Injection Of Androgen Research Articles

Impacts of synthetic androgen and estrogenic antagonist administration on growth performance, sex steroids hormones, and immune markers of male and female broilers

The influence of synthetic androgen and estrogenic antagonists (Tamoxifen) on body characteristics and immune response of male and female broilers and the correlation between sex hormone levels were estimated in our experiment. One day old chicks were sexed, and chicks of each sex were randomly distributed on three experimental treatments; the first treatment group (TAM20) chicks were supplied with estrogenic antagonist tamoxifen citrate 20 mg/kg body weight through oral administration for four times every other day from third until ninth d; Androgen treatment chicks were injected intramuscular with veterinary androgen AD GAN@ (Boldenone Undecylenate 50 mg) 1 cm/10 kg body weight at fifth and ninth day, and the third treatment was control. Androgen treatment reported the highest feed intake with the lowest for TAM20 treatment. Concerning carcass characteristics, early androgen injection increased breast percentage significantly compared to TAM20 treatment. Androgen supplementation increased significantly comb the percentage. However, TAM20 decreased it particularly compared to control. Moreover, the percentage of comb and shanks was substantially higher for males than females. Concerning the effects of both treatments on sex hormones, androgen showed favorable effects on testosterone and estrogen compared to Tamoxifen 20 treatment. On the other hand, the administration of TAM 20 improves phagocytic activity compared to androgen administration.

The Relationship Between Sex Hormones, Immune Response and Productive Performance of Broiler Chickens

Numerous researchers hypothesized that testosterone had a "double-edged sword" effect, encouraging the development of secondary sexual features which are thought to be a healthy signal, while also suppressing immunological function. The relationship between external appearance of birds and its immune performance was little approached. The relationship between sex hormones, immune response and productive performance of males and females broiler were evaluated in this work. One day old chicks were sexed and chicks of each sex were randomly distributed into three experimental treatments, 1. TAM20 treatment chicks were supplied with estrogenic antagonist tamoxifen citrate at a dose of 20mg/kg body weight through oral administration; 2. Androgen treatment chicks were injected intramuscularly with synthetic veterinary androgen (Boldenone Undecylenate 50mg) at a dose of 1cm/ 10kg body weight and 3. The control treatment. Tamoxifen and androgen supplementation had no significant effects on final body weight, weight gain, or feed conversion ratio (at 45 days), although the androgen treatment had the significantly highest feed intake and the TAM20 treatment had the lowest. Moreover, differences between males and females for final body weight, weight gain, feed intake and feed conversion ratio were not significant. Androgen injection increased breast percentage significantly compared to TAM20 treatment and numerically compared to control treatment. Also, Androgen supplementation increased significantly comb percentage; however TAM20 decreased it significantly compared to control. Concerning the effects of both treatments on level of sex hormones, androgen showed favorable effects on both testosterone and estrogen when compared to Tamoxifen 20 treatment. On the other hand, administration of TAM 20 improves phagocytic activity as compared to androgen administration. Phagocytic index, productive performance, and carcass traits did not substantially associated with either testosterone and or estrogen blood levels.

Mitochondria in Sex Hormone-Induced Disorder of Energy Metabolism in Males and Females.

Androgens have a complex role in the regulation of insulin sensitivity in the pathogenesis of type 2 diabetes. In male subjects, a reduction in androgens increases the risk for insulin resistance, which is improved by androgen injections. However, in female subjects with polycystic ovary syndrome (PCOS), androgen excess becomes a risk factor for insulin resistance. The exact mechanism underlying the complex activities of androgens remains unknown. In this review, a hormone synergy-based view is proposed for understanding this complexity. Mitochondrial overactivation by substrate influx is a mechanism of insulin resistance in obesity. This concept may apply to the androgen-induced insulin resistance in PCOS. Androgens and estrogens both exhibit activities in the induction of mitochondrial oxidative phosphorylation. The two hormones may synergize in mitochondria to induce overproduction of ATP. ATP surplus in the pancreatic β-cells and α-cells causes excess secretion of insulin and glucagon, respectively, leading to peripheral insulin resistance in the early phase of type 2 diabetes. In the skeletal muscle and liver, the ATP surplus contributes to insulin resistance through suppression of AMPK and activation of mTOR. Consistent ATP surplus leads to mitochondrial dysfunction as a consequence of mitophagy inhibition, which provides a potential mechanism for mitochondrial dysfunction in β-cells and brown adipocytes in PCOS. The hormone synergy-based view provides a basis for the overactivation and dysfunction of mitochondria in PCOS-associated type 2 diabetes. The molecular mechanism for the synergy is discussed in this review with a focus on transcriptional regulation. This view suggests a unifying mechanism for the distinct metabolic roles of androgens in the control of insulin action in men with hypogonadism and women with PCOS.

