A. Palumbo

Management of treatment-emergent peripheral neuropathy in multiple myeloma

Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions.

Immunohistochemical localization of renin and angiotensin II in human ovaries.

Ovaries from six women with normal menstrual cycles, a follicle wall biopsy specimen from a gonadotropin-stimulated preovulatory ovary, and a corpus luteum of pregnancy were examined by immunohistochemistry for the presence of immunoreactive renin and angiotensin II. Both antisera densely stained thecal and stromal cells (interstitial complex) and luteal cells. Whereas granulosa cells in developing follicles were either unstained or lightly stained, the heavily luteinized granulosa cells of the preovulatory stimulated follicle were strongly positive for immunoreactive renin and angiotensin II. These anatomic findings are consistent with gonadotropin-stimulated local production of both renin and angiotensin II in the human ovary and support the functional roles proposed for the ovarian renin-angiotensin system in follicle development, ovulation, and luteal function and during pregnancy.

Immunohistochemical localization of renin and angiotensin in the ovary: comparison between normal women and patients with histologically proven polycystic ovarian disease *

OBJECTIVE This study was designed to test the hypothesis that the ovarian renin-angiotensin system may play a role in polycystic ovarian disease (PCOD). DESIGN The immunohistochemical distribution of renin and angiotensin in ovaries from seven women with histologic diagnosis of PCOD was compared with that of normal ovaries. RESULTS The large cystic follicles of polycystic ovaries (PCO) presented intense immunostaining for renin and angiotensin in both theca and granulosa cells (GCs). In developing follicles of normal ovaries, the immunostaining was restricted to the theca cell layer, with the exception of the immediately preovulatory follicles which displayed intense positivity of granulosa as well as theca cells. Atretic follicles of normal ovaries showed staining of both theca and GCs. In both normal and PCO, patches of hilus cells were intensely stained. Luteal cells also consistently stained both in normal ovaries and in the occasional corpus luteum present in polycystic ovaries. CONCLUSIONS This study highlights the link between the ovarian renin-angiotensin system and those ovarian compartments known to be actively engaged in androgen secretion and/or luteinization and suggests that there may be an association between the ovarian renin-angiotensin system and PCOD.

Immunocytochemical localization of angiotensin II immunoreactivity and demonstration of angiotensin II binding in the rat ovary

The cellular localization of angiotensin II immunoreactivity and the presence of angiotensin II binding in rat ovaries were studied. Angiotensin II immunohistochemical staining was demonstrated throughout the corpora lutea of gonadotropin-stimulated immature rats and pseudopregnant adult rats, as well as in some stromal and thecal cells surrounding large antral follicles. No immunostaining was observed in granulosa cells of preantral or antral rat follicles or in ovaries from unstimulated immature rats. With in vitro autoradiography, specific, saralasin-suppressible 125I-angiotensin II binding was demonstrated in normal cycling rat ovaries: diestrus greater than proestrus greater than estrus. The combined findings of angiotensin II immunostaining in ovarian follicles and corpora lutea and of cycle-related angiotensin II binding support the hypothesis of a functional role for the ovarian renin-angiotensin system.

Prospective evaluation of automated follicle monitoring in 58 in vitro fertilization cycles: follicular volume as a new indicator of oocyte maturity

OBJECTIVES To assess the practical use of SonoAVC in an IVF program, and to establish new criteria for hCG administration based on follicular volume. DESIGN Prospective clinical study. SETTING Private IVF Center. PATIENT(S) Fifty-eight women with infertility undergoing IVF. INTERVENTION(S) Two dimensional (2D) and three dimensional (3D) scanning on the day of hCG administration. MAIN OUTCOME MEASURE(S) Image quality, mean follicular diameter obtained by 2D and 3D sonography, follicular volume, number of oocytes retrieved, number of mature oocytes, time needed for each examination. RESULT(S) Approximately 60% of the patients included in this study had good image quality and could be monitored by 3D scans with subsequent application of the SonoAVC software. When image quality is good, measurements obtained by the automated mode are comparable to those obtained manually in 62% of cases. Automated monitoring is significantly quicker than conventional manual monitoring. Follicles with a measured volume >/=0.6 cc on the day of hCG administration are associated with the finding of mature oocytes at the time of egg retrieval. CONCLUSION(S) SonoAVC allows reliable evaluation of stimulated ovaries, and may help us establish new criteria for timing hCG administration based on follicular volume estimation rather than follicular size. Software improvements are needed to improve universal patient use.

