Women & HIV  

Italian Study Finds HIV Delays Sexual Maturation in Boys & Girls Infected by their Mothers
AIDS August 17, 2001, 15:1527±1534 (Maurizio de Martino for the Italian Register for HIV Infection in Children

These study authors conclude that perinatal HIV-1 infection interferes with sexual maturation. Age at onset of puberty was not related to clinical and immunological condition, antiretroviral treatment, weigh for height and age at onset of severe disease or immune suppression.

The authors discuss how this occurs with other childhood diseases and the authors suggest that perhaps abnormal growth hormone production or release, coupled with decreased androgen secretion, may be involved. The study authors discuss potential biases of the study such asthe potential genetic predisposition inherited from family, socioeconomic status of the baby, illicit drug use by mother or sexual partner, and increased risk of neglect by the mother based on her conditions. However, the authors conclude that they do not feel these biases change their conclusions that HIV delays puberty in perinataly infected children.

This multicentre longitudinal study was designed to define the age at entry into each Tanner stage in children with perinatal HIV-1 infection. The study group was selected from the dataset of the Italian Register for HIV Infection in Children, a large cohort prospectively evaluated with homogeneous criteria since 1985 and representative of children with perinatal HIV-1 infection in Italy puberty. This information is not available in the original data collection sheets of the register but is routinely registered in each paediatric centre at every visit. Reproducibility of data was based on the use of the standardized criteria of Tanner and Whitehouse. The paediatrician appointed at each centre ensured the quality of information.

This longitudinal study showed that delayed sexual maturation is associated with perinatal HIV-1 infection, particularly in girls. As a median, the onset of puberty is delayed by about 2 years in girls and 1 year in boys. This means that entry into the late Tanner stages is delayed by about 2.5 years in girls and 1.5 years in boys. These results are in line with findings described for other chronic childhood diseases, including HIV-1 infec- tion in haemophiliac boys. Study have shown that HIV-1 itself causes delayed pubertal development. Infected haemophiliac boys have a delayed sexual maturation compared with uninfected haemophiliac boys. It has been also shown that the delay in development of HIV-1-infected haemophiliac boys is not directly related to the disease progression.

Another finding in our study is that the delay in sexual maturation is more severe in girls than in boys. Compared with boys, girls have approximately a 1 year greater delay in the onset of puberty and accumulate a further 6 month delay during puberty. In several childhood chronic conditions, development, including sexual maturation, is more affected in girls than in boys, possibly as a result of differing sensitivity of the pituitary to gonadotrophin-releasing hormone. In fact, delay in the onset of puberty is a less common complaint among girls than among boys but is more likely to have an underlying pathological cause. In chronic renal failure, for example, puberty is particularly delayed in girls. Other long-term diseases such as haemoglobin defects, chronic anaemias, haemosiderosis, respiratory insufficiency in patients with severe asthma or cystic fibrosis, and chronic hepatic and intestinal diseases are causes of delayed puberty, particularly in girls. The mechanisms that lead to delayed development and sexual maturation in HIV-1-infected children remain unknown. Inadequate caloric intake does not have a significant role.

Extensive endocrine testing in haemophiliac boys suggests that abnormal growth hormone production or release, coupled with decreased androgen secretion, may be involved. Endocrine dysfunction is probably more complex in perinatally infected children and includes an euthyroid sick syndrome, accompanied by increased basal thyrotrophin levels, reduced free thyroxine levels and low levels of insulin growth factor 1 (IGF-1) and IGF-binding protein 3. This condition is partly related to proinflammatory interleukin overproduction triggered off by HIV-1. HIV-1-induced immune dysfunction could be a mechanism causing a delayed sexual maturation through altered neural control of puberty.

There are some potential biases in this study to consider:

The timing of sexual maturation is determined by the interaction of inheritance with several environmental factors. Race-related biases were avoided by taking into consideration just Caucasian children in both the study and control groups. Information concerning the timing of sexual maturation of the parents of HIV-1- infected children could not be taken into account because in most cases either one or both parents had already died or were unidentifiable. In some cases, the children were living in foster families. Reliable information concerning other potentially influencing factors (such as the distribution of HIV-1-infected and control children according to family size, socioeconomic class, living in rural or urban communities or living at high altitudes) was not available. However, the estimated difference in age at the onset of puberty for these environmental factors is approximately 3 months and the fact that large numbers of children were considered in our study reduces any bias.

Other biases may derive from illicit drug use in the mothers or their sexual partners and consequent low socieconomic status of perinatally HIV-1-infected children. These children have an increased risk of preterm birth and both prenatal and postnatal growth retardation. There is an increased risk of neglect (because of continuous maternal drug use) and they may also suffer as a result of parental ill-health and multiple bereavement. Most of these parameters were available to us for the perinatally HIV-1-infected children but were not available for the control children. These biases were, therefore, impossible to control. The most appropriate control group (in order to control these biases rigorously) would be the uninfected siblings of perinatally HIV-1-infected children. Unfortunately, our dataset of uninfected siblings who had reached pubertal age and were regularly followed-up was insufficient. We are aware that unfavourable environmental factors may have some role in delaying sexual maturation in perinatally HIV-1-infected children, but it is unlikely that these biases can invalidate our findings. This is especially true if we consider that haemophiliac boys with bloodborne HIV-1 infection (and who do not have such unfavourable environmental factors) have a similar delay in their sexual maturation.

From a speculative point of view, understanding the mechanisms by which HIV-1 interferes with sexual maturation may shed light on the physiology of the pubertal process itself [5]. In practice, we must consider that there are now sizeable cohorts of perinatally HIV-1-infected children in industrialized countries who are approaching adolescence. Most of them will fail to reach the height of their peers and their physical appearance will exacerbate their feeling of being both different and sickly. Part of the linear growthfailure could be attributed to the delay in puberty they suffer. A deeper knowledge of the mechanisms that lead to delayed puberty could guide development-promoting strategies, saving much psychological distress for these adolescents. Furthermore, better understanding of the mechanisms leading to delayed puberty in girls and boys with perinatally acquired HIV-1 infection might lead to appropriate treatment when required.

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