Two cyp17 genes perform different functions in the sex hormone biosynthesis and gonadal differentiation in Japanese flounder (Paralichthys olivaceus)

P450c17, a key enzyme in the steroid generation pathway, plays an important role in the production of sex steroid and cortisol. In this study, two cyp17 gene isoforms, Pocyp17-I and Pocyp17-II were isolated from Paralichthys olivaceus gonads. Domain architecture analysis of Pocyp17-I and Pocyp17-II revealed that they had three regions important to enzymatic function. Structural analysis showed that Pocyp17-I and Pocyp17-II had 8 and 9 exons respectively, and the difference was caused by the insertion of an extra intron (intron1) in the latter. Quantitative real-time polymerase chain reaction results indicated that the expression of these two genes showed sexually dimorphism that Pocyp17-I and Pocyp17-II were highest expressed in testis and ovary, respectively. The in situ hybridization analysis of gonads indicated that Pocyp17-I and Pocyp17-II mRNA were both detected in oocytes, spermatocytes and Sertoli cells. After injection of androgen and estrogen (17α-methyltestosterone, 17β-estradiol) of different concentrations, the expression level of Pocyp17-I decreased significantly (P < 0.01), whereas estrogen had no influence on Pocyp17-II, but androgen upregulated the expression of Pocyp17-II (P < 0.05). Moreover, Pocyp17-I expression level was down-regulated significantly by NR0b1 but up-regulated by NR5a2 (P < 0.05), whereas Pocyp17-II expression level was down-regulated significantly by NR0b1 and NR5a2 (P < 0.05). All these results demonstrated that there were differences in expression patterns, feedback actions of sex hormones and transcriptional regulations between cyp17-I and cyp17-II, which revealed that cyp17-I and cyp17-II might perform different functions in sex hormones biosynthesis and gonadal differentiation in Japanese flounder.

Animal models of polycystic ovary syndrome: A review of hormone-induced rodent models focused on hypothalamus-pituitary-ovary axis and neuropeptides.

BackgroundPolycystic ovary syndrome (PCOS) is a common endocrine disorder among women of reproductive age and a major cause of infertility; however, the pathophysiology of this syndrome is not fully understood. This can be addressed using appropriate animal models of PCOS. In this review, we describe rodent models of hormone‐induced PCOS that focus on the perturbation of the hypothalamic‐pituitary‐ovary (HPO) axis and abnormalities in neuropeptide levels.MethodsComparison of rodent models of hormone‐induced PCOS.Main findingsThe main method used to generate rodent models of PCOS was subcutaneous injection or implantation of androgens, estrogens, antiprogestin, or aromatase inhibitor. Androgens were administered to animals pre‐ or postnatally. Alterations in the levels of kisspeptin and related molecules have been reported in these models.ConclusionThe most appropriate model for the research objective and hypothesis should be established. Dysregulation of the HPO axis followed by elevated serum luteinizing hormone levels, hyperandrogenism, and metabolic disturbance contribute to the complex etiology of PCOS. These phenotypes of the human disease are recapitulated in hormone‐induced PCOS models. Thus, evidence from animal models can help to clarify the pathophysiology of PCOS.

Roles of Two Sox9 Genes during Gonadal Development in Japanese Flounder: Sex Differentiation, Spermatogenesis and Gonadal Function Maintenance.

The transcription factor sox9 has been implicated in cartilage formation and testis determination in mammals. Here, two duplicates of sox9 were found in Japanese flounder (Paralichthys olivaceus) named Posox9a and Posox9b, respectively. Phylogenetic and gene structure analyses revealed that Posox9a and Posox9b were homologous to that of teleosts and tetrapods. Quantitative real-time polymerase chain reaction (qRT-PCR) showed that both Posox9a and Posox9b expressed higher in testis than in ovary of adult tissues. The in situ hybridization (ISH) analysis of gonads showed that Posox9a and Posox9b mRNA were both detected in oocytes, Sertoli cells and spermatocytes. During sex differentiation, the expression of Posox9a exhibited obvious sexual dimorphic expression from 60 days after hatch (dah) with higher expression in male preferred individuals than female preferred individuals and increased gradually from 30 to 100 dah. A similar pattern was detected in Posox9b expression. After injection of androgen (17α-methyltestosterone) of different concentrations, the expression level of Posox9b increased significantly, whereas Posox9a did not change obviously. These results indicated that the two sox9 genes of Japanese flounder had converse functions in sex differentiation, whereas their differences in 17α-methyltestosterone administration were obvious and worthwhile for exploring evolutionary and adaptive significance. This study provided a foundation for further exploration of the roles of Posox9 genes during the sex determination and differentiation, spermatogenesis and gonadal function maintenance of Japanese flounder.

