Low-dose Androgen Research Articles

Skeletal muscle function is altered in male mice on low-dose androgen receptor antagonist or estrogen receptor agonist

Skeletal muscle function is altered in male mice on low-dose androgen receptor antagonist or estrogen receptor agonist

Early diagnosis and treatment strategies for pediatric growth hormone deficiency

Over the last century, adult height has shown a marked increase, largely attributed to advancements in nutrition and healthcare. Monitoring child growth is crucial for the early identification of growth-related disorders. One such condition is the underperformance of the pituitary gland, which can lead to a deficiency in growth hormone, manifesting as short stature. Therapeutic interventions, such as growth hormone therapy and low-dose androgen therapy, have proven effective. These treatments utilize synthetic hormones to foster normal growth. Prompt and accurate diagnosis, coupled with precise treatment, is critical to empower individuals to reach their maximum growth potential and alleviate associated health concerns. Future research should aim to deepen our understanding of the interplay between pituitary cells, uncover additional genetic factors contributing to short stature, and enhance growth hormone replacement therapies. Such progress will significantly bolster the diagnostic and therapeutic strategies for children with growth impairments.

Skeletal Muscle Function Is Altered in Male Mice on Low-Dose Androgen Receptor Antagonist or Estrogen Receptor Agonist.

In males, skeletal muscle function may be altered by shifts in either circulating testosterone or estrogen. We examined the effect of acute (2-week) exposures to 17α-ethinyl estradiol (EE2), an estrogen receptor (ER) agonist, or flutamide, an androgen receptor (AR) antagonist, on the contractile function of individual skeletal muscle fibers from slow-contracting soleus and fast-contracting extensor digitorum longus muscles from adult male mice. Single fiber specific tension (force divided by cross-sectional area) was decreased with flutamide treatment in all myosin heavy chain (MHC) fiber types examined (I, IIA, and IIB); similar effects were observed with EE2 treatment but only in the fastest-contracting MHC IIB fibers. The decreases in maximally Ca2+-activated specific tension were primarily a result of fewer strongly bound myosin-actin cross-bridges, with flutamide treatment also showing lower myofilament lattice stiffness. Myosin-actin cross-bridge kinetics were slower in MHC IIA fibers in flutamide-treated mice, but faster in EE2-treated mice, indicating that contractile velocity may be affected differently in this fiber type, which is commonly expressed in human skeletal muscle. Importantly, these effects were observed in the absence of outcomes previously used to evaluate ER agonists or AR antagonists in rodents including weight of reproductive organs or mammary gland morphology. Our findings indicate that substantial shifts in skeletal muscle function occur in male mice following acute exposures to low doses of a pharmacological ER agonist and an AR antagonist. These results suggest that countermeasures to maintain physical function may be needed early in situations that induce similar ER agonist and AR antagonist conditions.

Biphasic transcriptional and posttranscriptional regulation of MYB by androgen signaling mediates its growth control in prostate cancer

MYB, a proto-oncogene, is overexpressed in prostate cancer (PCa) and promotes its growth, aggressiveness, and resistance to androgen-deprivation therapy. Here, we examined the effect of androgen signaling on MYB expression and delineated the underlying molecular mechanisms. Paralleling a dichotomous effect on growth, low-dose androgen induced MYB expression at both transcript and protein levels, whereas it was suppressed in high-dose androgen-treated PCa cells. Interestingly, treatment with both low- and high-dose androgen transcriptionally upregulated MYB by increasing the binding of androgen receptor to the MYB promoter. In a time-course assay, androgen induced MYB expression at early time points followed by a sharp decline in high-dose androgen-treated cells due to decreased stability of MYB mRNA. Additionally, profiling of MYB-targeted miRNAs demonstrated significant induction of miR-150 in high-dose androgen-treated PCa cells. We observed a differential binding of androgen receptor on miR-150 promoter with significantly greater occupancy recorded in high-dose androgen-treated cells than those treated with low-dose androgen. Functional inhibition of miR-150 relieved MYB suppression by high-dose androgen, while miR-150 mimic abolished MYB induction by low-dose androgen. Furthermore, MYB-silencing or miR-150 mimic transfection suppressed PCa cell growth induced by low-dose androgen, whereas miR-150 inhibition rescued PCa cells from growth repression by high-dose androgen. Similarly, we observed that MYB silencing suppressed the expression of androgen-responsive, cell cycle-related genes in low-dose androgen-treated cells, while miR-150 inhibition increased their expression in cells treated with high-dose androgen. Overall, these findings reveal novel androgen-mediated mechanisms of MYB regulation that support its biphasic growth control in PCa cells.

