Traditional surgical approaches to uterine fibroids: abdominal myomectomy and hysterectomy.

Abdominal myomectomy and hysterectomy remain the traditional treatment of large symptomatic uterine myomas. The preoperative indications for abdominal myomectomy or hysterectomy must be clearly evaluated and delineated avoid unnecessary intervention. There appears to be an increasing trend toward expectant management for asymptomatic uterine myomas. Women should consider the options of myomectomy and hysterectomy when their symptoms are severe enough to warrant intervention and the benefits of intervention outweigh the risks. The advantages and disadvantages of preoperative medical also must be addressed before intervention. The factors influencing the choice of therapy seem to be strongly dependent on both the patient and physician preferences. A clinical approach to abdominal myomectomy in patients with infertility and repetitive miscarriage has been presented in this chapter. The rapid development and use of minimally invasive innovations and adjunctive medical therapies has provided clinicians with a wealth of alternatives. A practical and cost-effective approach based on the data currently available have been presented; however, there remains a paucity of prospective randomized data to evaluate and compare the effectiveness and safety of these alternative treatments to abdominal myomectomy and hysterectomy. Future studies should help define the optimal candidates for traditional surgical treatment with abdominal myomectomy and hysterectomy.

Advances in uterine leiomyoma research: the progesterone hypothesis.

Uterine leiomyomas are monoclonal tumors. However, the factors involved in their initiation and growth remain poorly understood. The neoplastic transformation of myometrium to leiomyoma likely involves somatic mutations of normal myometrium and the complex interactions of sex steroids and local growth factors. Traditionally, estrogen has been considered the major promoter of myoma growth. The purpose of this review is to highlight the biochemical, histologic, and clinical evidence that supports an equally important role for progesterone in the growth of uterine myomas. Biochemical studies suggest that progesterone, progestins, and the progesterone receptor modulate myoma mitotic activity. A hypothesis to explain the pathogenesis of myomas is presented.

Multinucleation in normally fertilized embryos is associated with an accelerated ovulation induction response and lower implantation and pregnancy rates in in vitro fertilization-embryo transfer cycles.

OBJECTIVE: To determine if multinucleation in normally fertilized embryos is indicative of poor developmental or clinical pregnancy prognosis and to examine the ovulation induction characteristics associated with multinucleation. DESIGN: Retrospective review. SETTING: A tertiary care institution. PATIENT(S): Patients undergoing IVF-ET cycles (exclusive of other assisted reproductive technologies). MAIN OUTCOME MEASURE(S): Cycles in which embryos had at least 1 multinucleated blastomere were compared with cycles in which all blastomeres exhibited no nucleus or a single nucleus (control). RESULT(S): When >50% of transferred embryos contained multinucleated blastomeres there was a significant reduction in implantation (3.4% vs. 14.7%), clinical pregnancy (9.1% vs. 29.1%), and live birth rates (7.5% vs. 27.6%) when compared with transfers of control embryos. In conjunction with this finding, multinucleate cycles had higher E2 levels and more follicles on the day of hCG administration, a higher number of oocytes retrieved, a higher fertilization rate, and more embryos transferred per patient than did the cycles that produced control embryos. When multinucleated embryos were present, but not transferred, the developmental capacity of the sibling embryo was reduced. CONCLUSION(S): The evaluation of nuclear status using simple light microscopy is predictive of embryo developmental capacity and should be included in the embryo scoring system. The presence of multinucleated blastomeres in normally fertilized embryos is associated with a more effusive response to gonadotropin therapy and is indicative of a poor developmental outcome and lower clinical pregnancy rates.

Cytogenetic abnormalities in uterine myomas are associated with myoma size.

Uterine leiomyomata (myomas) are associated with a variety of characteristic cytogenetic abnormalities. The significance of these chromosomal aberrations in the pathobiology of myomas remains to be determined. The present study investigated the relationship between myoma cytogenetic abnormalities and size. A total of 114 myoma specimens were obtained from 92 patients undergoing myomectomy or hysterectomy. The maximum diameter of each myoma was measured and a portion of each myoma obtained for cytogenetic analysis. Karyotypes were analysed and categorized as normal, abnormal (non-mosaic) or mosaic. Cytogenetic analyses revealed 73 (64%) normal, 20 (18%) abnormal (non-mosaic), and 21 (18%) mosaic karyotypes. Mean myoma diameter was 6.5+/-0.44 cm with a range of 0.4-27 cm. Differences between the mean myoma diameter of specimens with normal versus abnormal karyotypes was determined by the Kruskal-Wallis test. The mean myoma diameter among specimens with abnormal (non-mosaic) karyotypes was significantly greater than myomas with normal karyotypes (10.2+/-5.9 versus 5.9+/-4.2 cm; P < 0.001). The proportion of abnormal (non-mosaic) karyotypes in myomas >6.5 cm was compared to myomas <6.5 cm by chi2-analysis; myomas >6.5 cm demonstrated a significantly higher proportion of abnormal (non-mosaic) karyotypes when compared to myomas <6.5 cm (75 versus 34%; P < 0.02). In summary, a significant relationship exists between clonal cytogenetic abnormalities and myoma size, suggesting that chromosomal abnormalities associated with individual myomas enhance myoma growth.

