Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women.

The effects of soy protein (40 g/d) containing moderate and higher concentrations of isoflavones on blood lipid profiles, mononuclear cell LDL receptor messenger RNA, and bone mineral density and content were investigated in 66 free-living, hypercholesterolemic, postmenopausal women during a 6-mo, parallel-group, double-blind trial with 3 interventions. After a control period of 14 d, during which subjects followed a National Cholesterol Education Program Step I low-fat, low-cholesterol diet, all subjects were randomly assigned to 1 of 3 dietary groups: Step I diet with 40 g protein/d obtained from casein and nonfat dry milk (CNFDM), Step I diet with 40 g protein/d from isolated soy protein containing 1.39 mg isoflavones/g protein (ISP56), or Step I diet with 40 g protein/d from isolated soy protein containing 2.25 mg isoflavones/g protein (ISP90). Total and regional bone mineral content and density were assessed. Non-HDL cholesterol for both ISP56 and ISP90 groups was reduced compared with the CNFDM group (P < 0.05). HDL cholesterol increased in both ISP56 and ISP90 groups (P < 0.05). Mononuclear cell LDL receptor mRNA was increased in subjects consuming ISP56 or ISP90 compared with those consuming CNFDM (P < 0.05). Significant increases occurred in both bone mineral content and density in the lumbar spine but not elsewhere for the ISP90 group compared with the control group (P < 0.05). Intake of soy protein at both isoflavone concentrations for 6 mo may decrease the risk factors associated with cardiovascular disease in postmenopausal women. However, only the higher isoflavone-containing product protected against spinal bone loss.

Modulation of implantation-associated integrin expression but not uteroglobin by steroid hormones in an endometrial cell line.

In order to test the hypothesis that integrin and uteroglobin (UG) expression in cultured endometrial cells are affected by hormone treatment, Ishikawa-CH endometrial cancer cells were cultured and exposed to oestradiol or oestradiol and progesterone regimens and assayed using immunohistochemistry. We evaluated the intensity of immunohistochemical staining for the integrin monomers alpha(v) and beta1, the dimers alpha(v)beta3 and alpha(v)beta6, and for the secretory protein uteroglobin under various experimental conditions. Cells grown in control media stained positively for the integrin monomers alpha(v) and beta1, the dimer alpha(v)beta3, and for UG. Oestradiol and sequential oestradiol/progesterone reversibly suppressed staining for the dimer alpha(v)beta3. Hormone treatment had no effect on the staining of the beta1 and alpha(v) monomers or UG. The alpha(v)beta6 dimer antibody did not stain under any experimental treatment conditions. These data indicate that expression of the integrin complex alpha(v)beta3 is reversibly suppressed by oestradiol in Ishikawa cells and that these cells may be a good model for studying hormone-driven molecular changes in endometrium.

Increasing clinical pregnancy rates after IVF/ET. Can immunosuppression help?

OBJECTIVE: To evaluate the safety and efficacy of immunosuppression as an adjunct to improving the success of in vitro fertilization/embryo transfer (IVF-ET). STUDY DESIGN: A randomized, double-blind, placebo-controlled clinical trial. RESULTS: Seventy-five patients were randomized to receive either prednisone (39 patients, 51%) or placebo (36 patients, 49%). Patients in both groups had similar ages and numbers of preembryos transferred. CONCLUSION: Both the implantation and clinical pregnancy rates were higher in the prednisone group (16% vs. 11% and 43.5% vs. 32.3%, respectively). However, these differences did not achieve statistical significance. Evaluation of the ongoing pregnancy rate revealed little difference between the prednisone-treated patients (30.7%) and those receiving placebo (28.0%). There were no side effects reported by patients in either group.

Comparison of magnetic resonance imaging and transvaginal ultrasonography with hysterosalpingography in the evaluation of women exposed to diethylstilbestrol.

OBJECTIVE: To compare the ability of magnetic resonance imaging (MRI) and transvaginal ultrasound (TV-US) with that of hysterosalpingography (HSG) in detecting uterine abnormalities caused by in utero diethylstilbestrol (DES) exposure. STUDY DESIGN: The study was a prospective MRI and TV-US blind comparison of DES-exposed and nonexposed subjects who had had previous HSG for infertility evaluation. RESULTS: MRI identified uterine constrictions in 60% of patients and T-shaped uteri in 25% of DES-exposed patients with HSG-confirmed abnormalities. TV-US did not identify uterine constrictions or T-shaped uteri in DES-exposed patients. CONCLUSION: HSG must still be considered the preferred method in evaluating DES-related uterine abnormalities. HSG-defined uterine abnormalities associated with in utero DES exposure were variably identified by MRI and not at all by TV-US.

