Best Practice & Research Clinical Obstetrics and Gynaecology Vol. 22, No. 2, pp. 333–339, 2008 doi:10.1016/j.bpobgyn.2007.07.006 available online at http://www.sciencedirect.com 6 Hormonal treatments for adenomyosis Luigi Fedele * MD Professor, Head of Department Stefano Bianchi MD Assistant Professor Giada Frontino MD Resident Fondazione Policlinico, Mangiagalli e Regina Elena, Clinica Ostetrica e Ginecologica II, Universita` di Milano, Istituto Luigi Mangiagalli, Via della Commenda 12, 20122 Milano, Italy Like endometriosis and uterine myomas, adenomyosis presents the typical characteristics of oestrogen-dependent diseases. The medical treatment of adenomyosis is based on the hormonal dependency of the disease and its strongly debated similarities with endometriosis. Infact, despite the evident differences between the two conditions, the therapies that treat endometriosis effectively have also been successful for the treatment of adenomyosis. Although the two diseases have distinct epidemiological features, they have the same ‘target tissue’ for hormonal therapy, namely ectopic endometrium. Recognized approaches are systemic hormonal treatments, which are generally used for endometriosis and are capable of suppressing the oestrogenic induction of the disease, and local hormonal treatment that targets the ectopic endometrium directly. Gonadotropin-releasing hormone agonists, danazol and intrauterine levonorgestrel- or danazol-releasing devices have been used in the treatment of adenomyosis. Despite the solid rational basis for its hormonal treatment, few studies have been performed on medical therapy for adenomyosis. Key words: adenomyosis; medical therapy; levonorgestrel-IUD; pelvic pain; menorrhagia. Adenomyosis is characterized by the presence of endometrial glands and stroma within the myometrium. The ectopic endometrium is typically surrounded by reactive, hypertrophic and hyperplastic myometrium.1 The disease can range from small microscopical isolated endometrial islands within the myometrium to extensive infiltration of uterine walls, or grossly visible nodules without a capsule, allowing clear distinction * Corresponding author. Tel.: þ39 02 55032318; Fax: þ39 02 50320252. E-mail address: [email protected] (L. Fedele). 1521-6934/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved. 334 L. Fedele et al from normal myometrium.2 The former situation is more common and is referred to as ‘diffuse adenomyosis’, while the latter case describes nodular adenomyosis (also called ‘adenomyomas’) which is relatively rare. There are many uncertainties regarding the true incidence of the disease and the correlation with its commonly associated symptoms, namely metrorrhagia and pelvic pain.3 These doubts are due to the fact that it is impossible to confirm or exclude the presence of adenomyosis without prior adequate pathological assessment of the uterus, and there is no consensus regarding which histological diagnostic criteria should be applied for diagnosis of the disease.1,4–7 Study populations have invariably been constituted by women undergoing hysterectomy for menorrhagia and an enlarged uterus, especially in the fifth decade of life, so it should not be surprising that adenomyosis is commonly believed to be prevalent in women between 40 and 50 years of age. In fact, there are insufficient data, i.e. hysterectomies, regarding younger women. From the literature, it can be estimated that adenomyosis is present in approximately 20–30% of women who undergo hysterectomy3, and that, at least in the more severe forms of endometrial infiltration, there is a causal relationship between the disease, metrorrhagia and dysmenorrhoea.8,9 The relationship between adenomyosis, metrorrhagia and pelvic pain is less clear in the more limited forms, and the correlation between adenomyosis and infertility, which is strongly maintained by some authors10,11, needs to be confirmed. With the exception of some nodular lesions, conservative surgical treatment is impracticable as it is not possible to isolate the adenomyotic tissue distinctly, so hysterectomy is the only rational and complete procedure. Recently, imaging studies for the diagnosis of adenomyosis by magnetic resonance imaging (MRI) and transvaginal ultrasound have shown these methods to be accurate and reliable.12–16 The definition of imaging diagnostic criteria for adenomyosis has allowed effective assessment of the medical treatments and of new conservative operative techniques, i.e. uterine artery embolization and MRI-focused ultrasound surgery.17 The medical treatment of adenomyosis is based on the hormonal dependency of the disease and its strongly debated similarities with endometriosis. Despite the evident differences between the two conditions, the therapies that treat endometriosis effectively have also been successful for the treatment of adenomyosis. Although the two diseases have distinct epidemiological features, they have the same ‘target tissue’ in common for hormonal therapy–ectopic endometrium. RATIONAL BASIS OF HORMONAL MEDICAL THERAPY Like endometriosis and uterine myomas, adenomyosis presents the typical characteristics of oestrogen-dependent diseases. In fact, it is absent before menarche and regresses rapidly after menopause. Studies on hormone–ligand binding in adenomyosis report that oestrogen receptors are always present, whereas progesterone receptors are found less frequently.18 Androgen receptors have also been encountered in adenomyotic tisssue. The first studies in adenomyosis demonstrated that the levels of receptors for sex steroids were generally lower than those present in the endometrium, although this was disclaimed recently.19 Aromatase is an enzyme that converts androgens to oestrogens, i.e. D4-androstenedione in oestrone, and can be found in adenomyotic tissue.20,21 The enzyme oestrone sulphatase