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PubMed1988

Influence of androgenic status on the alpha 2/beta-adrenergic control of lipolysis in white fat cells: predominant alpha 2-antilipolytic response in testosterone-treated-castrated hamsters.

The aim of this study was to evaluate the influence of castration with or without testosterone propionate (TP) administration (one daily injection of 1 mg for 10 days) on the fat cell lipolytic activity in male hamsters. Basal and maximal lipolytic responses to the pure beta-adrenergic agonist isoproterenol, the mixed alpha 2-and beta-adrenergic agonist epinephrine, and the nonadrenergic compounds ACTH and 3-isobutyl-1-methylxanthine were all reduced by half in castrated animals. TP treatment restored these defective responses to control values, except the response to epinephrine which remained paradoxically unchanged. Sensitivity of lipolysis to epinephrine was unimpaired by castration but markedly reduced (10-fold) in TP-treated castrated hamsters. The antilipolytic potencies of the alpha 2-component of epinephrine and of the two alpha 2-agonists, UK 14304 and clonidine, were reduced by half in castrated animals, and returned to a value slightly higher than control after TP treatment. These changes in lipolysis were accompanied by parallel alterations in the stimulated cAMP responses to isoproterenol and forskolin but not to epinephrine. The latter was either unimpaired by castration or was clearly inhibited after TP treatment. Castration also induced a 2-fold decrease in the inhibitory potency of clonidine toward forskolin-stimulated cAMP production. Finally, these changes in the potency of clonidine were accompanied by parallel variations of the number of fat cell alpha 2-adrenoreceptors. These results indicate that testosterone in vivo, while increasing the beta-adrenergic lipolytic action of catecholamines (possibly through enhancement of the adenylate cyclase activity), promotes, to a greater extent, their alpha 2-adrenoreceptor-mediated antilipolytic potency. By providing the first demonstration that the androgenic status controls the functional alpha 2/beta-adrenergic balance in fat cells, this study also emphasizes the potential importance of such a control in the mechanisms underlying the sex-related differences in adipose tissue regional distribution and fat cell size.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Effect of passive immunization to gonadotropin-releasing hormone (GnRH) using GnRH antiserum on the mitotic activity of gonadotrophs in castrated male rats.

In order to reveal the mechanism of elevation in the mitotic activity of gonadotrophs in the pituitary gland of castrated rats, passive immunization to GnRH designed to block the activity of GnRH in castrates was performed, and changes in the mitotic activity of pituitary gonadotrophs and mammotrophs were studied. The increased serum levels of gonadotropins and their subunits in castrates were dramatically suppressed by the administration of rabbit anti-GnRH serum (RAGnRH). However, this treatment had no effect on the serum levels of PRL, suggesting that the passive immunization to GnRH used in this study was only effective in blocking the hormonal activity of GnRH to the gonadotropin secretion. Mitosis of the gonadotrophs in normal rat anterior pituitary was rarely observed, but it was dramatically increased by castration. This elevated mitotic activity of gonadotrophs in the castrated rats was significantly suppressed by the administration of RAGnRH. On the other hand, mitotic activity of mammotrophs was decreased by castration. This diminution in the mitotic activity of mammotrophs was not changed by administration of RAGnRH. These results showed that GnRH is an important factor for stimulation of gonadotroph cell proliferation in castrated rats.

Animals↗
PubMed1988

In vivo neurotransmitter levels in the anterior pituitary of freely behaving intact and castrated male rats determined with push-pull perfusion and high pressure liquid chromatography coupled with electrochemical detection.

Push-pull cannulae were implanted into the anterior pituitary lobes of intact and castrated male rats, and perfusate samples were assayed for neurotransmitter concentrations with HPLC coupled with electrochemical detection. Epinephrine, which was not obtained in any of the five intact males, was detectable in three of five castrated male rats. Norepinephrine rose from nondetectable to high levels after castration in all animals. In contrast to dopamine, which was significantly decreased in castrated males, levels of 3,4-dihydrophenylacetic acid and 5-hydroxyindolacetic acid were significantly increased in castrated vs. intact male rats. Homovanillic acid was rarely detected in either intact or castrated males. These results demonstrate that the push-pull perfusion technique can be used to measure neurotransmitter levels in the anterior pituitary lobes of living rats. More importantly, after castration a distinct rise in norepinephrine and epinephrine accompanied by a decrease in dopamine was clearly detected, suggesting that these neurotransmitters may play an important role directly at the pituitary.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Urokinase-type plasminogen activator is increased in the involuting ventral prostate of castrated rats.