Clinical profile of hereditary angioedema from a tertiary care centre in India

IntroductionHereditary angioedema (HAE) is a clinical condition which could be fatal if not identified and managed appropriately. Knowledge of this condition is mostly confined to individual case reports and literature reviews in India. In this retrospective study we describe HAE cases which presented to a tertiary care centre in India over a period of three and half years. Materials and methodsClinical case records of forty-two HAE patients diagnosed based on clinical and laboratory features were accessed after due approval from the Ethics committee. C1 esterase inhibitor (C1 INH) and C4 levels were measured using nephelometry. All relevant data was entered into Microsoft EXCEL worksheet and analysed using simple statistical tools. ResultsAmong the 42 patients diagnosed as having HAE, 37 had low C1INH levels and were diagnosed to have type 1 HAE. The remaining 5 had normal C1 INH levels and were considered probable HAE based on family history and response to HAE specific treatment. The median age of onset of symptoms was 15 years (range 5–49) and median age at diagnosis, 27.5 years (range 5–55). The median delay in diagnosis was 10 years (range 1–27 years). Family history of HAE was observed in 52.6% and 29% reported deaths in the family with HAE like disease. Low dose androgens or tranexamic acid or both were prescribed in 64.2% of the patients. Orofacial edema was the commonest clinical presentation (76%) followed by edema of the extremities (38%), GI tract symptoms (19%) and genital involvement (11.9%). ConclusionMany cases of HAE may be going undetected in India. There is a need for clinical awareness and laboratory means to accurately identify and administer appropriate treatment.

Abstract 4476: A novel nonsense mutation in androgen receptor confers resistance to CYP17 inhibitor treatment in prostate cancer

Abstract Background: The standard treatment for prostate cancer (PCa) is androgen deprivation therapy (ADT) that blocks AR transcriptional activity, which is responsible to the initiation and progression of PCa. However, ADT invariably leads to the castration-resistant PCa (CRPC) with restored activity of AR. CRPC can be further treated with more intensive ADTs, including CYP17-inhibitors to block intratumoral androgen synthesis and more potent AR antagonist. By analyzing the tumor mRNA from a CRPC patient biopsy who developed resistance to CYP17-inhibitor treatment, we identified a novel nonsense AR mutation on ligand binding domain (Q784*), which produces a C-terminal truncated form of AR protein containing only a fraction of ligand binding domain (LBD) and may mimic the function of some AR splice variants. We hypothesized that AR-Q784* may gain the androgen-independent activity, or may enhance the transcriptional activity of full-length AR (AR-FL) under low androgen environment through dimerization with AR-FL. Method: Luciferase reporter assays were applied to assess the transcriptional activity of AR-Q784* in absence or presence of androgens, and with or without AR-FL. Immunoblotting and immunofluorescence assays were used to examine the protein stability and cellular localization of AR-Q784*. Chromatin immunoprecipitation assays were also used to assess the chromatin binding ability of AR-Q784*. Moreover, the stable cell line that expresses endogenous AR-FL and tetracycline-inducible AR-Q784* was generated to determine the transcription activity on AR target genes and assess the effects on cell proliferation, particularly under low dose androgen condition. Result: Although it was constitutively expressed in nucleus, AR-Q784* does not elicit transcriptional activity despite the conditions of ligands. However, when it was co-expressed with AR-FL, AR-Q784* can enhance AR-mediated transcriptional activity and thus increased PCa cell proliferation particularly under low androgen conditions. Mechanistically, AR-Q784* can dimerize with AR-FL, enhance DNA binding ability of AR-FL, and strengthen AR recruitment of p300 coactivator. Conclusion: We show that CYP17 inhibitor treatment in CRPC may select for a distinct class of AR mutations/variations, including nonsense (AR-Q784*) or point-deletion mutations within LBD and certain splice variants that only lose a fraction of LBD domain. This class of AR mutants/variants is transcriptionally inactive but can enhance the activity of AR-FL due to their abilities of constitutive DNA binding and dimerization with AR-FL. However, this enhancing activity of those AR mutants/variants can be prevented by antagonist treatments such as enzalutamide. Therefore, this study provides an additional rationale for treating PCa patients with combination therapy of abiraterone and enzalutamide, which may prevent the selection for such AR mutations/variations in CRPC. Citation Format: Dong Han, Jude Owiredu, Kevin Valencia, Changmeng Cai. A novel nonsense mutation in androgen receptor confers resistance to CYP17 inhibitor treatment in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4476. doi:10.1158/1538-7445.AM2017-4476

