EC Gynaecology

Uterine leiomyomata (UL) are smooth muscle tumors of the uterus. They are commonly called as fibroids, grossly round, well circumscribed and encapsulated solid nodules. About 20% to 80% of women develop fibroids by the age of fifty. UL cause abnormal uterine bleeding, pelvic pain, pressure, infertility, repetitive abortions. Early menarche, age, obesity, endocrine changes, family history, ethnicity are the main risk factors. In addition to hormonal factors, various gene polymorphisms and variants have been associated with UL susceptibility. Among them somatic variants in second exon of MED12 gene were around 70% - 85% globally, but in the South Indian population there were approximately 40% variants of MED12 and Collagen gene missense variants rs36117715 and rs 2270669 increasing UL susceptibility in women.

Keywords: Uterine Leiomyomata; Somatic Mutations; Missense Variants; Codon 58

1. Anne Zimmermann., et al. “Prevalence, symptoms and management of uterine fibroids: an international internet-based survey of 21,746 women”. BMC Womens Health 12 (2012): 6.
2. T P Venu., et al. Fibroid removal accounts for 30 per cent of operations in city hospital (2016).
3. Gordon P Flake., et al. “Etiology and Pathogenesis of Uterine Leiomyomas: A Review”. Environmental Health Perspectives8 (2003): 1037-1054.
4. Sato F., et al. “Early normal menstrual cycle pattern and the development of uterine leiomyomas”. Journal of Women's Health and Gender-Based Medicine3 (2000): 299-302.
5. Velebil P., et al. “Rate of hospitalization for gynecologic disorders among reproductive-age women in the United States”. Obstetrics and Gynecology5 (1995): 764-769.
6. Sato F., et al. “Body fat distribution and uterine leiomyomas”. Journal of Epidemiology3 (1998): 176-180.
7. Radin RG., et al. “Intake of fruit, vegetables, and carotenoids in relation to risk of uterine leiomyomata”. The American Journal of Clinical Nutrition6 (2011): 1620-1631.
8. Baird DD., et al. “African Americans at higher risk than whites for uterine fibroids; ultrasound evidence”. American Journal of Epidemiology 147 (1998): S90.
9. Okolo S., et al. “Incidence, aetiology and epidemiology of uterine fibroids”. Best Practice and Research Clinical Obstetrics and Gynaecology4 (2008): 571-588.
10. Luoto R., et al. “Heritability and risk factors of uterine fibroids--the Finnish Twin Cohort study”. Maturitas1 (2000): 15-26.
11. Peddada SD., et al. “Growth of uterine leiomyomata among premenopausal black and white women”. Proceedings of the National Academy of Sciences of the United States of America50 (2008): 19887-19892.
12. Halder SK., et al. “Vitamin D inhibits proliferation of human uterine leiomyoma cells via catechol-O-methyltransferase”. Fertility and Sterility1 (2011): 247-253.
13. Holzmann C., et al. “Genome-wide acquired uniparental disomy as well as chromosomal gains and losses in an uterine epithelioid leiomyoma”. Molecular Cytogenetics 7 (2014): 19.
14. Ridker PM., et al. “Rationale, design, and methodology of the Women's Genome Health Study: a genome-wide association study of more than 25,000 initially healthy American women”. Clinical Chemistry2 (2008): 249-255.
15. Sato F., et al. “Familial aggregation of uterine myomas in Japanese women”. Journal of Epidemiology3 (2002): 249-253.
16. Treloar SA., et al. “Pathways to hysterectomy: insights from longitudinal twin research”. American Journal of Obstetrics and Gynecology1 (1992): 82-88.
17. Sanz Orteqa J., et al. “Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome”. The American Journal of Surgical Pathology1 (2013): 74-80.
18. Alam NA., et al. “Fumarate hydratase (FH) mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer”. British Journal of Dermatology1 (2005): 11-17.
19. Navarro A., et al. “Genome-wide DNA methylation indicates silencing of tumor suppressor genes in uterine leiomyoma”. PLoS One3 (2012): e33284.
20. Wei LH., et al. “Histone deacetylase 6 regulates estrogen receptor alpha in uterine leiomyoma”. Reproductive Sciences8 (2011): 755-762.
21. Fitzgerald JB., et al. “Role of microRNA-21 and programmed cell death 4 in the pathogenesis of human uterine leiomyoma”. Fertility and Sterility3 (2012): 726-734.e2.
22. Ono M., et al. “Side population in human uterine myometrium displays phenotypic and functional characteristics of myometrial stem cells”. Proceedings of the National Academy of Sciences of the United States of America47 (2007): 18700-18705.
23. Saxena SP., et al. “DDT and its metabolites in leiomyomatous and normal human uterine tissue”. Archives of Toxicology6 (1987): 453-455.
24. Walker CL. “Role of hormonal and reproductive factors in the etiology and treatment of uterine leiomyoma”. Recent Progress in Hormone Research 57 (2002): 277-294.
25. Shimomura Y., et al. “Up-regulation by progesterone of proliferating cell nuclear antigen and epidermal growth factor expression in human uterine leiomyoma”. The Journal of Clinical Endocrinology and Metabolism6 (1998): 2192-2198.
26. Lee EJ., et al. Gene expression profiles of normal uterine myometrium and leiomyoma and their estrogen responsiveness in vitro (2010).
27. Adams A., et al. Regulation of estrogen (E)and progestin (P) receptors (R) in leiomyomas during the cycle and leuprolide acetate treatment (1993).
