Breast cancer and fertility preservation.

Many women affected with breast cancer are in their reproductive prime and at the time of their initial diagnosis have not yet started or completed their families. Improvements in outcomes for patients with breast cancer means longer survival times and oftentimes cures. Unfortunately, many of the treatments, while life-saving, are toxic to the finite supply of oocytes and diminish a woman's chance of future childbearing. After the initial shock of the cancer diagnosis has worn off, women are coming to the realization that their diagnosis is not a death sentence. Women that have not completed their families need to be informed about available options to protect their reproductive organs from the cancer treatments. The currently available options for fertility preservation should be discussed with every patient who is in their reproductive years prior to initiating any treatments. Fertility specialists should work closely with oncologists to counsel patients about the risks, if any, of the recommended treatment on their future fertility and discuss options to preserve potential fertility before starting treatments.

Gene therapy and intracytoplasmatic sperm injection (ICSI) - a review.

Human gene therapy (HGT), the treatment or prevention of disease by gene transfer is, regarded by many, as a potential revolution in medicine, because gene therapies target the causes of disease, whereas most current drugs treat the symptoms. Micro-assisted fertilization in the form of intracytoplasmatic sperm injection (ICSI) has truly revolutionized the treatment options for couples with impaired semen quality, and those with both obstructive and non-obstructive azoospermia. ICSI involves the injection of a single sperm directly into the cytoplasm of a mature egg (oocyte) using a glass needle (pipette). Fertilization with this technique occurs in 50%-80% of injected oocytes, but may damage a small percentage of them. With gene therapy, there are new and varied strategies for gene transfer and genome sequence manipulation with improved methodologies that use the technique of microinjection such as the intracytoplasmatic sperm injection-mediated transgenesis (ICSI-Tr), active transgenesis or the pronuclear microinjection technique. This review will look at these methods as well as their potential applications and limitations.

A decision analysis of treatments for obstructive azoospermia.

BACKGROUND: Treatments for post-vasectomy obstructive azoospermia include vasectomy reversal, microsurgical epididymal sperm aspiration (MESA) or percutaneous testicular sperm extraction (TESE) with IVF/ICSI. We examined the cost-effectiveness of these treatments. METHODS: A decision analytic model was created to simulate treatment. Outcome probabilities were derived from peer-reviewed literature and the Society for Assisted Reproductive Technologies database. Procedural costs were derived from a sampling of high-volume IVF centers and the Medicare Resource Based Relative Value Scale. Indirect costs of complications, lost productivity and multiple gestation pregnancies were considered. Sensitivity analyses were performed. RESULTS: Vasectomy reversal was more cost-effective than either MESA or TESE under all probability conditions. In 1999, vasectomy reversal demonstrated superior cost-effectiveness to TESE and MESA ($19,633 versus $45,637 and $48,055, respectively, equivalent to $25,321 versus $58,858 and $61,977 in 2005 dollars). In 2005, vasectomy reversal ($20,903) remained the most cost-effective treatment over TESE ($54,797) and MESA ($56,861). The cost-effectiveness of all treatments improved over projections by inflation. The relative cost-effectiveness of the therapies was unchanged over time. CONCLUSIONS: Vasectomy reversal appears more cost-effective than percutaneous TESE and MESA for treatment of obstructive azoospermia when the impact of indirect costs is considered. The absolute cost-effectiveness of all therapies improved over time. These results may be tailored with institution-specific data to allow more individualized results.

Maternal serum levels of interferon-gamma and interleukin-2 soluble receptor-alpha predict the outcome of early IVF pregnancies.

BACKGROUND: Elevated maternal serum levels of interleukin-2 soluble receptor-alpha (IL-2 sRalpha), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) have been associated with pregnancy loss. The aim of our study was to evaluate the predictive value of these cytokines in the outcome of early IVF pregnancies. METHODS: One hundred and fifty-nine consecutive IVF patients who were subsequently diagnosed to have a biochemical pregnancy (n = 23), a first-trimester miscarriage (n = 19) or a normal term delivery (n = 117) were included in this study. Serum was collected from the initial pregnancy test, 11 days after a day 3 embryo transfer, and all samples were analysed for IL-2 sRalpha, TNF-alpha and IFN-gamma by commercially available enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: IL-2 sRalpha levels were significantly higher in patients with an early pregnancy loss compared with patients with a normal term delivery (849.5 +/- 69.6 versus 693.5 +/- 31.2 pg/ml, P = 0.02), and a cut-off point of IL-2 sRalpha >1000 pg/ml predicted a poor pregnancy outcome (44.4 versus 22.7% pregnancy loss, IL-2 sRalpha >or=1000 versus IL-2 sRalpha <1000 pg/ml; P = 0.02). IFN-gamma-positive patients had twice the risk for poor IVF pregnancy outcome compared with IFN-gamma-negative subjects (40.8 versus 20.0%, respectively; P < 0.02), including a significantly lower implantation rate (37.6 +/- 0.05 versus 50.0 +/- 0.03%, respectively; P = 0.02). There was no difference in pregnancy outcome based upon serum levels, or the ability to detect the presence of TNF-alpha. No differences in levels of these cytokines were found based on the aetiology of the patients' infertility. CONCLUSIONS: Elevated maternal serum levels of IL-2 sRalpha and IFN-gamma as early as 11 days after embryo transfer are associated with poor IVF pregnancy outcome.