Achieving multiple-order embryo transfer identifies women over 40 years of age with improved in vitro fertilization outcome.

OBJECTIVE: To define factors in patients > or = 40 years that may improve outcome and provide prognosis for success in IVF-ET. DESIGN: Retrospective. SETTING: University infertility center. PATIENTS: Patients (n = 501) undergoing IVF-ET from 1987 to 1994. INTERVENTIONS: IVF-ET (n = 713 cycles) with GnRH-analogue suppression and hMG stimulation. MAIN OUTCOME MEASURES: We evaluated data including age, diagnosis, prestimulation (day 3) FSH and E2, hMG ampules used, days of monitoring, follicle number and size, maximum E2, ova retrieved, cancellation rate, clinical pregnancy, nidation, and miscarriage rates. RESULTS: Overall, patients > or = 40 years had significantly decreased pregnancy rates (PRs), response to stimulation, and increased miscarriage rates. However, if these patients had four or more embryos transferred, their response and PRs (34.4% per ET) were not significantly different from younger women (47.7% per ET). The majority (77.8%) of pregnancies in women > or = 40 years occurred when four or more embryos were transferred. CONCLUSION: A subset (49%) of women > or = 40 years undergoing IVF-ET will respond to ovarian stimulation well enough to result in four or more embryos available for transfer with a resultant PR similar to that observed in younger patients. We recommend consideration of an attempt at IVF-ET before recommending oocyte donation.

Immunocytochemical localization of growth factors and their receptors in human pre-embryos and Fallopian tubes.

We utilized indirect immunocytochemistry to demonstrate the presence of growth factors and their receptors in human pre-embryos and Fallopian tubes. In pre-embryos, only transforming growth factor-alpha (TGF-alpha) and the intracellular domain of epidermal growth factor receptor (EGFR) were found at the 4-cell stage. In 8- to 14-cell pre-embryos, TGF-alpha, the intracellular and extracellular domains of EGFR, and insulin-like growth factor-I and its receptor were found. Antibodies against TGF-alpha stained all Fallopian tube specimens, while the extracellular domains of EGFR was only found in specimens from patients with either blood type A or AB. These results suggest a cross-reactivity between the extracellular domain of the EGFR and blood group antigens. Our novel demonstration of growth factor receptor staining in human pre-embryos shows that growth factor receptor localization is dependent on the developmental stage of human pre-embryos. We have also established a potentially important link between the Fallopian tube which secretes growth factors and the localization of growth factor receptors in pre-embryos. These findings are compatible with the hypothesis that tubal secretions are embryotrophic for the early development of the pre-embryo.

Prognostic value of day 3 estradiol on in vitro fertilization outcome.

OBJECTIVE: To evaluate the prognostic value of day 3 E2 levels, independent of day 3 FSH levels, on responses to ovulation induction and subsequent pregnancy rates (PRs) in IVF-ET patients. DESIGN: Prospective, observational. SETTING: University-based tertiary care and private reproductive endocrine-infertility units. PATIENTS AND INTERVENTIONS: A total of 225 patients underwent 292 IVF cycles with luteal phase GnRH agonist suppression and hMG stimulation. MAIN OUTCOME MEASURES: We evaluated response and outcome data including age, day 3 FSH and E2 levels from a menstrual cycle before IVF, ampules of hMG used, maximum E2 level, cancellation rates, and clinical PR. RESULTS: Despite similar age, number of ampules of hMG, and peak E2 levels, patients with an elevated E2 level (E2 > or = 80 pg/mL) (conversion factor to SI unit, 3.671) on day 3 of a cycle before IVF-ET achieved a lower PR per initiated cycle (14.8% versus 37.0%) and had a higher cancellation rate (18.5% versus 0.4%) compared with those with E2 levels < 80 pg/mL. Even when patients with elevated FSH levels (FSH > or = 15 mIU/mL) (conversion factor to SI unit, 1.00) were excluded (leaving 279 cycles), those with an elevated day 3 E2 still had a lower PR per initiated cycle (14.8% versus 38.9%) and maintained a higher cancellation rate (18.5% versus 0.4%). When the day 3 E2 was > or = 100 pg/mL there was a 33.3% cancellation rate and no pregnancies were achieved. CONCLUSION: Patients who presented with an elevated day 3 E2 (> or = 80 pg/mL) in a cycle before IVF-ET had a higher cancellation rate and achieved a lower PR independent of FSH level. A day 3 E2 level, in addition to a day 3 FSH level, appears very helpful in prospectively counseling patients regarding cancellation risk and ultimate IVF-ET success.