Androgen Treatment Effects on Motor Function, Cognition, and Behavior in Boys with Klinefelter Syndrome

To examine the effects of early low-dose androgen on motor, cognitive, and behavioral function in prepubertal boys with Klinefelter syndrome (47,XXY). Double-blind trial of 84 boys, ages 4-12 years, randomized to oxandrolone (Ox; 0.06?mg/kg daily; n?=?43) or placebo (Pl; n?=?41) for 24 months. Standardized assessments were performed at baseline and every 12 months for 24 months evaluating motor, cognitive, and behavioral function. The 24-month outcomes were better in the Ox vs. Pl group on 1 of 5 primary endpoints (motor function/strength): Bruininks Visual-Motor scale (P?=?.005), without significant differences between the 2 groups for the other 4 components. Secondary analyses suggested improvement in the Ox vs. Pl group in the anxiety/depression (P?=?.03) and social problems (P?=?.01) scales on the Child Behavior Checklist, anxiety (P?=?.04) on the Piers Harris Self Concept Scale, and interpersonal problems (P?=?.02) on the Children's Depression Inventory, without significant differences in hyperactive or aggressive behaviors. This double-blind, randomized trial demonstrates that 24 months of childhood low-dose androgen treatment in boys with Klinefelter syndrome benefited 1 of 5 primary endpoints (visual-motor function). Secondary analyses demonstrated positive effects of androgen on aspects of psychosocial function (anxiety, depression, social problems), without significant effects on cognitive function, or hyperactive or aggressive behaviors. ClinicalTrials.gov: NCT00348946.

Effects of Oxandrolone on Cardiometabolic Health in Boys With Klinefelter Syndrome: A Randomized Controlled Trial.

Klinefelter syndrome (KS) is a common condition in males, resulting in androgen deficiency and cardiometabolic diseases. These interrelated conditions may be present in prepubertal boys with KS. To determine whether supplemental low-dose androgen has a beneficial effect on body composition in prepubertal boys with KS. We conducted a secondary analysis of a randomized, double-blind, placebo-controlled clinical trial in 93 boys with KS aged 4 to 12 years. Oral oxandrolone (Ox) 0.06 mg/kg/d or placebo for 2 years. The primary outcome was percent body fat standard deviation score (%BF SDS) at 2 years. Secondary outcomes included additional measures of cardiometabolic health and safety. The %BF SDS at 2 years was significantly lower in the treatment (0.29 ± 0.76 SDS) compared with placebo group (0.81 ± 0.72 SDS) after adjusting for age and baseline %BF SDS (95% confidence interval for the difference between means -0.86 to -0.19 SDS, P = 0.009). Ox resulted in lower triglycerides (P = 0.043), but also lower high-density lipoprotein (HDL) cholesterol (P < 0.001) and a more rapid advancement in bone age (P = 0.011). Ox has positive effects on measures of cardiometabolic health in prepubertal boys with KS; however, it does lower HDL cholesterol and advance bone age.

