Effect of ovarian suppression with gonadotropin-releasing hormone agonist on glucose disposal and insulin secretion.

Several lines of evidence suggest that ovarian hormones influence glucose homeostasis, although their exact role in humans has not been clearly defined. In the present study, we sought to test the hypothesis that ovarian hormones regulate glucose homeostasis by examining the effect of pharmacologically induced ovarian hormone deficiency on glucose disposal and insulin secretion. Young, healthy women with regular menstrual patterns were studied during the follicular and luteal phases of their cycle at baseline and after 2 mo of treatment with gonadotropin-releasing hormone agonist (GnRHa; n = 7) or placebo (n = 6). Using hyperglycemic clamps, in combination with stable isotope-labeled (i.e., (13)C and (2)H) glucose tracers, we measured glucose disposal and insulin secretion. Additionally, we assessed body composition and regional fat distribution using radiologic imaging techniques as well as glucoregulatory hormones. Ovarian hormone suppression with GnRHa did not alter body composition, abdominal fat distribution, or thigh tissue composition. There was no effect of ovarian suppression on total, oxidative, or nonoxidative glucose disposal expressed relative to plasma insulin level. Similarly, no effect of ovarian hormone deficiency was observed on first- or second-phase insulin secretion or insulin clearance. Finally, ovarian hormone deficiency was associated with an increase in circulating adiponectin levels but no change in leptin concentration. Our findings suggest that a brief period of ovarian hormone deficiency in young, healthy, eugonadal women does not alter glucose disposal index or insulin secretion, supporting the conclusion that ovarian hormones play a minimal role in regulating glucose homeostasis. Our data do, however, support a role for ovarian hormones in the regulation of plasma adiponectin levels.

Resolution of endometrial hyperplasia with adjuvant anastrozole treatment in postmenopausal breast cancer: a case report.

BACKGROUND: Endometrial hyperplasia in patients with a history of breast cancer presents a therapeutic dilemma. The standard conservative therapy for hyperplasia, high-dose progestins, is contraindicated in breast cancer. Anastrozole, an aromatase inhibitor, is becoming first-line adjuvant therapy for breast cancer in postmenopausal women and may have protective effects on the endometrium. CASE: A 51-year-old, obese woman with a history of breast cancer presented with a 2-day history of heavy postmenopausal bleeding. Endometrial biopsy demonstrated simple hyperplasia without cellular atypia. After consultation with the patient's oncologist, the patient received adjuvant anastrozole therapy for the breast cancer; it led to resolution of the endometrial hyperplasia. CONCLUSION: Adjuvant therapy with anastrozole may be beneficial in resolving endometrial hyperplasia in patients with breast cancer.

Ovarian suppression with a gonadotropin-releasing hormone agonist does not alter insulin-stimulated glucose disposal.

OBJECTIVE: Aging is associated with reduced tissue sensitivity to insulin. In women, these age-related changes may be accelerated by menopause. The effect of ovarian hormone deficiency on tissue insulin sensitivity in humans, however, has not been defined clearly. Thus, the goal of this study was to evaluate the effect of suppression of endogenous ovarian hormone production on insulin-stimulated glucose disposal. DESIGN: Randomized, single-blind, placebo-controlled trial. SETTING: General clinical research center. PATIENTS: Thirteen healthy, nonobese premenopausal women. INTERVENTION(S): Insulin-stimulated glucose disposal was determined by hyperinsulinemic (40 mU/m(2)/min) clamp during the early to midfollicular and midluteal phase of the menstrual cycle. Volunteers then received 2 months of treatment with the GnRH agonist (GnRHa) leuprolide acetate (n = 6) or placebo (n = 7) and were retested. MAIN OUTCOME MEASURE(S): Total, oxidative, and nonoxidative insulin-stimulated glucose disposal. RESULT(S): Because no effect of cycle phase was found on total, oxidative, or nonoxidative glucose disposal, pretreatment follicular and luteal phase values were averaged. Treatment with GnRHa had no effect on total glucose disposal (GnRHa: 10.6 +/- 0.9 to 10.8 +/- 0.9 vs. placebo: 10.2 +/- 0.7 to 10.4 +/- 1.0 mg/kg fat-free mass/min, P = .99). Similarly, there was no effect of GnRHa administration on oxidative (GnRHa: 2.77 +/- 0.58 to 3.89 +/- 0.58 vs. placebo: 2.74 +/- 0.42 to 3.33 +/- 0.62 mg/kg fat-free mass/min, P = .52; n = 6 and 6, respectively) or nonoxidative (GnRHa: 7.82 +/- 0.68 to 6.91 +/- 0.66 vs. placebo: 7.94 +/- 0.72 to 7.79 +/- 0.99 mg/kg fat-free mass/min, P = .59; n = 6 and 6, respectively) components of glucose disposal. CONCLUSION(S): Our results suggest that endogenous ovarian hormones do not regulate tissue responsiveness to insulin or intracellular pathways of glucose disposal.

