Pregnancy, Estrogen Exposure, and the Development of Otosclerosis: A Case-Control Study of 1196 Women.

OBJECTIVE: This study sought to determine whether a history of pregnancy or bilateral oophorectomy is associated with subsequent otosclerosis development or disease severity. STUDY DESIGN: Population-based case-control study. SETTING: Olmsted County, Minnesota. METHODS: Women diagnosed with otosclerosis were matched to 3 women without otosclerosis based on age and historical depth of medical records. Associations of prior delivery and bilateral oophorectomy with subsequent development of otosclerosis and with pure-tone average (PTA) at the time of otosclerosis diagnosis were evaluated. RESULTS: We studied 1196 women: 299 cases of otosclerosis and 897 matched controls. The odds ratio for the association of ≥1 delivery with otosclerosis was 1.16 (95% confidence interval [CI] 0.85-1.60; P = .35). Odds ratios for the associations of 1, 2, 3, or ≥4 deliveries with otosclerosis were 1.22 (0.83-1.80), 1.09 (0.71-1.68), 1.28 (0.77-2.12), and 1.00 (0.54-1.84), respectively. The odds ratio for the association of prior bilateral oophorectomy with otosclerosis was 1.12 (0.58-2.18; P = .73). In cases with otosclerosis, PTA at diagnosis was not significantly higher for women with ≥1 delivery as compared with those without (median 45 dB hearing loss [HL] [interquartile range {IQR} 36-55] vs 43 [IQR 34-53]; P = 0.18) but was significantly higher for women with bilateral oophorectomy compared with those without (median 54 dB HL [IQR 44-61] vs 44 [IQR 34-53]; P = .03). CONCLUSION: These data do not support a relationship between endogenous estrogen exposure and development of otosclerosis. Women with otosclerosis who had a history of pregnancy did not have significantly worse hearing at the time of diagnosis, suggesting that pregnancy is not associated with disease severity.

Increased maternal serum placental growth hormone variant in pregnancies complicated by otosclerosis.

OBJECTIVE: To investigate the potential role of maternal serum concentrations of placental growth hormone variant (GH-V), insulin-like growth factor (IGF) 1 and 2, and IGF-binding proteins (IGFBP) 1 and 3 in pregnancies complicated by otosclerosis. METHOD: Otosclerosis cases (n = 22) and age, ethnicity-matched controls (n = 22) were selected in a nested case-control study. Maternal serum hormone concentrations at 26 and 34 weeks of gestation were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Concentrations of all measured hormones except IGFBP-1 were increased as gestation progressed. Maternal serum GH-V concentrations at 26 and 34 weeks of gestation were significantly increased in the otosclerosis group, when compared to the control group (2.53 ± 0.17 ng/ml vs. 1.78 ± 0.19 ng/ml, P = 0.036; 4.34 ± 0.31 ng/ml vs. 3.12 ± 0.18 ng/ml, P < 0.001, respectively). Maternal serum IGF-1 concentrations at 34 weeks in otosclerotic patients were significantly higher than in the controls (589.1 ± 21.4 ng/ml vs. 499.7 ± 17.8 ng/ml, P < 0.001). The increase of IGF-1 was not observed at 26 weeks of gestation. Serum IGF-2, IGFBP-1 and IGFBP-3 at either 26 or 34 weeks were unaltered between the two groups. CONCLUSION: Maternal serum concentrations of GH-V and IGF-1 were altered in pregnancy complicated by otosclerosis, suggesting that the GH-IGF axis may contribute to the development of this condition during pregnancy.

Oxidative stress in otosclerosis.

OBJECTIVES: Otosclerosis is a disease involving abnormal bone turnover in the human otic capsule that results in hearing loss. Several hypotheses have been suggested for the etiopathogenesis of otosclerosis; however, its etiology remains unclear. METHODS: This study evaluated the correlation between otosclerosis and levels of paraoxonase-1 (PON1), arylesterase, total antioxidant status, total oxidant status (TOS), oxidative stress index (OSI), total sulfhydryl (-SH) groups, lipid hydroperoxide, and ceruloplasmin in the serum of otosclerosis patients and healthy subjects with respect to oxidative stress. RESULTS: In our study, TOS and OSI levels were higher in the otosclerosis patients than in the controls. The PON1 levels showed that oxidative stress was severe, and as a result, antioxidants were consumed and depleted. DISCUSSION: When an imbalance between oxygen free radical production and antioxidative defense mechanisms occurs, reactive oxygen species levels may increase, which in turn may damage cells and tissues through the peroxidation of phospholipid membrane structures. The body initially responds with increased antioxidant production, but if the oxidative stress is severe, decreased antioxidant levels may result. This study reports expression levels of oxidative stress species in otosclerosis patients.

