Mitchell S. Rein

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.

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.

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. Genes Chromosom Cancer 17:1–6 (1996).

Fibroid and myometrial steroid receptors in women treated with gonadotropin-releasing hormone agonist leuprolide acetate * †

The reduction in uterine and fibroid volume associated with the chronic administration of a gonadotropin-releasing hormone agonist (GnRH-a) is thought to be secondary to the analogue induced hypoestrogenic state. Our hypothesis was that the concentration of bioactive estrogen receptors (ER) and progesterone receptors (PR) may be important in the regulation of fibroid growth. The purpose of this study was to determine ER and PR content in fibroids and myometria from women pretreated with GnRH-a compared with controls. Tissue was obtained from 20 premenopausal women with uterine fibroids who were randomized to receive either leuprolide acetate depot, 3.75 mg intramuscularly every 28 days for four injections (n = 10) or placebo (n = 10) before myomectomy. The mean fibroid ER and PR content was significantly greater than the mean myometrial ER and PR content. The mean fibroid ER content for GnRH-a-treated patients was significantly greater than in placebo-treated patients (143.3 +/- 22.8 versus 36.1 +/- 14.3 fmol/mg). The mean fibroid PR and the mean myometrial ER and PR content were not significantly different between treatment groups. Clinically, the significant increase in fibroid ER may be an explanation for the rapid regrowth of fibroids observed after the cessation of GnRH-a therapy.

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.

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.

The reproducibility of the revised American Fertility Society classification of endometriosis

OBJECTIVE To assess the degree of intraobserver and interobserver variability in endometriosis staging using the revised American Fertility Society (AFS) classification of endometriosis. DESIGN Videotapes of laparoscopies of 20 patients with endometriosis were each scored twice by five observers. SETTING The reproductive endocrine unit of a tertiary care, university-affiliated hospital. SUBJECTS Five subspecialty-certified reproductive endocrinologists. INTERVENTIONS None. MAIN OUTCOME MEASURES Variability in assigned score was measured for each of the five components of the AFS classification, as well as total scores and stage of endometriosis. RESULTS There was considerable variability in the scores assigned to each videotape, both by the same observer and by different observers. The grand total score, which ranged from 0 to 90, varied with an SD of 13.44 when a single patient was rated twice by the same observer and varied with an SD of 17.12 when a single patient was rated by two different observers. Among individual components of the score, the greatest variability occurred in endometriosis of the ovary and cul-de-sac obliteration, with less variability observed for peritoneum endometriosis and for ovarian and tubal adhesions. Comparison of intraobserver and interobserver scores resulted in a change in endometriosis stage in 38% and 52% of patients, respectively. There were statistically significant differences in mean endometriosis scores among the observers in four of the five anatomic categories examined. CONCLUSIONS Intraobserver and interobserver variability was high for ovarian endometriosis and cul-de-sac subscores using the revised AFS classification of endometriosis.

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.

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.

Adverse effects of leuprolide acetate depot treatment

One hundred two premenopausal women with uterine myomas were treated with LA depot. All women experienced adverse effects during GnRH-a treatment. The majority experienced symptoms attributed to a rapid and sustained decrease in circulating estrogen concentrations beginning 2 to 7 weeks after initiation of treatment. A smaller percentage of women experienced transient adverse effects due to the initial surge and subsequent rapid decline of gonadal steroids. The mechanism of other adverse effects (e.g., arthralgias) remains unclear. Only 6% of women terminated LA treatment before 12 weeks because of the severity of adverse effects.