Effect of testosterone,raloxifene and estrogen replacement on the microstructure and biomechanics of metaphyseal osteoporotic bones in orchiectomized male rats

Introduction  Currently, osteoporosis research is rarely undertaken in males but an increase in male life expectancy in the company of hypogonadism suggests the necessity for potential therapeutic options. Materials and methods   In this study, the changes in bone structure under standardized testosterone- (T), raloxifene- (R) and estrogen (E)-supplemented diets were analyzed in osteoporotic castrated male rats. Results   Unexpected biomechanical results could be only explained by the histomorphometry, but not by BMD measurements obtained from the qCT. All tested substances showed a significant improvement in the trabecular network (trabecular bone area for C: 2.55 mm², T: 4.25 mm², R: 4.22 mm² and E: 4.28 mm²), and suggests that the bone structure was preserved. For the metaphyseal cortical bone, a significant loss was detected in T (CBP: 18.7%) compared to R (CBP: 30.0%), E (CBP: 26.8%) and even to the osteoporotic control (CBP: 28.6%). This explains the observed early mechanical final failure after T supplementation. However, due to the preserved trabecular bone in T, the occurrence of the first microfractures (yL: 49 ± 21.4 N) was significantly later than in the osteoporotic control (yL: 39.5 ± 15.5 N). Raloxifene performed well in hindering the bone loss associated with osteoporosis. However, its effect (yL: 83.3 ± 16.5 N) did not approach the protective effect of E (yL: 99.2 ± 21.1 N). Conclusion  Testosterone only preserved the deterioration of the trabecular bone but not of the cortical bone. Raloxifene prevented the bone loss associated with osteoporosis at all bony structures. This effect did not approach the protective effect of estrogen on trabecular bone, but it is more suitable for male individuals because it has no feminizing effects on the subject.     

雷洛昔芬联合仙灵骨葆对骨质疏松骨微结构和生物力学性能的影响

目的探讨雷洛昔芬联合仙灵骨葆对骨质疏松大鼠骨微结构及其生物力学性能的影响。探讨其调控骨吸收与骨形成及其防治骨质疏松症的作用机制。方法 6月龄40只SD大鼠在骨质疏松造模之后,随机分为正常组、假手术组、模型组、干预1组、干预2组,每组8只。造模手术1周后,干预1组采用经口灌胃雷洛昔芬6.2 mg/(kg·d),干预2组采用经口灌胃雷洛昔芬6.2 mg/(kg·d)+仙灵骨葆250 mg/(kg·d),而正常组、假手术组、模型组采用经口灌胃注射用水。12周后应用组织病理学分析及组织计量学测定;利用Van Gieson胶原纤维染色法观察胶原纤维沉积变化;ELISA测定血清蛋白聚糖活性。分离右侧股骨进行三点弯曲试验,检测股骨生物力学性能。结果对照组骨小梁粗厚、有完整的成骨细胞区。模型组骨小梁稀疏细薄、细胞核固缩;与对照组相比,模型组胶原纤维明显减少,蛋白聚糖含量明显增加,最大载荷(FM)下降,差异均有统计学意义(均P0.05)。干预组骨小梁排列较紧密。干预2组较干预1组,胶原纤维明显增加,蛋白聚糖活性降低,最大载荷(FM)差异具有统计学意义(P0.01)。结论雷洛昔芬联合仙灵骨葆较雷洛昔芬单独用药可以显著改善骨质疏松大鼠的骨基质代谢,促进成骨,显著加强骨生物力学性能。     

Estrogen and raloxifene improve metaphyseal fracture healing in the early phase of osteoporosis. A new fracture-healing model at the tibia in rat

Background  

Fracture healing in osteoporosis is delayed. Quality and speed of fracture healing in osteoporotic fractures are crucial with regard to the outcome of patients. The question arises whether established antiosteoporotic drugs can further improve fracture healing.     

Femoral metaphysis bending test of rat: introduction and validation of a novel biomechanical testing protocol for osteoporosis

Background  

The diaphysis bending test is generally accepted to assess the biomechanical properties of bone in osteoporotic animals. However, bone strength loss was more pronounced at the metaphysis than diaphysis. Therefore, the biomechanical test should be focused on the metaphysis. This study aimed to validate a novel biomechanical test for femoral metaphysis in ovariectomized rats.     

