Kenneth A. Steingold

Biologic effects of transdermal estradiol.

Abstract We conducted a dose–response study in 23 postmenopausal women to compare the physiologic effects of transdermal estradiol and oral conjugated equine estrogens. The doses studied were 25, 50, 100, and 200 μg of transdermal estradiol per 24 hours, and 0.625 and 1.25 μg of oral conjugated estrogens. Transdermal estradiol increased circulating concentrations of estradiol and estrone. Oral conjugated estrogens also raised the levels of estrogen, particularly estrone. Both preparations lowered gonadotropin levels, decreased the percentages of vaginal parabasal cells, increased the percentage of superficial cells, and lowered urinary calcium excretion. The effects of 0.625 and 1.25 mg of oral estrogens were similar to those of 50 and 100 μg of transdermal estradiol per 24 hours, respectively. Oral estrogens significantly increased circulating levels of renin substrate, sex-hormone–binding globulin, thyroxine-binding globulin, and cortisol-binding globulin; transdermal estradiol had no effect. The higher...

Evolution of a highly successful in vitro fertilization-embryo transfer program

During the first 2 1/2 years of operation of the University of California at Los Angeles in vitro fertilization-embryo transfer program, 47 clinical pregnancies were achieved in 154 laparoscopies for oocyte aspiration (31%). Two of these pregnancies were achieved through transfer of cryopreserved embryos when ongoing pregnancy did not result from embryo transfer in the stimulated cycle. An increase in clinical implantation was noted with a reduction of transfer volume and proportion of air, with 34% of laparoscopies being followed by clinical pregnancy over the last 18 months. No difference in the rate of clinical pregnancy was noted relative to uterine depth or position. The high rate of multiple implantation (47%) suggested a high level of embryo quality. The success rate was attributed to a strong ovarian, human menopausal gonadotropin stimulation, accurate timing of human chorionic gonadotropin, a high oocyte retrieval rate, meticulous laboratory technique, atraumatic, high-fundal transfer of embryos, and initiation of embryo cryopreservation.

Long-term administration of gonadotropin-releasing hormone agonist and dexamethasone: assessment of the adrenal role in ovarian dysfunction *

OBJECTIVE To examine the possible impact of abnormal adrenal steroidogenesis on the ovarian dysfunction seen in polycystic ovarian disease (PCOD). DESIGN Prospective analysis of blood sampling monthly for 6 months, then three times weekly for 90 days. SETTING Tertiary institutional outpatient care. PARTICIPANTS Six anovulatory women with a diagnosis of PCOD. INTERVENTION Six-month suppression with gonadotropin-releasing hormone agonist (GnRH-a) followed by suppression with dexamethasone (DEX) for 90 days. MAIN OUTCOME MEASURES Serum levels of testosterone (T), androstenedione (A), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), cortisol, estradiol (E2), progesterone (P), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and bioactive LH. RESULTS Gonadotropin-releasing hormone agonist administration suppressed greater than 60% of the circulating levels of T and A, suggesting an ovarian origin. Minimal changes of DHEA, DHEAS, and cortisol were seen. With the addition of DEX, there was greater than 90% suppression of the total circulating A, T, DHEA, DHEAS, and cortisol, supporting the adrenal origin of the non-GnRH-a suppressible androgens. Excessive ovarian T and A secretion returned during the 90-day recovery study period in spite of rises of FSH concentrations that changed the ratio of FSH to LH in all subjects. Four of the six women failed to ovulate. In comparison of the women who did and did not ovulate during recovery, no differences in absolute levels or changes in concentrations of steroids or gonadotropins could be detected. CONCLUSIONS Using sequential and simultaneous administration of GnRH-a and DEX, we were able to delineate the contributions of the ovaries and adrenals to the abnormal steroidogenesis seen in PCOD. Despite prolonged suppression of ovarian and then adrenal steroidogenesis, ovarian dysfunction, evidenced by abnormal androgen production, returned with cessation of agonist administration.

Danazol inhibits steroidogenesis by the human ovary in vivo

Gonadotropins, estradiol (E2), and the steroid precursors of ovarian estrogen secretion were examined in women on danazol to clarify actions of the medication on hypothalamic-pituitary-ovarian function. Follicle-stimulating hormone was not altered acutely after a single maximal dose or chronically during therapy, whereas a slight but significant increase in luteinizing hormone was noted during the 6 months of treatment. During danazol treatment, there was a blunted response of E2 to injections of human menopausal gonadotropins. The progestin and androgen precursors of E2 were reduced, with the exception of 17-hydroxypregnenolone, which was significantly increased. This 17-hydroxylase enzyme block persisted in spite of dexamethasone suppression of adrenal function. Therefore, the reduced ovarian secretion of E2 in women receiving danazol is due in part to reductions of ovarian precursor steroids for E2 synthesis, consequent to a direct ovarian action of the medication.

Transvaginal ultrasound scanning of ovarian follicles

The transvaginal approach to ultrasound scanning is a practical method complementary to the transabdominal technique for the minority of cases where, regardless of technological refinements, anatomic constraints require an alternative port of access to the pelvic cavity.

