Clinical use of nafarelin in the treatment of leiomyomas. A review of the literature

OBJECTIVE: To review the efficacy and safety of nafarelin in the treatment of leiomyomas. STUDY DESIGN: A literature review of published clinical trials was conducted. Six studies, including a total of 602 patients with leiomyomas, were reviewed. Patients received intranasal nafarelin, 50-400 micrograms twice daily for three to six months. Vaginal bleeding patterns, leiomyoma and uterine size, surgical conditions and adverse effects were assessed. RESULTS: Nafarelin consistently suppressed estrogen production, reduced leiomyoma and uterine size, and controlled menorrhagia. The significant reduction in uterine bleeding and amenorrhea resulting from administration of nafarelin was associated with a rise in mean hemoglobin concentrations. In addition, nafarelin improved hematologic parameters in women with and without anemia. Nafarelin was well tolerated, although hot flushes were the most commonly reported adverse events. Measured bone mineral density decreased significantly during treatment, although by six to nine months post-treatment, it increased to values not significantly different from baseline. The adverse effects of nafarelin were generally reversible after treatment withdrawal. CONCLUSION: Nafarelin treatment of women with symptomatic leiomyomas effectively decreases uterine bleeding; improves hematologic parameters; manages symptoms of menometrorrhagia, dysmenorrhea and pelvic discomfort; reduces uterine and myoma size; and is well tolerated. Reduction in bone mineral density occurs, but levels return to, or near, baseline levels within six months after treatment.     

45岁以上子宫内膜异位症患者的临床特点及分析

目的:探讨45岁以上子宫内膜异位症(内异症)患者的临床特点和治疗。方法:回顾性分析我院手术治疗的288例45岁以上内异症患者的临床资料。结果:288例患者主要临床表现为盆腔包块(76.7%)、痛经(49.3%)、异常阴道流血(29.2%);术中发现合并其他妇科疾病者76.0%,其中妇科恶性肿瘤或癌前病变5.9%;根治性手术60.4%,保留卵巢功能的手术34.7%,保留生育功能的手术4.9%;术后73例(25.3%)行假孕治疗,18例(6.3%)行假绝经治疗;78例(27.1%)行激素替代治疗。随诊超过6个月者175例(60.8%),复发率2.9%(5/175)。结论:45岁以上内异症临床表现不典型,常与其他激素依赖性疾病并存,合并妇科恶性肿瘤及癌前病变的几率较高,建议行根治性手术,术后进行激素替代治疗不增加复发。     

Transdermal hormone replacement therapy in postmenopausal women with uterine leiomyomas.

OBJECTIVE: To evaluate the effects of transdermal hormone replacement therapy (HRT) on uterine and leiomyoma size and on uterine bleeding patterns in postmenopausal women with uterine leiomyomas. METHODS: The required sample size was calculated to be 30 subjects per group to detect an effect on the size of one standard deviation (SD) with an alpha value of 0.05 (two-sided) and a power 1 - delta = 0.8. At the end of the study, the power analysis showed a value of beta = 0.826. Seventy postmenopausal women with uterine leiomyomas were enrolled and treated for 12 cycles of 28 days each with transdermal 17 beta-estradiol (E(2)) patches plus oral medroxyprogesterone acetate continuously added (group A) or with calcium carbonate (group B). At entry and every three cycles, uterine and leiomyoma dimensions were measured by transvaginal ultrasonography. To evaluate the effect of transdermal HRT on the characteristics of uterine bleeding, 35 healthy postmenopausal women without uterine leiomyomas (group C) were enrolled and treated with the same regimen as group A. A daily diary was used to record the abnormal uterine bleeding episodes, and a rank scale was used to assess the severity of bleeding. RESULTS: There were no significant changes in mean uterine or leiomyoma size between groups A and B, or in each group compared with basal values. No significant difference was detected between groups A and C in uterine bleeding patterns. CONCLUSION: Transdermal HRT did not increase the size of uterine leiomyomas or affect uterine bleeding patterns in postmenopausal women.     