Effect of a daily supplement of soy protein on body composition and insulin secretion in postmenopausal women.

OBJECTIVE: To determine whether a supplement of soy protein improves body composition, body fat distribution, and glucose and insulin metabolism in postmenopausal women without diabetes compared with an isocaloric casein placebo. DESIGN: Randomized, double-blind, placebo-controlled 3-month trial. SETTING: Clinical Research Center. PATIENT(S): Fifteen postmenopausal women. INTERVENTION(S): Computed tomographic scans at L4/L5, dual energy x-ray absorptiometry, hyperglycemic clamps. MAIN OUTCOME MEASURE(S): Total fat, total abdominal fat, visceral fat, subcutaneous abdominal fat, and insulin secretion. RESULT(S): Weight by dual energy x-ray absorptiometry did not change between groups (+1.38 +/- 2.02 kg for placebo vs. +0.756 +/- 1.32 kg for soy, mean +/- SD). Total and subcutaneous abdominal fat increased more in the placebo group than in the soy group (for differences between groups in total abdominal fat: +38.62 +/- 22.84 cm(2) for placebo vs. -11.86 +/- 31.48 cm(2) for soy; subcutaneous abdominal fat: +22.91 +/- 28.58 cm(2) for placebo vs. -14.73 +/- 22.26 cm(2) for soy). Insulin secretion, visceral fat, total body fat, and lean mass did not differ between groups. Isoflavone levels increased more in the soy group. CONCLUSION(S): A daily supplement of soy protein prevents the increase in subcutaneous and total abdominal fat observed with an isocaloric casein placebo in postmenopausal women.

Insulin resistance with hormone replacement therapy: associations with markers of inflammation and adiposity.

OBJECTIVE: This study was undertaken to determine whether insulin resistance associated with combination hormone replacement therapy (HRT) is mediated by changes in serum markers of inflammation or in serum adipocyte hormones. STUDY DESIGN: Forty-five postmenopausal women, aged 55 +/- 7 years, were examined from a randomized, double-blind placebo-controlled trial evaluating the effect of HRT on insulin-stimulated glucose disposal and body composition. Volunteers were randomly assigned to conjugated estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg vs placebo for 1 year. At baseline and at 1 year, body composition was assessed by dual photon x-ray absorptiometry scans; body fat distribution was measured by computed tomographic scans at the L4/L5 vertebral disk space; insulin sensitivity was measured by euglycemic hyperinsulinemic clamp; interleukin-6 (IL-6), leptin, and adiponectin were measured by enzyme-linked immunosorbent assay; and c-reactive protein (CRP) was measured by radioimmunoassay. RESULTS: HRT increased CRP by 121% compared with a 32% increase with placebo (P = .03); HRT decreased glucose disposal by 17% compared with no change with placebo (P = .04) as reported previously. HRT did not affect body composition, body fat distribution, IL-6, leptin, or adiponectin. The increase in CRP did not correlate with the decrease in glucose disposal in the HRT group (R = 0.11, P = .65). CONCLUSION: Treatment with HRT for one year increases CRP, but does not alter IL-6, adiponectin, or leptin. The change in CRP was not, however, related to the decrease in glucose disposal with HRT treatment.