A comparison of bone mineral densities among female athletes in impact loading and active loading sports.

The purpose of this study was to compare bone mineral densities (BMD) of collegiate female athletes who compete in impact loading sports; volleyball players (N = 8) and gymnasts (N = 13), to a group of athletes who participate in an active loading sport; swimmers (N = 7), and a group of controls (N = 17). All of the volleyball, swimming, and control subjects were eumenorrheic (10-12 cycles/year), whereas two of the gymnasts were amenorrheic (0-3 cycles/year), eight were oligomenorrheic (4-8 cycles/year), and three were eumenorrheic (10-12 cycles/year). Lumbar spine, proximal femur, and total body BMD were measured with dual-energy X-ray absorptiometry. The groups were compared with respect to the following regions: lumbar spine (L1-4); femoral neck; Ward's triangle; right and left arms; right and left legs; pelvis; and torso. When controlling for differences in height and weight the impact loading group (volleyball and gymnastic) had significantly greater BMD at the lumbar spine, femoral neck, Ward's Triangle, and total body when compared to the active loading (swimming) and control groups. The regional analysis from the total body scan revealed that the gymnasts had significantly (p < 0.05) greater BMD than all other groups at the right and left arm sites. The impact loading groups (gymnastic and volleyball) had a greater BMD in the legs and pelvis than the active loading (swimming) and control groups. Furthermore, the impact loading group had a greater torso BMD than the control group. There were no differences at any site between the active loading group (swimming) and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Lineage tracing demonstrates that blastomeres of early cleavage-stage human pre-embryos contribute to both trophectoderm and inner cell mass.

We injected a fluorescent lineage tracer (Texas Red-lysine-dextran) into individual blastomeres of donated human diploid 2- to 8-cell pre-embryos and cultured them to blastocysts. Once pre-embryos reached the expanded blastocyst stage, they were fixed and examined in a scanning confocal microscope to identify the location of fluorescent tracer. In successfully injected pre-embryos that developed to expanded blastocysts, we found that randomly injected blastomeres formed both trophectoderm (TE) and inner cell mass (ICM). More labelled progeny were found in TE than in ICM. Our results show that individual early blastomeres are not yet committed to form either TE or ICM but instead can form both rudiments.

Utility of in vitro fertilization at diagnostic laparoscopy.

OBJECTIVE: To compare stimulation and outcome variables for IVF in stimulated cycles when ova are retrieved during diagnostic infertility laparoscopy versus transvaginal ultrasound (US) directed retrieval and to investigate the presence of unexpected failed fertilization in the diagnostic laparoscopy group, which allows an opportunity to diagnosis an etiology of infertility based on gamete interaction. DESIGN: Consecutive patients who needed infertility diagnostic laparoscopy and agreed to combination with IVF were compared with concurrent patients undergoing transvaginal US IVF. Male factor screening parameters (semen analysis, sperm penetrating assay) and resultant fertilization were analyzed for these patients. SETTING: The George Washington University Hospital, a tertiary referral center offering assisted reproductive technologies. Patients for diagnostic laparoscopy combined with IVF were enrolled in the Program of Oocyte Retrieval at Diagnostic Laparoscopy (PORDL). PARTICIPANTS: One hundred twenty-four women enrolled for diagnostic laparoscopy combined with IVF; 237 women were concurrently enrolled for transvaginal US IVF. RESULTS: Response variables (number of follicles, days of monitoring, ampules of hMG, maximum E2) between the two groups were similar. Outcome variables (ova retrieved, ova fertilized, ova cleaved, clinical pregnancy rate per embryo transferred) were similar despite a significantly higher number of embryos transferred for the transvaginal US group. The clinical pregnancy rate per cycle was similar, 26% versus 28% for the women in the transvaginal US versus those women in the PORDL group, as was the clinical pregnancy rate per ET, 31% versus 34%, respectively. The number of fertilized ova for each group was not significantly different: 5.5 +/- 0.3 for the transvaginal group versus 4.8 +/- 0.4 for the PORDL group. Patients in the PORDL group with a known male factor (group B) had a lower fertilization rate than those with no male factor (group A). Within the group A with no detectable male factor prospectively, 17.2% had unexpectedly poor fertilization (group A1), whereas the rest of the group A patients had higher fertilization rates as was expected (group A2). The clinical pregnancy rate per ET for group A1 was 0% compared with 43.4% for the group A2 patients. CONCLUSIONS: In vitro fertilization can be successfully performed during diagnostic laparoscopy yielding comparable results to transvaginal ultrasound IVF while gaining diagnostic information concerning sperm-ova interaction (i.e., fertilization).