Infrequent low dose testosterone treatment maintains male sexual behavior in Syrian hamsters

Testosterone (T) secreted in short pulses several times each day is essential for the maintenance of male sex behavior (MSB) in mammals. Blood T concentrations are relatively low during inter-pulse intervals. Assessment of androgenic influences on MSB of rodents has, with very few exceptions, involved either injections of pure or esterified hormones dissolved in oil or implantation of constant release capsules that generate supraphysiological and/or constantly elevated T concentrations. The minimum daily concentration of T necessary to maintain and restore MSB when T is delivered as a discrete short pulse remains unspecified; nor is it known whether infrequent T pulses in the physiological range sustain MSB. To address these questions, we varied T injection concentrations and frequencies in castrated, sexually-experienced Syrian hamsters. All males injected daily with an aqueous vehicle failed to display the ejaculatory reflex 5 weeks after castration. Once daily 15 μg subcutaneous T injections both maintained and restored MSB, whereas once daily 5 μg T injections resulted in fewer males ejaculating and longer ejaculation latencies. Substantially higher T doses were required to restore MSB in previous studies when T was administered in an oil vehicle. 50 μg T maintained MSB in most hamsters injected once every 4 or 7 days, despite long intervals between injections during which circulating T was undetectable or well below physiological concentrations. Some T regimens that maintained MSB were associated with subnormal seminal vesicle and ventral prostate weights. The demonstration that relatively brief, infrequent elevations of T are sufficient to support MSB provides a useful model to assess the neuroendocrine basis of MSB and raises the possibility that infrequent low dose androgen replacement protocols may restore sex behavior to hypogonadal men without inducing some of the negative side-effects associated with more frequent, higher dose treatments.

Hormonal influences on sexually differentiated behavior in nonhuman primates

Sexually dimorphic behavior in nonhuman primates results from behavioral predispositions organized by prenatal androgens. The rhesus monkey has been the primary primate model for understanding the hormonal organization of sexually dimorphic behavior. Historically, female fetuses have received high prenatal androgen doses to investigate the masculinizing and defeminizing effects of androgens. Such treatments masculinized juvenile and adult copulatory behavior and defeminized female-typical sexual initiation to adult estrogen treatment. Testosterone and the nonaromatizable androgen, 5α-dihydrotestosterone, produced similar effects suggesting that estrogenic metabolites of androgens are not critical for masculinization and defeminization in rhesus monkeys. Long duration androgen treatments masculinized both behavior and genitalia suggesting that socializing responses to the females’ male-like appearance may have produced the behavioral changes. Treatments limited to 35 days early or late in gestation differentially affected behavioral and genital masculinization demonstrating direct organizing actions of prenatal androgens. Recent studies exposed fetal females to smaller doses of androgens and interfered with endogenous androgens using the anti-androgen flutamide. Low dose androgen treatment only significantly masculinized infant vocalizations and produced no behavioral defeminization. Females receiving late gestation flutamide showed masculinized infant vocalizations and defeminized interest in infants. Both late androgen and flutamide treatment hypermasculinized some male juvenile behaviors. Early flutamide treatment blocked full male genital masculinization, but did not alter their juvenile or adult behavior. The role of neuroendocrine feedback mechanisms in the flutamide effects is discussed. Sexually differentiated behavior ultimately reflects both hormonally organized behavioral predispositions and the social experience that converts these predispositions into behavior.

Effects of adjuvant androgen on anemia and nutritional parameters in chronic hemodialysis patients using low-dose recombinant human erythropoietin.

Background:Recombinant human erythropoietin (epoetin) has greatly contributed to improvement of the anemia of chronic renal failure patients on hemodialysis. However, the reduced erythropoietic effect to epoetin and its high cost have induced lots of supplementary treatments. Therefore, we performed a prospective study to evaluate the effects of adjuvant low-dose androgen therapy in patients using a lower-dose of epoetin than the commonly recommended dose on anemia and the nutritional parameters.Methods :17 patients of hemoglobin (Hgb) less than 9 g/dL even after being treated with 1,000 U epoetin subcutaneously (s.c.) 3 times per week on a stable status for more than 6 months, who were on hemodialysis at our institution were examined. They were injected with the same dose of epoetin s.c. and nandrolone decanoate 100 mg intramuscularly (i.m) weekly for another 6 months. Blood test was performed every month before therapy for 6 months and after therapy for 6 months and the mean values were reviewed for comparison.Results:Hgb (7.75±0.9 vs 8.99±1.39 g/dL, p <0.01) and hematocrit (Hct) (23.68±2.85 vs 26.66±3.91%, p <0.01) were apparently changed before and after adjuvant therapy. Hgb and Hct, weekly dose of epoetin were not statistically different in 9 male patients before and after adjuvant therapy. The weekly dose of epoetin was not statistically different in 8 female patients, but Hgb and Hct (8.02±0.6 vs 9.72±1.31 g/dL, 24.54±1.7 vs 28.74±3.06%, p <0.01) were statistically different before and after adjuvant therapy. In comparison between male and female groups, weekly doses of epoetin and nandrolone decanoate were significantly greater in the female group than the male group (epoetin: 50.66±6.23 vs 61.18±8.76 U/kg/week, nandrolone decanoate: 1.69±0.2 vs 2.04±0.29 mg/kg/week, p <0.05).Conclusion :Our data show that the adjuvant androgen therapy is effective for the anemia of hemodialysis patients who did not recover from anemia even after being continuously treated with low-dose epoetin.

