Oral Gonadotropin-Releasing Hormone Antagonists in the Treatment of Uterine Myomas: A Systematic Review and Network Meta-analysis of Efficacy Parameters and Adverse Effects.

OBJECTIVE: The aim of this systematic review is to gather and synthesize evidence regarding the use of oral gonadotrophin-releasing hormone (GnRH) antagonist for the treatment of bleeding associated with uterine myomas. DATA SOURCES: Web of Science, and MEDLINE databases were searched electronically on March 5, 2021, using combinations of the relevant Medical Subject Headings terms and keywords. The search was restricted to the English language and to human studies. METHODS OF STUDY SELECTION: Only randomized controlled trials involving patients with heavy menstrual bleeding associated with uterine myomas treated with different doses of oral nonpeptide GnRH antagonists with or without add-back therapy were included. Studies comparing oral nonpeptide GnRH antagonists with treatments other than placebo were also excluded. TABULATION, INTEGRATION, AND RESULTS: A total of 5 randomized trials including 2463 women were included in the analyses. Included studies were found to be at low risk of bias. When treatments were compared against placebo, the top 3 treatments for bleeding suppression were elagolix 600 mg, 400 mg, and 200 mg without add-back. Elagolix 600 mg without add-back therapy had a significantly higher risk of amenorrhea than lower doses of elagolix with and without add-back and relugolix as well. Uterine volume changes were more pronounced in therapies without add-back. All treatments were associated with significantly improved quality of life scores, both for myoma symptom-related and overall health-related scores. With the exception of relugolix with high-dose add-back, all treatments significantly increased low-density lipoprotein (LDL) levels. Again, all treatment modalities except for elagolix 200 mg without add-back significantly increased LDL-to-HDL ratio. The increase was highest for treatment without add-back therapy. CONCLUSION: Oral GnRH antagonists seem to be effective for myoma-associated bleeding and for improving quality of life. The safety profile is acceptable for short-term use, but lipid metabolism is affected.

Biological differences between focal and diffuse adenomyosis and response to hormonal treatment.

RESEARCH QUESTION: Is there any difference in ovarian steroid receptor expression and pattern of fibrosis in focal and diffuse adenomyosis and response to hormonal treatment? DESIGN: Prospective controlled study where biopsy samples were prospectively collected after surgery from 30 women with focal adenomyosis, 21 women with diffuse adenomyosis and 20 women with uterine myoma. Some of these women underwent 3-6 months of treatment with gonadotrophin-releasing hormone agonist (GnRHa) before surgery. Tissue expression of oestrogen receptor (ER) and progesterone receptor (PR) was analysed by immunohistochemistry. Distribution of tissue fibrosis was examined by Masson's trichrome staining with computer-based image analysis of fibrosis in tissues derived from women with and without adenomyosis. RESULTS: There was no difference in ER/PR expression in gland cells/stromal cells of adenomyotic lesions on the ipsilateral side of focal adenomyosis and the anterior/posterior walls of diffuse adenomyosis. Compared to myoma tissues, a relatively decreased expression of ovarian steroid receptors was observed in both focal and diffuse adenomyosis. Image analysis of tissue fibrosis indicated more fibrosis in both focal and diffuse adenomyosis compared to fibrosis in the myometrium derived from women with uterine myoma. The pattern of fibrosis was no different in tissues derived from GnRHa-treated and -untreated women with focal and diffuse adenomyosis. CONCLUSIONS: No difference was found in the expression of ER/PR and entity of fibrosis between women with focal and diffuse adenomyosis regardless of GnRHa treatment. A lower expression of ER/PR compared to myoma tissue potentially clarifies the biological rationale of non-response to hormonal therapies for adenomyosis.

Submyometrial vasopressin injection before microwave ablation of vascular-rich submucosal myomas: a preliminary case study.

Purpose: Vascular-rich myomas are resistant to treatment involving transcervical microwave myolysis. To overcome cooling by blood perfusion, we injected dilute vasopressin solution into the space between the myometrium and the surface of the vascular-rich myomas. Material and Methods: Seven outpatients [age (mean ± SD age), 44.9 ± 3.9 years] with a single symptomatic vascular-rich submucosal myoma measuring 4.2-9.2 cm (6.5 ± 2.5 cm) underwent transcervical microwave myolysis and microwave endometrial ablation. Before microwave irradiation, dilute vasopressin solution was injected into the space between the myometrium and the surface of the vascular-rich myoma. We assessed the changes in the volumes of the vascular-rich myomas and blood hemoglobin levels before and 3 and 6 months after treatment. In addition, improvements in menorrhagia and satisfaction after the operation were assessed using visual analog scales. Results: Submyometrial injection of dilute vasopressin effectively reduced the abundant blood flow. The vascular-rich myomas were necrotized and shrank significantly by 69.0% at 3 months and 72.4% at 6 months after the operation (p < .05). Blood hemoglobin levels significantly increased at 3 months (p < .01). In addition, the visual analog scale results indicated that menorrhagia improved subjectively and the patients were satisfied with the results of the operation. Conclusions: Vasopressin injection before transcervical microwave myolysis leads to extended necrosis of vascular-rich submucosal myomas.

