Benign prostatic hyperplasia
Testosterone T substitution in hypogonadal men results in growth of the prostate gland. T effects are mediated via the androgen receptor AR. The length of the CAG n polymorphism of the AR gene is negatively associated with transcriptional activity and might account for variations in prostate growth during substitution therapy. In hypogonadal men aged 18—69 yr, we assessed prostate volume Prostatavolumen von 25 cm by transrectal ultrasonography and determined AR CAG n, sex hormone levels, and anthropometric measures.
Average prostate size increased from Prostate growth per year and absolute prostate size under substituted T levels 6. Other significant predictors were initial prostate size negative for growth Prostatavolumen von 25 cm and positive for absolute size and age positive for both growth rate and absolute size.
The odds ratio for men with CAG n less Prostatavolumen von 25 cm 20, compared with those with CAG n of 20 or more to develop a prostate size of at least 30 ml under T substitution, was 8. This observation was strongly age dependent with a more pronounced odds ratio in men older than 40 yr. This first pharmacogenetic study on androgen substitution in hypogonadal men demonstrates a marked influence of the AR gene CAG n polymorphism on prostate growth.
T deprivation will result in an involution of the prostate gland, and administration of androgens to hypogonadal patients will lead to growth of this organ into the age-corresponding range.
It is the population of glandular ephithelial cells that are androgen sensitive, and the balance of cell renewal and death requires T for stability 1 — 7.
T effects are mediated via the androgen receptor AR and the significant amount of variation in T responsiveness that is observed in hypogonadal men receiving substitution therapy could hypothetically be facilitated by a pharmacogenetic mechanism involving the AR.
A respective candidate is the CAG repeat [ CAG n] polymorphism of the AR gene on the X chromosome, which normally ranges between 9 and 37 triplets 8 — 10 and encodes for a variable number of glutamine residues in the aminoterminal domain of the receptor.
The number of CAG n is inversely associated with the transcriptional activity of testosterone target genes 11 A length beyond 37 repeats leads to Kennedy disease spinobulbar muscular atrophywhich is caused by irregular processing of the AR protein The disease is also characterized by marked hypoandrogenic traits e. Frequently, but not uniformly, CAG n length within the normal range has clinical implications for androgen effects in eugonadal men, which have been demonstrated on a cross-sectional basis.
This refers to bone density 15endothelial function and lipid levels 16body composition in relation to leptin and insulin levels 17and spermatogenesis 1819 as well as depression 20alopecia 21and behavioral aspects Effects on prostate tissue as the most prominent androgen-sensitive organ have also Prostatavolumen von 25 cm reported: studies stratifying for lifestyle factors and multidimensional matching of controls in a sufficient number of subjects show an increased risk Prostatavolumen von 25 cm prostate cancer 923 — 26 as well as benign prostate hyperplasia in patients with lower numbers of CAG n, hence increased androgenicity 27e.
Extending these findings to pharmacogenetic considerations, an influence of the CAG n polymorphism on efficacy of hormonal male contraception was recently reported in 85 healthy men, showing better inhibition of spermatogenesis in Prostatavolumen von 25 cm with longer triplet residues in the subgroup of those subjects with not fully suppressed gonadotropin secretion An earlier study of 75 Prostatavolumen von 25 cm in contraceptive trials without such a subgroup classification could not Prostatavolumen von 25 cm such results The above-mentioned modulations of androgen activity by the CAG n polymorphism were observed in eugonadal men.
It can be speculated that the sudden exposure to androgens on initiation of substitution therapy in hypogonadal men, which is often accompanied by impressive changes in androgen-sensitive tissues, is modulated to an even larger degree by the AR CAG n polymorphism. We addressed Prostatavolumen von 25 cm question in the first pharmacogenetic study on androgen substitution in hypogonadal men by using a longitudinal design.
One hundred thirty-one untreated hypogonadal men aged 19—69 yr Table 1 presenting for examination and possible treatment of hypogonadism-related symptoms lasting for at least 2 yr were included in this retrospective analysis. Previous androgen treatment as well as diabetes mellitus, arterial hypertension, dyslipoproteinemia, medication of any kind, or drug abuse led to exclusion of patients. Patients gave written informed consent to the investigations. Data are mean and sdfor the AR polymorphism and also range.