Commentary on Huggins and Hodges: "Studies on Prostatic Cancer".

See related article by Huggins and Hodges, [Cancer Res 1941;1:293–7][1] . Visit the Cancer Research 75th Anniversary [timeline][2]. “Studies on Prostatic Cancer: I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate

Ameliorative effect of androgen therapy tear on film stability in castrate female rats

Background Prevalence of dry eye is significantly inceasing in postmenopausal women than that in men, suggesting that sex hormone plays a role in the pathogenesis of dry eye. In addition, dry eye might become worse following estrogen therapy in postmenopausal women. However, whether application of androgen can ameliorate dry eye is being concerned. Objective This study was to investigate the effect of androgen on tear film of ovariectomized female rats. Methods Forty-eight 3-month-old sexually mature female Wistar rats were randomized into the normal control group, sham group, ovariectomy (OVX) model group and testosterone-injected group. OVX models were established by bilateral ovaries enucleation in the rats of the model group and testosterone-injected group, and then androgen (3.75 mg/kg) was intramuscularly injected since 5 months after OVX at 3-day interval for 6 weeks. Only intraperitoneal fat was cut off in the sham group. In 6 weeks after injection of androgen, serum androgen concentration detected and Schirmer Ⅰtest (SⅠt), tear film break-up time (BUT) were performed. The rats were sacrificed to prepare the corneal and conjunctival samples. The expression of MUC5AC in conjunctival tissue was examined by immunofluorescence staining, and the microstructure of corneal cellular surface was observed under the scanning electron microscope before and 6 weeks after application of androgen. Animals in this study were treated in accordance with Animal Experimentation Ethic Committee Guidelines of Southern Medical University and the study protocol was approved by Ethic Committee of this University. Results The mean serum testosterone concentration was (1.83±0.12)ng/ml, and SⅠt or BUT was (3.63±0.26)mm/5 minutes or (3.73±0.38)seconds, respectively, in the OVX model group, which was significantly declined in comparison with (2.56±0.14)ng/ml, (7.47±0.66)mm/5 minutes or (9.57±0.76)seconds in the normal control group (all at P=0.000). However, the serum testosterone concentration was (3.38±0.24)ng/ml, SⅠt was (6.37±0.45)mm/5 minutes and BUT was (7.54±0.55)seconds in the testosterone-injected group, which was significantly higher than that in the OVX model group (all at P=0.000). The positive staining of MUC5AC in rat conjunctival tissue weakened in the OVX model group compared with the normal control group, and the fluorescence intensity in the testosterone-injected group was stronger than that in the OVX model group. Regularly arranged microvilli and cell metabolism hiatus on the surface of corneal cells were seen in the normal control group and the sham group; while the microvilli were shorter and irregularly arranged, and the cell metabolism hiatus were disappeared in the OVX model group. However, microvilli and cell metabolism hiatus were close to normal ones in the testosterone-injected group. Conclusions Deterioration of tear secretion and instability of tear film are are probably associated with the lower serum androgen levels in castrated female rats. Systemic supplement of androgen can promote tear secretion, improve tear film stability and alleviate ocular surface damage. Key words: Dry eye/therapy; Tears/secretion; Ovariectomy; Androgens/drug therapy; Disease models, animal; Rats, Wistar; Female

A Combination of Fast-Clearance Nandrolone Plus Low-intensity Aerobic Exercise Improves RBC Indices in Anemic Aging Mice.