Hysterectomy in Veterans Affairs Medical Centers

OBJECTIVE: To examine the indications and surgical morbidity for women veterans who underwent hysterectomies in Department of Veterans Affairs Medical Centers (VAs). METHODS: Data on hysterectomies performed in VAs from 1991 to 1997 were abstracted from a surgical quality improvement program. RESULTS: Records of 1722 women who had hysterectomies in VAs over 6 years were examined. Women were predominately white (62%) and their average age was 42.5 years. Operations included abdominal (74%), vaginal (22%), and laparoscopic-assisted (4%) methods. The most common indications for surgery included uterine leiomyomas (31%), abnormal uterine bleeding (14%), and endometriosis (11%). Indications differed by race (P <.01); nonwhite women were most likely to have surgery for leiomyoma (51%), whereas white women had hysterectomies for leiomyomas (19%), abnormal bleeding (15%), endometriosis (13%), and genital prolapse (11%). The mean postoperative stay was significantly longer for abdominal hysterectomies (4.51 days) than either vaginal or laparoscopic-assisted hysterectomies (2.92 and 2.21 days, respectively; P <.001). The overall complication rate within 30 days was 9%, and the most frequent complication was urinary tract infection (3.3%). CONCLUSION: Women who underwent hysterectomies in VAs had low complication rates, comparable to hysterectomy complication rates in the United States generally.     

Xanthogranulomatous salpingitis and oophoritis associated with endometriosis and uterine leiomyoma presenting as intestinal obstruction

Xanthogranulomatous inflammation is a rare form of chronic granulomatous inflammation. Bacterial infections, immunosuppression, chronic inflammatory conditions, luminal obstruction, endometriosis, leiomyoma, abnormal lipid metabolism, ineffective antibiotic therapy, ineffective clearance of bacteria by phagocytes and chronic irritation of the urachal remnant have been implicated in the pathogenesis. There are very few reported cases of xanthogranulomatous salpingitis and oophoritis. We present such a case in a 34-year-old female, with primary subfertility for eight years, endometriosis, uterine leiomyoma, type II diabetes mellitus and a history of surgery for endometriosis and fibroids and surgical wound infection, who presented with symptoms of intestinal obstruction. The patient underwent emergency laparotomy followed by total abdominal hysterectomy and bilateral salpingo-oophorectomy. Histology revealed xanthogranulomatous salpingitis and oophoritis. Chronic inflammation due to inadequate treatment of bacterial infection, coupled with pelvic endometriosis and uterine leiomyoma may have led to xanthogranulomatous salpingitis and oophoritis.     

Ureteral mullerian carcinosarcoma (mixed mullerian tumor) associated with endometriosis occurring in a patient with a concentrated soy isoflavones supplementation

Malignant transformation and particularly malignant mixed mullerian tumor arising in extragenital endometriosis is extremely rare and occurs in the majority of cases after estrogen replacement therapy. We present a case of a 75-year-old woman who developed a ureteral malignant mullerian carcinosarcoma in a context of florid endometriosis. The patient had a history of total hysterectomy with bilateral salpingo-oophorectomy 30 years earlier for extensive endometriosis. Since 5 years, the patient has been on phytoestrogen supplementation consisting of 72 mg/day of superconcentrated soy isoflavones. This is the first case of ureteral mullerian carcinosarcoma arising in endometriosis foci after extensive phytoestrogen supplementation. Our data suggest that phytoestrogens at least in concentrated form may play a role not only in maintenance of endometriosis but also in its malignant transformation. Given the extraordinary popularity and availability of these dietary supplements, several studies are indispensable regarding their safety particularly in women with extensive endometriosis.     

Characteristics of uterine contractility during menses in women with mild to moderate endometriosis

Objective: To establish the role of uterine contractions in retrograde menstruation with subsequent abdominal implantation of endometrial tissue.

Design: Controlled prospective study.

Setting: University hospital-based study.

Patient(s): Infertile women with (n = 22) and without (n = 22) endometriosis.

Main Outcome Measure(s): Frequency, amplitude, and basal pressure tone of uterine contractions; correlation of contractions with retrograde bleeding and presence of viable endometrial cells; and dysmenorrhea before and 3 and 24 months after surgery.

