Estradiol and hemodynamics during ovulation induction.

Left ventricular size and stroke volume increase in human pregnancy and during estrogen administration in laboratory animals. In order to determine if elevated levels of endogenous estrogens in humans produce hemodynamic changes similar to those that occur during pregnancy, 14 patients were studied during ovulation induction at day 8 +/- 2 (SD) (proliferative phase) and at day 14 +/- 4 (midcycle) of their cycles. M-mode echocardiography was carried out with the patient in the left lateral decubitus, head down and head up positions. The mean serum estradiol level was 294 +/- 234 (SD) pg ml-1 at day 8 +/- 2 (treatment day) and it increased to 1503 +/- 531 pg ml-1 at day 14 +/- 4 (cycle day) of the same cycle. This change in serum estradiol was significant (P less than 0.001), associated with an increase in left ventricle diastolic dimension of 2.3 +/- 1.1 mm (P less than 0.001). During the same time period stroke volume and cardiac index correspondingly increased. Heart rate, fractional shortening, and blood pressure did not change and systemic vascular resistance decreased. Many of the cardiovascular adaptations of pregnancy are duplicated by high levels of endogenous estrogens and these changes are evident in as few as 6 days. Thus, we conclude that changes in endogenous estrogen correlate with certain cardiovascular parameters, the most striking of which is the left ventricular size. This may be one of the adaptive mechanisms by which the maternal circulation adapts to pregnancy.

Estrogen receptor gene expression in human uterine leiomyomata.

Estrogen and progestin are believed to be important physiological regulators of uterine leiomyoma growth. We recently showed that progesterone receptor messenger ribonucleic acid (mRNA) and protein levels are increased in human uterine leiomyomas compared with those in myometrial biopsy tissue obtained from the same patient. To further characterize the molecular mechanisms underlying abnormal growth of uterine leiomyomas, we analyzed biopsy samples of tumor and adjacent normal myometrium for estrogen receptor (ER) gene expression. Northern analysis indicated that ER mRNA levels were increased 1.4-to 12.6-fold in leiomyoma compared with myometrium in all patients examined (n = 11), whereas beta-actin mRNA was not different between the two groups. The size of the primary ER mRNA transcript was 6.2 kilobases in both leiomyoma and myometrium, indicating no gross mutation of the ER gene. An ER protein of 66 kilodaltons was detected by Western blot analysis, and quantitative immunoassay of ER revealed 9448 +/- 1955 fmol/mg DNA in leiomyoma compared to 2827 +/- 979 fmol/mg DNA in myometrial tissue. Scatchard analysis of 17 beta-estradiol binding to cell-free extracts revealed enhanced binding capacity (per mg DNA) in leiomyoma tissue (n = 6) of about 6-fold, whereas ER binding affinity was not substantially different between the leiomyoma and adjacent myometrial tissues. We propose that increased expression of progesterone receptor in leiomyoma is most likely a consequence of overexpression of functional ER that results in increased end-organ sensitivity to estradiol.

Treatment-seeking women at menopause: a comparison between two university menopause clinics.

OBJECTIVE: We wished to determine the expectations of women about the benefits of hormone replacement therapy (HRT) and how these expectations may be influenced by cultural factors and previous experience of disease by the patient or in their families. DESIGN: The attitudes of patients seeking HRT in Belfast, United Kingdom (n = 218) and Portland, USA (n = 100) were compared at their first clinic attendance using a questionnaire. Physical and mental health issues, previous use of HRT and continuance on treatment were compared. RESULTS: Belfast women were less healthy than their Portland counterparts, with a higher prevalence of cardiovascular disease and psychiatric disorders (p < 0.05). Belfast patients showed a significantly lower continuance with treatment (p < 0.01). Collectively, the patients ranked relief of menopausal symptoms as their main expectation from HRT followed by osteoporosis protection, psychiatric relief and cardioprotection. The Belfast group had higher expectations for the relief of psychological/psychiatric problems (p < 0.01). All women with a family history of cardiac disease or fractures were more concerned for the protective effects of HRT than those women with no relevant family history (p < 0.05). There were cultural difference in expectations from HRT with Belfast women expecting more psychological/psychiatric relief and therefore trying a greater number of preparations. CONCLUSIONS: These findings suggest that menopausal women in both countries are well informed about the potential protective benefits of HRT, and now expect an improvement in the quality of their lives well beyond the relief of menopausal symptoms.