Translocation breakpoints upstream of the HMGIC gene in uterine leiomyomata suggest dysregulation of this gene by a mechanism different from that in lipomas.

Uterine leiomyomata are the most common pelvic tumors in women and are the indication for more than 200,000 hysterectomies annually in the United States. Rearrangement of chromosome 12 in bands q14-q15 is characteristic of uterine leiomyomata and other benign mesenchymal tumors, and we identified a yeast artificial chromosome (YAC) spanning chromosome 12 translocation breakpoints in a uterine leiomyoma, a pulmonary chondroid hamartoma, and a lipoma. Recently, we demonstrated that HMGIC, which is an architectural factor mapping within the YAC, is disrupted in lipomas, resulting in novel fusion transcripts. Here, we report on the localization of translocation breakpoints in seven uterine leiomyomata from 10 to > 100 kb upstream of HMGIC by use of fluorescence in situ hybridization. Our findings suggest a different pathobiologic mechanism in uterine leiomyomata from that in lipomas. HMGIC is the first gene identified in chromosomal rearrangements in uterine leiomyomata and has important implications for an understanding of benign mesenchymal proliferation and differentiation.

A randomized clinical trial to evaluate the clinical effects of split- versus single-dose human menopausal gonadotropins in an assisted reproductive technology program.

OBJECTIVE: To compare the effect of twice (split) versus once (single) daily administration of hMG on assisted reproductive technology (ART) cycle parameters. DESIGN: A randomized clinical trial. SETTING: Hospital-based academic ART program. PATIENTS: A total of 171 patients undergoing their initial ART cycle were enrolled. All patients received one of two hMG regimens and were excluded from the study if they were receiving medications other than leuprolide acetate (LA) and hMG for ovulation induction. INTERVENTIONS: Subjects were randomized to receive an initial dose of 300 IU/d of hMG in either split-dose (i.e., 150 IU twice daily) or single-dose fashion for four successive days after down-regulation with LA. Thereafter, their daily dose was individualized, maintaining a split-or single-dose schedule. All cycles were managed in accordance with our standard ART protocols. MAIN OUTCOME MEASURES: Cancellation rate, total hMG requirements, number of days treated with hMG, E2 and P responses, oocyte yield and maturity, fertilization rate, total number of embryos, embryo quality, number of embryos transferred, implantation rate, clinical and ongoing-delivered pregnancy rates. RESULTS: Split-dose hMG administration resulted in a significantly higher implantation rate, but significantly lower normal and polyspermic fertilization rates than single-dose hMG administration. No significant differences were noted between the two dosage protocols with respect to the other outcome measures. CONCLUSIONS: Split-dose hMG administration may be associated with significantly higher implantation rates; single-dose hMG with significantly higher fertilization rates. Although our data also demonstrate a trend toward higher clinical and ongoing-delivered pregnancy rates with split-dose therapy, demonstration of a significant difference would require a multicenter trial. Based on our data, clinicians may want to consider split-dose therapy for patients with repeated implantation failures.

Dexamethasone during ovulation induction for in-vitro fertilization: a pilot study.