Result(s): Compared with controls, patients with endometriosis had uterine contractions with higher frequency (22.73 ± 5.66 osc/10 min vs. 11.09 ± 3.26 osc/10 min), amplitude (20.83 ± 3.94 mm Hg vs. 6.77 ± 2.83 mm Hg), and basal pressure tone (50.14 ± 16.30 mm Hg vs. 24.68 ± 6.14 mm Hg). Dysmenorrhea was scored as 4.09 ± 1.44 in patients with endometriosis and 0.86 ± 1.42 in controls. Retrograde bleeding was found in 73% of patients with endometriosis vs. 9% of controls, and only 45% of patients with endometriosis had viable endometrial cells in the cul-de-sac.

Conclusion(s): Endometriosis may result from abnormal myometrial contractility through tubal transportation, dissemination, and implantation of endometrial viable cells into the abdomen.     

Uterine Fibroid in a 16-Year-Old Adolescent Managed with a Fertility-Sparing Approach: A Case Report and Review of the Literature

BackgroundUterine fibroids are the most common benign tumor of the uterus in adult women. However, it is exceedingly rare in adolescents.CaseA 16-year-old girl presented with severe anemia and abnormal uterine bleeding. MRI of the pelvis demonstrated a 9-cm mass within the uterus concerning for leiomyoma or leiomyosarcoma. A fertility preserving myomectomy led to the final diagnosis of a benign uterine fibroid.Summary and ConclusionDespite the rare incidence of leiomyomas in adolescents, it is imperative that it is included in the differential diagnosis when young women present with abnormal uterine bleeding. A less common diagnosis to consider is leiomyosarcoma; however, this is histologically diagnosed. Thus, a fertility-preserving myomectomy permits for a diagnostic opportunity to rule out a potential malignancy.     

Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women.

OBJECTIVE: To evaluate the effects of raloxifene administration on uterine and uterine leiomyoma sizes in postmenopausal women. DESIGN: Prospective randomized, double-blind, placebo-controlled clinical trial. SETTING: Department of Gynecology, Obstetrics, and Pathophysiology of Human Reproduction, University of Naples "Federico II", Italy. PATIENT(S): Seventy spontaneous postmenopausal women affected by uterine leiomyomas. INTERVENTION(S): Twelve cycles (of 28 days each) of treatment with raloxifene (60 mg daily per os) or placebo. MAIN OUTCOME MEASURE(S): At entry and at every 3 cycles, uterine and uterine leiomyoma dimensions were measured by means of transvaginal ultrasound. The difference between uterine and leiomyoma volumes (Delta size) was calculated in all subjects. The characteristics of uterine bleeding and the side effects of the treatments were assessed using a daily diary. RESULT(S): After 6, 9, and 12 cycles of therapy, in subjects treated with raloxifene, the mean uterine and uterine leiomyoma size were significantly decreased, and the mean Delta size significantly increased in comparison with basal values and the placebo group. No significant differences in uterine bleeding were detected between the two groups. CONCLUSION(S): In postmenopausal women raloxifene appears to act selectively on uterine leiomyomas, reducing their size.     

Adenomyosis a variant, not a disease? Evidence from hysterectomized menopausal women in the Study of Women's Health Across the Nation (SWAN)

OBJECTIVE: Our study evaluates the symptoms commonly attributed to adenomyosis in women undergoing the menopausal transition. We hypothesized that adenomyosis is more commonly seen in women with fibroids, pelvic pain, abnormal uterine bleeding, and in the presence of endometriosis. DESIGN: Retrospective cohort. SETTING: Multisite community-based study. PATIENT(S): Enrollees in the Study of Women's Health Across the Nation who had hysterectomies. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Relationship of adenomyosis to presenting symptoms and other patient characteristics. RESULT(S): Adenomyosis was found in 48% of 137 patients. Frequencies of presenting symptoms were similar in those with and without evidence of adenomyosis. The same prevalence of fibroids was seen in the presence or absence of adenomyosis: 37% versus 43%, endometriosis, 3% versus 5%, abnormal bleeding, 27% versus 33%, or chronic pelvic pain in the presence of fibroids 12% versus 17%. CONCLUSION(S): Adenomyosis is a common diagnosis seen in hysterectomized specimens from women undergoing the perimenopausal transition. Adenomyosis is equally common in women who also have fibroids, endometriosis, pelvic pain, or abnormal uterine bleeding, and women who do not. Therefore, adenomyosis is an incidental finding, not the source of the symptomatology. It appears not to be a "disease" per se but rather a normal variant.     

