Installing oncofertility programs for breast cancer in limited versus optimum resource settings: Empirical data from 39 surveyed centers in Repro-Can-OPEN Study Part I & II.

PURPOSE: As a further step to elucidate the actual diverse spectrum of oncofertility practices for breast cancer around the globe, we present and discuss the comparisons of oncofertility practices for breast cancer in limited versus optimum resource settings based on data collected in the Repro-Can-OPEN Study Part I & II. METHODS: We surveyed 39 oncofertility centers including 14 in limited resource settings from Africa, Asia & Latin America (Repro-Can-OPEN Study Part I), and 25 in optimum resource settings from the United States, Europe, Australia and Japan (Repro-Can-OPEN Study Part II). Survey questions covered the availability of fertility preservation and restoration options offered to young female patients with breast cancer as well as the degree of utilization. RESULTS: In the Repro-Can-OPEN Study Part I & II, responses for breast cancer and calculated oncofertility scores showed the following characteristics: (1) higher oncofertility scores in optimum resource settings than in limited resource settings especially for established options, (2) frequent utilization of egg freezing, embryo freezing, ovarian tissue freezing, GnRH analogs, and fractionation of chemo- and radiotherapy, (3) promising utilization of oocyte in vitro maturation (IVM), (4) rare utilization of neoadjuvant cytoprotective pharmacotherapy, artificial ovary, and stem cells reproductive technology as they are still in preclinical or early clinical research settings, (5) recognition that technical and ethical concerns should be considered when offering advanced and innovative oncofertility options. CONCLUSIONS: We presented a plausible oncofertility best practice model to guide oncofertility teams in optimizing care for breast cancer patients in various resource settings.

Reduced expression of the epidermal growth factor signaling system in preeclampsia.

INTRODUCTION: The epidermal growth factor (EGF) signaling system regulates trophoblast differentiation, and its disruption could contribute to perinatal disease. We hypothesized that this pathway is altered in preeclampsia, a disorder associated with trophoblast apoptosis and failure to invade and remodel the uterine spiral arteries. METHODS: Six EGF family peptides and a truncated EGF receptor splice variant (p110/EGFR) were examined using immunohistochemistry in the trophoblast of placentas (N = 76) from women with preeclampsia, and compared to placentas from women of similar gestational age (GA) with preterm labor (PTL) or small for gestational age (SGA) fetuses, as well as normal term placentas. EGF, transforming growth factor-α (TGFA), and heparin-binding EGF-like growth factor (HBEGF) were evaluated using ELISA in maternal plasma from another 20 pregnancies with or without preeclampsia. Cell death was evaluated in the HTR-8/SVneo human cytotrophoblast cell line using TUNEL to evaluate the protective effects of EGF peptides. RESULTS: Trophoblast HBEGF, TGFA, and EGF were significantly reduced in preeclampsia compared to PTL and SGA, while p110/EGFR accumulated significantly on the surface of the chorionic villi (p < 0.05). Plasma EGF levels were significantly decreased in preeclamptic patients, compared to non-preeclamptic patients (p < 0.05). HBEGF, EGF, TGFA, epiregulin, and betacellulin each blocked cytotrophoblast cell death in vitro (p < 0.05). DISCUSSION: Three members of the EGF family are dysregulated in placentas with preeclampsia, whereas p110/EGFR, a potential EGF receptor antagonist, is overexpressed. These findings are consistent with the concept that disruption of the EGF signaling system contributes to aberrant trophoblast development associated with preeclampsia.

Heparin-binding EGF-like growth factor modulation by antiprogestin and CG in the baboon (Papio anubis).

The objectives of this study were to determine whether antiprogestin therapy or the infusion of human CG to mimic blastocyst transit in the baboon alters heparin-binding EGF-like growth factor expression during the window of implantation. During the menstrual cycle, heparin-binding EGF-like growth factor protein accumulation in the glandular epithelium was low in the proliferative phase and increased to maximal expression on d 5 and 10 postovulation. Stromal cells accumulated high levels of heparin-binding EGF-like growth factor in the proliferative phase, which decreased by d 5 postovulation. These transitional changes in both cell types were delayed when cycling baboons were treated with the antiprogestin ZK 137.316 during the luteal phase. The treatment with human CG had no effect on expression of heparin-binding EGF-like growth factor when compared with cycling baboons on d 10 postovulation and was comparable with that observed on d 18 and 22 of pregnancy. However, the superimposition of the antiprogestin with the human CG treatment also decreased expression in the epithelial cells. In summary, heparin-binding EGF-like growth factor accumulation in the epithelial glands is under the influence of progesterone and does not seem to be influenced by the paracrine secretion of trophoblast CG.