Perceived infertility-related stress correlates with in vitro fertilization outcome.

To determine the effect of perceived infertility-related stress on IVF outcome, all couples undergoing their first cycle of IVF were administered the Fertility Problem Inventory from May 2002 and April 2005 at our institution. Couples who conceived during their first cycle of IVF had significantly higher measures of need for parenthood and loss of sexual enjoyment, compared with couples who did not conceive. Couples who achieved ongoing pregnancies had higher scores on measures of a negative view of a child-free lifestyle, need for parenthood, and total stress than those who did not.

Testosterone replacement increases vasodilatory reserve in androgen-deficient female rats.

Testosterone replacement leads to increased coronary pressure-induced tone and vasodilatory reserve in oophorectomized rats. The mechanisms involve changes in endothelial nitric-oxide modulation of smooth-muscle constriction and are not a result of the peripheral conversion of T to estrogen.

Conservative treatment of placenta accreta.

Prolonged retained placenta causing a delayed postpartum hemorrhage is a relatively common occurrence. However, there is a dearth of medical literature describing fertility-preserving treatments when standard therapy fails. We present two cases in which protracted retained placenta due to placenta accreta was successfully treated by hysteroscopic resection. Two nulliparous women had spontaneous vaginal deliveries requiring manual placental extraction. Both experienced delayed postpartum hemorrhage and underwent suction curettage with ultrasound guidance. Both patients were found to have persistent products of conception with imaging consistent with placenta accreta. Both patients failed expectant management and subsequently underwent hysteroscopic resection with complete resolution of their symptoms. We conclude that hysteroscopic resection is a conservative therapeutic option for placenta accreta in stable patients.

Evidence against a role for ovarian hormones in the regulation of blood flow.

OBJECTIVE: To determine the effect of ovarian hormone deficiency on peripheral vascular function. DESIGN: Randomized, single-blind, placebo-controlled. SETTING: General clinical research center. PATIENT(S): Twelve healthy, lean, premenopausal women with regular menstrual cycles. INTERVENTION(S): Measurements were made during the early to midfollicular and midluteal phases of the menstrual cycle. Patients were then randomized to an 8-week course of gonadotropin-releasing hormone agonist (GnRHa) (n = 6) or placebo (n = 6) and retested. On each occasion, blood flow was assessed in the basal postabsorptive state and under euglycemic-hyperinsulinemic-hyperaminoacidemic conditions. MAIN OUTCOME MEASURE(S): Calf blood flow by venous occlusion plethysmography. RESULT(S): No differences in calf blood flow under postabsorptive (1.65 +/- 0.09 vs. 1.73 +/- 0.16 mL/100 g tissue per minute) or insulin-stimulated conditions (2.24 +/- 0.20 vs. 2.30 +/- 0.18 mL/100 g tissue per minute) were found between the follicular and luteal phases of the menstrual cycle, respectively; therefore, pretreatment data were averaged. Ovarian hormone suppression did not alter postabsorptive calf blood flow (GnRHa: 1.68 +/- 0.13 to 1.69 +/- 0.15; placebo: 1.69 +/- 0.21 to 1.64 +/- 0.14 mL/100 g tissue per minute) or the blood flow response to insulin infusion (GnRHa: 2.40 +/- 0.21 to 2.37 +/- 0.29; placebo: 2.10 +/- 0.28 to 2.19 +/- 0.35 mL/100 g tissue per minute). CONCLUSION(S): Variation in ovarian hormones associated with the menstrual cycle or short-term ovarian hormone deficiency induced by GnRHa do not affect calf blood flow under postabsorptive conditions or the response to hyperinsulinemia.