Anemia is a common health disorder in the aging population. Conventional therapy to treat anemia with recombinant erythropoietin (rhEpo) has limitations for elderly patients in part because endogenous Epo increases with age even before, and rises further after, anemia becomes apparent [1]. Androgen therapy, the mainstay for anemia treatments before the advent of rhEpo, thus deserves a reevaluation. Low testosterone is not only a marker, but also can be a cause, of anemia in the elderly [2-4]. Androgen-induced erythropoiesis is a long-standing clinical observation recently recapitulated in rodent models. A main disadvantage of androgen therapy is the concern for cardiovascular risk [5]. Noticeably, most clinical and animal studies use esterified androgen to prolong the drug half-life, sustaining tissue exposure to supraphysiological androgen stimulation. This may contribute to cardiac hypertrophy, at least in animal models [6]. We thus tested the effect of intermittent injection of a fast-clearance androgen (unesterified nandrolone) on RBC indices in older mice which developed anemia as a consequence of aging. We also tested whether adding a routine low-intensity aerobic exercise may enhance the effect of this intervention. The study was conducted on male C57BL/6 mice of 26 28 months, corresponding to the 50-40% strain survival window. Twenty-four anemic mice (hematocrit 29-37%) were evenly divided into four groups as control (c), nandrolone (n), exercise (ex) and exercise plus nandrolone (nex). Nandrolone or vehicle (sesame oil) was injected twice per week (100 mg/kg, 100 ul, sc). Body composition, grip-strength and blood were measured before and after the experiment. Animals were trained twice per week as described [6]. Serum nandrolone concentration was measured three days after injection using MASS and estimated to be 250 1,000 ng/ dl within hours post injection but drop to 3 5 ng/dL after 48 h. The steady-state concentration was substantially lower than serum testosterone propionate injected at half the dose [6]. To confirm that the nandrolone was functional, we performed Western analysis for splenic nuclear androgen receptor (AR). In the absence of androgenic ligands, AR is targeted to degradation without nuclear accumulation. As shown in Figure 1A, nuclear AR was undetected in control animals. At 24 h post injection, nandrolone increased nuclear AR but to a lesser extent compared to that induced by testosterone propionate, suggesting that nandrolone is sufficient to activate AR without sustaining high androgen concentrations in circulation. Treatment with nandrolone for two months did not change skeletal and cardiac muscle mass (not shown), compared to 30% historic increase of each after treatment with testosterone propionate following otherwise identical experimental protocols [6]. Changes in RBC indices for each animal were obtained by subtracting the baseline data from the final measurements. A numerical increase in hemoglobin (HgB) was induced by exercise and more by nandrolone; but each did not reach statistical significance. A combination of exercise and nandrolone, however, induced a significant increase in HgB (Fig. 1B). Similar effect was observed for RBC and hematocrit (Fig. 1C, D). Serum iron was not different among the four groups (Fig. 1E) but transferrin saturation (TSAT) was similarly increased by each intervention (Fig. 1F). TSAT is a measure of transferrin-bound iron, the major source of hemoglobin iron. Finally, we assessed the effect of each intervention on grip-strength for functional assessment. As shown in Figure 1G, grip-strength at baseline was somewhat higher in the control group. Two months later, all animals showed age-related loss in grip-strength, but this loss was attenuated by about 50% in animals that went through exercise or nanManuscript accepted for publication October 11, 2013

Beneficial effects of testosterone therapy on functional capacity, cardiovascular parameters, and quality of life in patients with congestive heart failure.

Background. According to the present evidences suggesting association between low testosterone level and prediction of reduced exercise capacity as well as poor clinical outcome in patients with heart failure, we sought to determine if testosterone therapy improves clinical and cardiovascular conditions as well as quality of life status in patients with stable chronic heart failure. Methods. A total of 50 male patients who suffered from congestive heart failure were recruited in a double-blind, placebo-controlled trial and randomized to receive an intramuscular (gluteal) long-acting androgen injection (1 mL of testosterone enanthate 250 mg/mL) once every four weeks for 12 weeks or receive intramuscular injections of saline (1 mL of 0.9% wt/vol NaCl) with the same protocol. Results. The changes in body weight, hemodynamic parameters, and left ventricular dimensional echocardiographic indices were all comparable between the two groups. Regarding changes in diastolic functional state and using Tei index, this parameter was significantly improved. Unlike the group received placebo, those who received testosterone had a significant increasing trend in 6-walk mean distance (6MWD) parameter within the study period (P = 0.019). The discrepancy in the trends of changes in 6MWD between study groups remained significant after adjusting baseline variables (mean square = 243.262, F index = 4.402, and P = 0.045). Conclusion. Our study strengthens insights into the beneficial role of testosterone in improvement of functional capacity and quality of life in heart failure patients.