28. Yoshida S., et al. “Cell-type specific actions of progesterone receptor modulators in the regulation of uterine leiomyoma growth”. Seminars in Reproductive Medicine3 (2010): 260-273.
29. Chen W., et al. “A novel selective progesterone receptor modulator asoprisnil (J867) inhibits proliferation and induces apoptosis in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells”. The Journal of Clinical Endocrinology and Metabolism4 (2006): 1296-12304.
30. Segars JH., et al. “The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy”. Human Reproduction Update2 (2014): 194-216.
31. Ren Y., et al. “Different effects of epidermal growth factor on smooth muscle cells derived from human myometrium and from leiomyoma”. Fertility and Sterility4 (2011): 1015-1020.
32. Liang M., et al. “Expression and functional analysis of platelet-derived growth factor in uterine leiomyomata”. Cancer Biology and Therapy1 (2006): 28-33.
33. Arici A., et al. “Transforming growth factor beta-3 is expressed at higher levels in leiomyoma where it stimulates fibronectin expression and cell proliferation”. Fertility and Sterility5 (2000): 1006-1011.
34. Gao Z., et al. “Up-regulation by IGF-I of proliferating cell nuclear antigen and Bcl-2 protein expression in human uterine leiomyoma cells”. The Journal of Clinical Endocrinology and Metabolism11 (2001): 5593-5599.
35. Wolańska M., et al. “Fibroblast growth factors (FGF) in human myometrium and uterine leiomyomas in various stages of tumor growth”. Biochimie2 (2006): 141-146.
36. Pasquapina Ciarmela., et al. “Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications”. Human Reproduction Update6 (2011): 772-790.
37. Lewicka A., et al. “Expression of Vascular Endothelial Growth Factor mRNA in human leiomyomas”. Gynecological Endocrinology6 (2010): 451-455.
38. Litovkin KV., et al. “Interleukin-6 -174G/C polymorphism in breast cancer and uterine leiomyoma patients: a population-based case control study”. Experimental Oncology4 (2007): 295-298.
39. Mehrad B., et al. “Chemokines as mediators of angiogenesis”. Thrombosis and Haemostasis5 (2007): 755-762.
40. Wolanska M., et al. “Extracellular matrix components in uterine leiomyoma and their alteration during the tumor growth”. Molecular and Cellular Biochemistry1-2 (1998): 145-152.
41. Moore AB., et al. “Human uterine leiomyoma-derived fibroblasts stimulate uterine leiomyoma cell proliferation and collagen type I production, and activate RTKs and TGF beta receptor signaling in coculture”. Cell Communication and Signaling 8 (2010): 10.
42. Catherino WH., et al. “Reduced dermatopontin expression is a molecular link between uterine leiomyomas and keloids”. Genes Chromosomes Cancer3 (2004): 204-217.
43. Carrino DA., et al. “Proteoglycans of uterine fibroids and keloid scars: similarity in their proteoglycan composition”. Biochemical Journal2 (2012): 361-368.
44. Dou Q., et al. “Differential expression of matrix metalloproteinases and their tissue inhibitors in leiomyomata: a mechanism for gonadotrophin releasing hormone agonist-induced tumor regression”. Molecular Human Reproduction11 (1997): 1005-1014.
45. Shaik NA., et al. “Polymorphic (CAG)n repeats in the androgen receptor gene: a risk marker for endometriosis and uterine leiomyomas”. Hematology/Oncology and Stem Cell Therapy1 (2009): 289-293.
46. Cha PC., et al. “A genome-wide association study identifies three loci associated with susceptibility to uterine fibroids”. Nature Genetics5 (2011): 447-450.
47. Mehine M., et al. “Genomics of uterine leiomyomas: Insights from high-throughput sequencing”. Fertility and Sterility3 (2014): 621-629.
48. Alam NA., et al. “Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency”. Human Molecular Genetics11 (2003): 1241-1252.
49. Netta Mäkinen., et al. “MED12, the Mediator Complex Subunit12 Gene, Is Mutated at High Frequency in Uterine Leiomyomas”. Science6053 (2011): 252-255.
50. Ruqia Firdaus., et al. “Multiple Mutations in Exon-2 of Med-12 Identified in Uterine Leiomyomata”. Journal of Reproduction and Infertility3 (2021): 201-209.
51. Aissani B., et al. “Follow-up to genome-wide linkage and admixture mapping studies implicates components of the extracellular matrix in susceptibility to and size of uterine fibroids”. Fertility and Sterility2 (2015): 528-34.e13.
52. Firdaus R., et al. “Association of Col6a3 Missense Variants with Uterine Leiomyomata”. International Journal of Scientific Research in Biological Sciences3 (2021): 14-18.
53. Schoenmakers EF., et al. “Identification of CUX1 as the recurrent chromosomal band 7q22 target gene in human uterine leiomyoma”. Genes Chromosomes Cancer1 (2013): 11-23.
54. Guarnaccia MM and Rein MS. “Traditional surgical approaches to uterine fibroids: abdominal myomectomy and hysterectomy”. Clinical Obstetrics and Gynecology2 (2001): 385-400.
55. Salama SA., et al. “Gene therapy of uterine leiomyoma: adenovirus -mediated herpes simplex virus thymidine kinase/ganciclovir treatment inhibits growth of human and rat leiomyoma cells in vitro and in a nude mouse model”. The Gynecologic and Obstetric Investigation2 (2007): 61-70.
56. Moravek MB., et al. “Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications”. Human Reproduction Update 21 (2015): 1-12.