Purpose. Prostate cancer that recurs during androgen deprivation therapy is referred to as androgen-independent. High levels of expression of androgen receptor and androgen receptor-regulated genes in recurrent prostate cancer suggest a role for androgen receptor and its ligands in prostate cancer recurrence.Experimental Design. Recurrent prostate cancer specimens from 22 men whose prostate cancer recurred locally during androgen deprivation therapy and benign prostate specimens from 48 men who had received no prior treatment were studied. Androgen receptor expression was measured using monoclonal antibody and automated digital video image analysis. Tissue androgens were measured using radioimmunoassay.Results. Epithelial nuclei androgen receptor immunostaining in recurrent prostate cancer (mean optical density, 0.284 ؎ SD 0.115 and percentage positive nuclei, 83.7 ؎ 11.6) was similar to benign prostate (mean optical density, 0.315 ؎ 0.044 and percentage positive nuclei, 77.3 ؎ 13.0). Tissue levels of testosterone were similar in recurrent prostate cancer (2.78 ؎ 2.34 pmol/g tissue) and benign prostate (3.26 ؎ 2.66 pmol/g tissue). Tissue levels of dihydrotestosterone, dehydroepiandrosterone, and androstenedione were lower (Wilcoxon, P ‫؍‬ 0.0000068, 0.00093, and 0.0089, respectively) in recurrent prostate cancer than in benign prostate, and mean dihydrotestosterone levels, although reduced, remained 1.45 nM. Androgen receptor activation in recurrent prostate cancer was suggested by the androgenregulated gene product, prostate-specific antigen, at 8.80 ؎ 10.80 nmol/g tissue.Conclusions. Testosterone and dihydrotestosterone occur in recurrent prostate cancer tissue at levels sufficient to activate androgen receptor. Novel therapies for recurrent prostate cancer should target androgen receptor directly and prevent the formation of androgens within prostate cancer tissue.

SUMMARY Two brothers are described with athyroidal hypothyroidism, spiky hair, choanal atresia, cleft palate, and bifid epiglottis. Polyhydramnios was present in the third trimester of each pregnancy. These abnormalities appear to represent a new syndrome. Case reportsThe brothers are the offspring of healthy, nonconsanguineous, Caucasian parents. The ages of the mother and father were 23 and 27 years respectively at the birth of their first infant. The family history is unremarkable.The first pregnancy proceeded until the third trimester when mild polyhydramnios was noted. Labour started spontaneously at 39 weeks' gestation and the infant was delivered by emergency caesarean section for fetal distress. Apgar scores were 7 and 9 at one and five minutes after delivery.The infant suffered repeated episodes of apparent airway obstruction. Shortly after birth, examination of the airways showed a palatal cleft extending to the posterior one-third of the hard palate. At the posterior edge of the defect the oropharynx had fused with the roof of the nasopharynx, completely obliterating the choanae. The epiglottis was hypoplastic and bifid but the larynx was of normal diameter. The jaw was retrognathic. Scalp hair was sparse and spiky. Neuromuscular tone was increased.The neonatal period was complicated by repeated apnoeic episodes which frequently followed feeds and were associated with opacities on the chest radiograph. Aspiration pneumonitis was considered §Present address: Clinical Genetics Unit, University of British Columbia, 4490Oak Street, Vancouver, BC V6H 3V5, Canada.Received for publication 13 August 1986. Revised version accepted for publication 8 March 1988. to be the most likely cause, although this was not substantiated radiologically.The choanae were repaired at six weeks of age and the cleft palate at 18 months; both operations were uneventful.The infant had been transferred from an area whicia was not served by the regional congenital hypothyroid screening programme at the time of birth. When this was appreciated at three months of age, screening was performed. The initial result showed a high TSH. A further serum sample was taken; the serum TSH was 181 IU/l (normal <5) and the free T4 concentration was 5 pmol/l (normal 60 to 150). No thyroid uptake was noted on I123 scan.At the age of three years the infant was functioning developmentally at a two year level. Delay was most marked in the cognitive and language fields. Physical growth has been normal. Hair growth has been slow and it was not until 18 months of age that sufficient hair had grown to cover the scalp. He had only required one hair cut in his life. Nail growth and teeth are normal. Sweating is normal and dermal ridge sweat pore count is normal.1The second infant was born two years after the first infant. Polyhydramnios was again present in the third trimester and emergency caesarean section was required for fetal distress. The Apgar scores were 6 and 9 at one and five minutes. Obstructed respiration was immediately observed and examinatio...

Transgenic mice carrying rat androgen-binding protein (ABP) genomic DNA express high amounts of testicular ABP and develop a progressive impairment of spermatogenesis. To understand the mechanism of these changes, we have studied the pattern of testicular germ cell proliferation from 7 to 360 days of age in wild-type (WT) control and transgenic homozygous (ABP-TG) mice by flow cytometry after labeling DNA in isolated germ cells with propidium iodide. At all ages studied, the body weight of the ABP-TG mice was lower than that of age-matched WT controls. Significantly reduced testicular weight and total germ cell number in the ABP-TG mice were evident from Day 30 and Day 60, respectively. Flow cytometric analysis of isolated germ cells revealed that the number of germ cells undergoing proliferation (S-phase cells) was identical in WT control and ABP-TG mice up to Day 14. Subsequently, the number of germ cells in S-phase was consistently higher in ABP-TG than in WT mice. The number of primary spermatocytes was significantly increased starting from Day 60, and the numbers of round and elongated spermatids were significantly reduced in the ABP-TG animals from Day 21 and Day 60 onwards, respectively. Immunocytometry for intracellular ABP at 90 days of age revealed that the percentage of ABP-containing germ cells was greater in ABP-TG than in WT mice. The continuous presence of ABP in mouse seminiferous tubules at greater than physiological concentrations facilitates the formation of primary spermatocytes but impairs subsequent transformation to round and elongated spermatids. Based on our observations and the analysis of the available literature, the most likely mechanism for production of these effects is sustained reduction in the bioavailability of androgens.

Tissue levels of testosterone and DHT did not differ by race. However, black men had higher tissue ASD and SHBG than white men. Higher tissue ASD did not result in a greater conversion of ASD to testosterone in the prostate of black men. Higher tissue SHBG may activate the androgen receptor through cyclic adenosine monophosphate dependent pathways.