We have investigated the content of plasminogen activators in the rat ventral prostate during castration. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and zymography demonstrated two major Mr-forms of plasminogen activators that were found to be strongly increased by castration; inclusion of quenching antibodies in the zymography and immunoblotting analysis identified these as urokinase-type plasminogen activator (u-PA) and its Mr 30,000 degradation product, respectively. A third, less abundant form, which was identified as tissue-type plasminogen activator, was also increased by castration. The induction of the plasminogen activators was prevented by treating the rats with 5 alpha-dihydrotestosterone. The increase in u-PA antigen was quantitated by the use of enzyme-linked immunosorbent assay. The increases in u-PA activity and antigen were traced back to a corresponding increase in u-PA messenger RNA (mRNA). By immunohistochemical methods, the u-PA was found to be present in scattered single cells at the surface of the epithelium facing the lumen of the glandular ducts. Such cells were present in control as well as in castrated rats, but their number increased after castration. In addition, after castration, u-PA immunoreactivity appeared in cells throughout the epithelium. These results suggest a role for plasminogen activation in castration-induced involution of the rat ventral prostate, and a role in the normal turnover of the rat ventral prostate epithelium.

Animals↗
PubMed1994

Induction of immature thymocyte proliferation after castration of normal male mice.

The physiological basis and immunological significance of thymic enlargement in castrate male animals is not known. We used normal male C57 Bl/6 mice to examine the contribution of in situ thymocyte proliferation to castration-induced enlargement of the thymus. Animals castrated at 8-10 weeks of age were compared to normal intact males. Thymocytes were examined 4-120 days after castration using flow cytometry to determine DNA content and thus the number of cells in active phases of the cell cycle. These properties were examined in unseparated thymocytes and in phenotypic subpopulations defined by expression of CD3, CD4, and CD8. For thymocytes obtained from intact control glands, a mean of 11.0 +/- 1.0% were in active phases of the cell cycle. The percentage of cycling thymocytes was increased to a mean of 22.5 +/- 1.9% in the week after castration (P < 0.001). This change occurred in the absence of significant thymic enlargement. At 8-10 days after castration, thymic weight increased abruptly to a new steady state which was double that of intact controls (78.0 +/- 4.1 vs. 39.1 +/- 2.6 mg; P < 0.001). In these enlarged glands, only 9.9 +/- 0.8% of cells were cycling, which was not significantly different than controls (P > 0.3). Proliferating cells identified in fixed thymus tissue sections after in vivo administration of bromodeoxyuridine were located in the subcapsular cortex and medulla. Analyses of thymocyte subpopulations indicated that most cycling cells had immature phenotypes (CD4+CD8+, CD4-CD8+, and CD3lo or CD3-). Castrate glands studied in the steady state period 8-120 days after surgery contained significantly fewer CD3+ cells than intact controls (P < or = 0.045). The findings suggest an intrathymic role for androgens in affecting generation of the mature T cell repertoire.

Animals↗
PubMed1995

Lobe-specific apoptotic cell death in rat prostate after androgen ablation by castration.

It is well established that androgens are central to regulation of the growth of the mammalian prostate gland. Conversely, androgen deprivation by castration induces rapid cell death in the ventral prostate via an apoptotic mechanism. To date, most studies of cell death in the rodent prostate have focused on the ventral lobe, with little attention directed to the dorsal and lateral lobes. The results presented herein demonstrate that cell death in the rat prostate gland caused by castration is lobe specific. In particular, castration caused decreases in wet weights and protein contents of all three prostatic lobes, but these events were more rapid and profound in the ventral than in the dorsal and lateral lobes. Reduced epithelial cell size was apparent in the three lobes as well. However, castration resulted in loss of DNA content in the ventral lobe only. To confirm this finding, and to examine apoptosis of individual cells, we used in situ labeling of fragmented DNA, supported by biochemical analysis of DNA integrity in agarose gels. With both approaches, significant cell death in response to castration was seen in the ventral lobe but not the dorsal and lateral lobes. Taken together, these results clearly indicate that there are lobe-specific differences in the response of the rat prostate to androgen ablation by castration, with apoptotic cell death occurring in the ventral lobe of the prostate but to a far lesser extent, if at all, in the dorsal and lateral lobes. Moreover, castration caused apoptotic death of both epithelial and stromal cells of the ventral prostate, with these cells dying throughout the ductal network of the ventral prostate rather than being restricted to a particular region. We suggest that lobe-specific differences in androgen responsiveness in the rat prostate may provide an appropriate model for the study of androgen-independent prostatic cell survival during tumor progression.