Angiotensin II induces apoptosis in human mural granulosa-lutein cells, but not in cumulus cells.

OBJECTIVE To test whether angiotensin II (AngII) could modulate apoptosis of human granulosa-lutein (GL) cells from gonadotropin-stimulated follicles. DESIGN In vitro assays on mural and cumulus granulosa cells. SETTING University laboratory and private IVF practice. PATIENT(S) One hundred six consecutive women undergoing 113 IVF cycles. INTERVENTION(S) Purified human GL mural or cumulus cells were cultured in serum-free media in the presence or absence of AngII with or without the AngII receptor blockers saralasin and CGP42112A. MAIN OUTCOME MEASURE(S) Detection of apoptosis using a fluorescent in situ marker for activated caspases. RESULT(S) Mural cells had approximately eightfold the amount of apoptosis compared with cumulus cells (average 0.23 vs. <0.03, respectively). With mural cells, AngII increased GL cell apoptosis versus untreated control samples (AngII 10(-)11 mol/L +6.5%; AngII 10(-9) mol/L +13.3%, and AngII 10(-7) mol/L +11.3%), an effect which was blocked by concurrent incubation with AngII receptor blockers. The AngII receptor blockers produced a significant decrease of apoptosis compared with control cultures (saralasin: 19.4%; CGP42112A: 28.9%). Neither AngII nor blockers had effect on cumulus cells. CONCLUSION(S) Preovulatory concentrations of AngII, most likely via AT2 receptors, increase apoptosis of cultured mural GL cells but have no effect on cumulus cells. Granulosa cells appear to be differentially regulated by AngII.

FSH receptor, KL1/2, P450, and PAPP genes in granulosa-lutein cells from in vitro fertilization patients show a different expression pattern depending on the infertility diagnosis

OBJECTIVE To study the expression of mRNA for Kit ligand 1 (KL1), KL2, FSH receptor (FSHR), pregnancy-associated plasma protein (PAPP) and P450 in granulosa-lutein cells from IVF patients and its relationship with the infertility diagnosis and IVF outcome. DESIGN In vitro assays. SETTING University laboratory and private IVF center. PATIENT(S) A total of 113 women undergoing IVF. INTERVENTION(S) Quantitative reverse-transcription polymerase chain reaction in granulosa-lutein cells from pooled follicles. MAIN OUTCOME MEASURE(S) Expression of mRNA for KL1, KL2, FSHR, PAPP and P450 in infertility patients with different infertility diagnoses. RESULT(S) Infertile patients with healthy ovaries show positive correlations among KL1, KL2, FSHR, PAPP, and P450 gene expression levels. In patients with ovarian disease, the correlation between KL1 and KL2 gene expression is maintained, but correlations between KL1/KL2 and FSHR, PAPP and P450 are not present except for KL1/FSHR in endometriosis and KL2/P450 in polycystic ovary syndrome. FSHR/KL1 and FSHR/KL2 expression correlates positively only in women who became pregnant. CONCLUSION(S) Findings in healthy human ovaries agree with the feedback model of bone morphogenetic protein 15-KL1/KL2 cross-talk between oocyte and granulosa cells described in other species. The complex relationship between the expression of these genes seems to be disrupted in patients with infertility of ovarian origin. A normal pattern of gene expression and feedback seems to be associated with pregnancy.

Expression Levels of the Oxidative Stress Response Gene ALDH3A2 in Granulosa-Lutein Cells Are Related to Female Age and Infertility Diagnosis.

