Opioid-induced hypogonadism: why and how to treat it.

BACKGROUND: Gonadal hormones are critical factors in modulating the experience of pain, as suggested by the several sex differences observed: women have a greater risk of many clinical pain conditions, and postoperative and procedural pain may be more severe in them than in men. A growing body of literature demonstrates the role of estrogen in the female pain experience, whereas less attention has been given to testosterone and its functions. Nevertheless, testosterone has an appreciable role in both women and men: adequate serum levels are required in males and females for libido and sexuality; cellular growth; maintenance of muscle mass and bone; healing; blood-brain barrier; and for central nervous system maintenance. Pain therapy, and particularly opioid therapy, has been shown to affect testosterone plasma levels. Thus, the chronic administration of pain killers, such as opioids, requires the physician to be aware of both the consequences that can develop due to long-term testosterone impairment and the available means to restore and maintain physiological testosterone levels. OBJECTIVE: The objective is to highlight to pain physicians that the endocrine changes occurring during chronic pain therapy can participate in the body dysfunctions often present in chronic pain patients and that there are possible hormone replacement methods that can be carried out in men and women to improve their quality of life. STUDY DESIGN: A comprehensive review of the literature. METHODS: A comprehensive review of the literature relating to opioid-induced hypogonadism, as well as other very common forms of hypogonadism, its endocrine effects, and possible therapeutic actions. The literature was collected from electronic and other sources. The reviewed literature included observational studies, case reports, systematic reviews, and guidelines. OUTCOME MEASURES: Evaluation of the endocrine changes described in chronic pain therapy was the primary outcome measure. The secondary outcome measures were functional improvement and adverse effects of hormone replacement. RESULTS: The results of the survey clearly show that sex hormone determination is very rare in pain centers. Given the complexity and widespread nature of pain therapy, there is a paucity of qualitative and quantitative literature regarding its endocrine consequences. The available evidence is weak for pain relief, but is consistent for many collateral effects, possibly deriving from pain therapy, such as fatigue, depression, and neurodegenerative diseases. LIMITATION: This is a narrative review without application of methodological quality assessment criteria. Even so, there is a paucity of literature concerning both controlled and observational literature for the endocrine effects of most analgesic drugs. CONCLUSION: Testosterone replacement suffers from old prejudices about its utility and safety. With this review we illustrate the available therapeutic choices able to maintain T concentration into physiological ranges and reduce nociception with a final goal of improving patients' quality of life.

Impact of testosterone on body fat composition.

An excessive food supply has resulted in an increasing prevalence of overweight and obesity, conditions accompanied by serious health problems. Several studies have confirmed the significant inverse correlation between testosterone and obesity. Indeed after decades of intense controversy, a consensus has emerged that androgens are important regulators of fat mass and distribution in mammals and that androgen status affects cellularity in vivo. The high correlation of testosterone levels with body composition and its contribution to the balance of lipid metabolism are also suggested by the fact that testosterone lowering is associated with important clinical disorders such as dyslipidemia, atherosclerosis, cardiovascular diseases, metabolic syndrome and diabetes. In contrast, testosterone supplementation therapy in hypogonadic men has been shown to improve the lipid profile by lowering cholesterol, blood sugar and insulin resistance. Leptin, ghrelin and adiponectin are some of the substances related to feeding as well as androgen regulation. Thus, complex and delicate mechanisms appear to link androgens with various tissues (liver, adipose tissue, muscles, coronary arteries and heart) and the subtle alteration of some of these interactions might be the cause of correlated diseases. This review underlines some aspects regarding the high correlations between testosterone physiology and body fat composition.

Within-host dynamics of the hepatitis C virus quasispecies population in HIV-1/HCV coinfected patients.