Improved Overall Survival Trends of Men with Newly Diagnosed M1 Prostate Cancer: A SWOG Phase III Trial Experience (S8494, S8894 and S9346)

Frequent prostate specific antigen testing for screening and monitoring prostate cancer has led to significant stage migration. We evaluated whether overall survival in hormone naïve patients with metastatic prostate cancer has improved during the era of prostate specific antigen use. We also assessed whether any patient subsets benefited differentially during this period. We compared overall survival in 3 sequential phase III trials of 3,096 men with hormone naïve, metastatic prostate cancer who received similar androgen deprivation therapy, including 2 trials performed before the prostate specific antigen era (S8494 and S8894) and the other done during this era (S9346). Overall survival was adjusted for patient and disease risk factors in the latter 2 trials. Subgroups were evaluated by interactions of risk factors with trial. Median overall survival was 30 months in S8494, 33 months in S8894 and 49 months in S9346. Adjusting for risk factors, there was a 22% lower risk of death in S9346 than in S8894 (HR 0.78, 95% CI 0.70, 0.87, p <0.001). The improvement in overall survival was greater in black American men (test of interaction p = 0.008). In S8494 and S8894 median survival for black men was 27 months, and 34 and 35 months for nonblack men, respectively. This racial difference disappeared in S9346 with overall survival of 48 and 49 months in black and nonblack men, respectively. Adjusting for risk factors, overall survival was significantly improved in the post-prostate specific antigen era trial. However, it cannot be concluded that this was attributable only to prostate specific antigen monitoring. Black men now have overall survival comparable to that of white men. Current estimates of survival should be used to design new trials in this population.

Animal models of polycystic ovary syndrome: a focused review of rodent models in relationship to clinical phenotypes and cardiometabolic risk

To review rodent animal models of polycystic ovary syndrome (PCOS), with a focus on those associated with the metabolic syndrome and cardiovascular disease risk factors. Review. Rodent models of PCOS. Description and comparison of animal models. Comparison of animal models to clinical phenotypes of PCOS. Animals used to study PCOS include rodents, mice, rhesus monkeys, and ewes. Major methods to induce PCOS in these models include subcutaneous injection or implantation of androgens, estrogens, antiprogesterone, letrozole, prenatal exposure to excess androgens, and exposure to constant light. In addition, transgenic mice models and spontaneous PCOS-like rodent models have also been developed. Rodents are the most economical and widely used animals to study PCOS and ovarian dysfunction. The model chosen to study the development of PCOS and other metabolic parameters remains dependent on the specific etiologic hypotheses being investigated. Rodent models have been shown to demonstrate changes in insulin metabolism, with or without induction of hyperandrogenemia, and limited studies have investigated cardiometabolic risk factors for type 2 diabetes and cardiovascular disease. Given the clinical heterogeneity of PCOS, the utilization of different animal models may be the best approach to further our understanding of the pathophysiologic mechanisms associated with the early etiology of PCOS and cardiometabolic risk.

Class I and II anabolic steroids produce opposite hedonic and rewarding effects in pubertal and adult mice

Anabolic androgenic steroids (AAS) are synthetic derivates of testosterone. There are approximately 60 different AAS compounds that can be classified in three classes based upon their chemical structure and metabolites. Even short exposure to AAS can produce mood and behavioral symptoms. In previous experiments, we found that class I and II AAS induce hedonic and rewarding effects in adult mice. Recently, NIDA reported that 1.4 – 2.2% of adolescents ever tried steroids. In this study, we aimed to determine if AAS have hedonic properties in adolescent male mice. Animals received alternate androgen injections in a conditioned place preference (CPP) for 10 days. In addition, anxiety behaviors were measured. Androgens tested were testosterone propionate (TP) and 17α‐methyltestosterone (17α‐meT), class I and class III AAS, respectively. Three doses were tested (0.075, 0.75 and 7.5 mg/kg) for each drug. We have found a shift in place preference in animals treated with 17α‐meT in all doses tested, while TP showed no effect. In exploratory‐based anxiety, using light‐dark transitions, we found an increase in this parameter only with 17α‐meT (7.5 mg/kg). Body and gonadal weight were not affected in any of the AAS treatments. Our results suggest that developmental age, hormonal environment and AAS metabolism are important modulators of hedonia and reward.

Classic Citations: Studies on Prostatic Cancer I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate* by Charles Huggins and Clarence V. Hodges