is also present21,22, and converts oestrone-3-sulphate, the most prevalent circulating oestrogen, into 17boestradiol. The combined activity of aromatase and oestrone sulphatase increases the local oestrogenic activity that, along with the circulating oestrogens, stimulates Hormonal treatments for adenomyosis 335 the growth of adenomyotic tissue through interaction with oestrogen receptors. The apoptosis suppressor gene product, blc-2, is also expressed constantly during the cycle.19 Blc-2 is normally expressed in a cyclic fashion, with peak levels during the proliferative phase.23 The local hyper-oestrogenic metabolic state, together with the anomalous expression of blc-2, may contribute to promote the ‘invasive’ and diffusive process of adenomyosis in the myometrium. MEDICAL THERAPY While medical therapy for endometriosis has always been of great interest and has been widely studied and applied in clinical practice, the same is not true for adenomyosis. Undoubtedly, the different age range of patients and the higher tendency towards definitive surgery, as well as the fact that it is impossible to obtain a pre-operative diagnosis, have all played an important role. However, even since the establishment of reliable instrumental diagnostic criteria, there has not been particular interest in medical treatment for adenomyosis. In this setting, an effective and well-tolerated medical therapy for its symptoms could allow a major reduction in surgical intervention. Gonadotropin-releasing hormone (GnRH) agonists, danazol and intrauterine levonorgestrel- or danazol-releasing devices have been used in the treatment of adenomyosis. Recognized approaches are systemic hormonal treatments, which are generally used for endometriosis and are capable of suppressing the oestrogenic induction of the disease, and local hormonal treatment that targets the ectopic endometrium directly. GnRH agonists GnRH agonists were the first drugs used in the treatment of adenomyosis. In 1991, Grow and Filer24 reported a case of symptomatic adenomyosis in which treatment with a GnRH agonist resulted in a reduction in uterine volume and resolution of symptoms. Other reports of small numbers of cases confirmed these findings.25,26 At the end of treatment, some patients conceived immediately24–29, while other patients experienced a progressive increase in uterine size and recurrence of symptoms. Similarly to endometriosis, in adenomyosis, interruption of suppressive hormonal therapy is followed by relapse of the disease and correlated symptoms within 6 months. These data suggest that therapy should be continued for longer periods of time, but prolonged treatment with GnRH agonists causes hypo-oestrogenism-related side-effects such as vaginal dryness, hot flushes and mood swings, and can lead to a significant reduction in bone mineral density. Such inconvenience may be limited by associating an add-back therapy, although specific studies on this therapeutic regime for the treatment of adenomyosis are lacking. GnRH agonists are highly effective in the reduction of uterine volume and alleviation of symptoms associated with adenomyosis, although their use for long periods of time is impracticable due to hypo-oestrogenic side-effects. Based on the scanty data published in the literature, treatment with a GnRH agonist for 3–6 months can be followed by a viable pregnancy. This therapy may therefore be indicated for women with diffuse adenomyosis seeking a pregnancy.29,30 Another indication may be preoperative therapy in cases of nodular adenomyosis. This specific approach lacks specific studies and although surgery may be facilitated due to reduced volume and 336 L. Fedele et al vascularization, the demarcation between normal tissue and the adenomyoma could be indistinct, thus increasing the risk of incomplete excision and early relapse. Oral contraceptives Various studies have shown that treatment with oral oestroprogestin contraceptives, especially when administered in a continuous modality, can effectively control the symptoms of endometriosis and limit disease progression.31 Unfortunately, no studies have evaluated this therapeutic approach in patients with adenomyosis. The administration of a cyclic oral contraceptive following therapy with a GnRH agonist has not been shown to prevent recurrence of pelvic pain and menorrhagia.25 Danazol There is limited experience in the literature regarding the use of systemic therapy with danazol in patients with adenomyosis. Danazol may exert its effect on adenomyosis as it does on endometriosis, i.e. through induction of a hypogonadic state, as well as its direct interaction with endometrial receptors for androgens and progesterone. As a consequence of this double effect, the endometrium undergoes hypo-atrophy. Ueki et al19 demonstrated that during systemic treatment with danazol, oestrogen receptor and bcl-2 protein concentrations were reduced in glands and stromal cells of adenomyosis, and were associated with an increase in apoptotic cell necrosis. This effect was markedly increased with danazol compared with leuprolide acetate, although, even after 6 months of therapy with danazol, menorrhagia and dysmenorrhea recurred within a few cycles of treatment suspension. Intra-uterine devices The insertion of an intrauterine device releasing 20 mg of levonorgestrel (Lng-IUD) daily has been demonstrated to induce marked atrophy of the endometrial glands and stromal decidualization.32 This device was originally studied for contraceptive purposes, but has been used successfully in many women with idiopathic menorrhagia and is deemed to be a therapeutic approach of choice for this condition.33 In some studies, the Lng-IUD has demonstrated effectiveness in women with adenomyosis-associated menorrhagia. Fedele et al34 assessed the Lng-IUD in 25 women between 38 and 45 years of