Plasma homocysteine, fasting insulin, and androgen patterns among women with polycystic ovaries and infertility.

OBJECTIVE: To measure plasma homocysteine, androgen, and insulin concentrations in women with normal and polycystic-appearing ovaries in an infertility setting. METHODS: Among women referred for infertility evaluation (n = 54), homocysteine, androstenedione, DHEAS, total testosterone, fasting insulin/glucose and methyltetrahydrofolate reductase (MTHFR) polymorphism status (C677T mutation) were studied. Ovaries were examined via transvaginal sonogram by one observer and scored as either normal (n = 18) or polycystic (n = 36). RESULTS: When polycystic ovaries were identified, mean total testosterone was significantly higher than when non-polycystic ovaries were present (p = 0.01), although no measured androgen was outside the normal reference range in either group. Average BMI was higher in the polycystic group, but the difference was not significant (p = 0.10). We observed a trend toward higher mean fasting insulin levels in women with polycystic ovaries, but this increase did not reach statistical significance (p = 0.07). Median plasma homocysteine was identical (7.0 mmol/l) in both populations, and no study subject exceeded the current recommended maximum reference value. CONCLUSIONS: In this population, the presence of polycystic ovaries was associated with higher serum androgens (especially total testosterone) although none of the measured androgens were above the normal range. While fasting insulin levels were also higher in this group, median plasma homocysteine levels were similar irrespective of ovarian morphology. Concomitant plasma homocysteine derangements in this population of young, lean patients with polycystic-appearing ovaries seem unlikely. Further studies are needed to clarify the role(s) of homocysteine in human reproductive physiology.

Transvaginal ultrasonographic identification of appendicitis in a setting of chronic pelvic pain and endometriosis.

Our patient had a history of chronic endometriosis and pelvic pain and complained of recent onset of right-sided abdominal pain, nausea, and vomiting. Transvaginal ultrasonography revealed a thick-walled mass superior and medial to the right ovary, which was thought to be an inflamed appendix. The woman was not pregnant, and the structure appeared to be anatomically separate from the uterus. Subsequent laparoscopy confirmed the diagnosis of acute appendicitis; uncomplicated laparoscopic appendectomy followed. In the setting of chronic endometriosis, other nongynecologic sources of acute pelvic pain must be considered. Surgical intervention is appropriate whenever clinical suspicion for an acute abdomen is high, and the a priori diagnosis of endometriosis should not result in operative delay.

The role of LH in ovarian stimulation: exogenous LH: let's design the future.

Historically, follicular stimulation protocols have included both FSH and LH in an attempt to mimic the physiology of normal human folliculogenesis. However, many recent gonadotrophin administration regimens have completely eliminated LH bioactivity. The importance and the amount of LH necessary for optimal follicular stimulation has been a topic of debate. Several recent studies have added to our understanding of the actions of androgens, oestrogens, gonadotrophins, and insulin on the follicle-oocyte unit, allowing a less speculative approach. Moreover, the availability of human gonadotrophins synthesized by recombinant DNA technology and gonadotrophin-releasing hormone (GnRH) antagonists, should soon permit a precise in-vivo assessment and re-evaluation of the historical 2-cell, two-gonadotrophin hypothesis. These pharmacological tools may also provide essential insights into the physiological roles of FSH and LH in human follicular development and oocyte maturation. The recombinant gonadotrophins give clinicians the unique opportunity to tailor ovarian stimulation regimens according to the patient's medical history, in an effort both to maximize oocyte yield and to improve oocyte quality.

The effect of hydrosalpinges on IVF-ET outcome.