I n 1941, Huggins and Hodges [1] published this classical article which established for the first time the relationship between testosterone (T) and prostate cancer (PCa). The goals of Huggins and Hodges were to present the values of serum phosphatases in normal men and patients with carcinoma of the prostate. Furthermore, they wanted to demonstrate that the serum levels of acid phosphatase were reduced in metastatic PCa by decreasing the activity of androgens and increased after androgens injections. Authors argued that there were evidences that the activity of phosphatases, mainly the acid one, in serum was found to provide objective indices of activity of PCa [2]. They evaluated alkaline and acid phosphatases of 40 normal men who served as controls to determine the normal range of enzymes levels, 21 men with benign prostatic hypertrophy, and of 47 men with carcinoma of the prostate. Eight patients who had carcinoma of the prostate with bone metastases and with moderate or great elevation of both phosphatases levels were submitted to bilateral orchiectomy. Five patients were injected with stilbestrol 1 mg or estradiol benzoate 1.66 to 3.32 mg daily, and two patients were injected with T propionate 1.25 mg daily before castration. In one patient, T was injected after castration. They also evaluated phosphatase levels in the cerebrospinal fluid of three patients and in the spermatocele fluid of one patient concurrently with the serum levels. They made serial observations of serum phosphatases 1 week before and 4 weeks after bilateral orchiectomy in four normal adult dogs. They found that of the 47 patients with PCa with or without bone metastases, 23 had both phosphatases levels in the range of the controls. Of the remaining 24, all had elevated levels of both alkaline and acid phosphatases. Of 25 patients with radiographic evidence of bone metastasis, 19 had elevated levels of both phosphatases. Alkaline phosphatase alone was increased in two cases, while acid phosphatase was within normal limits, and neither enzyme was increased in other four cases. There was no X-ray evidence of metastasis in 20 patients; in 16 men, both acid and alkaline phosphatases were normal; in three men, alkaline phosphatase was elevated, but in none of this group, the acid phosphatase level was increased. The authors did not report phosphatase levels in men with benign prostatic hypertrophy. After bilateral orchiectomy, the levels of acid phosphatase rapidly decreased (7 to 12 days); its levels usually persisted in a range slightly above or below the upper limits of the normal values and it was maintained at this value with slight fluctuation during the period of observation which in the longest case was 180 days. A rise was always observed in the value of alkaline phosphatase following castration followed by a decrease to or toward normal range. Serum phosphatases were within normal range in four dogs and therewere no changes after castration. © 2010 International Society for Sexual Medicine

Prostate Specific Antigen Half-Time and Prostate Specific Antigen Doubling Time as Predictors of Response to Androgen Deprivation Therapy for Metastatic Prostate Cancer

We determined the clinical significance of prostate specific antigen half-time and prostate specific antigen doubling time after the prostate specific antigen nadir as predictors of the response to androgen deprivation therapy for metastatic prostate cancer. A total of 131 patients with metastatic prostate cancer treated with androgen deprivation were included in this analysis. Clinicopathological features and cancer specific survival were compared among the patients who were divided according to prostate specific antigen half-time and prostate specific antigen doubling time after the prostate specific antigen nadir. Median followup was 53.0 months. Baseline and nadir prostate specific antigen did not differ between the patients with a short prostate specific antigen half-time (1 month or less) and those with a long prostate specific antigen half-time (longer than 1 month). Patients with a short prostate specific antigen half-time had a higher Gleason score, shorter nadir duration and shorter cancer specific survival. No differences were found between the patients with a short (6 months or less) and those with a long (longer than 6 months) prostate specific antigen doubling time after the prostate specific antigen nadir in terms of baseline prostate specific antigen, nadir prostate specific antigen, biopsy Gleason score and prostate specific antigen half-time. A short prostate specific antigen doubling time after the prostate specific antigen nadir was associated with shorter nadir duration and poorer median cancer specific survival. On multivariate analysis Gleason score, nadir prostate specific antigen and prostate specific antigen half-time remained independent predictors of an increase in prostate specific antigen after androgen deprivation therapy. Nadir prostate specific antigen, prostate specific antigen half-time and prostate specific antigen doubling time after the prostate specific antigen nadir were prognostic factors for cancer specific survival. The results of our study suggest that prostate specific antigen half-time and prostate specific antigen doubling time after the prostate specific antigen nadir are independent prognostic indicators for an increase in prostate specific antigen after androgen deprivation therapy and cancer related death in patients with metastatic prostate cancer treated with androgen deprivation.

