Management of leiomyomas in perimenopausal women.

Uterine leiomyomas, commonly called fibroids, are the leading indication for hysterectomy in the United States. Incidence increases with age from menarche to perimenopause. Regardless of their generally benign neoplastic character, uterine fibroids are responsible for significant morbidity in a large proportion of women of reproductive age. As uterine leiomyomas generally regress after menopause, the general attitude when women are approaching perimenopausal age is to avoid treatment and wait for menopause and a spontaneous resolution. When it is decided that treatment is needed, the choice for peri- and postmenopausal women is often hysterectomy. In the present paper we point out aspects of leiomyoma management that are unique to the perimenopausal period, and address future directions in care. We conclude that the management of uterine leiomyomas should not be overlooked in the perimenopausal period merely on the grounds that the pathology and symptoms are unlikely to persist after the menopause; on the other hand, opting for a quick resolution with total surgical removal of the uterus, as seen at present in many cases, should be avoided. Studies on the impact of therapy for fibroids should be performed not exclusively with premenopausal women but also with perimenopausal and postmenopausal women, both users and non-users of hormone replacement therapy.

Role of activin-A and myostatin and their signaling pathway in human myometrial and leiomyoma cell function.

CONTEXT: Uterine leiomyomas are highly prevalent benign tumors of premenopausal women and the most common indication for hysterectomy. However, the exact etiology of this tumor is not fully understood. OBJECTIVE: The objective of the study was to evaluate the role of activin-A and myostatin and their signaling pathways in human myometrial and leiomyoma cells. DESIGN: This was a laboratory study. SETTING: Myometrial and leiomyoma cells (primary and cell lines) were cultured in vitro. PATIENTS: The study included premenopausal women who were admitted to the hospital for myomectomy or hysterectomy. INTERVENTIONS: Primary myometrial and leiomyoma cells and/or cell lines were treated with activin-A (4 nM) and myostatin (4 nM) for different days of interval (to measure proliferation rate) or 30 minutes (to measure signaling molecules) or 48 hours to measure proliferating markers, extracellular matrix mRNA, and/or protein expression by real-time PCR, Western blot, and/or immunocytochemistry. RESULTS: We found that activin-A and myostatin significantly reduce cell proliferation in primary myometrial cells but not in leiomyoma cells as measured by a CyQUANT cell proliferation assay kit. Reduced expression of proliferating cell nuclear antigen and Ki-67 were also observed in myometrial cells in response to activin-A and myostatin treatment. Activin-A also significantly increased mRNA expression of fibronectin, collagen1A1, and versican in primary leiomyoma cells. Finally, we found that activin-A and myostatin activate Smad-2/3 signaling but do not affect ERK or p38 signaling in both myometrial and leiomyoma cells. CONCLUSIONS: This study results suggest that activin-A and myostatin can exert antiproliferative and/or fibrotic effects on these cell types via Smad-2/3 signaling.

Complex networks of multiple factors in the pathogenesis of uterine leiomyoma.

OBJECTIVE: To summarize the information regarding pathogenetic factors of leiomyoma formation and growth, and to make a simple integrated pathogenetic view of this tumor for further thinking to establish new therapeutic options. DESIGN: PubMed and Google Scholar searches were conducted to identify the relevant studies on pathogenesis of uterine leiomyoma, which are hereby reviewed and discussed. SETTING: Academic medical center. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Not applicable. RESULT(S): To date, the pathogenesis of uterine leiomyomas is not well understood. However, genetic alterations (especially MED12 and HMGA2) and involvement of epigenetic mechanisms (DNA methylation, histone modifications, and microRNA) in leiomyoma provide the clue of initiator of this tumor. Estrogens and P are considered as promoters of leiomyoma growth, and growth factors, cytokines, and chemokines are thought to be as potential effectors of estrogens and P. Extracellular matrix components are a major structural part of leiomyoma tissue that are abnormally orientated and can modify mechanical stress on cells, which leads to activation of internal mechanical signaling and may contribute to leiomyoma growth. CONCLUSION(S): Besides many genetics and epigenetic factors, the important link among the sex steroids, growth factors, cytokines, chemokines, and extracellular matrix and their involvement in cell proliferation, fibrotic processes, apoptosis, and angiogenesis are implicating a complex network in leiomyoma formation and growth. Those findings could provide information to establish future therapeutic options for the management of this tumor.