Whole-body gene expression by data mining.

To date, a comprehensive survey of the expression of lysyl oxidase (LOX), lysyl oxidase-like 1 (LOXL1), and lysyl oxidase-like 2 (LOXL2) has yet to be performed. The use of in vitro strategies to accomplish this task would prove daunting as it is both time-consuming and costly. We present a new in silico data mining strategy that directly addresses these limitations. Sequences corresponding to the 3' untranslated regions of LOX, LOXL1, and LOXL2 were individually queried against the human expressed sequence tag database (dbEST). In this manner, the entire tissue repertoire available in the dbEST was surveyed. This provided an estimate of the levels of mRNA transcripts in a variety of adult and fetal tissues. We have also employed this strategy to determine the pattern of expression and levels of a newly discovered gene, CGI-15. The veracity of this technique has been independently assessed by semiquantitative PCR analysis. The application of this technology is bounded only by the ever-growing information available in the GenBank, UniGene, and human EST databases. The utility of our data mining strategy to establish relative transcript levels in numerous tissues is presented.

Extracellular matrix composition and hypoxia regulate the expression of HLA-G and integrins in a human trophoblast cell line.

During human placentation, extravillous cytotrophoblast cells emerge from chorionic villi contacting the decidua to invade the uterine wall. When isolated from first-trimester placentae, cytotrophoblast cells undergo step-wise differentiation in vitro that recapitulates the phenotypic heterogeneity observed in vivo. We examined a cell line, HTR-8/SVneo, that has been established from human first-trimester cytotrophoblast to determine whether these cells possess some of the unique cytotrophoblast characteristics that have been described previously. Exposure during serum-free culture to hypoxic conditions (2% oxygen concentration) increased HTR-8/SVneo cell proliferation and reduced invasion of a three-dimensional basement membrane (Matrigel). During culture on surfaces coated with individual extracellular matrix proteins, HTR-8/SVneo cells expressed cytokeratin but not the trophoblast-specific major histocompatibility protein, HLA-G. However, HLA-G expression was induced in HTR-8/SVneo cells that contacted Matrigel. Expression of the alpha5 integrin subunit was relatively unaffected by matrix composition, whereas alpha1 was up-regulated and alpha6 was down-regulated after transferring cells to Matrigel. Hypoxia increased alpha6 and decreased both alpha1 and HLA-G expression on Matrigel. HTR-8/SVneo cells retain several important characteristics associated with primary cultures of first-trimester human cytotrophoblast cells, including their altered behavior in response to a changing maternal environment.

[Aging and physical activity]. / Altern und körperliche Aktivität.

Advancing age is accompanied by changes in the cardiovascular system with a rapid reduction of, among other things, cardiac output, respiratory capacity, and maximum oxygen absorption capacity. Changes in articular cartilage, muscles, and intervertebral ligaments are the cause for many degenerative diseases of old age and considerably restrict physical performance capacity in later years. Nevertheless, there is increasing evidence that a high level of activity during old age and thus an influence on the aging process can be achieved by constant training begun as early as young adulthood. This type of training must concentrate on improving muscle strength, general flexibility, and endurance. Thus, it is our task to perceive physical activity as a medical prescription for the aging population.

Multiple roles for heparin-binding epidermal growth factor-like growth factor are suggested by its cell-specific expression during the human endometrial cycle and early placentation.

Embryonic expression of the epidermal growth factor (EGF) receptor as well as embryonic and steroid-dependent uterine secretion of its ligand, heparin-binding EGF-like growth factor (HB-EGF), are temporally associated with the period of blastocyst implantation. We examined the temporal cell type-specific expression of HB-EGF in human endometrium during the menstrual cycle by immunohistochemistry and in situ hybridization. Early first trimester implantation sites were also examined to determine HB-EGF protein levels in decidual and fetal tissues. In the endometrial stroma, HB-EGF protein expression increased markedly during the late proliferative phase and then decreased in the early secretory phase. By contrast, luminal and glandular epithelial cells as well as blood vessel endothelium accumulated the protein between midcycle and cycle day 20, with peak expression observed during the period of uterine receptivity for implantation. HB-EGF expression decreased dramatically at the end of the cycle, before menses. Spatiotemporal expression of HB-EGF messenger ribonucleic acid demonstrated a similar pattern. During early pregnancy, HB-EGF immunostaining was noted in the decidua and in both villous and extravillous trophoblast populations. These findings suggest that HB-EGF promotes implantation and trophoblast invasion through paracrine and autocrine signaling as cells penetrate the stroma and displace the arteriole endothelium.