Plasma ascorbate concentrations and blood cell dehydroascorbate transport in patients with diabetes mellitus.

Rates of dehydroascorbate uptake by blood granulocytes and mononuclear cells are slower, and plasma ascorbate concentrations are lower, among persons with diabetes mellitus than in nondiabetic subjects. These measurements do not correlate with one another or with simultaneously measured plasma glucose or glycosylated hemoglobin; they do not differ with type of diabetes or mode of treatment. In those diabetic granulocytes that exhibit slow dehydroascorbate uptake, maximal velocity (Vmax) transport rates for dehydroascorbate, 2-deoxyglucose, and 3-O-methylglucose are decreased, each to the same degree, while Km values for transport of these ligands are not different from those observed in nondiabetic cells. Since diffusion of these ligands is facilitated by a common transporter, these observations may reflect decreased numbers of glucose transporters in the plasma membranes of some diabetic leukocytes.

Acute visual loss during pregnancy after bromocriptine-induced ovulation. The elusive tumor.

The evaluation of patients complaining of amenorrhea with or without galactorrhea has been greatly enhanced by the availability of serum prolactin determinations and advances in diagnostic radiology. Likewise, the treatment of these patients with ergot derivative has resulted in the return of normal menses, and many pregnancies have been reported. The present report is of a patient with hyperprolactinemic amenorrhea-galactorrhea successfully treated with bromocriptine. A pregnancy followed resumption of menses, and a suprasellar cromophobeadenoma became manifest by producing blindness of the patient. The case is presented with recommendations for diagnosis and treatment.

Serial beta-hCG measurements in the early detection of ectopic pregnancy.

We investigated the sensitivity and specificity of serial serum hCG assays to diagnose early ectopic pregnancy in 50 asymptomatic women at risk. The initial two hCG values obtained at 2-5-day intervals were used to calculate doubling time and percentage increase. Twenty-five women had a viable intrauterine pregnancy, 14 an ectopic gestation, ten a spontaneous abortion, and one a molar pregnancy. A normal percentage increase and/or doubling time was observed in 64% of women who eventually proved to have an ectopic pregnancy. Ultimately, 85% of our patients demonstrated abnormal values when subsequent hCG pairs were analyzed. The sensitivity of these tests to diagnose asymptomatic ectopic pregnancy was 36%, with a specificity of 63-71%. We conclude that a normal rise in hCG production does not reliably differentiate an ectopic from an intrauterine pregnancy in the asymptomatic patient.

The fragmented intrauterine device: an unusual complication of a Lippes loop.

Fragmentation on removal of an effective and asymptomatic Lippes Loop is reported. The etiology of this event is hypothesized and the patient's managment is discussed. It is likely that fragmentation occurred as a result of material fatigue secondary to movement about the fixed, embedded tip. Surgical removal was effected.

Salpingitis isthmica nodosa: results of transcervical fluoroscopic catheter recanalization.