Animals↗
PubMed1999

Effects of castration and androgen replacement on erectile function in a rabbit model.

We investigated, in a rabbit model, the effects of castration and testosterone replacement on: 1) the hemodynamics of the corpus cavernosum; 2) alpha-1 adrenergic receptor protein expression; 3) neural NO synthase protein expression and activity; 4) phosphodiesterase type 5 activity; and 5) trabecular smooth muscle/connective tissue balance. One week after bilateral orchiectomy, animals were treated for 7 days with vehicle alone, testosterone, or estradiol. Intact control animals received vehicle only. Systemic arterial blood and intracavernosal pressures (ICP) were measured in each animal before and after electrical stimulation of the cavernosal nerve. Alpha1-adrenergic receptor protein expression was determined by ligand binding studies. NO synthase expression and activity were determined by Western blot analyses and conversion of L-arginine to citrulline, respectively. Phosphodiesterase type 5 activity was determined by hydrolysis of guanosine 3',5'-cyclic monophosphate (cGMP) in tissue extracts in the absence or presence of 100 nM sildenafil. Smooth muscle content was assessed by Masson's trichrome staining and computer-assisted histomorphometry. Castration significantly reduced ICP, but it did not alter systemic arterial blood pressure during stimulation of the cavernosal nerve. Testosterone, but not estradiol, treatment prevented the effects of castration and restored ICP to values similar to those obtained in intact animals. Castration reduced expression of alpha1-adrenergic receptor, and this reduction was prevented or reversed by testosterone replacement. Neural NO synthase protein expression and total activity were not altered significantly by castration or after testosterone replacement. However, phosphodiesterase type 5 activity increased in castrated animals treated with testosterone. Castration significantly reduced trabecular smooth muscle content, and this reduction was restored by testosterone (but not estradiol) treatment. The results of this study demonstrate that androgen deprivation alters the functional responses and structure of erectile tissue.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1986

Levels of plasma steroid glucuronides in intact and castrated men with prostatic cancer.

The levels of plasma dehydroepiandrosterone (DHEA), androst-5-ene-3 beta,17 beta-diol (delta 5-diol), testosterone (T), dihydrostestosterone (DHT), androstane-3 alpha,17 beta-diol (3 alpha-diol), androsterone (ADT), and the related glucuronide (G) derivatives were determined in intact and castrated men with prostatic cancer. The plasma concentrations of DHEA and DHEA-G were not significantly different in intact and castrated men while delta 5-diol as well as delta 5-diol-G were 50% lowered in castrated men. As expected, T and DHT concentrations were markedly lower in castrated men. These low plasma levels of T and DHT were accompanied by a decrease of 3 alpha-diol, ADT, T-G, 3 alpha-diol-G, and ADT-G levels. There was, in unoperated men, a positive correlation between the levels of DHEA and ADT-G as well as DHEA and DHEA-G, while T values were highly correlated with ADT-G and 3 alpha-diol-G levels. Furthermore, a significant relationship was found between DHEA and ADT-G as well as 3 alpha-diol-G in castrated men. Our data clearly demonstrate that ADT-G and 3 alpha-diol-G levels are more affected by castration than are the corresponding unconjugated steroids and suggest that these steroid glucuronides should be good markers of androgen metabolism. Moreover, the significant relationship between DHEA, ADT-G, and 3 alpha-diol-G in castrated men also suggests that approximately 30% of C-19 steroids from the adrenals are converted to T and DHT, which are further transformed into steroid glucuronides.

Aged↗
PubMed1991

Differential effect of 5 alpha-reductase inhibition and castration on androgen-regulated gene expression in rat prostate.