Syndrome of inappropriate antidiuretic hormone in a healthy woman after diagnostic laparoscopy and hysteroscopy: a case report.

BACKGROUND: Hyponatremia is common after major surgery. It is now recognized as a potential complication after minor surgery. Premenopausal women are more likely to suffer permanent brain damage or death from hyponatremic encephalopathy than are men or postmenopausal women. CASE: A 36-year-old woman, gravida 2, para 0, undergoing diagnostic laparoscopy and hysteroscopy for secondary infertility and an abnormal hysterosalpingogram, experienced mental status changes and hyponatremia 10 hours after otherwise-uncomplicated surgery. Early recognition and treatment led to a complete recovery. CONCLUSION: Symptomatic hyponatremia is a potential complication after minor surgery and must be recognized and treated to avoid a catastrophic outcome.

Novel modification of the vertical rectus abdominis myocutaneous flap for neovagina creation.

OBJECTIVE: We describe a modification of the traditional vertical rectus abdominis myocutaneous flap for neovagina creation and our experience to date. METHODS: Our modified vertical rectus abdominis myocutaneous flap uses a smaller flap size with a full-thickness skin graft posteriorly to decrease the size of the abdominal wall defect. We have used the modified vertical rectus abdominis myocutaneous flap in 18 patients between March 1998 and March 2004 to create a neovagina after exenterative surgery. RESULTS: The mean age of the patients was 54 years, and the mean body mass index was 27 (range 18-44). Twelve patients underwent a total pelvic, 5 anterior, and 1 posterior exenteration. Among the 13 patients requiring a colostomy, the vertical rectus abdominis myocutaneous flap was taken from the contralateral side. In these patients, the urostomy was brought out on the vertical rectus abdominis myocutaneous flap donor side. There has been only 1 partial flap loss, which eventually resulted in a fully epithelialized neovagina. Eight patients at last follow-up were sexually active. Two other patients have died from recurrent disease, and 2 are alive with recurrence. The other 6 patients have no evidence of recurrent disease and, although not sexually active at the time of this report, have a viable and adequate neovagina. All patients had a successful primary closure of the abdominal wound in a vertical fashion. Three patients had superficial abdominal wound breakdown, which healed by secondary intention. CONCLUSION: The modified vertical rectus abdominis myocutaneous flap allows for creation of an adequate neovagina with a smaller abdominal wall defect.

The effect of hormone replacement therapy on body composition, body fat distribution, and insulin sensitivity in menopausal women: a randomized, double-blind, placebo-controlled trial.

PURPOSE: After menopause, women gain abdominal fat and become less sensitive to insulin. We sought to determine whether hormone replacement therapy (HRT) reduced intraabdominal and sc abdominal fat and improved insulin sensitivity in early menopausal women. METHODS: Seventy-six postmenopausal women, age 51.6 +/- 3.9 yr with body mass index of 24.9 +/- 3.2 kg/m2, were randomized to conjugated estrogens (0.625 mg) plus medroxyprogesterone acetate (2.5 mg) or placebo daily. Women received a computed tomography scan at the L4-L5 vertebral disk space, a dual x-ray absorptiometry scan, and a euglycemic hyperinsulinemic clamp at baseline, 6 months, 1 yr, and 2 yr. RESULTS: Fifty-one women completed the trial and were analyzed (n = 26 on HRT and n = 25 on placebo). Intraabdominal fat, sc abdominal fat, total fat, percent fat, fat-free mass, and weight did not differ between treatment groups by time. Insulin sensitivity did not change in the placebo group, but decreased by 17% in the HRT group by 6 months and persisted at 2 yr (P < 0.01 for treatment by time effect). One year after the trial, insulin sensitivity increased by 25% in women who had taken HRT (P = 0.006 for treatment by time effect), to a level similar to those women in the placebo group. CONCLUSIONS: Conjugated estrogens plus medroxyprogesterone acetate reduce insulin sensitivity in menopausal women without affecting body composition or body fat distribution. The reduction in insulin sensitivity is reversible after discontinuing HRT.