Ethanol elevates c-Myc levels in cultured mouse preimplantation embryos.

A brief exposure to ethanol accelerates the rate of early mouse embryonic development in vitro, increasing blastocyst formation, trophoblast outgrowth, and implantation rates after embryo transfer. The physiological effects of ethanol during preimplantation development are associated with rapid changes in gene expression and apparently arise from the ability of ethanol to elevate cytoplasmic free Ca2+ and alter cellular signaling pathways. The purpose of this study was to examine whether the abundance of c-Myc, a transcription factor that promotes cell proliferation and is required for blastocyst development, is upregulated in mouse blastocysts challenged with ethanol. After exposure of mouse blastocysts to 0.1% (17.5 mM) ethanol, wc determined the levels of: 1) c-Myc mRNA, using reverse transcription and the polymerase chain reaction; and 2) c-Myc protein levels, using specific monoclonal antibodies. Within 10 min of exposure to ethanol, the relative abundance of c-Myc mRNA increased 6-fold, then rapidly returned to baseline levels within 1 hr. As expected, elevation of c-Myc mRNA by ethanol was attenuated in embryos that were first treated with the intracellular Ca2+ chelator, BAPTA-AM. Western blot analysis of solubilized embryos revealed that c-Myc mRNA was translated into a single 62-kD protein that increased in intensity 30 min after treatment with ethanol. Immunocytochemical staining demonstrated that c-Myc was localized exclusively in nuclei and that staining intensity increased significantly after 10 min. Peak levels of c-Myc protein were found 30 min after ethanol exposure and persisted for at least 2 hr. The c-myc proto-oncogene seems to be an immediate early response gene for ethanol that may regulate the transcription of other genes that influence early embryogenesis and growth.

Well-differentiated endometrial adenocarcinoma in an infertility patient with later conception. A case report.

BACKGROUND: The incidence of well-differentiated endometrial adenocarcinoma in reproductive-age women is approximately 5%. When the women desires to retain her future fertility in light of this diagnosis, choices of surgery vs. medical therapy may present a dilemma for both the physician and patient. CASE: A young infertility patient with well-differentiated endometrial adenocarcinoma conceived by ovulation induction and intrauterine insemination after medical therapy. She subsequently delivered vaginally, and follow-up dilatation and curettage revealed no evidence of recurrent carcinoma. CONCLUSION: This case illustrates that with close observation by endometrial sampling for histologic diagnosis and follow-up, medical therapy can be an option for treating this condition to allow future fertility. The patient must be extensively counseled, however, concerning the nearly 33% chance of progression or recurrence of disease. One must also stress the importance of frequent evaluation of symptoms and endometrial pathology postpartum, with endometrial sampling as indicated and discussion of definitive surgical therapy once fertility is no longer desired.

Androgens in preeclampsia.

OBJECTIVE: The purpose of the study was to determine whether maternal serum levels of androgens, especially testosterone, are higher in patients with preeclampsia than in matched normotensive control subjects. STUDY DESIGN: Serum testosterone, dehydroepiandrosterone sulfate, sex hormone binding globulin, and estradiol levels were measured in 16 subjects in the third trimester of pregnancy with documented preeclampsia and 26 healthy, normotensive women with similar maternal and gestational ages. All subjects were primigravid women with singleton pregnancies who were seen in the labor and delivery department at North Oakland Medical Centers in Pontiac, Mich. RESULTS: Total testosterone and free testosterone levels were significantly higher in patients with preeclampsia (213.6 +/- 25.9 ng/dL and 0.5 +/- 0.1 ng/dL, respectively) than in the control group (154.5 +/- 14.8 ng/dL and 0. 3 +/- 0.03 ng/dL, respectively). There were no significant differences in sex hormone binding globulin, dehydroepiandrosterone sulfate, and estradiol concentrations. There were also no significant differences in maternal age, gestational age, body mass index, and neonatal sex. CONCLUSION: Levels of the potent androgen testosterone were significantly higher in primigravid women with preeclampsia than in normotensive women with similar gestational and maternal ages. This difference may indicate a role for testosterone in the pathogenesis of preeclampsia.