Harvard-MIT Division of Health Sciences and Technology HST.071: Human Reproductive Biology Course Director: Professor Henry Klapholz HST 071IN SUMMARY FIBROIDS FIBROIDS • Smooth muscle tumors of the uterus ,very common; • Occur in more than one third of women over the age of 35 • Complaints include discharge, bleeding from the vagina, pain, pressure • Circumscribed -but not truly encapsulated • Tumor can be readily "shelled out." -is glistening gray • Composed of interdigitating bundles of smooth muscle. • Incidence in black women three times greater than in white women. • Strong hormonal relationship LOCATION • Intramural, subserosal, and submucosal • Subserosal and submucosal leiomyomas may become pedunculated • Submucosal leiomyomas most important -bleeding symptoms may occur • May occur in the cervix and broad ligaments as well • Few mitoses are present • Their spindle shape is readily apparent. • When the cells are cut across the nuclei appear round • Frequently undergo degeneration. -hyaline and cystic • Presence of large amounts of connective tissue -known as fibromyomas or "fibroids” • Bleeding symptoms caused in part by thinning of the overlying endometrium • Vessels are not capable of retracting in the usual manner • No basal zone from which the overlying thin layer of endometrium can regenerate • Submucous, pedunculated leiomyomas may prolapse • Necrosis in intramural leiomyomas -Only one artery supplies the leiomyoma • May calcify or undergo “red” degeneration ATYPICALITY • Atypicalities occur in leiomyomas -may be confused with leiomyosarcomas • Mitotic rate is characteristically less than 5 per 10 high-power fields • Intravascular leiomyoma -rare tumor -nodular masses of histologically benign smooth muscle growing within veins INCIDENCE & ETIOLOGY • Most common solid pelvic tumors in women • Clinically apparent in 20% to 25% of women during the reproductive years • Pathologic inspection of the uterus -present in more than 80% • Leiomyomas are clonal in origin o Classic paradigm – caused by and stimulated to grow by o Estrogen o Progesterone It is now clear that the following are responsible for fibroid growth o Transforming growth factor-s o Basic fibroblast growth factor o Somatic mutations of genes such as HMGI-C Fibroids are characterized by their location in the uterus o Subserosal leiomyomas o Intramural leiomyomas o Submucous leiomyomas • Few leiomyomas are actually of a single "pure" type • Most leiomyomas are hybrids that span more than one anatomic location • Increased incidence of leiomyomas in women of color • Risk is increased in women with greater body mass index • Decreased in women who smoke or who have given birthIN SUMMARY HST 071 FIBROIDS • Good epidemiological evidence to suggest that use of oral contraceptive • Birth control pills decreases the risk for leiomyomas • 20% and 50% of women with leiomyomas have tumor-related symptoms • Fibroids often cause – Abnormal uterine bleeding Prolonged menstrual flow (menorrhagia) Submucous leiomyomas appear to be particular– Pelvic pressure. – Increase in uterine size – Pressure of particular myomas on adjacent structures Colon -constipation Bladder -urinary frequency. Ureters -hydronephrosis – Recurrent miscarriage – Infertility – Premature labor – Fetal malpresentation – Complications of labor DIAGNOSIS • Easily determined by bimanual examination – Uterus is enlarged – Mobile – Irregular – Palpated abdominally above the symphysis • Ultrasonography most common method for diagnosis ly prone – Submucous fibroid can be missed on traditional ultrasonography • Magnetic resonance imaging (MRI) – Electron spin characteristics can often distinguish • Leiomyomas • Adenomyomas • Leiomyosarcomas • Primary therapy for patients with large or symptomatic leiomyomas is surgery • Hysterectomy is the most often • United States: more than 175,000 hysterectomies are performed yearly for leiomyomas o Diagnosis of leiomyoma the most common indication for this procedure o Hysterectomy, the only true "cure" for leiomyoma, is a surgical option when women are no longer interested in future pregnancies • Subtraction angiography o Easily visualize the fibroids and also embolize them in order to cause infarction o May dramatically reduce bleeding as well as size. • Myomectomy o 18,000 myomectomies are performed yearly o Myomectomy diminishes menorrhagia in roughly 80% o Significant risk for recurrence of leiomyomas o Ultrasonography evidence of recurrence in 25% to 51% of patients o 10% require a second major operative procedure • GnRH agonists (Lupron, Naferelin, Gosserelin) o Induce a hypo estrogenic pseudo menopausal state o Fibroids are dependent on estrogen for their development and growth o Hypo estrogenic state causes shrinkage o Uterine volume has been shown to decrease 40% to 60% after 3 monthsIN SUMMARY HST 071 FIBROIDS o Induces amenorrhea – increase iron stores and hemoglobin concentrations o Cessation of GnRH agonist treatment results in rapid re-growth o GnRH agonist treatment is useful as a pre-surgical treatment o Not a long-term treatment option • Androgenic agents – Danazol – Gestrinone • Progestins – Medroxyprogesterone acetate (Provera) – Depo medroxyprogesterone acetate (Depo-Provera) – Norethindrone • Do not consistently decrease uterine or fibroid volume • Mechanism of action is thought to be the induction of endometrial atrophy • Often not successful in controlling significant menorrhagia • Somatic mutation is the initial event in most tumorigenesis • Somatic mutations include a variety of chromosomal aberrations Point mutations or Chromosomal loss or gain. • Large chromosomal abnormalities such as translocations and deletions often detected with standard cytogenetic karyotypes • Independent monoclonal origin of individual myomas • Suggests somatic mutations offer a selective growth advantage to the mutated myocyte Variety of chromosomal rearrangements • Most common 12q14-15 and 7q22 • Heterogeneity of the cytogenetic abnormalities • Different somatic mutations may be involved in myoma tumorigenesis • Unique somatic mutations in individual myomas • Biologic basis for the differential responsiveness of individual myomas to a variety of