Bone mineral density measurements in otosclerosis using dual-energy X-ray absorptiometry.

OBJECTIVES: This study aims to evaluate patients with otosclerosis with respect to bone mineral density (BMD) at different regions of interest (ROI), using dual-energy X-ray absorptiometry (DXA). DESIGN: Cross-sectional controlled study. SETTING: Tertiary referral hospital. PARTICIPANTS: The patients with a definite diagnosis of otosclerosis confirmed intra-operatively were defined as the study group (n = 30). The control group consisted of volunteer, healthy subjects with normal hearing (n = 43). MAIN OUTCOME MEASURES: Following an audiometric evaluation, a venous blood sample was obtained and a single BMD measurement using DXA was applied to each participant. RESULTS: The mean BMD, T and Z scores were higher in the otosclerosis group than in the control group in all the regions considered, but not significantly; only the L2-L3 lateral BMD and its T and Z scores were significant (P = 0.036, P = 0.029 and P = 0.036, respectively). CONCLUSION: This study shows that the BMD does not decrease in the presence of otosclerosis despite its genetic and metabolic relevance with osteoporosis. Concerning the L2-L3 lateral BMD measurements, the BMD increased in otosclerosis.

Osteoprotegerin expression and sensitivity in otosclerosis with different histological activity.

Otosclerosis is a complex bone dystrophy of the human otic capsule leading to conductive and sensorineural hearing loss. Since otosclerosis may, at least in part, be considered as an autoimmune-inflammatory disease, disturbed balance of TNF-alpha and osteoprotegerin (OPG) expression has been implicated in the pathological bone remodeling. It has been supposed that active otosclerosis is characterized by decreased or missing local OPG production with invariable OPG sensitivity of the otosclerotic foci. Ankylotic stapes footplates (n = 41) removed by stapedectomy were processed to histological examination, OPG-specific RT-PCR, tissue culturing and alkaline-phosphatase (AP) activity assessment, respectively. OPG concentration of serum specimens (n = 41) was measured by ELISA. Cortical bone fragments harvested from the external ear canal were used as negative controls of otosclerosis. Among 41 ankylotic stapes footplates, 22 active and 19 inactive otosclerosis cases were histologically diagnosed. OPG expression was significantly lower (p < 0.001) in active otosclerosis compared to inactive cases. Osteoclast cultures originated from active otosclerotic foci showed a considerable susceptibility against external OPG dosage, which resulted in a significant decrease of AP activity (p < 0.001). In contrast, OPG serum levels were in the normal range (5-100 ng/ml) indicating a non-systemic bone resorption. In conclusion, secondary decreased local OPG production might play an important role in the pathogenesis of otosclerotic bone remodeling disorder. As to previous and current results, decreased OPG sensitivity of lesion-forming cells should be excluded. These observations may indicate the potential role of recombinant OPG treatment in early stages of otosclerosis.

Decreased measles virus-neutralizing activity in sera from otosclerotic patients.

HYPOTHESIS: Any kind of depressed systemic anti-measles reaction can lead to the induction of a local immune response in the inner ear and possibly to reactivation of bone turnover in this region. METHODS: Different dilutions of sera were tested for neutralizing activity against a constant viral concentration. The ability of measles virus to infect and replicate in the cell monolayer was detected by enumeration of living and growing cells with a colored reaction. RESULTS: Virus-neutralizing activity in the sera of patients with confirmed otosclerosis was significantly weaker than in that of healthy controls. When age- and sex-matched pairs were compared, the neutralizing activity in the healthy counterpart was higher in 5 cases. Nearly complete viral neutralization was achieved with samples containing inactivated complement and in IgG-containing fractions, but not in immunoglobulin-depleted samples. CONCLUSION: The present study is consistent with measles virus participation at least in the initiation of some cases of otosclerosis.

Antimeasles immunoglobulin G in sera of patients with otosclerosis is lower than that in healthy people.

BACKGROUND: There is some evidence for an inflammatory process as a driving force in otosclerosis. Two popular hypotheses for the induction of this chronic inflammation have been proposed: an autoimmune phenomenon induced by an otic capsule specific antigen and measles virus infection. METHODS: Antibodies against measles virus hemagglutinin, polymerase, nucleocapsid, and matrix proteins were evaluated in sera from otosclerotic patients and in sera from healthy age-and sex-matched controls by use of the Western blot analyses. RESULTS: Significant differences were not detected between healthy men and women or between otosclerotic men and women. There were significantly stronger reactions against all viral proteins in the group of healthy women as compared with otosclerotic women despite a high standard deviation. The group of healthy male blood donors demonstrated significantly stronger reactions against polymerase and nucleocapsid proteins. Healthy blood donors again demonstrated stronger reaction compared with respective otosclerotic patients in a separate reaction for viral matrix protein. CONCLUSION: Our observation is consistent with viral participation in otosclerotic pathogenesis, but it is difficult to say if the diminished antimeasles humoral response is a consequence or the cause for a local measles infection. In light of the present data, we can discuss autoantibodies in otosclerosis as a sign of autoimmunity triggered by measles virus.

