David R. Meldrum

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...

Female reproductive aging—ovarian and uterine factors

Objectives To review published data on ovarian and uterine aging in the human female. Data Identification Literature review. Study Selection Studies examining the effect of age on oocyte quality and uterine receptivity. Results There is clear evidence in women having in vitro fertilization (IVF) and in normal oocyte donors that oocyte quality declines with age. Three studies of oocyte donation, one study of IVF, and multiple studies in subhuman mammalian species have all shown reduced implantation with aging, and endometrial biopsies in women over age 35 having IVF have shown a high incidence of delayed or absent secretory maturation. In one study of oocyte donation, the reduced rate of pregnancy in women over age 40 was corrected by doubling the dose of progesterone (P) administered to prepare the endometrium for implantation. Conclusions Conflicting opinions regarding the effect of aging on uterine receptivity in recipients of donated oocytes appear to have been because of use of high doses of P replacement. When doses more closely approximating physiological levels have been used, a decline of implantation with increasing age has been clearly demonstrated. Oocyte donation, through the use of oocytes from young normal women and an increased level of P replacement to aging recipients, corrects both of these defects.

Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation.

OBJECTIVE To assess the efficacy, safety, and local tolerance of ganirelix acetate for the inhibition of premature luteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation (COH). DESIGN Phase III, multicenter, open-label randomized trial. SETTING In vitro fertilization (IVF) centers in North America. PATIENT(S) Healthy female partners (n = 313) in subfertile couples for whom COH and IVF or intracytoplasmic sperm injection were indicated. INTERVENTION(S) Patients were randomized to receive one COH cycle with ganirelix or the reference treatment, a long protocol of leuprolide acetate in conjunction with follitropin-beta for injection. OUTCOME MEASURE(S) Number of oocytes retrieved, pregnancy rates, endocrine variables, and safety variables. RESULT(S) The mean number of oocytes retrieved per attempt was 11.6 in the ganirelix group and 14.1 in the leuprolide group. Fertilization rates were 62.4% and 61.9% in the ganirelix and leuprolide groups, respectively, and implantation rates were 21.1% and 26.1%. Clinical and ongoing pregnancy rates per attempt were 35.4% and 30.8% in the ganirelix group and 38.4% and 36.4% in the leuprolide acetate group. Fewer moderate and severe injection site reactions were reported with ganirelix (11.9% and 0.6%) than with leuprolide (24.4% and 1.1%). CONCLUSION(S) Ganirelix is effective, safe, and well tolerated. Compared with leuprolide acetate, ganirelix therapy has a shorter duration and fewer injections but produces a similar pregnancy rate.

LOWER PREGNANCY RATE WITH PREMATURE LUTEINIZATION DURING PITUITARY SUPPRESSION WITH LEUPROLIDE ACETATE

The relationship of the circulating level of progesterone (P) on the day of human chorionic gonadotropin (hCG) injection to occurrence of clinical pregnancy was examined in 133 leuprolide acetate human menopausal gonadotropin (hMG) in vitro fertilization cycles in women having at least three embryos transferred. Progesterone concentrations greater than 0.5 ng/mL were associated with a significantly lower rate of pregnancy (12/59, 20%) compared with less than 0.5 ng/mL (40/74, 54%, P less than 0.005). The higher P cycles were associated with greater patient age and hMG dose, although these relationships appeared to be indirect. Luteinizing hormone (LH) concentrations remained suppressed. Ovarian stimulation may cause excessive luteinization and an adverse cycle outcome even in the presence of low LH levels. Prospective use of P levels may be helpful to determine optimal hCG timing.

Blastocyst culture and transfer: analysis of results and parameters affecting outcome in two in vitro fertilization programs

OBJECTIVE To determine whether previously described advanced blastocyst development and high implantation rates are confirmed in an expanded multicenter trial. DESIGN Retrospective review. SETTING Two private assisted reproductive technology units. PATIENT(S) One hundred seventy-four patients who underwent blastocyst culture and transfer. INTERVENTION(S) Culture of all pronucleate embryos in sequential media to the blastocyst stage (day 5) followed by ET. MAIN OUTCOME MEASURE(S) The number and percentage of blastocysts developed, implantation rates, pregnancy rates, and parameters that affected outcome were analyzed. RESULT(S) Only 3 of 174 patients failed to achieve blastocyst-stage ET. The mean blastocyst development rate was 48%. The ongoing pregnancy rate was 66.3% per oocyte retrieval, with a mean (+/-SE) of 2.2 +/- 0.05 blastocysts transferred and an implantation rate of 48% per blastocyst transferred. CONCLUSION(S) Blastocyst culture and transfer is an effective means of treating patients who respond well to gonadotropins. High pregnancy rates can be accomplished with low numbers of embryos transferred. Patients who failed to achieve ET were rare.