Castration reduces prostate size and causes intraprostatic testosterone (T) and dihydrotestosterone (DHT) to fall to very low levels. 5 alpha-Reductase inhibition also reduces prostate size, but results in a marked increase in intraprostatic T levels. To compare the effects of 5 alpha-reductase inhibition and castration on prostate physiology, male Sprague-Dawley rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride for up to 9 days. To be sure that finasteride itself did not directly affect gene expression, an additional group of rats was castrated and given finasteride for 4 days. The prostates were weighed, intraprostatic RNA, DNA, and androgen levels were measured, and mRNAs for two androgen-regulated genes, prostate steroid-binding protein (PSBP; an androgen-induced gene) and testosterone-repressed prostate message (TRPM-2), were quantitated by Northern and slot blot analyses. Finasteride caused a 95% reduction in intraprostatic DHT levels and a 10-fold increase in intraprostatic T levels. Finasteride, as expected, caused a pronounced decrease in prostate weight (45% on day 4). DNA content fell correspondingly (48% on day 4). Intraprostatic DNA (micrograms of DNA per gland) on day 4 was 328 +/- 53 in control rats, 171 +/- 10 in finasteride-treated rats (P less than 0.001 compared to controls), 115 +/- 2 in castrated rats (P less than 0.05 compared to finasteride), and 107 +/- 43 in finasteride-treated plus castrated rats (P = NS compared to castration alone). There were no significant differences in DNA levels among the groups when expressed per mg prostate tissue, indicating that mean prostate cell size was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

5-alpha Reductase Inhibitors↗
PubMed1991

Isolation and characterization of cDNA clones for castration-induced mRNAs in the rat ventral prostate.

To identify gene products involved in castration-induced involution of the rat ventral prostate, we constructed a subtraction cDNA library of the ventral prostate from rats castrated for 48 h. The library was screened with subtracted cDNA probes enriched for sequences with a low copy number expressed in intact or castrated rats. As a result of differential screening, 48 cDNA clones representing 10 different induced mRNAs were isolated. The time course of these mRNA inductions after castration was examined. Within the first 24 h after castration, the level of mRNAs for these cDNA clones was significantly increased and it reached its peak by 48-72 h after castration. Although mRNAs for these cDNA clones were expressed in various tissues from intact rats, an increase in mRNA as a response to castration was observed only in the ventral prostate. Partial sequence analyses of the 10 cDNA clones indicate that three cDNA clones represent rat glutathione S-transferase Yb-1, Yb-2 and Yb-3 subunit mRNA sequences, but for others respective homologues could not be found in a search of the GenBank database (release 67).

Animals↗
PubMed1989

Effect of castration on epididymal sperm storage in male musk shrews (Suncus murinus) and mice (Mus musculus).

Reproductively mature male musk shrews and mice were bilaterally castrated. Epididymal sperm numbers and motility were assessed 0, 2, 4 and 6 weeks after surgery. Seminal vesicle weights and plasma concentrations of total androgens were also measured. In male musk shrews, 30% of the original epididymal sperm numbers were still present 2 weeks after castration and motile spermatozoa were present in 2 of 7 individuals. By 4 and 6 weeks after castration the numbers of spermatozoa remaining declined to about 10% and no sperm motility was noted. Seminal vesicle weights were maintained at about 30% of their original size even up to 6 weeks after castration. In male mice, epididymal sperm numbers, seminal vesicle weights, and androgen levels declined more dramatically after castration. Although androgen concentrations in gonadally intact male musk shrews were approximately 50% of the values in male mice, after castration the concentrations in musk shrews were approximately 2-fold higher than in mice at all times. The results suggest that post-castration retention of epididymal sperm and seminal vesicle weights in the male musk shrew as compared with male mice, is facilitated either by a relatively greater adrenal contribution to circulating androgen levels and/or greater target tissue sensitivity.

Androgens↗
PubMed1993

Differential effects of adrenalectomy on the prolactin-induced suppression of LH and FSH secretion after castration in male rats.

