Andrew J. Friedman

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.

A randomized, double-blind trial of a gonadotropin releasing-hormone agonist (leuprolide) with or without medroxyprogesterone acetate in the treatment of leiomyomata uteri *

A randomized, double-blind study was performed on 16 women to compare the efficacy of daily subcutaneous (SC) injections of leuprolide acetate (LA; TAP Pharmaceuticals, North Chicago, IL) plus oral placebo tablets (group A, n = 7) with SC LA plus oral medroxyprogesterone acetate (The Upjohn Company, Kalamazoo, MI; group B, n = 9) in the treatment of leiomyomata uteri. Patients in group A had a significant reduction in uterine size from a pretreatment volume of 601 +/- 62 cm3 (mean +/- standard error) to a mean uterine volume of 294 +/- 46 cm3 at 24 weeks of therapy (P less than 0.01). Group B patients had a reduction in uterine volume from 811 +/- 174 cm3 to 688 +/- 154 cm3, which was not statistically significant. However, only one patient in group B experienced hot flashes, whereas six patients in group A had this symptom (P less than 0.01). Both groups demonstrated significant increases in mean hemoglobin concentrations, hematocrits, and serum iron levels at 24 weeks of therapy compared with pretreatment levels.

A randomized, placebo-controlled, double-blind study evaluating the efficacy of leuprolide acetate depot in the treatment of uterine leiomyomata

Thirty-eight premenopausal women with uterine leiomyomata were enrolled in a randomized, double-blind, placebo-controlled study evaluating the efficacy of depot leuprolide acetate (LA), a gonadotropin-releasing hormone agonist, in decreasing uterine volume. Eighteen women received intramuscular (IM) depot LA 3.75 mg every 4 weeks for 24 weeks (group A); 20 women received IM placebo with the same injection schedule (group B). Group A patients had a mean reduction in pretreatment uterine volume from 505 +/- 93 cu cm (mean +/- standard error of the mean) to 305 +/- 57 cu cm after 12 weeks (P less than 0.05 versus pretreatment) and 307 +/- 57 cu cm after 24 weeks of therapy (P less than 0.05 versus therapy (P less than 0.05 versus pretreatment). At 3 months after cessation of therapy, the mean uterine volume in group A had increased to 446 +/- 92 cu cm (P less than 0.05 versus week 24). Group B patients had no significant change in uterine volume over the 24-week treatment period. These results suggest that depot LA therapy may significantly decrease uterine volume in patients with leiomyomata, but that regrowth of uterine size occurs shortly after cessation of therapy.

Serum steroid hormone profiles in postmenopausal smokers and nonsmokers

Morning serum steroid levels were determined in postmenopausal chronic smokers and nonsmokers. Postmenopausal smokers (n = 9) had significantly elevated levels of cortisol, progesterone (P), 17-hydroxyprogesterone (17-OHP), androstenedione, and testosterone compared with nonsmokers (n = 16). The increases were most significant for cortisol (P less than 0.001) and 17-OHP (P less than 0.0005). Estrone, estradiol, dihydrotestosterone, and dehydroepiandrosterone sulfate did not differ between the groups. P to estrogen ratios tended to be higher in the smoking population. The significantly elevated P levels observed in the group of postmenopausal smokers may explain, in part, the epidemiologic finding that women smokers have a decreased incidence of endometrial carcinoma. In addition, the hypercortisolism associated with smoking may increase the risk of osteoporosis.