Oxidative stress (OS) plays an important role in all physiological processes. The effect of OS on cellular processes is modulated by the ability of the cell to express genes implicated in the reversal of lipid, protein, and DNA injury. Aldehyde dehydrogenase 3, member A2 (ALDH3A2) is a ubiquitous enzyme involved in lipid detoxification. The objective of this study was to investigate the expression of ALDH3A2 in human granulosa-lutein (GL) cells of women undergoing in vitro fertilization (IVF) and its relationship with age, infertility diagnosis, and IVF outcome variables. Relative expression levels of ALDH3A2 were determined by quantitative reverse transcription–polymerase chain reaction. To investigate the effect of age on ALDH3A2 expression, 72 women between 18 and 44 years of age with no ovarian factor (NOF) were analyzed. To evaluate the effect of infertility diagnosis on ALDH3A2 expression, the following groups were analyzed: 22 oocyte donors (ODs), 24 women >40 years old (yo) with tubal or male factor and no ovarian pathology, 18 poor responders (PRs), 19 cases with endometriosis (EM), and 18 patients with polycystic ovarian syndrome (PCOS). In NOF, ALDH3A2 expression correlated positively with age and with the doses of follicle-stimulating hormone and luteinizing hormone administered and negatively with the number of total and mature oocytes. When different groups were analyzed, ALDH3A2 expression levels were higher in patients >40 yo and in PR compared to OD. On the contrary, EM and PCOS levels were lower than expected for age. These data suggest that GL cell ALDH3A2 expression levels correlate with age, cause of infertility, and ovarian response to stimulation.

The Ovarian Renin–Angiotensin System (OVRAS) A Major Factor in Ovarian Function and Disease

This contribution summarizes the pivotal role of the ovarian renin–angiotensin system (OVRAS) in ovarian physiology and disease, with particular emphasis on human clinical implications and established translational applications. The presence of a complete OVRAS in all studied species has been known for decades. The OVRAS has major effects on follicle development/atresia and ovulation and steroid hormone secretion, that is, it is necessary for normal reproduction. It is well established that OVRAS activity is regulated by gonadotropins and depends on activation of proteases in the area of growing follicles. Angiotensin and angiotensin receptors are widely distributed in the ovarian follicle, preovulatory theca and granulosa cells, and postovulatory mural granulosa-lutein cells and regulate steroidogenesis. Molecular blockade of the OVRAS inhibits oocyte maturation and ovulation. Pathologically abnormal OVRAS function has been associated with infertility, polycystic ovarian syndrome (PCOS), ovarian hyperstimulation syndrome (OHSS), and ovarian cancer. Both hyperandrogenism in PCOS and third space fluid accumulation in OHSS have been convincingly linked to overexpression of renin and angiotensin. Blockade of angiotensin receptors is under study for the treatment of gynecologic cancer, OHSS, and PCOS. However, a full understanding of the OVRAS and translational applications is lacking. In part, this is due to the discovery in recent years of previously unknown renin–angiotensin system (RAS) components and novel functions of “classical” RAS components that remain to be integrated into translational studies; newer, more specific agents to block RAS components are available only now for such research and treatment. The need for further studies is evident.

Oxidative Stress in Granulosa-Lutein Cells From In Vitro Fertilization Patients

Ovarian aging is associated with gradual follicular loss by atresia/apoptosis. Increased production of toxic metabolites such as reactive oxygen species (ROS) and reactive nitrogen species as well as external oxidant agents plays an important role in the process of ovarian senescence and in the pathogenesis of ovarian pathologies such as endometriosis and polycystic ovary syndrome (PCOS). This review provides a synthesis of available studies of oxidative stress (OS) in the ovary, focusing on the most recent evidence obtained in mural granulosa-lutein (GL) cells of in vitro fertilization patients. Synthesis of antioxidant enzymes such as peroxiredoxin 4, superoxide dismutase, and catalase and OS damage response proteins such as aldehyde dehydrogenase 3, member A2 decreases with aging in human GL cells, favoring an unbalance in ROS/antioxidants that mediates molecular damage and altered cellular function. The increase in OS in the granulosa cell correlates with diminished expression of follicle-stimulating hormone receptor (FSHR) and a dysregulation of the FSHR signaling pathway and may be implicated in disrupted steroidogenic function and poor response to FSH in women with aging. Women with endometriosis and PCOS have lower antioxidant production capacity that may contribute to abnormal follicular development and infertility. Further investigation of the signaling pathways involved in cellular response to OS could shed light into molecular characterization of these diseases and development of new treatment strategies to improve reproductive potential in these women.