PURPOSE: Our purpose was to determine if the presence of a hydrosalpinx effects the outcome of in vitro fertilization (IVF)-embryo transfer. METHODS: We performed a retrospective analysis of IVF cycle stimulation sheets. RESULTS: A total of 1000 patients with tubal factor infertility was analyzed. There were 60 hydrosalpinx patients who underwent 116 initiated cycles with 106 embryo transfers, compared to 940 control patients undergoing 1428 initiated cycles with 1150 embryo transfers. Both groups had a similar response to ovarian stimulation, number of oocytes retrieved, and number of embryos transferred. The hydrosalpinx group had a significantly higher preclinical loss rate (22/59 = 37% vs 80/566 = 14%; P = 0.001), a significantly lower implantation rate (55/352 = 16% vs 795/3795 = 21%; P = 0.013), a trend toward a reduced delivery rate per transfer (28/106 = 26% vs 387/1150 = 34%; P = 0.066), a significantly higher ectopic pregnancy rate (5/59 = 8% vs 16/566 = 3%; P = 0.04), and a similar spontaneous abortion rate (9/37 = 24% vs 99/486 = 20%; P = 0.28) compared to the control tubal factor group. CONCLUSIONS: This study demonstrates a decrease in implantation rates and an increase in preclinical miscarriages and ectopic pregnancies in patients with hydrosalpinges compared to tubal-factor patients without sonographic evidence of dilated fallopian tubes.

Characteristics of consecutive in vitro fertilization cycles among patients treated with follicle-stimulating hormone (FSH) and human menopausal gonadotropin versus FSH alone.

OBJECTIVE: To compare the endocrine responses of patients who first received hMG plus FSH, then were treated in a subsequent cycle with FSH alone. DESIGN: Retrospective study. SETTING: An academic research environment. PATIENT(S): Ninety-six women with pituitary down-regulation who underwent two sequential IVF treatments, the first with combined hMG and FSH and the second with FSH alone. MAIN OUTCOME MEASURE(S): Duration of stimulation, serum estradiol level on the day of hCG administration, amount of gonadotropin used, number of oocytes retrieved, number of oocytes fertilized, and selected preembryo morphologic features. RESULT(S): No difference in the mean duration of stimulation was observed between the treatment cycles among patients who received hMG and FSH (11.9 days) followed by FSH alone (11.7 days). The mean number of oocytes retrieved, the mean number of oocytes fertilized, the percentage of preembryo fragmentation, and the preembryo cell number at transfer did not differ significantly between the stimulation protocols. The cumulative amount of gonadotropin used during stimulation was slightly greater in the cycles stimulated with FSH alone, but this difference was not significant (29.4 ampules of hMG plus FSH versus 31.8 ampules of FSH alone). Serum estradiol levels measured on the day of hCG administration during stimulation with hMG and FSH (1,382 pg/mL) were higher than those measured during stimulation with FSH alone (1,149 pg/mL). CONCLUSION(S): Follicular response and preembryo quality were not significantly different when patients were treated first with hMG and FSH and then with FSH alone in a subsequent cycle. Similarities in ovarian response and preembryo characteristics, as well as differences in estradiol patterns seen in each stimulation setting, should be anticipated when patients receive these protocols.

Evolution of pregnancies and initial follow-up of newborns delivered after intracytoplasmic sperm injection.

OBJECTIVE: To analyze the in vivo development of embryos conceived after intracytoplasmic sperm injection (ICSI), as well as obstetric outcome, occurrence of chromosomal abnormalities, and rate of congenital malformations in neonates born as a result of this treatment. DESIGN: Retrospective study. SETTING: University-based in vitro fertilization (IVF) clinic. PATIENTS: A total of 751 couples in whom the male partners were presumed to be the cause of repeated failed IVF attempts or whose semen parameters were unacceptable for conventional IVF treatment. INTERVENTIONS: Analysis of pregnancies resulting from 987 ICSI cycles; pregnancy outcome data were obtained from the records of obstetrician-gynecologists and/or pediatricians. MAIN OUTCOME MEASURES: Pregnancy rates, obstetric outcome, and frequency of chromosomal abnormalities and congenital malformations. RESULTS: The overall clinical pregnancy (fetal heartbeat) rate was 44.3%, with a resultant delivery rate per ICSI cycle of 38.7% (n=382). In 8 of 11 miscarriages for which cytogenetic data were available, an autosomal trisomy was found, and 7 additional pregnancies were terminated because of a chromosomal abnormality after prenatal diagnosis. There was an equal distribution of vaginal vs cesarean deliveries (n=192 and n=190, respectively). Of the 578 neonates resulting from treatment by ICSI, 15 (2.6%) presented with congenital abnormalities (9 major and 6 minor abnormalities). However, this frequency of malformations is lower than that observed in offspring born after standard IVF at our institution. Furthermore, when pregnancy outcome of ICSI vs IVF was analyzed in terms of semen origin, no differences were found in the frequency of miscarriages or in the rate of congenital malformations. CONCLUSIONS: The evolution of pregnancies and occurrence of congenital malformations following treatment by ICSI were within the range observed with standard in vitro fertilization.

