The effect of Norplant on glucose metabolism under hyperglycemic hyperinsulinemic conditions.

OBJECTIVES: To assess the impact of a levonorgestrel-releasing implant contraceptive (Norplant; Wyeth-Ayerst Laboratories, Philadelphia, PA) on glucose metabolism. DESIGN: Prospective evaluation of insulin action and secretion in women under hyperglycemic hyperinsulinemic clamp conditions in the midfollicular phase before and 8 weeks after Norplant placement. SETTING: Yale University Clinical Research Center. PARTICIPANTS: Seven previously normally cycling, nonobese, nondiabetic women participated in the study. INTERVENTIONS: Norplant insertion. MAIN OUTCOME MEASURES: Basal levels of glucose and insulin, as well as glucose-mediated insulin secretion, glucose uptake, and tissue sensitivity to insulin were assessed using the hyperglycemic hyperinsulinemic clamp technique before and after Norplant insertion. RESULTS: Norplant placement did not alter the fasting glucose or insulin levels. However, it was associated with a significant 37% increase in the first phase insulin response from a control level of 51 +/- 8 to 70 +/- 10 microU/mL (conversion factor to SI unit, 7.175), and a significant 48% increase in the second phase insulin response from 60 +/- 5 to 89 +/- 8 microU/mL. In association with this increase in insulin levels after Norplant insertion, total mean body glucose uptake (M) increased from 8.08 +/- 0.91 to 9.53 +/- 0.95 mg/kg per minute. However, when expressed as the total body glucose uptake per unit of insulin, the M:I ratio (a measure of tissue sensitivity to insulin) decreased significantly from a mean of 0.12 +/- 0.02 to 0.10 +/- 0.01 mg/kg per minute per microU/mL. CONCLUSION: Although Norplant insertion does not alter basal glucose and insulin levels, tissue sensitivity to insulin under hyperglycemic hyperinsulinemic conditions is decreased after Norplant insertion.

PIP: Earlier studies on the effect of oral contraceptive (OC) use on glucose metabolism have resulted in mixed findings. OCs containing levonorgestrel have been reported as having the greatest effect on glucose metabolism and insulin response. This article reports on the effect of Norplant on glucose metabolism in 7 women. Hyperglycemic clamp studies were also performed on the study subjects in the midfollicular phase before and 8 weeks after Norplant insertion. Statistical analysis was performed using the paired t-test. Blood samples for glucose and insulin measurements were taken every 10 minutes during the 30-minute basal period, at 2-minute intervals during the initial dextrose introduction phase, and in intervals of 5-10 minutes for the remaining time. Total study time was 2 hours. There was no significant difference between measurements before and after Norplant use. However, it was associated with a significant 37% increase in the first-phase insulin response from 51 +or- 8 to 70 +or- 10 mcU/ml and a significant 48% increase in the second-phase insulin response from 60 +or- 5 to 89 +or- 8 mcU/ml. Tissue sensitivity to insulin decreased with Norplant use.

Aberrant estradiol flare despite gonadotropin-releasing hormone-agonist-induced suppression is associated with impaired implantation.

Our results confirm the previous report that rapid suppression by GnRH-a is favorable relative to delayed suppression (1). They further indicate that the pattern of E2 production during GnRH-a-induced ovarian suppression may be predictive of cycle outcome. We suggest that imperfect pituitary suppression of bioactive LH as indicated by an aberrant rise in E2 during GnRH-a down-regulation may compromise oocyte quality and ultimately impair implantation. Further study of follicular phase E2 response to GnRH-a suppression may provide a prognostic marker for implantation.

Ovulation induction with GnRH agonist and human menopausal gonadotropins: response in patients with one versus two ovaries.

OBJECTIVE: To examine the effect of oophorectomy on response to gonadotropin releasing hormone-agonist/human menopausal gonadotropin (GnRH-a/hMG) for in vitro fertilization (IVF). DESIGN: Retrospective review. SETTING: Tertiary care academic institution. PATIENTS: Ninety-one infertile patients undergoing IVF. Eighty-four women had two ovaries and seven had only one ovary. RESULTS: There was no difference observed between women with one versus two ovaries with regard to response to medications, hormone production, number of oocytes retrieved and fertilized, or the number of embryos cleaved and transferred. CONCLUSION: Women with only one ovary are at no reproductive disadvantage when undergoing ovulation induction for IVF.