Quantitative and qualitative changes in lipids, lipoproteins, apolipoprotein A-I, and sex hormone-binding globulin due to two doses of conjugated equine estrogen with and without a progestin.

OBJECTIVE: To determine whether the quantitative and qualitative effects on lipoproteins differ between two doses of conjugated equine estrogen before and after progestin administration. METHODS: We randomized 103 postmenopausal women into a control group and into two groups receiving either 0.625 mg or 1.25 mg of conjugated equine estrogen for 4 months and then the same estrogen dose plus cyclic medroxyprogesterone acetate for 8 months. RESULTS: Both estrogen doses similarly lowered (P < .01) low-density lipoprotein (LDL) cholesterol and raised (P < .01) high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, triglyceride levels of all lipoproteins, and sex hormone-binding globulin capacity. Cyclic addition of the progestin reduced HDL cholesterol (P < .01) and apolipoprotein A-I (P < .05), but not LDL cholesterol in either estrogen group. A greater lowering of HDL cholesterol (P < .05) in response to the progestin was seen with the 0.625-mg dose of estrogen. Estrogen-induced triglyceride enrichment of HDL and LDL was not reversed by the progestin. CONCLUSION: The only significant quantitative difference in lipoprotein levels between the doses of conjugated equine estrogen before or after administration of medroxyprogesterone acetate was a greater decline in HDL cholesterol levels with the lower dose after 4 months of the progestin. This difference was not sustained over time. There were no differences between doses in the estrogen-induced triglyceride enrichment of lipoproteins, and these qualitative changes were not affected by the progestin.

The effect of test protocol instructions on the measurement of muscle function in adult women.

Consideration of the anatomy of the nervous system and events (ie., age, physical training, motor learning) that invoke changes in neural regulatory mechanisms and other bodily systems renders the impact of the type of instruction used to elicit a maximal effort in the assessment of muscle function across age, among different muscle groups, and for different parameters of muscle function tenuous. Hence, the efficacy and effect of using two types of instructions (rate vs. strength) on the assessment of the isometric functional capacity of six muscle groups were examined in women (N = 143) aged 25-74 years. The subjects were categorized by age into 10, 5-year groups. Measures of maximal force (MF), maximal rate of force increase (MR), total impulse (TI), time to MF (MFT), time to MR (MRT), and plateau time (PLT, time between 90% MF and MF) were obtained from the force-time recordings of maximal voluntary isometric contractions of the finger flexors, thumb extensors, elbow flexors and extensors, and ankle dorsiflexors and plantar flexors. Repeated measures analyses of variance indicated that instruction type influenced (p < .05) the magnitude and pattern of the force-time recordings, with the degree of difference dependent upon the muscle group and parameter of muscle function examined. Use of the rate instruction yielded greater MRs (40.9-541.0 N/sec) than the strength instruction. The strength instruction elicited greater MFs (6.4-326.7 N), longer MFTs (0.72-1.50 sec), MRTs (0.05-0.15 sec) and PLTs (0.31-0.79 sec), and greater TIs (25.1-1,079.8 N-sec) than the rate instruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Economic impact of hospitalizations for lower abdominal adhesiolysis in the United States in 1988.