Pseudoaneurysm of the uterine artery requiring bilateral uterine artery embolization.

OBJECTIVE: To report a case of uterine artery pseudoaneurysm which initially failed unilateral uterine artery embolization that subsequently responded to bilateral embolization. DESIGN: A case report. SETTING: University hospital. PATIENT(S): 32-year-old G(2) P(1) female. INTERVENTION(S): Left uterine artery embolization followed by right uterine artery embolization 1 day later. MAIN OUTCOME MEASURE(S): Vaginal bleeding, hemoglobin. RESULTS: Unilateral uterine artery embolization failed to control vaginal bleeding. Repeat embolization of the contralateral side was successful. CONCLUSIONS: Uterine artery embolization is an effective method of treating delayed postpartum hemorrhage secondary to a pseudoaneurysm of the uterine artery.

Implementation of assisted reproductive technologies following conservative management of FIGO grade I endometrial adenocarcinoma and/or complex hyperplasia with atypia.

OBJECTIVE: The objective was to report a series of infertility therapy outcomes following conservative management of endometrial adenocarcinoma and/or complex hyperplasia with atypia. METHODS: A retrospective review of the University of Iowa assisted reproductive technology database was performed. All women presenting with International Federation of Obstetrics and Gynecology (FIGO) grade I uterine adenocarcinoma and/or complex hyperplasia with atypia were assessed for type and duration of medical management, initial, interim treatment, and preinfertility treatment endometrial biopsy (BX) findings. Assessment of infertility treatment outcomes and postinfertility endometrial biopsy findings were performed. All of the pathology samples were re-reviewed at the Gynecologic Oncology Tumor Board to confirm the diagnosis by a pathologist with a particular expertise in gynecologic pathology. RESULTS: Four infertile women, three nulligravid and one primigravid, were evaluated with the diagnosis of FIGO grade 1 endometrial adenocarcinoma and/or complex hyperplasia with atypia desiring to preserve fertility. Two women with FIGO grade 1 endometrial adenocarcinoma were successfully treated with high-dose progestational agents resulting in normal proliferative endometrium. In addition, both women with complex hyperplasia with atypia were successfully treated with progestins and/or ovulation induction. Successful pregnancy outcomes were achieved for three of the four women with assisted reproductive technology. A total of five successful pregnancies and eight healthy live-born infants were achieved among three women. One of the four women was unable to conceive despite three cycles of in vitro fertilization. Hysterectomy was performed for recurrent complex hyperplasia with atypia. In our series, we found it can take 3-10 months (mean, 6.25 months; median, 6 months) to obtain benign endometrium preceding infertility therapy. CONCLUSION: This report demonstrates that conservative management of well-differentiated endometrial adenocarcinoma and/or complex hyperplasia with atypia followed by aggressive assisted reproduction is an option to highly motivated and carefully selected women.

Presumed antepartum amniotic fluid embolism.

BACKGROUND: Amniotic fluid embolism is seldom recognized in nonperipartum patients. The pathophysiology is uncertain and diagnosis imprecise, making management after stabilization difficult. CASE: A 37-year-old woman at 28 weeks' gestation presented with signs and symptoms consistent with amniotic fluid embolism including disseminated intravascular coagulopathy. A ventilation-perfusion scan demonstrated unmatched perfusion defects, but other radiographic studies were negative; the patient was treated with heparin. Four days after presentation she had spontaneous rupture of membranes followed by hypoxemia, necessitating cesarean delivery. A pulmonary arteriogram after the operation showed multiple filling defects; the patient was discharged on warfarin. CONCLUSION: Amniotic fluid embolism is a difficult diagnosis to make, at best. Anticoagulation may be a therapeutic option.

Preoperative serum vascular endothelial growth factor levels: significance in ovarian cancer.