Endostatin induces proliferation of oral carcinoma cells but its effect on invasion is modified by the tumor microenvironment.

The turnover of extracellular matrix liberates various cryptic molecules with novel biological activities. Endostatin is an endogenous angiogenesis inhibitor that is derived from the non-collagenous domain of collagen XVIII. Although there are a large number of studies on its anti-tumor effects, the molecular mechanisms are not yet completely understood, and the reasons why endostatin has not been successful in clinical trials are unclear. Research has mostly focused on its anti-angiogenic effect in tumors. Here, we aimed to elucidate how endostatin affects the behavior of aggressive tongue HSC-3 carcinoma cells that were transfected to overproduce endostatin. Endostatin inhibited the invasion of HSC-3 cells in a 3D collagen-fibroblast model. However, it had no effect on invasion in a human myoma organotypic model, which lacks vital fibroblasts. Recombinant endostatin was able to reduce the Transwell migration of normal fibroblasts, but had no effect on carcinoma associated fibroblasts. Surprisingly, endostatin increased the proliferation and decreased the apoptosis of cancer cells in organotypic models. Also subcutaneous tumors overproducing endostatin grew bigger, but showed less local invasion in nude mice xenografts. We conclude that endostatin affects directly to HSC-3 cells increasing their proliferation, but its net effect on cancer invasion seem to depend on the cellular composition and interactions of tumor microenvironment.

Comparison of the inhibitory effect of gonadotropin releasing hormone (GnRH) agonist, selective estrogen receptor modulator (SERM), antiprogesterone on myoma cell proliferation in vitro.

Uterine myomas are the most common gynecologic tumor in women of reproductive age. Treatment options of uterine myomas consist of surgical, medical and interventional therapy such as uterine artery embolization or myolysis. Given that it is the most common type of tumor in women of reproductive age, the treatment of uterine myomas must prioritize uterine conservation. There are several drugs for medical treatment of uterine myoma such as gonadotropin releasing hormone (GnRH) agonist, selective estrogen receptor modulator (SERM) and antiprogesterone. The objective of this study was to compare the effect of GnRH agonist, SERM, and antiprogesterone in the treatment of uterine myomas in vitro. The effect of drugs was evaluated through the cell viability assay in cultured leiomyoma cells, western blot analysis of proliferating cell nuclear antigen (PCNA), and BCL-2 protein expression. As a result, mifepristone single-treated group represents the most significant reduction in myoma cell viability and proliferation. When pretreated with leuprolide acetate, raloxifene shows more significant reduction in myoma cell viability and proliferation than mifepristone. This study suggests one of the possible mechanisms how medications act on uterine myoma, especially at the molecular level.

Effect of Lichong decoction on expression of Bcl-2 and Bcl-2-associated X protein mRNAs in hysteromyoma model rat.

OBJECTIVE: To study on effects of Lichong decoction on expression of apoptosis-controlling genes, Bcl-2 and Bcl-2-associated X protein (Bax) mRNAs in hysteromyoma tissue of the hysteromyoma model rat. METHODS: Fifty Wistar female rats were randomly divided into a normal group, a model group, a Lichong decoction group, a Guizifuling capsule group and a Mifepristone group. The hysteromyoma rat model was established by intraperitoneal injection of exogenous estrin and progestogens. Pathological examination of uterine tissue, uterine coefficient and uterine transverse diameter were made under optic microscope and expressions of Bcl-2 and Bax mRNAs in uterine tissue in the groups were detected with real-time fluorescent quantitative polymerase chain reaction (PCR) technique. RESULTS: After treatment, under microscope it was found that in the Lichong decoction group myometrium thinned, muscle fiber slightly overgrowth or long and thin, regular arrangement, inserting phenomenon of inner circular muscle and external longitudinal muscle was occasionally or not seen in the Lichong decoction group. The uterine coefficient and the uterine transverse diameter significantly decreased (P < 0.01), and Bcl-2 mRNA expression significantly decreased (P < 0.01) and Bax mRNA expression significantly increased in hysteromyoma tissue (P < 0.01) in the Lichong decoction group as compared with the model group. CONCLUSION: Therapeutic effects of Lichong decoction on hysteromyoma is related with decrease of Bcl-2 mRNA expression and increase of Bax mRNA expression.