Much has been written about adhesion formation and prevention. Little is known about the number and cost of hospitalizations during which adhesiolysis is performed. This report describes the number of hospitalizations and days of care attributable to adhesiolysis in the United States and estimates the costs associated with these stays. The cost per hospital day and associated surgeons' fees are based on prevailing nationwide charges. During 1988, there were 281,982 hospitalizations during which adhesiolysis was performed, accounting for 948,727 days of inpatient care. These hospitalizations were responsible for an estimated $1,179.9 million in expenditures, of which $925.0 million was associated with hospital costs and $254.9 million with surgeons' fees. This estimate does not include outpatient costs and indirect costs. The results of this study demonstrate substantial costs associated with hospitalizations for adhesiolysis. Further understanding and prevention of adhesions may help to reduce unnecessary morbidity and mortality rates.

Mineral and water content of the fat-free body: effects of gender, maturation, level of fatness, and age.

Variability associated with the effects of gender, level of fatness (LOF), maturation (ML), and age on the mineral (MFFB) and water (WFFB) content of the fat-free body (FFB) was investigated in 188 males and 144 females, aged 8 to 17 years. Measures of body density, bone mineral content, total body water, and skin-fold thicknesses were obtained. FFB was calculated using a multicomponent model based on body density and adjusting for variability in body water and mineral content. Subjects were classified by ML as prepubescent, pubescent, and postpubescent. Subjects were also grouped by LOF as lean, average, and obese based on percentile rankings from the age-related norms of the National Children and Youth Fitness Study. Least squares multiple regression analysis using weighted orthogonal contrasts to account for sample size differences revealed significant (p<.01) gender, ML, gender x LOF, and gender x ML effects for MFFB; however, no significant (p>.05) effects between, or within, gender were noted for WFFB. Significant ML, and nearly significant (p>.056) LOF x ML, effects were found for MFFB in the males. In contrast, only ML was significant within the female sample for MFFB. These results were upheld when age, rather than ML, was used in the analysis. The overall relative increase in MFFB across ML was greatest in the obese (17.4%, 9.3%) and least in the lean (11.3%, 6.3%) males and females, respectively. A significant increase in MFFB across ML was observed in both genders; however, the pattern and magnitude of increase is dependent upon LOF considered. Hence, consideration of gender, ML, LOF and age is essential in estimating body composition in children.

Gonadotropins enhance HLA-DR antigen expression in human granulosa cells.

OBJECTIVES: To determine whether HLA-DR expression in the human ovary is controlled by endocrine or immune mediators, we examined the effects of several lectins, lymphokines, and hormones on granulosa cells in vitro. STUDY DESIGN: HLA-DR antigens were detected by indirect immunofluorescence on granulosa cells obtained at oocyte retrieval for in vitro fertilization. RESULTS: When cultured with concanavalin A, pokeweed mitogen, phytohemagglutinin, interleukin-1, or interleukin-2, granulosa cells failed to express HLA-DR antigens. Both interferon alfa and interferon beta induced only a modest expression of HLA-DR molecules (4.1% +/- 0.9% and 2.5% +/- 0.8%, respectively) in comparison with the marked increase in HLA-DR expression (25.2% +/- 2.8%), when granulosa cells were exposed to interferon gamma. The gonadotropins follicle-stimulating hormone and human chorionic gonadotropin alone were unable to induce HLA-DR antigens, but acted synergistically with interferon gamma to enhance expression in a dose-dependent manner. The addition of 0.1 and 10 IU/ml of follicle-stimulating hormone with 10,000 IU/ml of interferon gamma significantly increased expression by 11.5% +/- 2.5% and 15.5% +/- 2.7%, respectively, over that of interferon gamma alone. Similarly, 1 and 10 IU/ml of human chorionic gonadotropin produced a 7.8% +/- 2.0% and 12.4% +/- 2.2% increase in HLA-DR expression over baseline. CONCLUSION: These studies demonstrate that factors from both the immune and endocrine systems can interact to control HLA-DR expression in the ovary.

Expression of the insulin-like growth factor (IGF)-I and -II and the IGF-I and -II receptor genes during postnatal development of the rat ovary.

