosis and primary infertility. They also observed that a majority of women with focal adenomyosis had associated endometriosis, supporting the common presence of these two conditions.

Overall, these studies suggest that adenomyosis can have a detrimental effect on reproductive outcomes, including decreased pregnancy rates and increased risk of miscarriage. It also highlights the potential association between adenomyosis and endometriosis.

Treatment

Cytoreductive surgery

Since the first procedure to treat adenomyosis surgically by Hyams,^[40] various surgical approaches have been added to the arsenal of treatment.

Surgical treatment options for adenomyosis include laparoscopic or open procedures, with the goal of either partially or completely removing the adenomyotic tissue. Partial reduction can be achieved through techniques such as wedge resection or a transverse H incision on the uterus,^[41] followed by the removal of the adenomyotic tissue using diathermy or a cold knife. The uterine walls are then sutured using various methods such as U-sutures, figure-of-eight sutures, or interrupted sutures. Closure of the uterine wall can be done by overlapping the seromuscular layer in a double or triple flap layers method. The complete triple flap technique is effective for both diffuse uterine adenomyosis and nodular adenomyosis, and it helps reduce^[42] the risk of uterine rupture during pregnancy.

Systematic reviews have been conducted on uterine surgery for adenomyosis. One review^[43] reported that complete excision resulted in an 82.0% reduction in dysmenorrhea and a 68.8% reduction in menorrhagia, with a pregnancy rate of 60.5%. Partial excision led to an 81.8% reduction in dysmenorrhea and a 50.0% decrease in menorrhagia, with a pregnancy rate of 46.9%. Tan et al.^[44] analyzed the role of surgery in infertile women with focal and diffuse adenomyosis and found that the mean pregnancy rates were 52.7% for focal adenomyosis and 34.1% for diffuse adenomyosis. No difference was noted in the pregnancy rate between natural or IVF conception with or without gonadotropin-releasing hormone agonist pre-treatment. Patients with focal adenomyosis had better pregnancy outcome after conservative surgery than those with diffuse adenomyosis. Diffuse adenomyosis was associated with an increased risk of uterine rupture and preterm birth.

A study done by Kishi et al.^[45] factors can impact fertility outcomes following uterine surgery for adenomyosis, including a history of IVF treatments, the presence of posterior wall adenomyosis, and the age of the patient. Younger women who had previous IVF failure had a higher chance of successful pregnancy following surgery.^[45]

Wang et al.^[46] studied the role of surgical intervention in the management of subfertile women with symptomatic extensive uterine adenomyosis. They observed that surgical intervention, either alone or in combination with GnRH agonist therapy, was found to be more effective in managing symptoms and improving pregnancy and delivery rates compared to GnRH agonist therapy alone.

One major drawback of uterine surgery for adenomyosis is the increased risk of uterine rupture during pregnancy, which is higher compared to pregnancies after myomectomy^[47,48] (>1.0 vs 0.26%).

Otsubo et al.^[49] observed that maintaining an adequate thickness of the uterine wall, preferably between 9 and 15 mm, is important for conception and the prevention of uterine rupture.

Osada et al.^[50] reviewed surgical methods available for the treatment of adenomyosis. They inferred that it is feasible to treat focal adenomyosis lesion laparoscopically. However, for diffuse adenomyosis, laparotomy or laparoscopically assisted laparotomy is suggested as a better alternative. Laparotomy is safer than laparoscopy as in open surgery the entire lesion can be completely excised to prevent the recurrence. Additionally, good reconstruction of the myometrial circumvents uterine rupture during pregnancy.

Other alternatives

High-intensity focused ultrasound (HIFU) is a novel noninvasive modality that can be used for the treatment of adenomyosis. A study showed that HIFU in combination with GnRHa^[51] for the treatment of adenomyosis can effectively decrease the symptoms as well as reduce the size of lesions as compared to used HIFU alone.

Radiofrequency ablation^[52] is also a newly introduced treatment modality for adenomyosis. It is also minimal invasive method that can be used for short-term pain relief in symptomatic adenomyosis patients. Further studies are needed to evaluate its impact on other factors such as irregular bleeding, fertility, pregnancy outcome, and quality of life.

CONCLUSION

Adenomyosis is a benign pathology of uterus that is emerging as a cause of infertility. It is associated with decreased implantation, pregnancy loss, and preterm birth. Treatment of infertility in these patients remains a challenge for the clinicians with the present modalities. Conservative medical treatment along with fertility sparing surgery done alone or in combination have been used to improve fertility outcomes for the patients. Treatment should be appropriately individualized depending upon age, duration of infertility, previous failed treatment, and ovum preservation. Further research is still warranted to explore new, more effective, safe, and less invasive treatment of women with infertility due to adenomyosis.