Hyperprolactinaemia inhibits gonadotrophin secretion in males and females of many species. The aim of this study was to determine the role of the adrenal gland in mediating the inhibitory effects of prolactin by contrasting the effects of acute hyperprolactinaemia on LH and FSH secretion in adrenal-intact and adrenalectomized rats with and without physiological corticosterone replacement. Adult male rats were administered purified ovine prolactin every 12 h (2.4 mg per injection s.c.) beginning at the time of castration. Blood samples were collected every 3 h for 36 h, then every 12 h until 10 days after castration. Ovine prolactin significantly reduced LH secretion in all groups from approximately 15 to 48 h after castration. In contrast, plasma FSH concentrations were reduced by ovine prolactin from 21 to 48 h only in the adrenal-intact rats and not in the adrenalectomized or adrenalectomized plus corticosterone groups. In all groups, ovine prolactin inhibited endogenous prolactin secretion in rats by short-loop autofeedback as soon as 3 h after the first ovine prolactin injection and throughout the 10 days of the study. Adrenalectomy per se, with or without corticosterone replacement, also had a differential effect on LH and FSH secretion after castration, causing only a transient delay in the rise in LH after castration, but inducing a significant and long-lasting inhibition of FSH secretion. The results demonstrate that ovine prolactin-induced suppression of LH secretion after castration occurs with or without the adrenal glands. Suppression of FSH secretion after castration by ovine prolactin, however, may involve an adrenal component.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1992

Changes of autonomic receptors following castration and estrogen administration in the male rabbit urethral smooth muscle.

Effects of castration and estrogen administration on the distribution of autonomic receptors in the male rabbit urethral smooth muscle were examined. Thirty-eight mature Japanese white rabbits were used. Eight rabbits were used as untreated control. The other 30 rabbits were castrated and 10 of them were administered intramuscularly with 5 mg/kg estrogen 3 times a week for 4 weeks from 12 weeks after castration. Autonomic receptor densities in the urethral smooth muscle were measured by radioligand binding techniques. alpha 1-Adrenergic and muscarinic cholinergic receptor densities decreased significantly after castration and were not affected by estrogen administration. alpha 2-Adrenergic receptor density increased slightly after castration and markedly after estrogen administration. beta-Adrenergic receptors were not affected either by castration or estrogen administration. No significant changes were observed in any receptor affinities. These results demonstrate the effects of castration and estrogen administration on the autonomic receptors in the male rabbit urethral smooth muscle.

Animals↗
PubMed2000

Effects of castration and testosterone replacement on peritoneal histamine concentration and lung histamine concentration in pubertal male rats.

Mast cells, which are the main source of histamine, are significantly affected by sex steroids. The present study was undertaken to determine the effects of bilateral castration and testosterone replacement on peritoneal histamine concentration and lung histamine concentration in pubertal male rats (Wistar strain). Three groups of animals were used in this study: (1) untreated castrated animals, (2) castrated animals subjected to androgen replacement by injection of propionate of testosterone, and (3) intact males as a control group. Castration alone produced a dramatic reduction in peritoneal histamine concentration. In addition, androgen replacement was effective in restoring the histamine concentration to the normal value detected in the control males (P<0.05, Kruskal-Wallis test). On the other hand, there was no significant variation in the lung histamine concentration between control males, untreated castrated males and castrated males that received androgen replacement (P<0.05, Kruskal-Wallis test). These results demonstrate for the first time that castration markedly reduces the peritoneum histamine concentration in pubertal male rats, and testosterone replacement prevents the decrease. Further, these procedures do not affect lung histamine concentration, demonstrating that mast cells from different tissues may respond differently to the same biological factors.

Animals↗
PubMed1995

Plasma cortisol and white blood cell responses in different breeds of bulls: a comparison of two methods of castration.

To determine plasma cortisol and white blood cell response to castration, Angus (n = 12, 21.4 mo of age), Hereford (n = 6, 21.2 mo of age), and Brahman (n = 24, 20.3 mo of age) bulls nearing maturity were either left intact as uncastrated controls (CON), surgically castrated (SUR) after lidocaine, or castrated by latex rubber banding (BAN). Before and through 35 d after castration (castration = d 0), animals were weighed and blood samples were collected for analysis of cortisol and total white blood cell (WBC) count at 2-, 3-, or 7-d intervals. There was a treatment x breed interaction for ADG from d 0 to 7 (P < .05). From d 0 to 14, 0 to 21, 0 to 28, and 0 to 35, ADG tended to be lower for SUR and BAN animals than for CON animals (castrated vs CON, P < or = .13). No significant differences in ADG were observed between SUR and BAN animals during these times. On d 0, from just before treatment to just after treatment, plasma cortisol concentration increased 3.2 ng/mL for SUR and .1 ng/mL for BAN (SEM = +/- .5 ng/mL; SUR vs BAN, P < .03). From d 0 pretreatment to d 2 after treatment, plasma cortisol concentration increased 1.5 ng/mL for castrated (SUR = 2.0 and BAN = 1.1 ng/mL) and decreased 1.6 ng/mL for CON (SEM = +/- .7 ng/mL; P < .04). Plasma cortisol concentration was negatively correlated (P < .001) with BW (r = -.17) and BW change (r = -.19).(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Local↗
PubMed1988