Hormone therapy: a revolution in understanding prostate cancer

Until the middle of the 20th century, little knowledge of the behaviour of prostate cancer existed and awareness of its exquisite sensitivity to hormones had not been realised. The conventional understanding was that prostate cancer was an autonomous, self-perpetuating, and fatal malignant disease, the progression of which could not be changed by external manipulation. In 1941, Charles Brenton Huggins, a Canadian-born American surgeon, revolutionised our understanding of prostate cancer and irrevocably changed the approach of physicians in managing and researching the treatment of neoplastic disease in general. His pioneering work heralded the era of rational drug therapy for all cancers and earned Huggins the Nobel Prize in Physiology and Medicine in 1966. Charles Huggins graduated from Harvard Medical School (Boston, MA, USA) in 1924. In 1927, he was appointed to the surgical faculty at the University of Chicago (Chicago, IL, USA) where he became Professor of Surgery in 1936. Subsequently, in 1966, he became the second surgeon to win a Nobel Prize in Medicine, with a comment from the Nobel Committee proclaiming Huggins’ work had “already given many years of an active and useful life to patients with advanced cancer over the entire civilized world—patients who would have been lost to other forms of therapy”. Many have suggested that his ground-breaking discoveries, fi rst published in 1941, should have been acknowledged by the committee at a much earlier date. In the original study by Huggins and Hodges (his student), eight patients with metastatic disease to bone were selected from an initial group of 47 patients with prostate cancer. All eight patients underwent bilateral orchidectomy; however, before this procedure, fi ve were started on daily injections of stilboestrol or oestradiol benzoate, and three were injected with daily testosterone propionate. Serum acid-phosphatase concentrations decreased in patients who received oestrogen injection before the procedure and increased in those who received testosterone propionate. From these fi ndings, Huggins and Hodges concluded that prostate cancer was receptive to androgenic activity in the body and that metastatic prostate cancer was inhibited by eliminating circulating androgens—either by surgical orchidectomy or by administration of oestrogens. Moreover, they also showed that prostate cancer was activated by androgen injections. These fi ndings have provided the scientifi c basis for the contemporary treatment of prostate cancer. For nearly 30 years after this seminal report by Huggins and Hodges, patients with advanced prostatic carcinoma were managed either by surgical orchidectomy or oestrogens, until it was shown that treatment with oestrogens resulted in substantial thromboembolic and cardiovascular complications. This fi nding stimulated further research into alternative hormonal treatments, which culminated in the development of various antiandrogens (eg, cyproterone acetate and fl utamide) and most notably synthetic luteinising-hormonereleasing-hormone (LHRH) agonists in the 1970s. The therapeutic eff ectiveness of LHRH in achieving medical castration has yet to be surpassed. Although these hormonal treatments were originally used to manage patients with metastatic disease, androgen ablation therapy is now used in a neoadjuvant or adjuvant setting in combination with surgery or radiation in patients with locally advanced disease only or in those with biochemical relapse after radical treatment for localised disease. The epic work by Huggins and Hodges will remain a cornerstone in the annals of medical literature because it initiated the use of endocrine therapy in the management of disseminated prostate cancer and showed that the course of neoplastic disease could be changed by rational external intervention. One can state with certainty that there are few articles in science, which have had, or will have, such a lasting impact.

Quantifying the impact of androgen therapy on the female larynx

Objective To describe the timing of changes in fundamental frequency of the female voice following androgen therapy during female to male gender reassignment. Methods A 33-year-old female semi-professional singer undergoing gender reassignment and intramuscular androgen injections was examined at monthly intervals to monitor the impact of therapy on the voice. Laryngostroboscopy and acoustic analysis were performed simultaneously to monitor for potential laryngeal pathology. Results Pretreatment mean fundamental frequency (MF 0) was 228.45 Hz and ranged from 140.26 Hz to 430.64 Hz. Between month 3 and month 4 of treatment, MF 0 declined to 116.52 Hz and ranged from 90.75 Hz to 201.07 Hz. Shimmer increased from 3.4% to 7.8%. Noise to harmonics ratio (NHR) also increased from 0.12 to 0.17. The patient has continued to sing semi-professionally despite these changes in laryngeal function. Conclusion Androgen therapy exerted a profound change on mean fundamental frequency between the third and fourth months of treatment. In addition, pitch range was reduced in a commensurate fashion. Patients undergoing androgen therapy may undergo a significant change in speaking voice between the third and fourth months of therapy. Moreover, though these changes may exert a profound impact on the singing voice, patients undergoing gender reassignment may still be able to achieve personal and professional success in their singing careers.

Change in Prostate Specific Antigen Following Androgen Stimulation is an Independent Predictor of Prostate Cancer Diagnosis