The significance of psammoma bodies that are found incidentally during endometrial biopsy

OBJECTIVE: The purpose of this study was to elucidate the significance of psammoma bodies that are found incidentally during endometrial biopsy. STUDY DESIGN: We reviewed the medical records of 11 women who were found to have psammoma bodies during endometrial biopsy over an 18-month period and extracted data that included demographic information, extent of evaluation, and pathologic findings. RESULTS: Ten women were postmenopausal and underwent endometrial biopsy for abnormal uterine bleeding while using combined hormone replacement. Most women underwent dilation and curettage with hysteroscopy plus either laparoscopy or ultrasonography. Notable findings included: 5 women with endometrial polyps, 2 women with endometriosis, 1 woman with endosalpingiosis, and 1 woman with a mature cystic teratoma. No endometrial or adnexal malignancies were identified. CONCLUSION: This series represents the largest series to date regarding psammoma bodies that have been found incidentally during endometrial biopsy. All psammoma bodies were associated with benign findings. Further evaluation of the endometrial cavity with hysteroscopy or sonohysterography, plus some form of adnexal assessment, is a reasonable definitive evaluation scheme.     

Ethnicity and mode of delivery in 'low-risk' first-time mothers, East London, 1988-1997

OBJECTIVE: To test whether serum monocyte chemotactic protein-1 (MCP-1) chemokine levels correlate with endometriosis in infertile women. STUDY DESIGN: A group of women with endometriosis (n = 18, infertile) was compared with patients with uterine leiomyoma (n = 16, fertile), unexplained infertility (n = 5, infertile), and healthy women (n = 16, fertile). MCP-1 expression levels were evaluated by ELISA assay. The data obtained were statistically analyzed using the Mann-Whitney test. P-Values <0.05 were considered as significant. RESULTS: MCP-1 concentrations (median; range of values) in serum were as follows: women with endometriosis (221; 101-635 pg/ml), women with unexplained infertility (167, 114-234 pg/ml), women with uterine leiomyoma (137; 88-200 pg/ml), and healthy donors (123; 98-194 pg/ml). Significant differences were observed in the women with endometriosis compared with those with uterine leiomyoma (p = 0.02) and healthy donors (p = 0.002). Among the women with endometriosis, the level of significance in MCP-1 level at rAFS stages III-IV was higher than that at rAFS stages I-II compared with healthy donors and women with leiomyoma (p = 0.002 and p = 0.02, respectively). CONCLUSIONS: These data show that an increased level of MCP-1 can characterize infertile women with endometriosis. However, further studies are needed to be able to determine whether increased MCP-1 chemokine expression can be related to infertility or is a result of endometriosis progress.     

Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study

OBJECTIVE: To determine whether the frequency and severity of dysmenorrhea are reduced in women with symptomatic endometriosis in whom a levonorgestrel-releasing intrauterine device (Lng-IUD) is inserted after operative laparoscopy compared with those treated with surgery only. DESIGN: Open-label, parallel-group, randomized, controlled trial. SETTING: A tertiary care and referral center for patients with endometriosis. PATIENTS(S): Parous women with moderate or severe dysmenorrhea undergoing first-line operative laparoscopy for symptomatic endometriosis. INTERVENTION(S): Randomization to immediate Lng-IUD insertion or expectant management after laparoscopic treatment of endometriotic lesions.Proportions of women with recurrence of moderate or severe dysmenorrhea in the two study groups 1 year after surgery and overall degree of satisfaction with treatment.Moderate or severe dysmenorrhea recurred in 2 of 20 (10%) subjects in the postoperative Lng-IUD group and 9/20 (45%) in the surgery-only group. Thus, a medicated device inserted postoperatively will prevent the recurrence of moderate or severe dysmenorrhea in one out of three patients 1 year after surgery. A total of 15/20 (75%) women in the Lng-IUD group and 10/20 (50%) in the expectant management group were satisfied or very satisfied with the treatment received. CONCLUSION(S): Insertion of an Lng-IUD after laparoscopic surgery for symptomatic endometriosis significantly reduced the medium-term risk of recurrence of moderate or severe dysmenorrhea.     