Effects of sera from patients given various anesthetics on preimplantation mouse embryo development in vitro

This study compared the effects of sera from patients given various anesthetics on in vitro mouse preimplantation embryo development. Patients electing bilateral laparoscopic tubal sterilization were subjected to general anesthesia with nitrous oxide (N2O) that included either isofluorane (ISO/N2O) as an inhalant or fentanyl or morphine (FEN/MOR/N2O). The addition of sera collected 1 hr after anesthetic induction significantly reduced the numbers of two-cell mouse embryos that developed to blastocyst in the ISO/N2O group as compared to that of preanesthesia sera. In contrast, no detrimental effects were revealed from sera of patients given FENIMOR/N2O. Comparison of sera from patients given ISO/N2O and FEN/MOR/N2O for laparoscopic oocyte retrieval and from patients given spinal anesthesia and/or i.v. sedation for ultrasonic retrieval also revealed a decrease in mouse embryo development in the ISO/N2O group, but no differences were seen in the other anesthetic regimens. ISO/N2O anesthesia was also associated with a significantly decreased fertilization rate of mature oocytes retrieved. However, no significant effect of ISO/N2O anesthesia on IVF pregnancy rates could be demonstrated. These studies indicate that embryo toxic effects can be detected in sera from patients given ISO/N2O and that this anesthetic may be detrimental to the success of in vitro fertilization and embryo transfer.

Treatment of severe androgen excess due to ovarian hyperthecosis with a long-acting gonadotropin-releasing hormone agonist☆

A 31-year-old nulligravid patient presented with irregular menses, severe hirsutism, and infertility. Evaluation revealed marked increases of serum androstenedione and testosterone levels and a possible ovarian mass. At operation a cystic teratoma was removed from the left ovary and bilateral wedge resection revealed severe ovarian hyperthecosis. After operation only a transient decrease of androstenedione and testosterone was noted and the patient failed to ovulate or improve clinically. Subsequently a long-acting gonadotropin-releasing hormone agonist was administered daily for 6 months, which reduced circulating delta 4-steroids and estrogens to levels approximating those of castrated women. Immediately after discontinuation of treatment, ovulation induction was successfully achieved with human menopausal gonadotropin. This report introduces a new therapeutic approach to the problem of severe ovarian hyperthecosis and may provide an opportunity for childbearing in these patients.

Optimization of hydrogen-ion concentration during aspiration of oocytes and culture and transfer of embryos

Rapid and marked shifts in pH can have deleterious effects on oocytes and embryos. Such shifts are most likely to occur during laparoscopy and examination of gametes and embryos. We studied the rate of pH change of follicular fluid and bicarbonate- and phosphate-based media during exposure to 100% CO2 with a constant surface area to volume ratio. All solutions tested developed a pH below the physiological range of 7.30–7.50 within 2 min of expoure to 100% CO2. We also examined the rate of increase in pH due to CO2 loss from media in room air within standard organ culture dishes and tubes after exposure to ambient conditions for 2 min, the pH of modified Hams F-10 medium in organ culture dishes rose above the physiological range. We have used a needle laparoscope to confirm intraperitoneal placement prior to the insufflation of a 5% CO2 gas mixture for loparoscopic oocyte retrieval. We have carried out all examinations of oocytes and embryos within a pediatric isoette equipped with an automatic CO2 controller to maintain a 5% CO2 environment. We have transferred embryos in 15% fetal cord serum to avoid the alkaline pH associated with a high concentration of equilibrated heat-inactivated preovulatory serum. These simple techniques can optimize the hydrogen-ion concentration of media during the entire process of in vitro fertilization and embryo transfer.

Pituitary function before, during, and after chronic gonadotropin-releasing hormone agonist therapy

OBJECTIVE To examine possible adverse effects on pituitary function of long-term administration of gonadotropin-releasing hormone agonist (GnRH-a). DESIGN Prospective analysis of blood sampling before, during, and after GnRH-a therapy. SETTING Tertiary institutional outpatient care. PATIENTS Twelve normally ovulatory women with a diagnosis of endometriosis. INTERVENTIONS Six-month suppression with GnRH-a. MAIN OUTCOME MEASURES Serum levels of follicle-stimulating hormone, luteinizing hormone, free thyroxin index, cortisol (F), growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH). RESULTS Basal and stimulated values of gonadotropins, PRL, F, TSH, and GH were normal and unchanged by 6 months of GnRH-a after resumption of menses. CONCLUSIONS Utilizing dynamic pituitary function tests, we were unable to demonstrate an adverse effect of long-term GnRH-a therapy on pituitary function.

Long-term administration of gonadotropin-releasing hormone agonist and dexamethasone: Assessment of the adrenal role in ovarian dysfunction

used postoperatively. Success rates within the adjuvant 5fluorouracil and laser alone arms were essentially the same (9 of 18 vs. 8 of 20). In contrast, outcome in the interferon group was significantly better than that for the other two arms combined (27 of 33 [82%] vs. 17 of 38 [45%]; chi* 10.31; P < 0.002). Moreover, 18 of 21 failures (86%) in the first two arms and 3 of 6 failures (50%) in the interferon arm were ‘rescued’ from the need for a second laser surgical procedure by crossover to either the 1 or 3 MIU interferon regimen. Results from this open-label, randomized clinical trial suggest that even a relatively low dose of recombinant interferon, used in combination with effective surgical debulking, can markedly reduce the risk of postoperative recurrence.