Routine pituitary suppression with leuprolide before ovarian stimulation for oocyte retrieval

Pituitary suppression with leuprolide acetate (LA) was used before and during ovarian stimulation with human menopausal gonadotropins in 45 consecutive women having their first cycle of in vitro fertilization embryo transfer (IVF-ET). As anticipated, a low rate of cycle cancellation (6.7%) was necessary for poor responses. Follicles were allowed to develop to a larger diameter than with our prior protocol without LA. On the day of human chorionic gonadotropin (hCG), 11.5 + 0.7 follicles of at least 1.0 cm were visualized; 11.7 + 0.9 oocytes were retrieved; 67.5% fertilized and 6.7 + 0.6 normal embryos were available for transfer. Of the 3.4 + 0.1 embryos transferred per patient, 24.6% implanted. The rates of clinical pregnancy per retrieval and per stimulation were 54% and 47%, respectively, of which 23.8% aborted. Routine use of LA resulted in a highly efficient level of ongoing pregnancy per initiated cycle, and therefore may produce a superior first cycle for IVF-ET.

Role of vascular endothelial cell growth factor in Ovarian Hyperstimulation Syndrome.

Controlled ovarian hyperstimulation with gonadotropins is followed by Ovarian Hyperstimulation Syndrome (OHSS) in some women. An unidentified capillary permeability factor from the ovary has been implicated, and vascular endothelial cell growth/permeability factor (VEGF) is a candidate protein. Follicular fluids (FF) from 80 women who received hormonal induction for infertility were studied. FFs were grouped according to oocyte production, from group I (0-7 oocytes) through group IV (23-31 oocytes). Group IV was comprised of four women with the most severe symptoms of OHSS. Endothelial cell (EC) permeability induced by the individual FF was highly correlated to oocytes produced (r2 = 0.73, P < 0.001). Group IV FF stimulated a 63+/-4% greater permeability than FF from group I patients (P < 0. 01), reversed 98% by anti-VEGF antibody. Group IV fluids contained the VEGF165 isoform and significantly greater concentrations of VEGF as compared with group I (1,105+/-87 pg/ml vs. 353+/-28 pg/ml, P < 0. 05). Significant cytoskeletal rearrangement of F-actin into stress fibers and a destruction of ZO-1 tight junction protein alignment was caused by group IV FF, mediated in part by nitric oxide. These mechanisms, which lead to increased EC permeability, were reversed by the VEGF antibody. Our results indicate that VEGF is the FF factor responsible for increased vascular permeability, thereby contributing to the pathogenesis of OHSS.

Postmenopausal hot flushes: A disorder of thermoregulation

The changes in cutaneous and body temperature and cutaneous conductance during hot flushes in eight postmenopausal women were studied. The vasomotor changes occurred approx. 45 sec after the patients experienced the initial subjective symptoms of the attacks. The rise in skin conductance appeared to be a more reliable index of the flushing episode than did the change in skin temperature. On the basis of the changes recorded it is suggested that the hot flush syndrome may represent a specific thermoregulatory disorder rather than being due to a non-specific central autonomic discharge. The episodes may be triggered by a neuroendocrine imbalance following the disruption of ovarian function and fall in estrogen production. In assessing the frequency and severity of hot flushes, and the effects of treatment, objective measurements of skin and core temperature and skin conductance should replace subjective criteria.

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.

Estrogen Replacement Therapy: Indications and Complications

Estrogen replacement therapy is one of the most controversial issues in the field of reproductive medicine. Indications for its use include hot flashes, vaginal atrophy, and risk of osteoporosis. Risk of heart disease may also be an indication but this use has not been firmly established. The role of estrogen replacement therapy in aging changes of skin needs clarification. Complications of therapy include endometrial cancer, breast cancer, hypertension, hyperlipidemia, and gallbladder disease. The last three complications presumably result from hepatic actions of estrogen replacement therapy.