BMI, Body mass index. There is evidence that this clinical entity often evolves with advancing age A current pituitary tumor was excluded by magnetic resonance imaging scans in those patients with subnormal gonadotropin levels or a blunted response to a GnRH challenge. Especially in patients with secondary hypogonadism, other endocrine axes were regularly assessed. Subjects substituted with GH were not included. Because this length Prostatavolumen von 25 cm out of the normal range 9—37, see above and was distinct from the distribution of the other patients see Table 1his data were not included in the analysis but are reported separately.
The yr-old patient was diagnosed with idiopathic hypogonadotropic hypogonadism LH and FSH levels below normal with 0. Because of suspicion of Kennedy disease, the patient was referred to the neurological department. Although the diagnosis of spinobulbar muscular atrophy could not be confirmed by electromyography, the patient showed distinct features of the disease such as muscle cramps after physical exertion as well as gynecomastia and tongue fasciculations after prolonged speech.
According to current knowledge, onset of the disease at a later time point in life is probable for this patient The patient was treated with two weekly injections of T enanthate and demonstrated a weak improvement of androgen-dependent parameters.
Reliable continuity of treatment was documented by regular visits including assessment of T levels indicating effective therapy. Treatment modalities included T Prostatavolumen von 25 cm mg 2—3 wk im, scrotal T patches, oral T undecanoate at least two to four capsules per day with meals ; patients with secondary hypogonadism desiring paternity received combined treatment of sc injections of human menopausal gonadotropin three times per week and human chorionic gonadotropin hCG two times per week.
Table 2 details distribution of treatment modalities among patients. Timepoint: 1 baseline values; 2 reassessment under therapy. All blood sampling was performed between and h. To test for effective T substitution, samples from patients being treated with im-injected T enanthate Prostatavolumen von 25 cm obtained at time points indicating individual average levels, preferentially in the second week after injection Patients treated with the transdermal scrotal T system or oral T undecanoate were sampled 2—5 h after administration of the patch or capsules.
Serum from those men treated with hCG was obtained 2—3 d after the last sc injection. Sampling was performed before prostate palpation and transrectal ultrasonography. Analysis of the AR gene microsatellite residues was performed as previously published In the Klinefelter patients, two X chromosomes were present patients with more than two X chromosomes were not included ; hence, two alleles of the AR gene were found.
In case of different CAG n alleles 22 of 40 patientsthe mean Prostatavolumen von 25 cm calculated and used for further analysis because, without biopsy, it could not Prostatavolumen von 25 cm determined whether inactivation of X chromosomes was skewed in the prostate tissue.
A high-resolution transrectal ultrasonography probe 7. Contact gel was used inside and outside a sterile latex sheath, and patients were examined while lying on the left side with knees drawn upward.
Accuracy of the method was determined by two investigators in 19 healthy men with reassessment of prostate size after 8 wk. Prostate volume in these men ranged from All variables were checked for normal distribution by the Kolmogorov-Smirnov one-sample test for goodness of fit.
In case of PSA levels, analysis was performed on logarithmically transformed data. Data were analyzed using a cross-sectional and longitudinal approach. The cross-sectional approach demonstrates differences among subjects, and parameters modulating treatment effects in individuals inner-patient contrasts can be detected only by longitudinal methods.
Thus, predictors of baseline and final prostate volume were subjected to analysis of covariance ANCOVA using parameters mentioned in Table 3 for the cross-sectional approach, and, similarly, ANCOVA for repeated measurements was calculated for the longitudinal analysis Table 4. Prostate growth per year was slightly, but nonsignificantly, dependent on the duration of treatment with higher values in shorter treatment periods.
This suggests that prostate growth could be more pronounced shortly after initiation of therapy in comparison with longer-term treatment. Accordingly, growth per year was corrected for this slight, nonsignificant linear association with duration of treatment. Growth per year was calculated on the basis of treatment days. P values and the direction of influence are given.