Androgen therapy for ageing men: the implications for arterial disease

Steroid hormones such as oestradiol and testosterone have long been viewed as a key to long-term health. Although men do not undergo the precipitous fall in endogenous steroid hormone levels characteristic of the menopause, there is substantial interest in the therapeutic potential of low dose androgen therapies to maintain mental, skeletal and other aspects of health. Testosterone and other androgens seem to conform to the "clutch pedal" theory of hormone action. In terms of atherosclerosis, if plasma androgen levels are too low they may cause disease, but, if they are too high, atherosclerosis may also become a problem. Thus, the rationale for the use of low doses of androgens in ageing males is becoming compelling. Studies of arterial disease surrogates, such as plasma protein levels, may help optimise these therapies but the final answer on disease can only come from formal placebo-controlled trials of clinical endpoints.

An Aged Rat Model of Partial Androgen Deficiency: Prevention of Both Loss of Bone and Lean Body Mass by Low-Dose Androgen Replacement

An Aged Rat Model of Partial Androgen Deficiency: Prevention of Both Loss of Bone and Lean Body Mass by Low-Dose Androgen Replacement

An aged rat model of partial androgen deficiency: prevention of both loss of bone and lean body mass by low-dose androgen replacement.

The aim of this study was to evaluate the effects of different doses of androgen replacement, both on body composition and bone, in an aged male orchidectomized rat model. Testosterone was administered by 0.5, 1, and 2.5-cm sc SILASTIC implants (release of, respectively, 11.5, 23, and 55 microg/day) to aged (12 months old, +/- 550 g) male orchidectomized Wistar rats during a 15-week experimental period. T 0.5 only partially prevented decrease of ventral prostate and seminal vesicle weight, compared with an intact group that received an empty implant (Intact). The 1-cm implant (T 1) completely prevented decrease of both seminal vesicles and ventral prostate weight. The 2.5-cm implant (T 2.5) was clearly supraphysiological, as demonstrated by significant hypertrophy of both androgen-sensitive organs. Serum testosterone was lower in T 0.5 and T 1 (0.38 +/- 0.06 ng/ml and 0.92 +/- 0.06 ng/ml, respectively) and higher in T 2.5 (2.4 +/- 0.28. ng/ml), compared with both Intact (1.6 +/- 0.23 ng/ml) and the baseline group(1.6 +/- 0.11 ng/ml). As expected, orchidectomized rats that received an empty SILASTIC implant had significantly lower bone mineral content (-7.9%), apparent density (-5.7%), and lean body mass (-10.8%), as measured by dual-energy x-ray absorptiometry, without significant changes in body weight and fat mass, compared with Intact. Also, cancellous (-50.3%) and cortical (-1.8%) volumetric density, as measured by peripheral quantitative computed tomography, were decreased in the tibia. Bone turnover, as measured by serum osteocalcin and urinary deoxypyridinoline excretion, was increased in orchidectomized rats that received an empty SILASTIC implant. T 0.5 prevented all changes, not only in bone mineral content, density, and turnover but also in lean body mass. Moreover, there were no significant differences, for all these parameters, between the different doses of testosterone replacement. In conclusion, low-dose androgen replacement does not lead to lower bone mineral density, higher bone turnover, and lower lean body mass in aged male rats, whereas complete androgen deficiency does. Therefore, the threshold concentration of testosterone necessary for prevention of both bone and lean body mass loss in aged male rats is clearly lower than for prostate and seminal vesicles.