The purpose of the present study was to determine whether adrenal androgen suppression with dexamethasone (DEX) during ovulation induction improves the outcome of in-vitro fertilization (IVF) cycles. A total of 25 patients with serum dehydroepiandrosterone sulphate (DHEAS) concentrations > 2.5 micrograms/ml were randomized to receive either 0.5 mg DEX daily or placebo during ovulation induction with leuprolide acetate down-regulation plus human menopausal gonadotrophins (HMG). Nine patients undergoing a subsequent IVF cycle were crossed over to the other treatment group. Ovarian responsiveness and IVF outcome variables analysed included number of follicles > 12 mm in diameter, serum oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration, number of ampoules of HMG administered, number of oocytes retrieved, percentage of oocytes fertilized, number of embryos transferred, implantation rate and numbers of clinical pregnancies and live birth pregnancies. The 31 randomized IVF cycles revealed a trend towards a higher implantation rate for the placebo-treated group compared to the DEX-treated group (24 versus 10%; P = 0.07). The remainder of the IVF cycle variables revealed no statistically significant differences. In conclusion, the suppression of adrenal androgens with DEX in women with DHEAS concentrations > 2.5 micrograms/ml appears to have no beneficial effects on ovarian responsiveness or clinical or live birth pregnancy rates.

Identification of a YAC spanning the translocation breakpoints in uterine leiomyomata, pulmonary chondroid hamartoma, and lipoma: physical mapping of the 12q14-q15 breakpoint region in uterine leiomyomata.

Uterine leiomyomata are the most common tumors in women and can cause abnormal uterine bleeding, pelvic pain, and infertility. Approximately 200,000 hysterectomies are performed annually in the U.S. to relieve patients of the medical sequelae of these benign neoplasms. Our efforts have focused on cloning the t(12;14)(q14-q15;q23-q24) breakpoint in uterine leiomyoma to further our understanding of the biology of these tumors. Thirty-nine YACs and six cosmids mapping to 12q14-q15 have been mapped by fluorescence in situ hybridization to tumor metaphase chromosomes containing a t(12;14). One YAC spanned the translocation breakpoint and was mapped to tumor metaphases from a pulmonary chondroid hamartoma containing a t(12;14)(q14-q15;q23-q24) and a lipoma containing a t(12;15)(q15;q24); this YAC also spanned the breakpoint in these two tumors, suggesting that the same gene on chromosome 12 may be involved in the pathobiology of these distinct benign neoplasms.

Progesterone: a critical role in the pathogenesis of uterine myomas.

Uterine leiomyomas are monoclonal tumors. However, the factors involved in their initiation and growth remain poorly understood. The neoplastic transformation of myometrium to leiomyoma likely involves somatic mutations of normal myometrium and the complex interactions of sex steroids and local growth factors. Traditionally, estrogen has been considered the major promoter of myoma growth. The purpose of this review is to highlight the biochemical, histologic, and clinical evidence that supports an equally important role for progesterone in the growth of uterine myomas. Biochemical studies suggest that progesterone, progestins, and the progesterone receptor modulate myoma mitotic activity. Several clinical trials demonstrate that progestins inhibit and/or reverse the ability of hypoestrogenism induced by a gonadotropin-releasing hormone agonist to shrink uterine myomas, suggesting a critical role for progesterone in growth of myomas. A new hypothesis to explain the pathogenesis of myomas is presented.

Translocations in 7q22 define a critical region in uterine leiomyomata.

Rearrangements involving the long arm of chromosome 7 in uterine leiomyoma are widely recognized and comprise one of the major cytogenetic subgroups of these tumors. To approach a molecular genetic investigation of this subgroup for identification of a gene(s) involved in the biology of uterine leiomyomata we have analyzed breakpoints in the del(7q) subgroup in a series of myomas karyotyped in our laboratory. Herein we report the cytogenetic analysis of 11 uterine leiomyomata: eight with interstitial deletions in the long arm of chromosome 7 and three with translocations in 7q. These translocations provide further support for 7q22 as the critical band in the del(7q) subgroup.

Long-term medical therapy for leiomyomata uteri: a prospective, randomized study of leuprolide acetate depot plus either oestrogen-progestin or progestin 'add-back' for 2 years.