NS, Not significant; no entry, not included in this Prostatavolumen von 25 cm of analysis. Treatment with hCG or oral T undecanoate resulted in a nonsignificant trend to lower prostate growth per year. Which parameter influences effects of T substitution on final prostate size in individual patients inner-patient contrasts? NS, Not significant. The overall significance of ORs was calculated Prostatavolumen von 25 cm asymptotic significance according to Mantel-Haenszel; homogeneity of subgroups was tested Prostatavolumen von 25 cm to Breslow-Day.
Significance levels of respective differences in distribution are calculated according to Fisher. ORs Prostatavolumen von 25 cm given for the probability to have a prostate size of at least 30 ml under T substitution comparing men with less than 20 CAG repeats to those with longer residues.
Anthropometric data and length of CAG n were similar in men with primary and secondary hypogonadism Table 1. In addition, no such differences were observable among the groups receiving different treatment modalities. Time between start of therapy and final investigation was homogenous among the respective subgroups as well as the significant increase of T levels from the clearly hypogonadal into the midnormal range Table 2.
The volume of the prostate gland increased significantly during treatment, an observation that was Prostatavolumen von 25 cm among subgroups concerning diagnosis or treatment modality Table 2.
Data from the patient with 38 triplets, which were not included in the statistical evaluation, are shown in parentheses. Further analysis by ANCOVA included influences of age and initial prostate volume as well as duration of treatment and T levels achieved by treatment because these parameters also had an effect on outcome Table 3. Advanced age contributed to prostate growth as well as higher T levels Prostatavolumen von 25 cm 3. A larger initial prostate size resulted in slower Prostatavolumen von 25 cm, although the total size under therapy was larger Prostatavolumen von 25 cm these patients Table 3.
A trend to lower speed of organ growth was observed in patients being treated with hCG or oral testosterone undecanoate vs. ANCOVA for repeated measurements revealed parameters exerting significant influence on individual therapy inner-patient contrasts : The effects of T substitution on final prostate size were Prostatavolumen von 25 cm by longer CAG n, but advanced age, baseline prostate volume, and duration of therapy had an enhancing effect Table 4.
This is in good agreement Prostatavolumen von 25 cm the cross-sectional results Table 3. The groups were then analyzed for the presence of a prostate size of 30 ml or more under treatment. No difference was seen between groups 2 and 3; hence, these were combined to increase power for the calculation of ORs between group 1 and the others. It could be shown that the chance to develop a large prostate under T substitution was, on average, 8 times higher for the group with CAG n less than This effect was age dependent and more pronounced in men older than Prostatavolumen von 25 cm yr Table 5.
Small prostate size and poor growth are in agreement with the results mentioned above. These first pharmacogenetic data on androgen substitution in hypogonadal men demonstrate an impressive modulation of the effects on prostate size and growth by the CAG n polymorphism of the AR gene.
Men with shorter triplet residues exhibit a more pronounced effect of T on speed of prostate growth as well as total organ size. It has been demonstrated previously that T administration to hypogonadal men increases prostate volume, but marked differences among patients were noted Prostatavolumen von 25 cm — 7.
The average growth of the prostate under T substitution see Table 2 reported here is in good agreement with previous results. Data on the influence of age and T levels on prostate size in hypogonadal men 17 are confirmed by the cross-sectional analysis of baseline values. The possible relation between benign hyperplasia of the prostate BPH and the CAG n polymorphism of the AR gene has previously been addressed by cross-sectional studies in eugonadal men.
The overgrowth of the tissue of the transition zone and periurethral area of the prostate is the pathophysiological correlate of BPH and can be histologically described as epithelial and fibromuscular hyperplasia Androgens modulate this process by binding to the AR under the conditions the prostate cell provides in terms of specific coactivators Binding Prostatavolumen von 25 cm these coactivators is modulated by the length of CAG n, which is the underlying mechanism suspected to influence the repeat polymorphism concerning transcriptional activity of target genes The putative influence of the CAG n polymorphism on prostate size in eugonadal men has been investigated by several groups in cross-sectional approaches.