OBJECTIVE: To investigate the role of transcervical tubal catheterization in diagnosis and treatment of proximal tubal obstruction associated with salpingitis isthmica nodosa. DESIGN: Retrospective case study. SETTING: University hospital and outpatient radiology practice. PATIENTS: Fifty-two women with proximal tubal obstruction associated with salpingitis isthmica nodosa. INTERVENTION: Selective salpingography and catheter recanalization using fluoroscopic guidance. MAIN OUTCOME MEASURES: The number of tubes visualized to the fimbria as a percentage of the tubes with proximal tubal obstruction on the initial hysterosalpingogram was determined as a measure of diagnostic efficacy. To evaluate the treatment potential of catheter recanalization, the patients were grouped according to tubal status at the conclusion of the procedure and subsequent pregnancies were evaluated. RESULTS: Forty-seven of 65 tubes (72%) with proximal tubal obstruction were recanalized successfully. Among the 19 women who were able to conceive only via a recanalized salpingitis isthmica nodosa tube, there were 6 live births (32%) and two tubal pregnancies (10%). CONCLUSION: Selective salpingography allows complete tubal diagnosis in almost three fourths of patients with proximal tubal obstruction and salpingitis isthmica nodosa. The radiographic diagnosis of salpingitis isthmica nodosa may be pressure dependent. Intrauterine pregnancies occur via recanalized salpingitis isthmica nodosa tubes, therefore catheter recanalization may be attempted before tubal microsurgery or IVF in patients with proximal tubal obstruction and associated salpingitis isthmica nodosa.

The use of gonadotropin-releasing hormone agonist to regulate oocyte retrieval time.

We investigated the use of a gonadotropin-releasing hormone agonist (GnRH-a) to assist in the synchronous entry of a fixed number of subjects into in vitro fertilization (IVF) and gamete intrafallopian tube transfer cycle. Using a protocol in which a GnRH-a was given in the follicular or luteal phase, the clinical pregnancy rate per procedure was 27%. We conclude that the use of a GnRH-a for synchronous cycles in IVF-embryo transfer is efficacious and results in acceptable pregnancy rates.

Oocyte donor screening: the selection process and cost analysis.

OBJECTIVE: To evaluate the selection process and cost of screening oocyte donors. DESIGN: Retrospective analysis. SETTING: University-based IVF program. PATIENT(S): Potential oocyte donors. INTERVENTION(S): Outcomes of all inquiries by individuals responding to recruitment advertisements for oocyte donors over a 10-month period were assessed. Recruitment and screening costs to bring a single donor into the program were calculated. MAIN OUTCOME MEASURE(S): The attrition rate for each step of the oocyte donor screening process was determined. The costs assessed over the study period included the following: advertisement, administrative, professional, ultrasound, and blood screening. The total cost to bring a single donor into the program was calculated. RESULT(S): Advertisements led to 315 phone inquiries from potential oocyte donors. Of these, a total of 223 (71%) voluntarily withdrew from the screening process, 54 (17%) were screened out for medical or psychological reasons, and 38 (12%) entered the active donor pool. The total cost to bring a single donor into the program was approximately 1,869 dollars. CONCLUSION(S): There was significant attrition in the screening process for oocyte donation that needs to be taken into account in determining the costs of managing the program.

The use of oral contraceptives to regulate oocyte retrieval.

This study was designed to determine the efficacy of using OCs prior to ovulation induction in an IVF-ET program. A total of 26 cycles were initiated after gonadotropin suppression with OCs and 22 laparoscopies (84.6%) were performed. A pregnancy rate of 22.7% per laparoscopy and 23.8% per ET was achieved. The results suggest that the use of OCs to regulate oocyte retrieval can result in acceptable pregnancy rates and facilitate efficient time use of IVF-ET personnel.

Intrauterine insemination outperforms intracervical insemination in a randomized, controlled study with frozen, donor semen.

OBJECTIVE: To assess the efficacy of intrauterine insemination (IUI) in a donor insemination program. DESIGN: Prospective randomized clinical trial. SETTING: Donor insemination program. PATIENTS, PARTICIPANTS: Women undergoing insemination were randomly assigned to receive either IUI or intracervical insemination for a maximum of six cycles. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Cycle fecundity rates between the two routes were compared. RESULTS: The monthly fecundity rate for intracervical insemination was 5.1% compared with 23% by IUI. By life table analysis, pregnancy rates for IUI were significantly higher than intracervical insemination (P = 0.02). CONCLUSIONS: Intrauterine insemination with quarantined donor sperm is superior to intracervical insemination.

