The insulin resistant subphenotype of polycystic ovary syndrome: clinical parameters and pathogenesis.

OBJECTIVE: This study was undertaken to compare clinical and biochemical characteristics of the insulin resistant (IR) and non-IR subphenotypes of polycystic ovary syndrome (PCOS). STUDY DESIGN: Infertile PCOS women were classified as IR (n=32) or non-IR (n=46) on the basis of fasting glucose and insulin levels. The incidence of acanthosis nigricans (AN), hirsutism, and ovulation in response to clomiphene citrate (CC) was compared between the 2 groups, along with serum levels of gonadotropins, and sex steroids. Blood samples from 28 PCOS patients and 8 controls were analyzed by enzymatic immunoassay for autophosphorylated insulin receptor (APIR) and total insulin receptor (TIR) content. RESULTS: Insulin resistance was associated with obesity (odds ratio [OR]=3.5, P <.05), AN (OR=6.0, P <.05), hirsutism (OR=3.1, P <.05), and resistance to CC (OR=5.0, P <.05). Mean levels of LH, LH/FSH ratios, and testosterone were lower in women with IR (11.5 +/- 6.8 mIU/mL, 2.0 +/- 1.0, and 56.6 +/- 29.0 ng/dL, respectively) compared with women without IR (15.0 +/- 13.4 mIU/mL, 2.4 +/- 1.5, and 72.5 +/- 29.8 ng/dL, respectively) (P <.05). Mean APIR/TIR ratios in IR women were lower than in non-IR women (P <.05 at 100 nmol/L of insulin) and controls (P <.01 at 1, 10 and 100 nmol/L insulin). CONCLUSION: Patients with IR are more likely to be obese and have AN, hirsutism, resistance to CC, and lower LH, LH/FSH ratios, and testosterone levels. Furthermore, IR patients appear to have defective autophosphorylation of the insulin receptor, a key element in insulin action, and a possible mechanism for IR in PCOS.

Accelerated endometrial maturation in the luteal phase of cycles utilizing controlled ovarian hyperstimulation: impact of gonadotropin-releasing hormone agonists versus antagonists.

OBJECTIVE: To evaluate the endometrium obtained during the luteal phase of controlled ovarian hyperstimulation (COH) cycles utilizing gonadotropin-releasing hormone (GnRH) antagonists, and to compare these findings with those obtained in cycles utilizing a GnRH agonist and with artificial cycles among recipients. DESIGN: Prospective evaluation of oocyte donors. SETTING: University-based in vitro fertilization (IVF) center. PATIENT(S): Fifteen oocyte donors undergoing standard COH were enrolled in 1 of 3 COH groups, and 40 recipients of oocyte donation were used as a control group. INTERVENTION(S): Controlled ovarian hyperstimulation and endometrial biopsy. MAIN OUTCOME MEASURE(S): Histological dating of endometrial biopsies, serum estradiol (E(2)) and progesterone levels. RESULT(S): On the day of oocyte retrieval, endometrial maturation was advanced by an average of 5.8 +/- 0.4 days in the antagonist group and 5.9 +/- 0.7 days in the agonist group. This advancement persisted on day 7 postoocyte retrieval. Serum progesterone levels were elevated before human chorionic gonadotropin (hCG) administration, but remained similar in both groups. CONCLUSION(S): Controlled ovarian hyperstimulation is associated with elevated progesterone levels in the late follicular phase and accelerated endometrial maturation in the subsequent luteal phase. No significant differences exist between preretrieval serial serum progesterone levels and luteal phase endometrial histology between cycles utilizing GnRH agonists or antagonists.

Treatment-associated serum FSH levels in very poor responders to ovarian stimulation.

PURPOSE: To compare treatment-associated follicle-stimulating hormone (FSH) response in patients undergoing controlled ovarian hyperstimulation with either microdose flare (MDF) leuprolide acetate or clomiphene citrate and human menopausal gonadotropin (CC/hMG). METHODS: Thirteen patients who were deemed poor responders underwent stimulation with one of two poor responder stimulation protocols (MDF group: n = 8; CC/hMG group: n = 5). Serum FSH, estrone (E1), estrone sulfate (E1S), and estradiol (E2) levels were measured at baseline, day 5 of medication, and on day of hCG administration. Ovarian and uterine responses were evaluated by ultrasound. RESULTS: Treatment-associated FSH levels were consistently higher in the group that took CC/hMG. However, serum E1, E1S, and E2 values were similar in both groups as were the number of oocytes retrieved and the endometrial echo complex. There were no differences between the two groups with regards to the quality of the oocytes obtained, fertilization rate, or the quality of the embryos. CONCLUSION: Clomiphene citrate, when administered in conjunction with exogenous hMG, is a more potent stimulator of FSH production than MDF leuprolide acetate among poor responders to ovarian stimulation. However, the number of oocytes is not increased.

The proto-oncogene c-kit is expressed in leiomyosarcomas of the uterus.