PURPOSE: To assess the clinical relevance of serum vascular endothelial growth factor (VEGF) levels in distinguishing patients with ovarian cancer from those with benign adnexal masses. EXPERIMENTAL DESIGN: Preoperative serum VEGF levels were assessed in 101 women with invasive epithelial ovarian cancer, 16 with low malignant potential (LMP) ovarian tumors, and 34 women with benign ovarian tumors. VEGF levels were determined using an ELISA (R&D Systems, Minneapolis, MN). RESULTS: Ovarian cancer patients had a mean preoperative VEGF level of 549 pg/ml (median 379 pg/ml), which was significantly higher than those with benign adnexal masses (mean 228 pg/ml, median 155 pg/ml; P < 0.001) and LMP tumors (mean 200 pg/ml, median 129 pg/ml; P < 0.001). There were no significant differences in VEGF levels between individuals with benign masses and LMP tumors. The ability of VEGF to differentiate malignancy from benign masses at a cutoff VEGF level of 246 pg/ml gave a sensitivity of 74%, a specificity of 71%, a positive predictive value of 88%, and a negative predictive value of 48%. VEGF levels were also significantly higher in patients with stage I ovarian cancer compared with those with benign disease or LMP tumors. Among patients with ovarian cancer, there were no significant differences in VEGF levels based on age, stage, grade, or level of cytoreduction. The presence of ascites was associated with a significantly higher VEGF level (mean 667 pg/ml, median 445 pg/ml versus mean 317 pg/ml, median 293 pg/ml; P < 0.001). Various preoperative VEGF levels were assessed as a predictor of survival, and a VEGF level >380 pg/ml was associated with a hazard ratio of 2.13 (P = 0.009) by univariate analysis. In multivariate analysis of age, stage, cytoreduction, preoperative CA-125, grade, ascites, and VEGF levels above 380 pg/ml, only VEGF levels >380 pg/ml (hazard ratio 2.33; P = 0.02) and advanced stage (hazard ratio 9.03; P = 0.004) were significant. CONCLUSIONS: Preoperative VEGF levels may be useful in differentiating benign adnexal masses from malignancy. Preoperative VEGF levels >380 pg/ml are an independent risk factor for death because of disease.

Preoperative CA 125 levels: an independent prognostic factor for epithelial ovarian cancer.

OBJECTIVE: To estimate the association of preoperative CA 125 levels with outcome in primary ovarian cancer patients. METHODS: One hundred forty-two patients with epithelial ovarian cancer, who had a serum CA 125 level drawn before surgery, were retrospectively evaluated. The relationship of preoperative CA 125 levels and various preoperative and postoperative variables was evaluated. CA 125 levels were determined using a solid-phase immunoassay. RESULTS: The median CA 125 value for all patients was 582 U/mL (range 7-52,930 U/mL). Preoperative CA 125 values did not correlate with increasing age (P =.40), but were found to be significantly associated with serous histology compared with other histology (median CA 125 of 870 versus 334 U/mL, P =.02), high-stage (III/IV) compared with low-stage (median CA 125 of 893 versus 174 U/mL, P <.001), high tumor grade (3) compared with grade 1 or 2 (median CA 125 of 928 versus 323 U/mL, P <.001), and the presence of ascites compared with absence of ascites (median CA 125 of 893 versus 220 U/mL, P <.001). Suboptimal cytoreduction (more than 1 cm residual) was associated with significantly higher CA 125 levels (1067 U/mL) compared with individuals with optimal cytoreduction (399 U/mL, P <.001). Preoperative CA 125 values less than 500 U/mL had a positive predictive value for optimal cytoreduction of 82%, but a poor negative predictive value of 48%. After adjusting for covariates, there was a significant association between CA 125 levels and disease-specific survival. As preoperative CA 125 levels increased, the risk of death increased except at the highest values of CA 125. CONCLUSION: Preoperative CA 125 is an independent risk factor for death due to disease in ovarian cancer, but not a reliable predictor of optimal cytoreduction.