age, with recurrent menorrhagia for at least 6 months and with a blood loss of >80 mL, as estimated by a pictorial blood loss assessment chart (PBAC). Adenomyosis was diagnosed through transvaginal ultrasound and confirmed on MRI in nine cases. The treatment was predicted to last for at least 12 months. Three months after Lng-IUD insertion, none of the patients reported persistence of menorrhagia and the PBAC score had decreased from 211 61 to 48 17. Although most of the patients had persistent spotting in the first months of treatment, by the end of the first year, 16 patients had regular cycles, three had oligomenorrhoea, two had amenorrhoea and only two had spotting. Two patients had discontinued treatment prematurely; one due to IUD expulsion after 2 months, and the other due to persistent irregular bleeding. All the other patients showed an important increase in haemoglobin levels, serum iron and ferritin without concomitant modifications in lipid metabolism and the coagulation asset. A moderate but significant decrease in uterine volume, measured at transvaginal ultrasound, was reported during treatment. Hormonal treatments for adenomyosis 337 In one case report, the insertion of an Lng-IUD in a woman with a grossly enlarged uterus with adenomyosis associated with dysmenorrhoea and menorrhagia resulted in a marked decrease in uterine size and resolution of the symptoms after 12 months.35 More recently, a short-term study confirmed the efficacy of the Lng-IUD in women with symptomatic adenomyosis. After 3 months, marked reduction in menstrual blood loss and resolution of dysmenorrhoea were observed, along with a significant reduction in uterine volume.36 The Lng-IUD has also been used in the postoperative treatment of patients after endometrial ablation for adenomyosis-associated menorrhagia. In a randomized study, Maia et al37 assigned 95 women who underwent endometrial ablation for symptomatic adenomyosis to Lng-IUD therapy or no further treatment. After 1 year of follow-up, the rate of amenorrhoea was higher in patients treated with the Lng-IUD. A second surgical procedure was required in 19% of patients in the expectant management group and in none of the patients treated with the Lng-IUD. Since adenomyosis is extremely difficult to resect completely through hysteroscopic ablation, and in consideration of the results obtained with Lng-IUD treatment, it should be discussed whether combined hysteroscopic–medical treatment may actually yield better results than medical treatment alone. In 2000, Igarashi et al38 described the effects of insertion of an IUD containing danazol in 14 women with symptomatic adenomyosis that had relapsed after previous systemic treatments with a GnRH agonist and/or danazol. During treatment, there was complete resolution of dysmenorrhea in nine patients, a reduction in four patients and no improvement in one patient. Excessive menstrual blood loss was abolished in 12 women, whereas no modification was observed in two women. The efficacy of this treatment was seen from the first cycle after insertion. Three of the four infertile women conceived after removal of the IUD. Of note, serum levels of danazol during treatment were below the limit of detection, and the typical side-effects associated with systemic administration were not reported. Ovulation and menstruation both occurred as in pretreatment cycles. No data are available regarding prolonged treatment or the contraceptive effectiveness of this device, which must be considered due to the potential teratogenicity of danazol. Aromatase inhibitors No studies on the use of aromatase inhibitors in patients with adenomyosis have been published. This treatment has its rational basis on the presence of aromatase P450 in eutopic and ectopic endometrium of patients with adenomyosis.39 This enzyme is typically found in the endometrium of women with endometriosis, adenomyosis and leiomyomas, but not in that of healthy women. The inhibition of this enzyme could decrease the synthesis of local oestrogens, thus constituting an important mechanism that is essential for development of the disease. CONCLUSIONS Despite the solid rational basis for its hormonal treatment, few studies have been performed on the medical therapy for adenomyosis. This lack of interest probably derives from the difficulty in achieving a pre-operative diagnosis and from the traditional demolitive approach that the clinician has maintained in regards to symptomatic patients with a suspected diagnosis of adenomyosis. A reversible medical alternative to hysterectomy does now exist– the Lng-IUD. This IUD has been widely assessed 338 L. Fedele et al in terms of contraceptive efficacy and in idiopathic menorrhagia, and has been shown to be extremely effective in resolving the symptoms associated with adenomyosis. Moreover, the side-effects are characterized mainly by irregular bleeding and amenorrhoea, while its metabolic impact seems modest Practice points An effective and well-tolerated medical therapy for symptomatic adenomyosis could allow a major reduction in surgical intervention. Systemic hormonal treatments have been used successfully in the treatment of symptomatic adenomyosis. The Lng-IUD is a reversible medical alternative to hysterectomy in these patients. Research agenda Despite the solid rational basis for its hormonal treatment, few studies have been performed on the medical therapy for adenomyosis. . REFERENCES 1. Ferenczy A. Pathophysiology of adenomyosis. Hum Reprod Update 1998; 4: 312–322. *2. Bergeron C, Amant F & Ferenczy A. Pathology and physiopathology of adenomyosis. Best Pract Res Clin Obstet Gynaecol 2006; 20: 511–521. 3. Vercellini P, Vigano P, Somigliana E et al. Adenomyosis: epidemiological factors. Best Pract Res Clin Obstet Gynaecol 2006; 20: 465–477. 4. 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