初学者使用环状弯曲与管芯塑形气管导管在预期非困难气道患者中的效果比较

目的 比较初学者使用环状弯曲与管芯塑形气管导管在预期非困难气道患者中气管插管的效果。方法 选择择期行全麻下气管插管的预期非困难气道患者126例,男60例,女66例,年龄18～64岁,BMI 18～30 kg/m²,ASAⅠ或Ⅱ级。采用随机数字表法将患者分为两组：环状弯曲组(RB组)和管芯塑形组(SB组),每组63例。麻醉诱导后由初学者实施气管插管。记录Cormack-Lehane分级(C-L分级)、喉外辅助按压情况、插管时间、插管次数、插管难易程度评分。记录麻醉诱导前基础值、诱导后、气管插管即刻、插管后1、5 min的HR、MAP及插管时并发症发生情况。记录术后2、24 h咽痛及声音嘶哑的发生情况。结果 两组C-L分级、喉外辅助按压比例、插管时间、插管次数、插管难易程度差异无统计学意义。RB组插管即刻及插管后1 min HR明显慢于SB组,MAP明显低于SB组(P<0.05)。RB组术后2、24 h咽痛及声音嘶哑发生率明显低于SB组(P<0.05)。结论 初学者在对预期非困难气道患者实施气管插管时,使用环状弯曲气管导管的插管时间及插管次数与管芯塑形气管...     

A rat osteoporotic spine model for the evaluation of bioresorbable bone cements.

BACKGROUND CONTEXT: As the aging population increases, the rising prevalence of osteoporosis-related spine fractures will have a dramatic impact on health care. At present, mainstay treatment relies on systemic medications intended to prevent diminishing bone mineral density (BMD) and bone mass. However, an adjunctive treatment strategy is to target specific areas of the skeletal system that are prone to clinically significant osteoporotic fractures. We term this strategy the "local treatment of osteoporosis" or osteoplasty. Potential use of osteoplasty involves the percutaneous injection of bioresorbable and bioactive bone cements into bones at risk of sustaining osteoporotic fractures. Calcium sulfate (CaSO(4)) is among the candidate bioresorbable bone cements with the material attributes desirable for potential application with osteoplasty, yet previous studies on the osteoconductive properties of CaSO(4) have been limited to animal models exhibiting normal bone biology and architecture. However, osteoporotic bone physiology may potentially interfere with the material properties of common osteoconductive biomaterials, such as that of CaSO(4). To further test this hypothesis, a suitable animal model is needed to evaluate the in vivo behavior of potential biomaterials in osteoporotic bone. PURPOSE: The purpose of this study is to evaluate the caudal (proximal tail) rat vertebral body as an appropriate system for the in vivo evaluation of bone cement performance in the osteoporotic spine. STUDY DESIGN: (1) Micro-computed tomography radiomorphometry study and (2) biomechanical vertebral compression analysis. METHODS: Female Sprague Dawley rats were ovarectomized (OVX) at age 8 weeks and subsequently maintained on a low-calcium diet for 3 months. Normal nonovarectomized female rats (NL) of similar age and size were maintained on regular rodent feed. Micro-CT analysis was performed on both the lumbar and caudal vertebrae (levels 5-7) of both groups. The following bone radiomorphometric parameters were determined: bone mineral density (BMD), average cortical thickness (ACT), average trabecular thickness (TbTh), and average trabecular spacing (TbSp). Strength and stiffness of both NL and OVX vertebral bodies were assessed under axial compression at 0.1 mm/s, whereas displacement (mm) and force (N) were measured at 10 Hz until completion to failure. After the implantation of an injectable form of CaSO(4) bone cement into caudal vertebrae, radiomorphometric analysis of cement volume, based on its unique CT absorption profile, was performed over the 8-week time period, as well as the subsequent bone response of both NL and OVX caudal vertebrae to CaSO4. RESULTS: OVX caudal vertebrae showed an 18% decrease in BMD, a 28% decrease in diaphyseal ACT, a 55% decrease in TbTh, and a 2.4-fold increase in TbSp compared with NL (p<.05). Additionally, lumbar vertebrae exhibited a 21% decrease in BMD, a 24% decrease in anterior body ACT, a 48% decrease in TbTh, and a 4.7-fold increase in TbSp (p<.05). Failure testing of OVX caudal vertebral bodies revealed a 29% decrease in strength and a 60% decrease in stiffness compared with NL (p<.01). After implantation into OVX caudal vertebrae, CaSO(4) cement exhibited a 50% decrease in initial cement volume at 2 weeks and complete resorption by 4 weeks, whereas CaSO(4) injected into NL vertebrae exhibited a 79% decrease in initial cement volume at 4 weeks, trace amounts at 6 weeks, and complete resorption by 8 weeks. At 8 weeks, NL vertebrae implanted with CaSO(4) cement exhibited increased cortical bone thickness compared with NL sham vertebrae. This CaSO(4) cement-mediated bone augmentation was altered in osteoporotic vertebrae that exhibited porous irregular cortical bone not noted in cement-treated NL vertebrae or OVX sham vertebrae. CONCLUSIONS: Future investigation of potential biomaterials intended for the local treatment of osteoporosis will require their study within an appropriate osteoporosis animal model. The OVX rat caudal spine exhibits pathologic bone changes consistent with the osteoporosis phenotype, including decreased BMD, diminished trabecular network density, cortical thinning, and decreased mechanical strength. These derangements in bone microarchitecture and physiology may contribute toward the accelerated cement resorption and altered bone response to CaSO4 observed in this study. Important advantages of the OVX rat caudal spine are the rapid and minimally invasive surgical exposure of the vertebral body and the ease of cement injection. We propose that the OVX rat caudal spine represents a valuable and cost-effective tool in the armamentarium of investigators evaluating biomaterials designed for implantation into the osteoporotic spine.     