OBJECTIVE: The proto-oncogene c-kit encodes for a 145-kDa transmembrane tyrosine kinase receptor. Interaction with its ligand, stem cell factor, is essential in the development of hematopoietic stem cells, mast cells, gametocytes, melanocytes, and interstitial cells of Cajal. C-kit expression has been identified in a number of different neoplasms that includes mastocytosis/mast cell leukemia, acute myeloblastic leukemia, seminoma/dysgerminoma, and gastrointestinal stromal tumors. This study examines c-kit expression in uterine endometrial stromal sarcomas, leiomyomas, and leiomyosarcomas using immunohistochemistry. METHODS: Archival tissue from 38 patients with the uterine mesenchymal tumors (16 leiomyosarcomas, 8 leiomyomas, 11 low-grade endometrial stromal sarcomas, and 3 high-grade endometrial stromal sarcomas) was stained with polyclonal antibody for c-kit. Modified avidin biotin (ABC) immunoperoxidase method was employed for antibody detection. Individual tumors were considered positive if more than 10% of the cells comprising the neoplasm displayed immunoreactive staining. Staining intensity was graded 1+ to 3+ and distribution graded as focal (10-30% of the cells), intermediate (30-60% of the cells), or diffuse (>60% of the cells). RESULTS: C-kit was positive in 12 (75%) of the 16 leiomyosarcomas. The staining was 3+ and diffuse in the majority of the positive tumors. C-kit expression was not detected in any of the 8 leiomyomas. Two of the 3 high-grade endometrial stromal sarcomas displayed c-kit positivity. Staining was diffuse and 3+ in both of these tumors. Expression of c-kit was observed in only 3 of the 11 low-grade endometrial stromal sarcomas. CONCLUSIONS: C-kit is expressed in uterine leiomyosarcomas and endometrial stromal sarcomas. Adjunctive diagnostic studies using c-kit may be useful in distinguishing leiomyosarcomas from benign leiomyomas in uterine tumors that offer uncharacteristic features. Furthermore, studies should investigate the prospect of treating these malignant tumors with tyrosine kinase inhibitors.

Human chorionic gonadotropin suppresses ovarian epithelial neoplastic cell proliferation in vitro.

OBJECTIVE: To quantify the in vitro effects of gonadotropins on benign, borderline, and malignant ovarian cell lines. DESIGN: In vitro cell culture. SETTING: Research laboratory. PATIENT(S): None. INTERVENTION(S): Three hormonally sensitive ovarian neoplastic cell lines were exposed to control medium, FSH (40 mIU/mL), hCG (200 mIU/mL), and a combination of FSH and hCG. MAIN OUTCOME MEASURE(S): Cellular proliferation measured by a colorimetric (MTT) assay. RESULT(S): Growth of the cell lines was similar when exposed to control or FSH. In the presence of hCG alone, the cell lines demonstrated decreased proliferation when compared to control or FSH alone. When hCG was given in combination with FSH, there was decreased proliferation of the cell lines compared to control or FSH alone. CONCLUSION(S): Growth of benign, borderline, and malignant ovarian epithelial cell lines is inhibited by hCG at levels, which are commonly achieved with hCG administration during ovulation induction or as a result of trophoblastic production in early pregnancy.

Pregnancy in the sixth decade of life: obstetric outcomes in women of advanced reproductive age.

CONTEXT: As a result of oocyte donation, women in their sixth decade of life are now able to conceive and carry pregnancies to term. However, little is known about pregnancy outcomes in this population. OBJECTIVE: To describe pregnancy outcomes in women aged 50 years or older who conceived after in vitro fertilization with donor oocytes. DESIGN AND SETTING: Retrospective analysis of cycles conducted at a US university assisted reproduction program during calendar years 1991-2001. PATIENTS: Seventy-seven postmenopausal women with no chronic medical conditions (mean [SD] age, 52.8 [2.9] years; range, 50-63 years) who underwent 121 embryo transfer procedures (89 fresh and 32 frozen). Pregnancy outcomes were ascertained by chart review and telephone follow-up. MAIN OUTCOME MEASURES: Maternal and neonatal outcomes. RESULTS: There were 55 clinical pregnancies for a total pregnancy rate of 45.5%. The live birth rate was 37.2%. Of the 45 live births, 31 were singletons, 12 were twins, and 2 were triplets, for which the mean (SD) gestational ages at delivery were 38.4 (2.1) weeks, 35.8 (2.8) weeks, and 32.2 weeks, respectively. Mean (SD) birth weights were 3039 g (703 g), 2254 g (581 g), and 1913 g, respectively. Apgar scores at 1 and 5 minutes were 8.2 (0.9) and 9.1 (0.5), respectively. Of singletons, 68% were delivered by cesarean, and all multiples were delivered by cesarean. Mild preeclampsia was noted in 25% of patients and severe preeclampsia in 10%. Gestational diabetes required diet modification in 17.5%, and 2.5% required insulin. CONCLUSIONS: Appropriately screened women aged 50 years or older can successfully conceive via oocyte donation and experience similar pregnancy rates, multiple gestation rates, and spontaneous abortion rates as younger recipients. During pregnancy, they appear at increased risk of preeclampsia and gestational diabetes. A majority can expect to deliver via cesarean. However, there does not appear to be any definitive medical reason for excluding these women from attempting pregnancy on the basis of age alone.