Treatment of women with leiomyomata with gonadotrophin-releasing hormone agonists (GnRHa) for > 6 months is not recommended because of concerns regarding adverse sequelae of prolonged hypoestrogenism. It has been postulated that addition of low-dose sex steroids to GnRHa treatment, i.e. 'add-back' therapy, may avert some of these adverse effects (accelerated bone resorption, vasomotor flushes) without altering the efficacy of GnRHa therapy. To evaluate the effects of long-term GnRHa therapy on uterine size, bleeding patterns, bone mass and lipids, 51 pre-menopausal women with leiomyomata were treated with the GnRHa leuprolide acetate depot, 3.75 mg every 4 weeks for 2 years. After 3 months of leuprolide therapy, the women were randomized to receive either low-dose continuous oestropipate, 0.75 mg daily, plus cyclic norethindrone, 0.7 mg on days 1-14 each month (the oestrogen-progestin add-back group) or higher-dose norethindrone, 10 mg daily (the progestin add-back group), for the remaining 21 months. Mean uterine volume decreased by 40% in both treatment groups during the first 3 months on leuprolide treatment. There was no significant change in uterine size following oestrogen-progestin add-back. However, mean uterine volume in the progestin add-back group increased to 87% of pre-treatment size by treatment month 12 and 95% of pre-treatment size by treatment month 24. Mean bone density of the lumbar spine as measured by dual X-ray absorptiometry decreased significantly by 2.6% during the first 3 months in all patients, but did not change significantly following steroid add-back in both treatment groups during the final 21 treatment months.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of androgen receptor DNA reveals the independent clonal origins of uterine leiomyomata and the secondary nature of cytogenetic aberrations in the development of leiomyomata.

Uterine leiomyomata are thought to be monoclonal neoplasms. Accordingly, investigations of clonality with G6PD isoforms used as a marker for X chromosome inactivation have suggested independent origins for multiple tumors within individual uteri. However, results from a recent study assessing methylation differences between DNA of active and inactive X chromosomes have been interpreted to suggest that multiple tumors may arise from a common precursor. We have examined the clonality of 36 leiomyomata from 16 patients by analyzing X chromosome inactivation as indicated by the methylation status of the X-linked androgen receptor gene. As shown by this assay, all informative leiomyomata were monoclonal in origin. In patients with multiple leiomyomata, a random distribution of inactivation between the X homologs was noted, consistent with an independent origin of each tumor. Cytogenetic analysis was also performed on short-term cell cultures of 27 of the 36 tumors. In each of two tumors that had both cells with a clonal karyotypic abnormality and karyotypically normal cells, DNA prepared from short-term cultures showed a monoclonal pattern of X inactivation identical to that of the leiomyoma from which they were derived. These data suggest that karyotypically normal cells present in short-term cultures of uterine leiomyomata are part of the tumor clone, and that clonal expansion of tumor cells precedes the development of cytogenetic aberrations.

Cervical ectopic pregnancy: results of conservative treatment.

PURPOSE: To review experience with early sonographic diagnosis and fertility-preserving treatment of cervical ectopic pregnancy. MATERIALS AND METHODS: The authors evaluated 12 consecutive cases of cervical ectopic pregnancy diagnosed with ultrasound (US) and treated with methods that successfully preserved the uterus. Gestational age, sonographic findings, means of conception, and method of treatment were recorded. RESULTS: Gestational age at diagnosis ranged from 5.0 to 7.9 weeks. Cardiac activity was documented in nine cases. Patients were treated as follows: transvaginal US-guided injection of potassium chloride into the embryo or gestational sac (n = 6), uterine artery embolization followed by dilation and evacuation (n = 4), dilation and evacuation after ligation of uterine artery branches (n = 1), and uterine artery embolization followed by administration of systemic methotrexate (n = 1). The cervical pregnancy was successfully ablated with one treatment in all cases. No patient required hysterectomy, and only one patient required transfusion. Two patients subsequently delivered healthy babies; three other patients have been able to conceive successfully. CONCLUSION: When cervical ectopic pregnancy is diagnosed early, US-guided termination or other conservative procedures allow preservation of the uterus, thus maintaining potential fertility.

Early diagnosis and treatment of cervical pregnancy in an in vitro fertilization program.

This is a report of three cervical pregnancies, one of which was a heterotopic twin cervical pregnancy that occurred in combination with a single intrauterine pregnancy. Transvaginal ultrasound examination was sufficient to establish the diagnosis in two of three patients, and MRI scanning was conclusive in the third. Early diagnosis lead to intervention before 7 weeks gestation in all cases with no complications. The incidence of cervical pregnancy may be higher in IVF-ET than recognized previously.

Glycoprotein hormones and their common alpha-subunit stimulate prolactin production by explant cultures of human leiomyoma and myometrium.