Severity of symptoms in primary dysmenorrhea--a Doppler study

OBJECTIVE: Doppler findings in women with severe symptoms of primary dysmenorrhea include high impedance to blood flow in uterine arteries with a preserved cyclic pattern throughout the whole cycle. Doppler findings in women who present with mild symptoms of primary dysmenorrhea are not yet documented. The aim of this study was to investigate possible differences in Doppler findings among women with mild and severe primary dysmenorrhea. STUDY DESIGN: One hundred and fifty four women were examined with color Doppler ultrasound: 50 in the control group, 60 in the mild and 44 in the severe primary dysmenorrhea subgroup. We calculated resistance index in uterine arteries in these women on the first day of the cycle, in the follicular (days 9-12) and the luteal (days 20-23) phase of the cycle and used analysis of variance for comparing results. RESULTS: The rate of visualization was 100% for uterine and arcuate arteries, 44-76% for the radial and 32-62% for spiral arteries, respectively. A significant difference in Doppler index values among the mild and severe dysmenorrheic group was observed in the luteal phase for the arcuate artery and in all the three measurement periods for the radial and spiral arteries. CONCLUSION: There is a difference in Doppler findings between women with mild and severe symptoms of primary dysmenorrhea.     

Eicosanoids in primary dysmenorrhea, endometriosis and menstrual migraine

This paper summarizes what has been learned over the years about the role of eicosanoids in the pathogenesis of primary dysmenorrhea, endometriosis and menstrual migraine. The role of prostaglandins (PGs) in the pathogenesis of primary dysmenorrhea is inferred from four main observations: firstly, the clinical symptoms of primary dysmenorrhea are similar to those induced by the administration of PGF2 alpha and PGE2 for the induction of labour; secondly, the increased production of PGs by the endometrium during the luteal and menstrual phases of ovulatory cycles is consistent with the occurrence of primary dysmenorrhea mainly in ovulatory cycles; thirdly, the concentrations of PGF2 alpha and PGE2 in the endometrium and menstrual fluid of dysmenorrheic women are significantly higher than in controls; fourthly, certain PG inhibitors have been proved to be effective in the treatment of dysmenorrhea. The change in PG production can explain the major symptoms of primary dysmenorrhea, including the increased uterine contractility, uterine ischemia and the lowering of the pain threshold to chemical and physical stimuli in the pelvic nerve terminals. Moreover, recent experimental data suggest that leukotrienes (LTs) might be among the alternative pathogenetic causes of primary dysmenorrhea. The data which support a relationship between eicosanoids and endometriosis are as follows: endometriotic tissue produces PGs; the peritoneal fluid concentration of PGF2 alpha increases significantly after the induction of endometriosis in laboratory animals; the concentration of PGs in peritoneal fluid of some patients with endometriosis is greater than in controls and, finally, the number and activation of pelvic macrophages which are able to synthesize eicosanoids increase in patients with endometriosis. Possible roles for eicosanoids in the pathogenesis of infertility and secondary dysmenorrhea induced by endometriosis have been suggested. Eicosanoids are probably also involved in the pathogenesis of menstrual migraine. Different types of PGs might play a role both in the initial vasoconstriction during the prodromal phase of migraine and in the vasodilation and sensitization to pain typical of the pain phase.     