The effect of operative technique and uterine size on blood loss during myomectomy: a prospective randomized study * †

OBJECTIVES To compare operative blood loss between two accepted blood loss-reducing techniques used during myomectomy and to evaluate the effect of preoperatively determined uterine volume on blood loss. DESIGN Subjects were stratified by ultrasound-determined uterine volume < 600 cm3 (n = 11) and > or = 600 cm3 (n = 10) and then randomized into treatment groups. The same radiologist, surgeons, and anesthetic induction technique were involved in every case. In the pharmacologic technique, diluted vasopressin (20 U in 20 mL normal saline) was injected into the serosa and/or myometrium overlying the fibroid(s) before the uterine incision(s). In the mechanical technique, a penrose drain tourniquet was passed through defects created in the broad ligaments at the level of the internal os and secured posteriorly, occluding the uterine vessels. In addition, vascular clamps were placed on the infundibulopelvic ligaments, occluding anastomotic blood flow through the ovarian vessels. RESULTS There was no difference in operative blood loss, operating time, preoperative and intraoperative mean arterial blood pressures, postoperative febrile morbidity, preoperative and postoperative hematocrits, transfusion rates, and length of hospital stay between groups. Blood loss was significantly greater for uteri with ultrasound-determined volumes > or 600 cm3 (627 +/- 175 mL, mean +/- SEM) than for those < 600 cm3 (228 +/- 49 mL). For all subjects, blood lost while operating on the uterus (mean, 379 mL; range, 35 to 1,968 mL) was positively correlated with the total weight of the fibroids resected and with time spent operating on the uterus. Total blood loss (mean, 418 mL; range, 42 to 1,968 mL) was also positively correlated with the time spent operating on the uterus and with total operating time. CONCLUSIONS There were no demonstrable differences in blood loss, morbidity, or transfusion requirements between subjects undergoing myomectomy using pharmacologic vasoconstriction and mechanical vascular occlusion techniques. Blood loss during myomectomy is primarily incurred while operating on the uterus and is correlated with preoperative uterine size, total weight of fibroids removed, and operating time.

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.

Extended use of transdermal norelgestromin/ethinyl estradiol: a randomized trial.

OBJECTIVE: To compare bleeding profiles and satisfaction among women using a norelgestromin/ethinyl estradiol (E2) transdermal contraceptive patch in an extended regimen to those among women using a traditional 28-day patch regimen. METHODS: Healthy, regularly menstruating women (N = 239) were randomly assigned (2:1 ratio) to receive the norelgestromin/ethinyl E2 transdermal patch in an extended regimen (weekly application for 12 consecutive weeks, 1 patch-free week, and 3 more consecutive weekly applications, n = 158) or a cyclic regimen (4 consecutive cycles of 3 weekly applications and 1 patch-free week, n = 81). Subjects recorded bleeding data daily and completed satisfaction questionnaires. Subjects and investigators provided overall assessments of the regimens. RESULTS: Extended use of the norelgestromin/ethinyl E2 transdermal patch resulted in fewer median bleeding days (6 compared with 14, P < .001), bleeding episodes (1 compared with 3, P < .001), and bleeding or spotting episodes (2 compared with 3, P < .001) compared with cyclic use during days 1–84; median numbers of bleeding or spotting days were similar between regimens (14 compared with 16, P = .407) during this time. Extended use delayed median time to first bleeding to 54 days compared with 25 days with cyclic (P < .001). Subjects were highly satisfied with both regimens. Although not statistically significant, slightly more adverse events were reported with the extended than with the 28-day regimen. CONCLUSION: Compared with cyclic use, extended use of the norelgestromin/ethinyl E2 transdermal patch delayed menses and resulted in fewer bleeding days. This regimen may represent a useful alternative for women who prefer fewer episodes of withdrawal bleeding. LEVEL OF EVIDENCE: I

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.

Severe obstetric complications after aggressive treatment of Asherman syndrome.

Thirty-three cases of Asherman syndrome from Yale-New Haven Hospital are presented. Restoration of menses occurred in 91% of patients with pregnancy resulting in 79% of all treated patients. Spontaneous abortion occurred in only one patient (4%), whereas viable pregnancies resulted 96% of the time. Severe obstetric complications excluding premature labor occurred in three cases (12%) and included placenta increta, uterine sacculation, and a paper-thin uterine fundus (ie, uterine dehiscence). These cases are discussed to reinforce considering treated patients with Asherman syndrome to be a high-risk obstetric population, and to counsel and manage these patients accordingly.