Varicocele and its effect on testosterone: implications for the adolescent

The treatment of varicoceles in adolescents is highly controversial. In contrast to adults with varicocele, fertility status is not yet known and it is not generally feasible to obtain a semen analysis in adolescents in order to guide treatment. Hence, the principal indication for surgery in teenagers is hypotrophy/atrophy of the left testis associated with a varicocele. Recent evidence in adults suggests that varicocele may be a cause of hypogonadism. If this is further documented in adults, it may be true in teens as well and indeed, might be an indication for early surgery. This is an important area for research in adolescents with a varicocele.     

Relationship between penile erection and the ratio of estradiol to testosterone: A retrospective study

Previous studies have found that the ratio of estradiol to testosterone (E2/T ratio) has a negative effect on sexual function, but the relationship between the E2/T ratio and erection of the penis is not clarified. We conducted a retrospective study of 183 patients with erectile dysfunction and 52 healthy men to investigate the relationship between penis base erection and tip erection. All participants underwent nocturnal penile tumescence tests and medical history checks and had relevant biochemical and endocrine indicators measured. The ratio of estradiol to testosterone was calculated. The relationship between E2/T ratio and erectile time of penile tip and penile base was determined by univariate analysis, multivariate analysis and stratification analysis. After adjusting for mixed factors, the results showed that the E2/T ratio had a more significant negative effect on the base of the penis compared with the tip of the penis (Hazard ratio: −4.34 95% CI: −6.52, −2.16 p = .0001). Moreover, when the effective erection time was ≥10 min, the negative effect of E2/T on penile root erection was more obvious (HR ratio: −4.46 95% CI: −6.50, −2.43 p < .0001). In summary, our study demonstrated a negative relationship between E2/T ratio and penile erection, particularly at the root of the penis.     

Daily testosterone and gonadotropin levels are similar in azoospermic and nonazoospermic normal men administered weekly testosterone: implications for male contraceptive development.

Weekly intramuscular administration of testosterone esters such as testosterone enanthate (TE) suppresses gonadotropins and spermatogenesis and has been studied as a male contraceptive. For unknown reasons, however, some men fail to achieve azoospermia with such regimens. We hypothesized that either 1) daily circulating serum fluoroimmunoreactive gonadotropins were higher or testosterone levels were lower during the weekly injection interval, or 2) monthly circulating bioactive gonadotropin levels were higher in nonazoospermic men. We therefore analyzed daily testosterone and fluoroimmunoreactive gonadotropin levels as well as pooled monthly bioactive and fluoroimmunoreactive gonadotropin levels in normal men receiving chronic TE injections and correlated these levels with sperm production. After a 3-month control period, 51 normal men were randomly assigned to receive intramuscular TE at 25 mg (n = 10), 50 mg (n = 9), 100 mg (n = 10), 300 mg (n = 10), or placebo (n = 12) weekly for 6 months. After 5 months of testosterone administration, morning testosterone and fluoroimmunoreactive follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured daily for a 1-week period between TE injections. In addition, fluoroimmunoreactive and bioactive FSH and LH levels were measured in pooled monthly blood samples drawn just before the next TE injection. In the 100-mg and 300-mg TE groups, mean monthly fluoroimmunoreactive FSH and LH levels were suppressed by 86%-97%, bioactive FSH and LH levels by 62%-80%, and roughly half the subjects became azoospermic. In the 1-week period of month 6, daily testosterone levels between TE injections were within the normal range in men receiving placebo, or 25 or 50 mg of weekly TE, but were significantly elevated in men receiving 100 or 300 mg of weekly TE. At no point during treatment, however, were there significant differences in daily testosterone or fluoroimmunoreactive gonadotropin levels, or monthly bioactive gonadotropin levels between men achieving azoospermia and those with persistent spermatogenesis. This study, therefore, demonstrates that neither monthly nor daily differences in serum testosterone, or fluoroimmunoreactive or bioactive gonadotropins explain why some men fail to completely suppress their sperm counts to zero with weekly TE administration. Innate differences in the testicle's ability to maintain spermatogenesis in a low-gonadotropin environment may explain persistent spermatogenesis in some men treated with androgen-based contraceptive regimens.     