HIV/HCV coinfected individuals under highly active antiretroviral therapy (HAART) represent an interesting model for the investigation of the role played by the immune system in driving the evolution of the HCV quasispecies. We prospectively studied the intra-host evolution of the HCV heterogeneity in 8 coinfected subjects, selected from a cohort of 32 patients initiating HAART: 5 immunological responders (group A) and 3 immunological non-responders (group B), and in two HCV singly infected controls not assuming drugs (group C). For all these subjects at least two serial samples obtained at the first observation (before HAART) and more than 1 year later, underwent clonal sequence analysis of partial E1/E2 sequences, encompassing the whole HVR1. Evolutionary rates, dated phylogenies and population dynamics were co-estimated by using a Bayesian Markov Chain Monte Carlo approach, and site specific selection pressures were estimated by maximum likelihood-based methods. The intra-host evolutionary rates of HCV quasispecies was 10 times higher in subjects treated with HAART than in controls without immunodeficiency (1.9 and 2.3 × 10(-3) sub/site/month in group A and B and 0.29 × 10(-3) sub/site/month in group C individuals). The within-host Bayesian Skyline plot analysis showed an exponential growth of the quasispecies populations in immunological responders, coinciding with a peak in CD4 cell counts. On the contrary, quasispecies population remained constant in group B and in group C controls. A significant positive selection pressure was detected in a half of the patients under HAART and in none of the group C controls. Several sites under significant positive selection were described, mainly included in the HVR1. Our data indicate that different forces, in addition to the selection pressure, drive an exceptionally fast evolution of HCV during HAART immune restoration. We hypothesize that an important role is played by the enlargement of the viral replicative space.

Rapid molecular evolution of human bocavirus revealed by Bayesian coalescent inference.

Human bocavirus (HBoV) is a linear single-stranded DNA virus belonging to the Parvoviridae family that has recently been isolated from the upper respiratory tract of children with acute respiratory infection. All of the strains observed so far segregate into two genotypes (1 and 2) with a low level of polymorphism. Given the recent description of the infection and the lack of epidemiological and molecular data, we estimated the virus's rates of molecular evolution and population dynamics. A dataset of forty-nine dated VP2 sequences, including also eight new isolates obtained from pharyngeal swabs of Italian patients with acute respiratory tract infections, was submitted to phylogenetic analysis. The model parameters, evolutionary rates and population dynamics were co-estimated using a Bayesian Markov Chain Monte Carlo approach, and site-specific positive and negative selection was also investigated. Recombination was investigated by seven different methods and one suspected recombinant strain was excluded from further analysis. The estimated mean evolutionary rate of HBoV was 8.6x10(-4)subs/site/year, and that of the 1st+2nd codon positions was more than 15 times less than that of the 3rd codon position. Viral population dynamics analysis revealed that the two known genotypes diverged recently (mean tMRCA: 24 years), and that the epidemic due to HBoV genotype 2 grew exponentially at a rate of 1.01year(-1). Selection analysis of the partial VP2 showed that 8.5% of sites were under significant negative pressure and the absence of positive selection. Our results show that, like other parvoviruses, HBoV is characterised by a rapid evolution. The low level of polymorphism is probably due to a relatively recent divergence between the circulating genotypes and strong purifying selection acting on viral antigens.

Telbivudine in the treatment of chronic hepatitis B: experience in HIV type-1-infected patients naive for antiretroviral therapy.

BACKGROUND: Telbivudine is a potent inhibitor of hepatitis B virus (HBV) replication without anti-HIV type-1 (HIV-1) activity demonstrated in vitro; however, very few clinical data on HIV-1-infected patients are available at present. Because it represents a therapeutic option in HIV-1-HBV-coinfected patients who do not require antiretroviral therapy, we strictly monitored three HIV-1-HBV-coinfected patients treated with telbivudine monotherapy for chronic hepatitis B. METHODS: We performed molecular analysis of HBV DNA and of HIV-1 reverse transcriptase and protease RNA and DNA sequences in three HIV-1-HBV-coinfected patients treated with telbivudine monotherapy. RESULTS: Despite a transient and deep reduction of HIV-1 RNA, observed in two of the three patients studied, no genotypic resistance mutations were detected on both HIV-1 and HBV viruses. CONCLUSIONS: Telbivudine therapy for 24 weeks showed a potent anti-HBV activity in HIV-1-positive, hepatitis B e antigen-positive patients with high HBV viraemia. No direct anti-HIV-1 activity of telbivudine was demonstrated and no genotypic resistance mutations to anti-HIV-1 drugs was found; however, the transient but deep reduction of HIV RNA, after telbivudine introduction, deserves further investigation and a strict monitoring of HIV-1 viraemia in HIV-1-infected patients on treatment with this drug.

Different evolutionary rates and epidemic growth of hepatitis B virus genotypes A and D.