Uterine fibroids treatment: do we have new valid alternative? Experiencing the combination of vitamin D plus epigallocatechin gallate in childbearing age affected women.

OBJECTIVE: Uterine myomas are the most common benign tumors in females, and at least 25% of affected patients experience symptoms severe enough to need treatment, like heavy hemorrhage, pelvic pain, and infertility. Currently, a non-invasive approach is preferred in women of childbearing age who desire pregnancy. The aim of our study was to determine the effect of oral supplementation with a combination of vitamin D plus epigallocatechin gallate (EGCG) and vitamin B6 in women with myomas. PATIENTS AND METHODS: Between April and December 2020, we enrolled 95 women of childbearing age, afferent to our hospital, displaying at least one myoma with a diameter <4 cm. Patients were divided in two groups: 41 women were treated daily with two tablets of 25 µg vitamin D + 150 mg EGCG + 5 mg vitamin B6 for 4 months; 54 women, representing the control group, received no treatment. Total volume and vascularization of myomas were analyzed ultrasonographically. Bleeding and pelvic pain was also evaluated, as well as patients' quality of life and health through questionnaire Short Form Health Survey (SF-36) and Patient Global Impression of improvement (PGI-I). RESULTS: After treatment myomas' total volume and peripherical vascularization significantly decreased respectively by 37.9% (p<0.001) and 7.7%. On the other hand, we observed an increase in myomas' volume by 5.5 % and of peripherical vascularization by 5% in the control group. The treated group reported an improvement in SF-36 (p<0.001) and PGI-I (85.4%) questionnaire scores. CONCLUSIONS: We demonstrated, in young women who want to preserve fertility, that the combined supplementation of vitamin D, EGCG, and vitamin B6 reduced myomas' volume and improved patients' quality of life, without side effects.

Lichong decoction inhibits micro-angiogenesis by reducing the expressions of hypoxia inducible factor-1α and vascular endothelial growth factor in hysteromyoma mouse model.

OBJECTIVE: To investigate the efficacy of Lichong decoction (LD) from Traditional Chinese Medicine, on micro-angiogenesis in a mouse model of hysteromyoma. METHODS: A mouse model of hysteromyoma was developed by orthotopic intrauterine injection of primary human myoma cells isolated from patients from the Beijing Obstetrics and Gynecology Hospital into CB-17 Scid mice. Mice were administered high-dose LD, low-dose LD, mifepristone or water (control) daily by gavage for 4 weeks. Uterine diameter and coefficient (uterine weight/body weight) were measured. Uterine morphology was assessed by light microscopy (hematoxylin and eosin) and transmission electron microscopy. Serum levels of estradiol, progesterone, follicle-stimulating hormone and luteinizing hormone (LH) were measured by enzyme-linked immunosorbent assay. Uterine protein expression of hypoxia inducible factor (HIF)-1α, CD31 and proliferating cell nuclear antigen (PCNA) was detected by immunohistochemistry. VEGF and HIF-1α mRNAs were quantified by RT-PCR. RESULTS: High-dose LD, low-dose LD and mifepristone reduced uterine diameter and coefficient, and attenuated the morphologic abnormalities associated with hysteromyoma. High-dose LD, low-dose LD and mifepristone inhibited hysteromyoma-induced micro-angiogenesis, as evidenced by a decrease in the number of new microvessels co-immunostaining for CD31 and PCNA (P < 0.01). High-dose LD and mifepristone lowered serum levels of estradiol, progesterone and LH (P < 0.05). High-dose LD, low-dose LD and mifepristone down-regulated HIF-1α mRNA and protein expressions and VEGF mRNA expression (P < 0.01). CONCLUSION: The inhibition of hysteromyoma by LD may involve reductions in HIF-1α and VEGF expression and suppression of micro-angiogenesis.

Oxytocin Administration in High-Intensity Focused Ultrasound Treatment of Myomata.