HLA-DQ beta 57 in Hispanic patients with insulin-dependent diabetes mellitus.

OBJECTIVE: The purpose of our study was to investigate the distribution of HLA-DQ beta-chain amino acid residue 57 (HLA-DQ beta 57) as a genetic marker of susceptibility for insulin-dependent diabetes mellitus in the Hispanic population. STUDY DESIGN: Fifteen patients of Puerto Rican descent with juvenile-onset insulin-dependent diabetes mellitus underwent human leukocyte antigen typing for HLA-DQ beta 57 by polymerase chain reaction amplification of the target genomic DQ sequence followed by hybridization of the polymerase chain reaction product to phosphorus 32-labeled allele-specific oligonucleotide probes. A control group of 44 Hispanic adults without diabetes who were undergoing human leukocyte antigen typing for tissue donation were concurrently typed for comparison. RESULTS: The Hispanic insulin-dependent diabetes mellitus group showed a significant increase in homozygosity for a non-aspartate amino acid (p = 0.023) over a control group of Hispanic subjects without diabetes. A high rate of heterozygosity for aspartate (53.3%) is found in Hispanic subjects with insulin-dependent diabetes mellitus as well. CONCLUSIONS: HLA-DQ beta 57 in the Hispanic population has a distribution distinct from HLA-DQ beta 57 in the Caucasian population. A single aspartate is not protective against insulin-dependent diabetes mellitus in Hispanic subjects.

The role of office hysteroscopy in in vitro fertilization.

Twenty-eight patients participated prospectively in a study to evaluate the impact of hysteroscopically detected uterine and cervical anomalies on the success rate of ET in an IVF-ET program. All participants had a normal intrauterine cavity by standard HSG. All the patients had a diagnostic office hysteroscopy under paracervical block before commencing COH. Because our IVF program does not include hysteroscopy as a requirement before undergoing IVF and because the significance of mild intrauterine abnormalities is not yet known, the hysteroscopic findings were not relayed to the personnel involved in the IVF-ET procedure. Sixteen patients (group I) had a normal hysteroscopic evaluation. Twelve patients (group II) had abnormal hysteroscopic findings including small uterine septa, small submucous fibroids, uterine hypoplasia and cervical ridges. Although no difference in patients or cycle characteristics was present, there was a significant difference in the clinical PR between patients in groups I and II. In conclusion, in an IVF-ET program patients with normal hysterography but abnormal hysteroscopic findings had a significantly lower clinical PR, demonstrating the importance of performing hysteroscopy before IVF-ET.

Luteinizing response to human chorionic gonadotropin does not predict outcome in gonadotropin releasing hormone agonist-suppressed/human menopausal gonadotropin-stimulated in vitro fertilization (IVF) cycles.

OBJECTIVE: The purpose of this study was to determine if early luteinizing potential in gonadotropin releasing hormone agonist (GnRH-a)-suppressed/human menopausal gonadotropin (hMG)-stimulated IVF cycles is predictive of cycle outcome. DESIGN, PATIENTS: The study was a prospective evaluation of 41 women beginning a GnRH-a-suppressed/hMG-stimulated IVF cycle. SETTING: The in vitro fertilization program of a tertiary care institution was the study setting. MAIN OUTCOME MEASURES: The main outcome measures were (1) estradiol (E2) and progesterone (P) levels on the day of human chorionic gonadotropin (hCG) administration and the following day and (2) the ovarian response to ovulation induction and clinical outcome. RESULTS: Ten of the 41 women achieved a clinical pregnancy (24.4%). There was no significant difference in progesterone (P) levels on the day of or the day following hCG administration between the pregnant and the nonpregnant groups. Both groups exhibited a significant rise in P level in response to hCG. There was no significant difference in E2 levels on the day of hCG between the two groups. The serum E2 did not rise significantly in response to hCG in either group. Patients who became pregnant had significantly more oocytes retrieved, fertilized, cleaved, and transferred. CONCLUSIONS: Clinical response and outcome in GnRH-a-suppressed/hMG-stimulated IVF cycles are not predicted by early luteinizing potential as indicated by the response of E2 or P to hCG.

Middle cerebral artery blood velocity during controlled ovarian hyperstimulation.