Historical perspective: William Adams, the forward bending test, and the spine of Gideon Algernon Mantell

William Adams described the Forward Bending Test for scoliosis in 1865. His understanding of the nature of the rotational element of scoliosis was given by a postmortem he performed on an eminent surgeon and geologist, Gideon Mantell. The clinical history of Dr. Mantell is well documented.     

Studies on seminiferous tubule fluid production in the adult rat: effect of hypophysectomy and treatment with FSH, LH and testosterone

Seminiferous tubule fluid production in adult rats was studied using the technique of unilateral efferent duct ligation (EDL), the production rate representing the difference in testis weight over the time since ligation. Following EDL, fluid production increases linearly for 6 h and linearly at a slightly slower rate for a further 18 h with a sharp decrease thereafter. No differences in fluid production were noted for rats aged between 90–310 days. Forty-eight hours after hypophysectomy there was a significant fall (26%) in fluid production prior to any significant decrease in testis weight. Fluid production continued to decline with time after hypophysectomy eventually reaching a plateau 16–44 days later at levels approximately 15% of those found in control rats. Treatment of rats hypophysectomized 4 days earlier with ovine FSH for 3 days did not restore fluid production, but treatment with ovine LH, testosterone propionate (TP) or FSH together with TP for a similar duration all restored fluid production to normal. On the other hand, treatment of intact adult rats with ovine LH significantly increased fluid production but the effect of treatment with testosterone alone did not reach significance. The results indicate that in the adult rat, seminiferous tubule fluid production is controlled principally by testosterone secreted by the Leydig cell in response to LH stimulation.     

The effects of ketoconazole on testosterone production and normal and malignant androgen dependent tissues of the adult rat

Ketoconazole is a potent inhibitor of the P450 series of enzymes that are essential for the production of androgens. In order to determine the effects of ketoconazole on androgen production and androgen dependent tissues in the rat, adult male rats were administered varying doses of ketoconazole every 12 hours. Serum testosterone declined to unmeasurable levels at ketoconazole doses of greater than 4 mg. This dose was sufficient to completely inhibit the testosterone surge induced by the administration of a potent luteinizing releasing hormone agonist. The ventral prostate weight of normal rats and the volume of the Dunning R3327H androgen dependent prostatic cancer declined at the same rate in animals treated with ketoconazole or castration. Ketoconazole may be an effective agent to treat androgen dependent diseases.     

女性酒渣鼻患者血清睾酮、二醇和月经的关系

为了探讨女性酒渣鼻患者血清睾酮、雌二醇水平及月经周期改变情况，作者用放射免疫分析法测定了２５例患者及２０例正常对照者血清睾酮及雌二醇水平，并调查了２５０例患者及１００例正常对照者月经周期变化情况。结果显示，患者血清中睾酮的平均值为５．２７ｎｍｏｌ／Ｌ，明显于对照组（ｔ＝２．９１，ｐ＜０．０１）。雌二醇平均值为５７４．６ｎｍｏｌ／Ｌ，与对照组无明显差异（ｔ＝０．１１，ｐ＞０．０５）。患者月经紊乱率为６９．６％，明显高于对照组（χ２＝３５．５５，ｐ＜０．０１）。可见，女性酒渣鼻患者血清睾酮升高，雌二醇正常，且多伴月经周期紊乱。     

Determination of prostatic secretion in rats: effect of neurotransmitters and testosterone.

To study the neuronal and hormonal control of prostatic secretion, the prostatic urethra was cannulated in urethane anesthetized rats. The volume of prostatic secretion was measured following infusion of cholinergic and adrenergic agonists intact animals. Prostatic secretion was elicited by norepinephrine, phenylephrine and carbachol; but not by clonidine, isoproterenol, pilocarpine, or acetylcholine. Phenylephrine and norepinephrine infusions caused a high initial rate of secretion, which then declined rapidly. Carbachol infusion, in contrast, produced a low but constant rate of secretion that was maintained for up to 1 hour. Histological examination of the prostate revealed contraction of smooth muscle surrounding prostatic ducts after infusion of phenylephrine and norepinephrine, but not carbachol. Prostatic secretion was also measured in castrated rats supplemented with various doses of testosterone. Testosterone exerted a dose dependent control of prostatic weight and secretory volume. These results indicate 1) alpha 1 receptor agonists can cause contraction of smooth muscle to expel fluid from the rat prostate, 2) carbachol induces prostatic secretion through a mechanism other than contraction of gland, and 3) testosterone has a primary role in controlling prostatic size.