We tested the hypothesis that a single exogenous androgen injection in men with low prostate specific antigen would provoke a differential prostate specific antigen response that would correlate with the presence and volume of cancer at biopsy. Following institutional review board approval 40 men with prostate specific antigen between 2.5 and 4.0 ng/ml were given 1 intramuscular injection of 400 mg testosterone cypionate at the start of the study. Prostate specific antigen and early morning serum testosterone were measured at baseline, 48 hours, and weeks 1, 2 and 4. All men underwent 12-core transrectal ultrasound guided biopsy at week 4. Of the 40 men 18 (45%) were diagnosed with prostate cancer. The mean change in prostate specific antigen from baseline to 4 weeks was 3.1 to 3.4 ng/ml (9.7%) in men found to have benign findings on biopsy compared to a mean increase of 2.9 to 3.8 ng/ml (29%) in those with prostate cancer (p = 0.006). The change in prostate specific antigen following androgen stimulation was significantly associated with the percent of tissue involved with cancer and it was an independent predictor of cancer diagnosis on univariate and multivariate analysis. An increase in prostate specific antigen following androgen stimulation in men with prostate specific antigen between 2.5 and 4.0 ng/ml was highly predictive of the subsequent diagnosis of prostate cancer and it correlated with disease volume. If these findings are corroborated, prostate specific antigen provocation may become an important strategy to identify men at risk for harboring prostate cancer and minimize the number undergoing unnecessary biopsies.

Timing of Androgen Deprivation Therapy and its Impact on Survival After Radical Prostatectomy: A Matched Cohort Study

We assessed the impact of the timing of androgen deprivation on disease progression after radical prostatectomy for patients with localized prostate cancer. We evaluated all patients who underwent radical prostatectomy between 1990 and 1999. Patients with pathological lymph node negative disease who received androgen deprivation therapy were then separated into 5 groups for analysis based on the time of hormone therapy initiation: 1--adjuvant androgen deprivation, 2--androgen deprivation therapy started at a postoperative prostate specific antigen of 0.4 ng/ml or greater, 3--at prostate specific antigen 1.0 or greater, 4--at prostate specific antigen 2.0 or greater and 5--at systemic progression. The first 4 groups were matched by clinical and pathological features to control groups who did not receive androgen deprivation after surgery using a nested, matched cohort design. Median followup for the entire cohort was 10 years. Clinical end points included systemic progression-free survival and cancer specific survival. After matching clinicopathological variables adjuvant androgen deprivation therapy was associated with improved 10-year systemic progression-free survival (95% vs 90%, p <0.001) and 10-year cancer specific survival (98% vs 95%, p = 0.009), although overall survival for these patients remained unchanged (84% vs 83%, p = 0.427). In contrast, we found that men who started hormonal therapy at a postoperative prostate specific antigen of 0.4 or greater, 1.0 or 2.0 did not have improved systemic progression-free or cancer specific survival. Adjuvant hormonal therapy modestly improves cancer specific survival and systemic progression-free survival after prostatectomy. The benefit of hormone therapy is lost when androgen deprivation is delivered at the time of prostate specific antigen recurrence or systemic progression.

Effects of sex hormones on genioglossal muscle activities, estrogen and androgen receptor expression in adult rat

To explore gene expression of estrogen receptor (ERalpha, ERbeta) and androgen receptor (AR) in genioglossal muscle (GG) of adult male rats, and to investigate the effects of sex hormones on GG activities, ERalpha, ERbeta and AR expression. GG samples were collected from 10 healthy adult male rats. Total RNA were extracted and subjected to fluorescent quantitative reverse transcription-polymerase chain reaction (FQ RT-PCR) for quantitative measurement of ERalpha, ERbeta and AR mRNAs. The other 24 male rats were randomly divided into 3 groups: control group, estrogen group (intramuscular injection of estrogen 0.1 mg/kg, twice a week) and androgen group (intramuscular injection of androgen 2.5 mg/kg, twice a week). The electromyographic activities (EMG) and contract tension of GG were investigated after 4-week treatment. The expression of ERalpha, ERbeta and AR was assessed by Western blot. The mRNA expression ratios of AR/GAPDH, ERalpha/GAPDH, ERbeta/GAPDH and ERalpha/ERbeta were (295.80 +/- 127.20), (2042.00 +/- 921.57), (65.96 +/- 29.57) and (36.83 +/- 19.66), respectively. The mRNA level of ERalpha was significantly higher than that of ERbeta (P < 0.01). Compared with the control group, the EMG of GG was intensified in the estrogen group (P < 0.01). GG contractility did not change significantly (P > 0.05), and ERalpha expression in GG was up-regulated by estrogen (P < 0.05); while in the androgen group, the EMG of GG was weakened (P < 0.05). P(t) and P(0) were slightly increased (P > 0.05) and the decline rate of P(0) was markedly quickened (P < 0.05). AR and ERbeta expressions were down-regulated by androgen (P < 0.05). Both AR and ER were expressed in GG of adult male rats, and ERalpha was expressed more abundantly than ERbeta. Estrogen could greatly improve activities of GG and stimulate the expression of ERalpha. Whereas, androgen could restrain activities of GG, impair its fatigue resistance capacity and inhibit the expression of AR and ERbeta.