The epidemiological history of HBV genotypes A and D and subgenotypes A2 and D3 was studied on 132 isolates drawn between 1980 and 2005 from patients living in a homogenous geographical area. Evolutionary rates and divergence dates were estimated and HBV demographic history was reconstructed by using a statistical approach based on coalescent theory. The evolutionary rate of A2 was significantly lower than that of D3. The growth rate of D3 epidemic was significantly faster than that of A2; both subgenotypes showed a decreasing growth rate from the mid-1980s. Our data suggest that the important discrepancies observed in the evolutionary rates of HBV genotypes A and D may reflect different population dynamics of their epidemics. These results show the usefulness of phylodynamic studies in reconstructing the history of epidemics due to highly variable DNA viruses, and in evaluating the long-term efficacy of prophylactic measures.

Description of a "trans-Saharan" strain of human T-lymphotropic virus type 1 in West Africa.

The aim of this study was to assess the prevalence and the molecular epidemiology of human T-lymphotropic virus type 1 (HTLV-1) in a group of pregnant women living in Guinea Bissau. We studied 427 consecutive pregnant women attending 10 centers for HIV-1 infection monitoring in Bissau. HTLV-1 infection was found in 2.6% of the patients. Phylogenetic analysis of the long terminal repeat region showed that 10 isolates were of the cosmopolitan subtype (HTLV-1a) and that only 1 was of the widespread Central African subtype (HTLV-1b). All the cosmopolitan isolates belonged to the HTLV-1aD subgroup, which was first described in North Africa and clustered with other Senegal and Guinea isolates to form a significant West African clade. Our data show a high prevalence of HTLV-1 in Guinea Bissau and suggest the existence of a trans-Saharan strain distributed in North and West Africa, which probably crossed the desert in the past as a result of contacts between nomadic and sedentary populations or along trading routes.

Phylogeny of human T cell lymphotropic virus type 1 in Peru: a high degree of evolutionary relatedness with South African isolates.

We investigated the prevalence and molecular epidemiology of human T cell lymphotropic virus type 1 in Peruvian HIV-1-positive subjects, and found a 10.1% prevalence in a consecutive series of 318 HIV-1-positive patients living in Lima. Phylogenetic analysis of the long terminal repeat of 10 patient isolates showed that all of them belonged to the HTLV-1aA (Transcontinental) subgroup. Although the majority of the Peruvian sequences included in the analysis formed a clade with other Latin American sequences, the isolates of three patients clustered significantly with South African strains. These data show a high prevalence of HTLV-1 infection in HIV-1-positive subjects living in Lima and confirm the presence in Latin America of HTLV-1 strains probably arising from South Africa.

High level of genetic heterogeneity in S and P genes of genotype D hepatitis B virus.

The genetic heterogeneity of hepatitis B virus (HBV) genotypes and subgenotypes was investigated by directly sequencing amplified PreS, S and P genes of HBV isolates obtained from the plasma of 99 subjects with chronic HBV infection. Genotype D showed the greatest intragenotypic and intrasubgenotypic divergence: in particular, the a determinant was mutated in 58.2% of the genotype D patients, two of whom showed prototypic vaccine-induced escape mutants at codon 145. Moreover, five sites under significant positive selection were found in the S protein of the D isolates: one in the a determinant and four in the highly hydrophobic C terminal. Our results suggest that careful surveillance of vaccine-induced escape mutants should be considered in populations with highly frequent genotype D infections, and raise questions concerning the possible relationship between the genetic heterogeneity, host immunity and pathogenicity of this HBV genotype.

Compartmentalization of hepatitis C virus quasispecies in blood mononuclear cells of patients with mixed cryoglobulinemic syndrome.