OBJECTIVE: To measure cerebral blood flow velocities using transcranial Doppler during ovulation induction after pituitary suppression. DESIGN: Women undergoing controlled ovarian hyperstimulation after pituitary suppression were prospectively studied. SETTING: Tertiary institution. PATIENTS: A microprocessor-controlled directional pulsed-wave adjustable hand held probe (2 MHz) was used to measure blood flow velocities and pulsatility indices in the right and left middle cerebral arteries (middle cerebral artery) in nine patients. Measurements of peak middle cerebral artery velocities (cm/s) and pulsatility index were obtained after achieving pituitary suppression with leuprolide acetate and repeated over several days after treatment with human menopausal gonadotropin (225 IU/d). RESULTS: There was a significant increase in the peak middle cerebral artery velocities (cm/s) of the patients measured at the time of pituitary suppression when compared with those obtained at the time of maximal estradiol (E2) (98 +/- 12 versus 105 +/- 12, P less than 0.03). The pulsatility index also showed a significant increase from 0.72 +/- 0.08 at the time of pituitary suppression to 0.82 +/- 0.04 at the time of maximal hyperestrogenism, P less than 0.002. Estradiol values obtained at the time of the transcranial Doppler examinations were normalized by transformation to their natural logarithms (LnE2). The middle cerebral artery velocities were significantly correlated with LnE2 levels (P less than 0.0001 and r = 0.93). CONCLUSION: Estrogen levels appear to be directly correlated with cerebral blood flow velocity and pulsatility index, implying an effect of ovarian steroids on cerebrovascular hemodynamics.

Corpus luteum function in successful in vitro fertilization cycles.

The function of the corpus luteum in early pregnancy has been subject to some controversy. The purpose of our study was to determine the life span of the corpus luteum in early pregnancy after successful GnRH-a/hMG stimulation in IVF-ET. The study consisted of a retrospective analysis of patients after 12 successful singleton intrauterine IVF-ET cycles. Serum samples were obtained during early pregnancy beginning 14 days after hCG administration. The levels of 17 alpha-OHP, hCG, P, and E2 were measured in each sample. A significant negative correlation was noted between 17 alpha-OHP and date from hCG. The x-intercept of the regression line allowed estimation of the life span of the corpus luteum to be 72 +/- 25 days. In conclusion, in GnRH-a/hMG-stimulated IVF-ET cycles that result in a singleton pregnancy, the functional life span of the corpus luteum averages 72 days.

Nafarelin versus leuprolide in ovulation induction for in vitro fertilization: a randomized clinical trial.

Gonadotropin-releasing hormone agonists vary in structure and route of administration. We performed this study to compare patient response to intranasal nafarelin acetate versus subcutaneous leuprolide acetate as adjuncts to ovulation induction for in vitro fertilization (IVF). Forty-two patients entering their first cycle of IVF were randomized to receive either nafarelin acetate or leuprolide acetate. Patient characteristics in the two groups did not differ significantly, nor did cycle cancellation rates or outcome. There was no significant difference in patient response as indicated by follicular phase serum levels of estradiol (E2), FSH, or LH, luteal phase E2, and progesterone. Luteal phase progesterone-dependent endometrial protein was significantly lower in those taking nafarelin acetate, though it remained in the normal range. However, those receiving nafarelin acetate required significantly less human menopausal gonadotropin (hMG) and had significantly more embryos frozen for later transfer than those receiving leuprolide acetate. Intranasal nafarelin acetate can be used successfully in ovulation induction regimens that include GnRH agonists. The use of nafarelin acetate may decrease a patient's hMG requirement and increase the number of frozen embryos available for later transfer as compared with leuprolide acetate. Further studies are needed to optimize the dosing regimen.

Imaging in endocrine disorders.

Imaging of the pituitary, adrenal and thyroid glands plays an integral role in the evaluation of endocrinopathies involving those glands. Magnetic resonance imaging is currently the study of choice in evaluating the pituitary. As for the adrenal, computed tomography and magnetic resonance are probably equally sensitive in detecting adenomas and carcinomas. The endocrinologic and radiologic evaluation of the thyroid gland involves the use of mainly nuclear medicine scanning and ultrasonography. Imaging is playing an increasingly critical role in the evaluation and differential diagnosis of various endocrine disorders involving the pituitary, thyroid and adrenal glands.