The difference in sex hormone dependence for gap junction formation in the muscles of uterine leiomyoma and normal myometrium

Gap junction is reported to be initiated by changes in levels of steroid hormones in the smooth muscle cells of myometrium. In order to clarify the difference in sex hormone dependence for gap junction formation in the muscles of uterine leiomyoma and normal myometrium, uterine leiomyoma and myometrial gap junctions, and serum estradiol and progesterone levels were determined simultaneously in 23 women who had undergone simple hysterectomy for leiomyomas of the corpus uteri. In all tissues of the myometrium from 23 women, at least three gap junctions were found between muscle cells in the series of photographs. On the other hand, there were 7 out of 23 uterine leiomyomas in which not even one gap junction was detected between muscle cells in the series of photographs. The phasic change in the number of gap junctions related to the menstrual cycle was detected in the muscles of uterine leiomyoma as well as normal myometrium. Uterine leiomyoma was characterized by less correlation between the number of gap junctions in the muscles and the concentration of serum sex steroids, compared with those of normal myometrium. Sex steroids may have a trophic effect on some uterine leiomyoma, but the sex hormone dependence of uterine leiomyoma for gap junction formation may be less than that of normal myometrium. The present study also showed that the increased gap junction formation in myometrial muscles from women with dysmenorrhea may be formed between myometrial cells in response to physiologic or pathologic stimuli, such as the production of local prostaglandins, and may result in hypercontraction of the uterus.     

A myxoid liposarcoma arising in a leiomyoma of the uterus: a case report

Background A liposarcoma is the most frequent soft tissue sarcoma found in adults, however, a liposarcoma arising in uterus is extremely rare. Indeed, a liposarcoma coexistent with a leiomyoma is even rarer and there is only one case has been reported in the English literature to date. Case We describe a case of the uterine liposarcoma arising in a leiomyoma in 48-year-old woman who presented with dysmenorrhea, brownish vaginal discharge, and a rapidly enlarging lower abdominal mass. The tumor emerged from the lower segment of the endometrium and filled the endometrial cavity as a polypoid lesion. The authors of this study documented the adipocyte origin of the tumor with immunohistochemical and electron microscopical studies, the available literature was reviewed and the possible histogenesis was discussed. Conclusion We herein report a case of very rare primary liposarcoma arising in a submucosal uterine leiomyoma.     

Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen

OBJECTIVE: To ascertain whether long-term reduction of pain is obtained by continuous administration of an oral contraceptive (OC) in women with endometriosis-associated recurrent dysmenorrhea that does not respond to cyclic OC use. DESIGN: Prospective, therapeutic, self-controlled clinical trial. SETTING: A tertiary care and referral center for patients with endometriosis. PATIENT(S): Fifty women who underwent surgery for endometriosis in the previous year and experienced recurrent dysmenorrhea despite cyclic OC use. INTERVENTION(S): Continuous use of an OC containing ethinyl estradiol (0.02 mg) and desogestrel (0.15 mg) for 2 years. MAIN OUTCOME MEASURE(S): Dysmenorrhea variation during cyclic and continuous OC use, evaluated with a 100-mm visual analog scale and a 0- to 3-point verbal rating scale, and degree of satisfaction with continuous OC treatment. RESULT(S): In the study period, amenorrhea, spotting, and breakthrough bleeding were reported by 19 (38%), 18 (36%), and 13 (26%) women. The mean +/- SD number of >7-day bleeding episodes with consequent 7-day OC suspension was 5.5 +/- 2.1. The mean +/- SD dysmenorrhea visual analog scale and verbal rating scale scores were 75 +/- 13 and 2.4 +/- 0.5 at baseline and 31 +/- 17 and 0.7 +/- 0.6 at 2-year follow-up, respectively. Moderate or severe side effects were reported by 7/50 (14%) women. At final evaluation, 13 (26%) women were very satisfied, 27 (54%) were satisfied, 1 (2%) was uncertain, 8 (16%) were dissatisfied, and 1 (2%) was very dissatisfied. CONCLUSION(S): Long-term continuous OC use can be proposed to women with symptomatic endometriosis and menstruation-related pain symptoms.     

Vaginal leiomyoma co-existing with broad ligament and multiple uterine leiomyomas

A 48 year old African American woman presented with bladder pressure leading to the diagnosis of broad ligament and multiple uterine leiomyomas. She was also found to have a lateral vaginal wall mass which was confirmed to be a leiomyoma. Unlike uterine leiomyomas, vaginal leiomyomas are uncommon and are most often found in Caucasian women. Cases of such co-existing tumors are rare and their etiologic relationship is uncertain. Received: 21 September 2000 / Accepted: 17 October 2000