Endometrial thickness appears to be a significant factor in embryo implantation in in-vitro fertilization.

To evaluate the role of endometrial thickness and pattern in in-vitro fertilization (IVF), these parameters were prospectively measured in 516 cycles of IVF with embryo transfer at our clinic. Pregnancy and embryo implantation rates were assessed for each mm of endometrial thickness and for each of three endometrial patterns. Embryo implantation, clinical and ongoing pregnancy rates were significantly higher in the patients with an endometrial thickness > 9 mm (24.4, 48.6 and 42.2% respectively) compared with those of < 9 mm (14.3, 16.0 and 11.7% respectively; P < 0.005). Endometrial thickness was negatively influenced by age and positively influenced by oestradiol concentration. The majority of patients (69.8%) exhibited a 'ring' endometrial pattern. Embryo implantation and clinical pregnancy (statistically significant), as well as ongoing pregnancy rates (not statistically significant), were lower in patients exhibiting the 'solid' pattern. Endometrial thickness is independent of pattern in its effect on pregnancy outcome. In conclusion, endometrial thickness > 9 mm as well as ring and intermediate endometrial patterns denoted a more favourable prognosis for pregnancy in IVF but thinner endometrium and those exhibiting a solid configuration had an acceptable pregnancy outcome.

Laparoscopic resection of a noncommunicating rudimentary uterine horn. A case report.

Patients who have a unicornuate uterus with a noncommunicating rudimentary horn that contains an endometrial cavity are at risk for endometriosis and obstetric complications. As in this case, resection of the rudimentary horn can be performed laparoscopically without increased risk to the patient and with some potential benefit.

The parental origin of the distal pronucleus in dispermic human zygotes.

The purpose of this investigation was to determine the parental origin of the pronucleus furthest from the second polar body (the distal pronucleus) in dispermic human zygotes. Intact dispermic embryos (n = 53) and those from which the distal pronucleus (n = 50) was removed at the zygote stage were biopsied after cleavage. Blastomeres were sexed using either coamplification of X and Y probes using a duplex polymerase chain reaction (PCR), or simultaneous fluorescence in situ hybridisation (FISH) with directly fluorochrome-labelled probes for chromosomes X, Y and 18. The ratio X/Y was determined in both groups of embryos by assessing a minimum of two blastomeres. If the pronuclei in dispermic zygotes are topographically in a fixed position, the X/Y ratio should change from 1:3 in dispermic embryos to 1:1 in enucleated ones. The ratio of embryos containing only an X chromosome and those with X as well as Y chromosomes in the intact dispermic zygotes was 1.0:2.3 which is similar to the theoretical ratio of 1:3. This ratio was 1.0:1.3 in dispermic zygotes from which the distal pronuclei were removed. This ratio is not significantly different from the 1:1 ratio based on a statistical analysis with a sample size of 50. These sex ratios would have been considered different if more than 200 enucleations had been performed. Although the ratio X/Y was altered following removal of distal pronuclei, suggesting frequent targeting of male pronuclei, accidental removal of the female pronucleus could not be excluded. This indicates that enucleation of dispermic zygotes could produce high yields of gynogenetic and androgenetic embryos for research purposes. Clinical application aimed at producing biparental zygotes may be hazardous, since mosaicism was common among enucleated embryos.

Red cell flexibility and platelet aggregation in patients with chronic obstructive vascular disease (COAD) and study of therapeutic approaches.

The red blood cell flexibility was studied in the blood of twenty patients with severe peripheral vascular disease and twenty matched controls. Patients exhibited significantly less red cell flexibility than controls. In both groups there was an inverse relationship between age and red cell flexibility. No correlation was found between red cell flexibility and sex or smoking history. Pentoxifylline, a xanthine derivative which inhibits phosphodiesterases and platelet aggregation, was found to increase red cell flexibility. This effect of the drug was greater on red cells with imparied flexibility than on normal cells. Various prostaglandins by contrast were found to decrease red cell flexibility, this could be compensated for by pentoxifylline. Forty patients with COAD were treated intravenously with PgE1. Significant inhibition of platelet aggregation and clinical improvement was noticed. It is suggested that combinations of PgE1 and pentoxifylline should be explored in clinical studies.