Effects of gender, time of castration, genotype and feeding regimen on lamb growth and carcass fatness.

Two concurrent trials were conducted to examine the effects of gender, time of castration, genotype and feeding regimen on lamb growth rate and carcass fatness. Trial 1 compared Polypay and Coopworth x Polypay male lambs either left intact or castrated early, mid or late in growth. Trial 2 compared Hampshire-sired lambs (females, early castrate wethers and late castrate wethers) from Suffolk x Coopworth dams and whiteface x Coopworth dams. Gender and time of castration significantly affected growth rate in Trial 1 but not in Trial 2. Rams were more efficient than wethers, but no other gender or time of castration effects on feed efficiency were observed. Delaying castration and pasture grazing both reduced fatness. Lambs grazed on irrigated pastures until they weighed 41 kg then finished in drylot had a lower dressing percentage than lambs fed in the drylot throughout, but USDA quality grades were similar. Substitution of Polypay genes by Coopworth genes in crossbred lambs did not significantly alter any of the fatness traits measured but increased ribeye area. Hampshire-sired lambs grew faster than whiteface lambs, particularly in drylot. They had a higher dressing percentage without increased fatness, apparently because of greater muscling in ribeye and leg.

Adipose Tissue↗
PubMed1986

Bone changes after castration in rats. A model for osteoporosis.

Bone changes 6-12 weeks after castration have been studied in 25 female and 27 male middle-aged rats. Castrated female rats gained more weight than their controls, but had decreased bone density and calcium and hydroxyproline content per cm3 bone volume of tibia. Castrated male rats did not differ from controls regarding body weight and the bone parameters. No influence of castration on the mechanical strength of the femora could be detected in either sex. At 2 weeks after castration, the circulating levels of immunoreactive calcitonin (iCT) were decreased in female rats compared to controls. In contrast, iCT was increased both in castrated male and female rats 10 weeks later. We conclude that castration of 6-month-old female rats causes osteoporosis, and therefore represents a promising experimental model for studying postmenopausal bone loss.

Animals↗
PubMed2006

Stem cells in prostate cancer: resolving the castrate-resistant conundrum and implications for hormonal therapy.

Androgen deprivation therapy (ADT) is initial systemic therapy for advanced prostate cancer and is used as an adjuvant to local therapy for high-risk disease, but responses in advanced disease are transient. Prostate cancer stem cells are a small fraction of tumor cells that give rise to malignant cells. Initial or acquired stem cell resistance to castration must therefore underlie castrate-resistant prostate cancer. We sought to review the evidence on cancer stem cells and androgen deprivation therapy to determine if prostate cancer stem cell resistance occurs from the outset, or if it is an acquired resistance. Prostate cancer stem cells do not express androgen receptor (AR) and hence should not be directly responsive to androgen deprivation therapy. However, castrate-resistant tumors that are derived from stem cells, have molecular changes such as amplification of the androgen receptor gene, or other genetic changes resulting in gain-of-function changes in AR, implying an acquired resistance to androgen deprivation. The origins of castrate-resistant tumors, with mechanisms such as androgen receptor gene amplification from androgen receptor negative prostate cancer stem cells, is an apparent conundrum. Insight into how this occurs may lead to new treatments that overcome or delay castrate-resistance. Herein, we review the evidence on cancer stem cells, the benefits of ADT, the biological basis of response to ADT, and mechanisms of castrate-resistance. We also explore the apparent conundrum of why AR-negative prostate cancer stem cells can give rise to castrate-resistant prostate cancer. We propose possible explanations that may resolve this conundrum and discuss implications for hormonal therapy.

Androgen Antagonists↗