Vascular endothelial growth factor levels in serum and follicular fluid of patients undergoing in vitro fertilization.

OBJECTIVE: To define the relationship between serum and follicular fluid (FF) levels of vascular endothelial growth factor (VEGF), E2, and P in patients undergoing IVF; to quantify the effects of hCG on serum levels of VEGF during early pregnancy, and to report serial measurements of serum and ascites fluid levels of VEGF in a patient with severe ovarian hyperstimulation syndrome (OHSS). DESIGN: Prospective observational study. SETTING: University IVF program. PATIENTS(S): Women undergoing conventional IVF, receiving donated oocytes or spontaneously conceiving. One patient hospitalized with severe OHSS. MAIN OUTCOME MEASURE(S): Concentrations of VEGF, E2, and P in serum, FF, or peritoneal fluid. RESULT(S): At the time of egg retrieval, FF VEGF concentrations were positively correlated with serum and FF P concentrations and with patient age. At 11 to 14 days after ET, pregnant recipients of autologous fresh embryos had higher serum VEGF levels than both nonpregnant recipients of autologous fresh embryos and pregnant recipients of donor eggs. Elevated serum VEGF levels in a patient with severe OHSS coincided with the clinical onset and recurrence of symptoms. CONCLUSION(S): In patients undergoing IVF, FF VEGF levels at the time of egg retrieval correlated with the degree of follicular luteinization. There is a significant ovarian contribution to circulating VEGF levels during early gestation. Elevated serum VEGF levels may be a factor in the etiology of OHSS symptoms.

An intrauterine insemination-ready cryopreservation method compared with sperm recovery after conventional freezing and post-thaw processing.

OBJECTIVE: To test a sucrose-glycerol cryoprotectant for IUI-ready sperm preparation. DESIGN: Semen aliquots from normozoospermic donors either were subjected to conventional semen freezing (TES and Tris yolk buffer in 7.4% final glycerol) with post-thaw processing or were preprocessed and frozen in HEPES-buffered human tubal fluid with 1% human serum albumin, 4% sucrose, and 6% glycerol. All aliquots were cooled to 4 degrees C, exposed to liquid nitrogen vapors, and stored in liquid nitrogen. Aliquots from each were processed by centrifugation resuspension or by centrifugation in Percoll (Pharmacia, Alameda, CA) before sperm parameters were analyzed. SETTING: University-based andrology laboratory. MAIN OUTCOME MEASURE(S): Recovery of motile sperm. RESULT(S): Percoll processing produced preparations with higher percentages of motile cells; however, cryopreserved sperm had a lower recovery of motile sperm compared with Percoll-processed fresh semen or centrifugation/resuspension-processed fresh or frozen samples. The percentages of sperm with normal morphologies were significantly increased in the IUI-ready samples compared with samples frozen conventionally. The IUI-ready Percoll-processed sample produced the best results, with a final mean motility of 36% and an overall yield of motile sperm of 17.4%. CONCLUSION(S): The sucrose-glycerol-based cryoprotectant produced an IUI-ready preparation with motile sperm recovery comparable to that of conventional semen cryopreservation but with improved percent morphology.

Gender after artificial induction of ovulation and artificial insemination.