Melatonin induces hyporeactivity caused by type II collagen in peripheral blood lymphocytes from patients with autoimmune hearing losses.

We have studied the behavior of peripheral blood lymphocytes in healthy controls and in patients with various hearing losses. These hearing losses were of an autoimmune origin in which type II collagen and melatonin were either present or absent, activated or not with concanavalin A (Con A). In patients with autoimmune hearing losses, the results showed lymphocytes that displayed hyporeactivity to type II collagen in terms of their proliferative activity in the presence of Con A. The hyporeactivity is specially relevant in those cells which are melatonin incubated. When different nosologic entities were studied, we observed similar lymphocyte hyporeactivity to type II collagen in bilateral sensorineural hearing loss, Ménière's disease and otosclerosis. We conclude that in the lymphocytes of patients with autoimmune hearing losses, there is hyporeactivity to type II collagen when compared to the hyporeactivity of lymphocytes in control groups. This hyporeactivity is revealed when the lymphocytes are activated in the presence of melatonin.

[Interleukin-1 beta and TNF alpha in serum of patients with otosclerosis]. / Interleukina 1 beta i TNF alfa w surowicy chorych z otoskleroza.

Levels of interleukin-1 beta and tumor necrosis factor--alfa were determined using immunoradiometric method in the serum of patients who have gone surgical treatment due to otosclerosis. Values of both cytokines were higher in the serum of patients as compared with the control group. As regards TNF-alfa these differences were statistically significant.

[Studies of perilymph protein fractions in patients with otosclerosis]. / Issledovanie belkovykh fraktsii perilimfy u bol'nykh otosklerozom.

Studies of the blood serum in 20 patients and perilymph in 10 patients with otosclerosis showed stability in concentration of total protein as compared with similar control data obtained from cadavers. In this case proteinograms of the blood serum and perilymph of patients with otosclerosis exhibit a statistically significant decrease in albumin and an increase in globulin fractions mainly at the expense of beta- and gamma-globulins with respect to the control. The data obtained evidence the presence of immunological disorders in patients with otosclerosis.

GC serum groups and otosclerosis.

Five genetic serum protein marker systems (HP, TF, GC, BF and PI) were studied in patients with otosclerosis and in controls. The distributions of GC phenotypes and alleles showed significant differences between patients and controls with an excess of the IF-allele and the IF-variant among the patients.

[Endogenous steroids and otosclerosis]. / Endogene Steroide und die Otosklerose.

The level of serum hydrocortisone dehydroepiandrosteron-sulphate and testosterone was measured in 11 men and 11 women suffering from otosclerosis, whose surgically removed stapes were histologically proven to be otosclerotic. In one third of the cases, the serum levels of steroid hormones were abnormal. Men had lower levels of dehydroepiandrosteron-sulphate, i.e. adrenocortical hypofunction, while women had higher levels of testosterone. Significant correlation was not shown with duration of symptoms, age, speech discrimination, pure tone audiogram, air-bone gap and/or any connection between otosclerosis and adrenocortical hypofunction. In patients with normal hormone serum levels the mean values of bone conduction did not exceed 15 dB on the speech frequencies, whereas in patients with otosclerosis, and altered levels of steroid hormone the threshold values on pure tone audiometry showed a hearing loss of 25 dB.

[Concentration of various bioelements in the serum of otosclerosis patients]. / La concentration de certains bioéléments dans le sérum des otoscléreux.

Serum biochemistry was monitored in 50 patients with otosclerosis confirmed surgically. Age distribution was 25 to 50 years (mean:30 years), and the group included 8 men. Constants determined were serum sodium, potassium, chlorine, iron, phosphorus, aluminium, magnesium, copper and alkaline phosphatase. All patients were free from systemic or metabolic disease. Results failed to demonstrate variations in sodium, potassium, iron, and chlorine concentrations when compared with controls, with non-significant differences in copper, magnesium, phosphorus, aluminium and alkaline phosphatases. These findings were observed both in young patients in whom the otosclerotic process is in the active phase, and in older patients, this excluding correlations between duration of the disease and variations in concentrations of specific ions. The presence of aluminium in the active otosclerotic process is therefore due to local factors of which the mechanism is unknown at the present time.