The aim of this study was to investigate the quasispecies heterogeneity of hepatitis C virus (HCV) in the plasma, cryoprecipitate, and peripheral lymphocytes of chronically infected HCV patients with mixed cryoglobulinemia (MC). We studied 360 clones from 10 HCV-positive patients with MC and 8 age-, gender- and HCV genotype-matched subjects with chronic HCV infection but without MC. A partial nucleotide sequence encompassing the E1/E2 region, including hypervariable region 1 (HVR1), was amplified and cloned from plasma, cryoprecipitates, and peripheral blood mononuclear cells (PBMC), and the genetic diversity and complexity and synonymous and nonsynonymous substitution rates were determined. Heterogeneous selection pressure at codon sites was evaluated. Compartmentalization was estimated by phylogenetic and phenetic (Mantel's test) approaches. The patients with MC had 3.3 times lower nonsynonymous substitution rates (1.7 versus 5.7 substitutions/100 sites). Among the subjects with HCV genotype 1, the MC patients had significantly less complexity than the controls, whereas the diversity and complexity were similar in the genotype 2 patients and controls. Site-specific selection analysis confirmed the low frequency of MC patients showing positive selection. There was a significant correlation between positive selection and the infecting HCV genotype. The quasispecies were less heterogeneous in PBMC than in plasma. Significant compartmentalization of HCV quasispecies was observed in the PBMC of four of nine subjects (three with MC) and seven of nine cryoprecipitates. In one subject with MC, we detected a 5-amino-acid insertion at codons 385 to 389 of HVR1. Our results suggest reduced quasispecies heterogeneity in MC patients that is related to a low selection pressure which is probably due to an impaired immune response, the HCV genotype, and/or the duration of the infection. The frequent HCV quasispecies compartmentalization in patients' PBMC suggests a possible pathogenetic significance.

High prevalence of human T-lymphotropic virus type 1 (HTLV-1) in immigrant male-to-female transsexual sex workers with HIV-1 infection.

Human T-lymphotropic virus type 1 and 2 (HTLV-1 and HTLV-2) infections in Europe are limited to intravenous drug users and migrants coming from areas in which they are endemic. A survey was undertaken of HTLV-1 and HTLV-2 infections in 393 recent immigrants: 167 HIV-1 positive subjects (including 52 male-to-female transsexual sex workers) and 226 pregnant HIV-1 negative women. The prevalence of HTLV-1 was 3.6% in the HIV-1 positive group and 0.9% in the HIV-1 negative group. The highest HTLV-1 prevalence in both groups was found in persons from Latin America, particularly those born in Peru (up to 26% in the HIV-1 positive group). All of the HIV-1/HTLV-1 co-infected individuals were male-to-female transsexual sex workers in whom the overall prevalence of HTLV-1 infection was 11.5%. HTLV-2 was only found in the HIV-1 positive group (prevalence 1.2%); all of the infected subjects were transsexual sex workers from Brazil (overall prevalence 6.4%). Phylogenetic analysis showed that all of the HTLV-1 isolates were of the cosmopolitan type, clustering with other strains circulating in the patients' birthplaces; the HTLV-2 isolates were of subtype 2a, and clustered significantly with other Brazilian strains. These results suggest the independent origin of each infection in the patient's birthplace. The data raise concerns about the further spread of HTLV infections mainly through the sexual route.

Increased risk of developing peripheral neuropathy in patients coinfected with HIV-1 and HTLV-2.

One thousand one hundred fifty-two HIV-1-positive patients were screened for HTLV-2 infection, and the AIDS-free coinfected individuals were consecutively included in a longitudinal study with the aim of investigating the role of HTLV-2 in the progression to AIDS and the development of specific neurologic diseases. Two matched HIV-1-positive/HTLV-2-negative controls for each coinfected individual were also enrolled in the study. HTLV-2 infection was found in 95 (8.2%) of the HIV-1-positive patients, 30 of whom were followed up for a median of 28.5 months. No significant differences were observed between them and the patients infected with HIV-1 alone in terms of the rate of decline in CD4 cell counts, progression to AIDS, or AIDS mortality, but they had an increased risk of developing peripheral neuropathy (hazard ratio, 3.3; 95% confidence interval, 1.3-8.0; p =.009). One coinfected patient developed myelopathy during the follow-up. In the second part of the study, aimed at preliminarily assessing the effect of highly active antiretroviral therapy (HAART) on the incidence of peripheral neuropathy, we extended our observations to two groups of coinfected and singly infected individuals receiving HAART. An 80% decrease in incidence of peripheral neuropathy was observed among both groups without any significant difference between them. These results support the hypothesis that HTLV-2 plays a role in the development of neurologic abnormalities in HIV-1-infected patients and suggest that the immune reconstitution due to HAART may limit the activity of HTLV-2 as an opportunistic agent.