Several studies on artificial insemination by donor (AID) semen have suggested that the gender of infants can be influenced by treatment of the women with clomiphene citrate (CC) and by the type of semen used (fresh versus cryopreserved). We conducted a 3-year prospective clinical trial to test these hypotheses. Two groups of pregnant women were evaluated. Group I (n = 130) comprised women whose ovulation was induced by CC; group II (n = 190) comprised those who conceived during spontaneous ovulatory cycles. In a total of 320 pregnancies, 55 spontaneous abortions occurred, 23.1% in group I and 13.2% in group II (P less than or equal to 0.05). Two tubal ectopic pregnancies occurred in group I. Of the 100 and 165 pregnancies carried to term in the treated and control groups, respectively, 11% and 1.8% involved twins (P less than or equal to 0.005). When only single births were considered, group I had 46.1% males in 89 term pregnancies, and group II had 60.5% males in 162 term pregnancies. Significantly more female offspring occurred in the group treated with CC (P less than or equal to 0.05). Because it is possible that a portion of the effects observed in this study were a function of cryopreservation of the AID semen, we compared data on frozen sperm with data on fresh sperm in terms of abortion, gender, and incidence of multiple births; there were no significant differences. Fertil Steril 40:481, 1983.

Fecundability trends among sperm donors as a measure of donor performance.

OBJECTIVE: To examine fecundability trends among sperm donors. DESIGN: Retrospective analysis. SETTING: University-based sperm bank and donor insemination program. PATIENT(S): Sperm donors and recipients. INTERVENTION(S): A group of recipients underwent IUI with cryopreserved donor sperm. Fecundability was calculated for 20 sperm donors over 800 insemination cycles. MAIN OUTCOME MEASURE(S): Average fecundability per donor was compared for the first 40 cycles of a donor's use and for those donors within a group of more fertile recipients. Sperm parameters, recipient ages, and number of unique recipients for each donor were analyzed. RESULT(S): Average donor fecundability is constant; however, individual donors demonstrated differences among their fecundabilities (overall mean, 0.09; range, 0.01-0.26). These differences persisted for donors among a group of more fertile recipients (overall mean, 0.12; range, 0.02-0.35). A donor's fecundability at 15 cycles is predictive of his future performance. CONCLUSION(S): Differences in fecundability exist among sperm donors which cannot be discerned through routine semen parameters. Sperm donor fecundability should be analyzed periodically, and directors of sperm banks should consider discontinuing use of a donor whose outcome is substandard.

Intrauterine insemination-ready versus conventional semen cryopreservation for donor insemination: a comparison of retrospective results and a prospective, randomized trial.

OBJECTIVE: To compare fecundity rates following intrauterine insemination (IUI) with donor sperm frozen conventionally versus an IUI-ready preparation. DESIGN: Both retrospective results and a prospective, randomized study where recipients were assigned to one of two sperm cryopreservation methods in each cycle of intrauterine insemination are reported. SETTING: University-based infertility practice, affiliated private practices, and andrology laboratory. PATIENT(S): Women desiring therapeutic insemination in an effort to establish pregnancy. INTERVENTION(S): Intrauterine insemination with donor sperm frozen conventionally or by an IUI-ready protocol. MAIN OUTCOME MEASURE(S): Cycle fecundity in donor IUI recipients. RESULT(S): In a retrospective analysis involving 642 inseminations in 209 recipients, 79 pregnancies were recorded for an overall pregnancy rate of 12.3% per insemination (or cycle): 11.3% with IUI-ready sperm and 13.9% with conventionally preserved sperm. In a follow-up prospective, randomized study, the pregnancy rate for IUI-ready sperm preparations was 36% per cycle (14 of 39) whereas that for conventionally preserved sperm was 19.6% per cycle (9 of 46). Thirteen of the 23 pregnancies occurred in the first study cycle of insemination; only two pregnancies were observed in patients undergoing more than four cycles of insemination. CONCLUSION(S): Cycle fecundity for IUI-ready donor sperm is equivalent to conventional cryopreserved sperm based on both prospective and retrospective assessments.

Prospective randomized double-blind trial of 3 versus 6 months of nafarelin therapy for endometriosis associated pelvic pain.