OBJECTIVES: The aim of the study was to evaluate the clinical efficacy of magnetic resonance-guided High-Intensity Focused Ultrasound (HIFU) in patients with symptomatic uterine fibroids (myomata) after application of oxytocin. METHODS: 156 women with symptomatic uterine fibroids were treated using MR-guided HIFU procedure. 51 patients had additional IV administration of 40 IU of oxytocin in 5% Glucose or 0,9% NaCl solution during therapy. Before and after the procedure we performed MR and measured initial perfused volume, final perfused volume, nonperfused volume (NPV), and treated volume ratio (TVR). The follow-up was up to 15 months to assess efficacy of treatment and relief of symptoms. RESULTS: Nonperfused volume was statistically significantly larger in oxytocin group than in control group (p=0.0019). The remaining parameters did not show significant difference between both groups. CONCLUSION: Oxytocin administration seems to improve efficiency of HIFU therapy although further research is required to assess its value. This study' clinical registration number is DRKS00014794.

Long-term use of progestogens--effects on endometriosis, adenomyosis and myomas.

Oral progestins, without an estrogen component, have been reported to be effective in the treatment of endometriosis, but not adenomyosis or myomas. The mode of action on the target tissue is still a matter of debate. Besides the importance of estrogens for the development and growth of endometriosis and myomas, progesterone seems to play an important role in the modulation of mitotic activity, local growth factors and growth factor receptors, as well as other paracrine mechanisms. Earlier studies postulated activities via steroid receptor mechanisms, as observed in the uterine mucosa and myometrium. Recent studies, however, have raised some doubts about this hypothesis. Effective new therapies for endometriosis have been introduced during the last 30 years and progestins now have a place in the symptomatic management of pain, bleeding and other symptoms caused by endometriosis, adenomyosis or myoma, particularly when long-term medication is indicated or when repeated courses of treatment are acceptable.

The use of levonorgestrel - IUD in the treatment of uterine myoma in Thai women.

OBJECTIVE: This study was designed to evaluate the potential usefulness of the levonorgestrel-releasing intrauterine device (LNG - IUD ; Mirena) in treating women with uterine myomas. DESIGN: Prospective before-and-after (comparing) study. SETTING: Department of Obstetrics and Gynecology King Chulalongkorn Memorial Hospital. SUBJECTS: Sixteen women with uterine myomas who intended to receive treatment with the LNG IUD. INTERVENTION(S): Clinical and ultrasound examinations were performed prior to and at 1, 3 and 6 months after the LNG IUD insertion. MAIN OUTCOME MEASURES: Myoma and Uterine volume, menstrual blood loss assessed with pictorial blood loss assessment charts and hematocrit. RESULTS: Use of the LNG IUD was associated with a statistically significant reduction in the total myoma volume, average uterine size and marked reduction in menstrual blood loss. After 6 months of use, the median total myoma volume decreased from 19.82 mL to 11.63 mL (p < 0.05), median pictorial blood loss assessment chart score declined from 89 to 3 (p < 0.05). Hematocrit level increased over 6 months of use. The most common side effects were bleeding disturbances (68.8%). No pregnancies occurred during the study. CONCLUSION: The LNG IUD was associated with a profound reduction in myoma and uterine volume. For women with myomas of this size, the LNG IUD provides effective medical treatment of bleeding.

Myoma migration: an unexpected "effect" with Ulipristal acetate treatment.

OBJECTIVE: Uterine myomas are one of the most common benign tumours, occurring in 20-40% of women of reproductive age. Ulipristal acetate (UPA) is a possible option for medical treatment of myomas. It induces amenorrhea and can reduce myoma volume before surgical treatment. Since its introduction in our department, we uncovered an unknown effect: migration of myoma. CLINICAL CASE REPORTS: We describe three clinical case of myoma migration following three months UPA pre-operative treatment. The first woman presented with a FIGO 2 myoma, which migrated in FIGO 3. A previously planned hysteroscopy converted into a laparoscopy. The second woman also presented with a FIGO 2 myoma, which migrated in FIGO 3. Initially, a hysteroscopy was planned, but ultimately surgery was no longer required. The third woman presented with a FIGO 2-5 myoma, which migrated in FIGO 1. The previously planned laparoscopy converted into a vaginal myomectomy. CONCLUSIONS: UPA induces a proapoptotic and anti proliferative effect of leiomyoma cells. It reduces expression of VEGF and reduces collagen deposition in the extracellular matrix. These mechanisms could induce migration of myoma. UPA as pre-operative treatment can induce migration of myoma and, therefore, can lead to perioperative conversion of surgery.

In vivo mechanisms of uterine myoma volume reduction with ulipristal acetate treatment.