OBJECTIVE: The purpose of this study was to examine the effect of the gonadotropins luteinizing hormone, follicle-stimulating hormone, and human chorionic gonadotropin on prolactin production by human leiomyomas and myometrium. A secondary goal was to explore the effect of thyroid-stimulating hormone and the alpha-subunit common to all these glycoproteins in the same system. STUDY DESIGN: Explant cultures were established, and harvested medium was assayed for total protein and prolactin. Dose-response studies were performed with follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin. A second set of studies was conducted with a single dose of human chorionic gonadotropin, thyroid-stimulating hormone, and alpha-subunit. RESULTS: Gonadotropins, thyroid-stimulating hormone, and alpha-subunit all stimulated prolactin production in both leiomyoma and myometrium. Prolactin production was significantly higher in leiomyoma than in myometrium. A positive effect of time, dose, and gonadotropin treatment on prolactin production was seen in each tissue. There was no treatment effect on total protein secretion. CONCLUSIONS: All four glycoprotein hormones and their common alpha-subunit stimulate prolactin production. This appears to be a specific effect.

The concentrations of collagen-associated amino acids are higher in GnRH agonist-treated uterine myomas.

OBJECTIVE: To test the hypothesis that the effects of estrogen reduction on uterine leiomyoma regression are mediated through changes in cell density or the extracellular matrix. METHODS: Uterine myomas were obtained from 20 women who had received randomly either the GnRH agonist leuprolide acetate depot for 3 months or placebo. The biochemical and morphologic characteristics studied included: total protein, DNA, and amino acid concentrations; histologic appearance; collagen content; and nuclear density. RESULTS: The absolute and relative concentrations of hydroxylysine, hydroxyproline, glycine, and proline were significantly greater (P < .05) in uterine myomas from patients pretreated with a GnRH agonist compared with placebo-treated controls. The GnRH agonist was also associated with trends toward increased mean total protein, DNA, and nuclear density, but the differences did not reach statistical significance. CONCLUSIONS: The concentrations of the amino acids contained in collagen were significantly greater in uterine myomas from patients treated with the GnRH agonist compared to myomas from placebo-treated controls. In addition, our observations suggest that the reduction in uterine myoma volume associated with GnRH agonist therapy is associated with alterations in the extracellular matrix.

Leuprolide acetate depot decreases the number of nucleolar organizer regions in uterine leiomyomata.

Women with symptomatic uterine myomas were randomized to receive LA depot or placebo for 12 weeks before myomectomy. Silver staining nucleolar organizer regions (AgNORs) per nuclei were assessed in the tissue obtained at the time of myomectomy. Myoma tissue from women treated with LA depot before myomectomy had significantly fewer AgNORs per nuclei than myoma tissue obtained from women treated with placebo. Leuprolide acetate depot may reduce the number of proliferating cells in myomas.

A prospective, randomized trial of gonadotropin-releasing hormone agonist plus estrogen-progestin or progestin "add-back" regimens for women with leiomyomata uteri.

Treatment of women with myomas with GnRH agonists (GnRH-a) for 3-6 months will result in profound hypoestrogenism, a significant but temporary reduction in uterine volume, and menstrual suppression. Long-term (i.e. > 6 months) treatment with a GnRH-a is not recommended because of accelerated bone resorption and the presence of hypoestrogenic symptoms. In this 2-yr study, women with myomas were treated with GnRH-a plus one of two steroid "add-back" regimens to minimize adverse sequelae of chronic hypoestrogenism. Fifty-one premenopausal women with large, symptomatic uterine myomas all received the GnRH-a, leuprolide acetate depot (LAD), every 4 weeks for 12 weeks at which time the women were randomized to receive LAD plus either an estrogen-progestin or progestin-only add-back regimen for an additional 92 weeks. Efficacy parameters assessed included serial uterine volumes, hemoglobin concentrations, and hematocrits; safety parameters evaluated included serial bone mineral density measurements, lipid profiles, and medication-related symptoms. This report analyzes the first 52 weeks of study data. Mean uterine volume decreased to 64% of pretreatment size at 12 weeks of LAD treatment in both groups. The estrogen-progestin add-back group had no significant regrowth of uterine volume, which was 75% of pretreatment size at treatment week 52; in contrast, the progestin add-back group had a mean uterine volume of 92% of pretreatment size by treatment week 52. Both groups demonstrated significant improvements in mean hemoglobin concentrations and hematocrits. The progestin add-back group had a significant decline in mean high density lipoprotein-cholesterol concentration, which was not seen in the estrogen-progestin add-back group. Finally, after a significant 3% bone loss during the first 12 weeks of treatment, bone mineral density stabilized in both add-back regimen groups. GnRH-a/steroid add-back regimens provide a useful long-term treatment strategy in women with large, symptomatic uterine myomas and may obviate the need for surgical intervention in selected cases. The estrogen-progestin add-back regimen was superior or equal to the progestin add-back regimen in all efficacy and safety parameters assessed.