OBJECTIVES: To determine the effectiveness of a 3-month course of nafarelin and, furthermore, to determine the long-term efficacy in patients treated for 3 and 6 months with nafarelin for symptoms associated with endometriosis. DESIGN: Double-blind, prospective, multicenter, clinical trial. SETTING: Fifteen reproductive endocrine clinics throughout the United States. PATIENTS: One hundred seventy-nine women with pelvic pain and endometriosis. INTERVENTIONS: Patients were assigned randomly to 3 months nafarelin followed by 3 months of placebo (n = 91) or to 6 months nafarelin (n = 88) in a prospective, randomized, double-blind multicenter trial. Patients were followed for 12 months after cessation of therapy. MAIN OUTCOME MEASURES: Patient-reported pain scores and physician-reported physical exam findings. RESULTS: Pain scores dropped significantly by the end of treatment in both groups. Symptoms recurred in both groups, and pain scores gradually increased during the follow-up period but always remained below baseline in both groups. No significant difference in efficacy was noted between the groups. A total of 26% of patients in each group underwent retreatment for recurrent symptoms. CONCLUSIONS: A 3-month course of nafarelin provided effective symptom relief for endometriosis. One year follow-up demonstrated continued pain relief but with gradual return of symptoms.

Medical treatment of endometriosis: a comparison of the suppressive effects of danazol and nafarelin on reproductive hormones.

OBJECTIVE: Patients with endometriosis were studied to investigate hormonal suppression by the gonadotropin-releasing hormone against nafarelin acetate compared with danazol. We hypothesized that the pattern, time course, and degree of gonadotropin and ovarian suppression would be different. DESIGN: The study included 16 patients who were randomized into one of three 6-month treatment protocols. SETTING: Patients were recruited from a university hospital setting. PATIENTS: Eligible candidates were 18 to 45 years of age, with regular menses and documented pelvic endometriosis. INTERVENTION: Six-month treatment protocols included nafarelin 800 or 400 micrograms/d, or danazol 800 mg/d. MAIN OUTCOME MEASURES: Serum estradiol (E2), progesterone (P), luteinizing hormone (LH), and follicle-stimulating hormone were determined before treatment and then monthly. Thirteen patients consented to a 12-hour hospital admission during the 5th and 6th month of treatment to determine LH pulse frequency and amplitude. RESULTS: Estradiol and P were suppressed in all groups, but E2 significantly more by nafarelin than danazol (P less than or equal to 0.01). Nafarelin, 800 micrograms, significantly depressed LH pulse amplitude compared with danazol (P less than or equal to 0.05). Two patients in the nafarelin group had the administration of their medication observed, and both demonstrated single, high-amplitude pulses immediately after administration. CONCLUSION: Nafarelin is a more potent LH and E2 suppressor than danazol, and the agonist effect of nafarelin may continue to provoke transient gonadotropin responses despite long-term therapeutic suppression.

Retreatment with nafarelin for recurrent endometriosis symptoms: efficacy, safety, and bone mineral density.

OBJECTIVE: To assess the efficacy, safety, and effect on bone mineral density of a 3-month course of retreatment with intranasal nafarelin acetate for recurrent symptoms of endometriosis. DESIGN: Multicenter, open-label, nonrandomized clinical trial. SETTING: Eleven hospital-based and private practices. PATIENT(S): Thirty-six women with endometriosis symptoms recurring after 3 or 6 months of treatment with nafarelin. INTERVENTION(S): Nasal nafarelin 200 micrograms twice daily for 3 months. MAIN OUTCOME MEASURE(S): Assessments for dysmenorrhea, dyspareunia, pelvic pain, tenderness, and induration. Measurement of bone mineral density of the lumbar spine. RESULT(S): Improvements from admission to the end of retreatment were significant for dysmenorrhea, pelvic pain, tenderness, induration, and dyspareunia. Three months after retreatment ended, mean symptom scores for dysmenorrhea and pelvic tenderness, although worse than at the end of retreatment, were still significantly better than scores at admission. Mean bone mineral density 3 months after retreatment was 0.56% lower than before retreatment and 1.94% lower than before initial treatment. CONCLUSION(S): Three-month nafarelin retreatment for recurrent endometriosis symptoms was effective and safe.