OBJECTIVE: To study the in vivo mechanisms of action of ulipristal acetate (UPA) on uterine myomas. DESIGN: Retrospective histologic and immunohistochemical (IHC) study of myomas. SETTING: Academic research unit. PATIENT(S): Among 59 women with symptomatic myomas who underwent myomectomy, 42 were treated preoperatively with UPA, while 17 were not. INTERVENTION(S): Histology and IHC were analyzed on tissue microarrays obtained from surgical specimens. MAIN OUTCOME MEASURE(S): Proliferation, apoptosis, extracellular matrix (ECM) remodeling, and matrix metalloproteinase 2 (MMP-2) expression. RESULT(S): Proliferation was low in all conditions, with no statistical difference between groups. Terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay showed an increase in cell death in UPA-treated myomas compared with untreated myomas, but only after short-term treatment; this was not associated with elevated levels of cleaved caspase-3. After long-term treatment, cell density was higher and the ECM volume fraction lower in UPA-treated myomas than in untreated myomas. MMP-2 expression was found to be increased after treatment, showing the highest level after long-term treatment, compared with untreated myomas. CONCLUSION(S): Regarding sustained clinical volume reduction of myomas, this study strongly points to multifactorial mechanisms of action of UPA, involving: 1) a persistently low cell proliferation rate; 2) a limited period of cell death; and 3) ECM remodeling concomitant with stimulation of MMP-2 expression.

Recurrence of myomas after myomectomy in women pretreated with leuprolide acetate depot or placebo.

The recurrence of myomas and myoma-related symptoms was evaluated in women participating in a randomized, double-blind, P-controlled study of the efficacy of LA depot before myomectomy. After 27 to 38 months of follow-up, the recurrence of myomas was found to be greater when at least four myomas were resected. Myoma recurrence was not associated with pretreatment or preoperative uterine volume, resected myoma mass, or preoperative medical therapy.

Combined oral contraceptives: health benefits beyond contraception.

It has been recognized for over 50 years that combined oral contraceptives (COCs) are also capable of offering health benefits beyond contraception through the treatment and prevention of several gynaecological and medical disorders. During the last years a constant attention was given to the adverse effects of COCs, whereas their non-contraceptive benefits were underestimated. To date, most women are still unaware of the therapeutic uses of hormonal contraceptives, while on the contrary there is an extensive and constantly increasing of these non-contraceptive health benefits. This review summarizes the conditions of special interest for physicians, including dysmenorrhoea, menorrhagia, hyperandrogenism (acne, hirsutism, polycystic ovary syndrome), functional ovarian cysts, endometriosis, premenstrual syndrome, myomas, pelvic inflammatory disease, bone mineral density, benign breast disease and endometrial/ovarian and colorectal cancer. The benefits of COCs in rheumatoid arthritis, multiple sclerosis, menstrual migraine and in perimenopause have also been treated for more comprehensive information. Using COCs specifically for non-contraceptive indications is still outside the product licence in the majority of cases. We strongly believe that these aspects are not of minor relevance and they deserve a special consideration by health providers and by the mass media, which have the main responsibility in the diffusion of scientific information. Thus, counseling and education are necessary to help women make well-informed health-care decisions and it is also crucial to increase awareness among general practitioners and gynaecologists.

Advances in management of uterine myomas.

Uterine myomas, the most common benign solid pelvic tumors in women, occur in twenty percent of them in reproductive years and form the most common indication for hysterectomy. Various factors affect the choice of the best treatment modality for a given patient. Asymptomatic myomas may be managed by careful follow up. Medical therapy should be tried as a first line of treatment for symptomatic myomas while surgical treatment should be reserved only for appropriate indications. Myomectomy would be preferred over hysterectomy in those wishing subsequent childbearing. Preoperative GnRH-analogue treatment reduces the myoma size and vascularity but may render the capsule more difficult to resect. Poor surgical risk women with large symptomatic myomas or those wishing to avoid major surgical procedures may be offered uterine artery embolization. Serial follow-up for growth and symptoms may be appropriate for asymptomatic perimenopausal women. The present article reviews the available therapeutic modalities for uterine myomas.

Regulation of dosage of conjugated equine estrogen is useful for add-back therapy.

In the hormonal treatment of uterine myomas, which are estrogen dependent, GnRH agonist (GnRHa) therapy has become widespread. However, the severe hypo-estrogenic state induced by the GnRHa gives rise to annoying side effects. Although the risk of these side effects may be reportedly modified when GnRHa is combined with estrogen (add-back therapy), it is difficult to target serum estradiol (E2) concentration to stay within the therapeutic window (20 approximately 50 pg/mL) by administering 0.625 mg conjugated equine estrogen (CEE)/day. Also, there is great individual variation in the circulating E2 concentration by administering the same dosage of CEE. Therefore, the use of smaller quantities of CEE in different dosages may approximate more closely to the clinical situation. This article focuses on the methods of administration of CEE combined with GnRHa for women with symptomatic uterine myomas.