Solution hybridization/RNase protection assays were used to study the developmental expression of the insulin-like growth factor-I (IGF-I), IGF-II, IGF-I receptor, and IGF-II/mannose-6-phosphate receptor genes in the rat ovary between postnatal days 1-80. Maximal IGF-I mRNA levels occurred during the 15- to 25-day postnatal period, and the level on day 20 represented a 9-fold increase over the baseline at earlier and later stages. IGF-II mRNA levels were maximal during the 1- to 5-day postnatal period and subsequently declined to undetectable levels after day 10. IGF-I receptor mRNA levels increased 10-fold to a maximum in the 20- to 25-day postnatal period. This pattern was similar to the developmental pattern of [125I]IGF-I binding in the ovary. Two apparent peaks of IGF-II/mannose-6-phosphate receptor mRNA levels were seen, on day 20 and between days 50-80. These specific and significant changes in the expression of the genes encoding the IGFs and their receptors suggest a role for the IGF system in postnatal ovarian development.

Maximal voluntary isometric force production characteristics of six muscle groups in women aged 25 to 74 years.

The age-related force production characteristics of six muscle groups in 143 women aged 25-74 years were examined. Measures of maximal force (MFR) were obtained on the finger flexors (FF), thumb extensors (TE), forearm flexors (FAF), forearm extensors (FAE), dorsi flexors (DF), and plantar flexors (PF) utilizing a linear voltage differential transducer. The subjects were categorized by age into ten 5-year groups. The magnitude of decline across age in MFR ranged from 36.2% (FAE) to 45.1% (PF). There were differences among muscle groups in the age at which a significant decline in MFR was first detected. The earliest drop off in MFR was observed in FF and FAF (45-49 years), while the latest significant decline across age was noted in FAE (65-69 years). Since the magnitude of maximal force decreases with age, and because these characteristics can not be entirely explained by age-related decrements in fat-free mass, it appears that the quality in addition to the quantity of senescent muscle tissue may be compromised. However, the magnitude of decline in maximal force is dependent upon the muscle group considered. © 1992 Wiley-Liss, Inc.

Effects of conjugated equine estrogen with and without three different progestogens on lipoproteins, high-density lipoprotein subfractions, and apolipoprotein A-I.

The effects of conjugated equine estrogen and subsequent cyclical progestogen supplementation on lipoprotein and apolipoprotein A-I levels were investigated in three groups of postmenopausal women. Unopposed conjugated equine estrogen (0.625 mg) lowered total cholesterol 4-8% and low-density lipoprotein (LDL) cholesterol 12-19% below pre-treatment levels in all three groups. Levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I were increased 9-13 and 9-18%, respectively, with unopposed estrogen. The increase in HDL cholesterol was mainly due to increases in the high-density lipoprotein2 (HDL2) subfraction. Addition of medroxyprogesterone acetate, norethindrone acetate, or d,l-norgestrel at doses shown previously to provide protection against endometrial hyperplasia reversed some of the beneficial estrogen effects, reducing levels of HDL cholesterol 14-17%, HDL2 cholesterol 22-37%, and apolipoprotein A-I 11-15% from those obtained with unopposed estrogen. The LDL cholesterol levels fell 12-19% with unopposed estrogen but remained 7-12% below baseline when progestogens were added. These observations demonstrate that after 3 months of treatment, all three progestogens reversed some of the favorable effects of unopposed estrogen on lipoproteins but permitted a continued modest reduction in LDL cholesterol.

Reproductive potential in survivors of childhood malignancy.

The aggressive use of multiple therapeutic modalities has led to a significant increase in the number of survivors of childhood malignancy. These forms of cancer therapy have important effects on multiple organ systems. This review article evaluates the long-term effect of therapy on the reproductive potential of both boys and girls. While alkylating agents have been shown to cause a 50% reduction in the fertility potential of boys, they have almost no adverse effect in girls. Other chemotherapeutic agents and combinations of chemotherapeutic agents have also been shown to cause a greater reduction in the reproductive potential of girls than boys. Radiation produces severe dose-related gonadal damage in both boys and girls. The effect of Hodgkin's disease, leukemia and their therapies are evaluated. Despite the known mutagenic potential of some forms of cancer therapy there has not been an increased frequency of congenital abnormalities in the offspring of survivors of childhood cancer. The use of oophoropexy and other forms of prophylactic therapy to limit toxicity are also considered.