Androgen Replacement Therapy and Women’s Health

Although androgen replacement has been in use for several decades for various gynaecological disorders, it has had few adherents in women’s health because of misconceptions that it is unphysiobgical and a male hormone. The potential role of androgens in the pharmacological management of menopausal hormone deficiency states remains to be firmly defined, but there has recently been renewed interest in the addition of low-dose androgen to the traditional estrogen replacement therapy. This is a welcome development because not all menopausal symptoms are adequately controlled with estrogen or estrogen/progestin therapy. Weight gain, increase in body hair and slight enlargement of the clitoris constitute the most important side effects experienced by androgen users. The purpose of this review is to discuss the role of androgens as an adjuvant to estrogen/progestin replacement therapy with the hope that the clinician will evaluate its incorporation into menopausal women’s health care.

Effect of low dose androgen and zinc sulfate on sperm motility and seminal zinc levels in infertile men

Beneficial effects of zinc therapy in some infertile patients with low seminal zinc concentrations and decreased sperm motility have been reported recently. The effects of zinc therapy, low-dose (5–10 mg/day) androgen therapy, and combination therapy of both zinc and low-dose androgen, on sperm motility and seminal zinc concentration were studied in patients referred to the andrology clinic. Low-dose androgen therapy increased seminal zinc concentrations and sperm motility, only when pretreatment seminal zinc concentrations were low. Furthermore, patients with low seminal zinc concentrations and poor sperm motility showed greater improvement of sperm motility and seminal zinc levels in response to zinc sulfate with fluoxymesterone than did fluoxymesterone alone or zinc sulfate alone, possibly due to a synergistic effect of zinc and androgen.

Bone marrow transplantation in severe aplastic anemia and acute leukemia

Much progress has been made in allogeneic bone marrow transplantation for severe aplastic anemia (SAA) and acute leukemia (AL). In SAA it was shown that hemopoietic chimerism and apparently permanent cures can be achieved in the majority of patients by conditioning with cyclophosphamide followed by bone marrow transplantation (BMT) from an HLA-identical sibling. The previous transfusion history is crucial for failure or success: untransfused patients do very well while graft rejection is an enormous problem in most polytransfused ones. We have shown that most patients without HLA-identical sibling donors can be adequately helped as well. After conditioning with ALG followed by transfusion of haploidentical marrow and low dose androgens there is partial to complete autologous hemopoietic reconstitution in virtually all patients. This points to the fact that most of these patients have pluripotent hemopoietic stem cells that are intact, but apparently unable to differentiate to mature cells, because they are inhibited by autoimmune mechanisms. The results of BMT in patients with endstage leukemia are modest. New pilotstudies with early marrow grafts, i.e. for ANLL in first remission and for ALL in second remission indicate that with this type of approach potentially over 50% of all patients with HLA-identical siblings can be cured. We recommend that HLA-typing should be performed early in families with SAA and AL and that the possibility of a marrow graft should be seriously considered before the patients have endstage disease. Marrow grafts are technically simple but they may pose enormous problems such as graft versus host reaction (GvH), interstitial pneumonia, graft rejection and leukemic recurrence. Therefore, the procedure should only be performed in highly specialized centers with much knowledge and experience in the immunobiology of bone marrow transplantation.

Development and decline of running behavior in rats with delayed anovulation

Running activity in an activity wheel develops slowly at puberty, reaching a maximum which is held until 100 days of age when a decline sets in. The purpose of this study was to determine whether changes in ovarian status play a role in the decline of running. The time of onset and decline of running in the peak levels achieved were comparable in intact rats, in rats ovariectomized at weaning age and given estradiol benzoate replacement in Silastic capsules and in rats rendered precociously persistent estrus as a result of neonatal treatment with 10 μg testosterone propionate (at 5 days of age). It can be concluded that the development of persistent estrus in rats treated neonatally with androgen is not preceded or accompanied by disturbances in running activity, that the early low dose androgen exposure does not alter the sensitivity of running activity to estrogen stimulation, and that the decline in running seen after puberty cannot be attributed to changes in ovarian status.

Treating the Subfertile Male Patient: Improvement in Semen Characteristics after Low Dose Androgen Therapy

Preliminary results suggest that the semen of selected patients can be improved after administration of low doses of fluoxymesterone and that the therapeutic regimen may be most beneficial for individuals with reduced sperm motility, abnormal semen morphology and/or low semen volume.