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Introduction

Prostate cancer (PCa) is the most common malignancy and the second most common cause of cancer-related deaths affecting men in developed countries.1 PCa incidence has risen over the recent decades. Factors responsible for this rise include aging population, obesity due to western dietary habits, and increasing use of prostate-specific antigen (PSA) testing.2 Prostate cells, normal or cancerous, are dependent upon androgens for survival and growth. Consequently, androgen deprivation therapy (ADT) (also called hormone therapy by some clinicians) is still the mainstay of PCa treatment. Surgical (bilateral orchiectomy) or chemical (pharmaceutical) interventions resulting in the reduction of serum testosterone or blockade of the androgen receptor, are referred to as ADT. Antiandrogens alone like flutamide, enzalutamide, and apalutamide (the modern derivatives) are not considered ADT but are used in combination with surgical or chemical castration. ADT was initially achieved by orchiectomy as the testes are the principal source of circulating androgens (producing nearly 95% of total); the remaining 5% are produced by the adrenal glands. Luteinizing hormone-releasing hormone (LHRH) agonists are the most widely used contemporary ADT modality usually offered when patients are diagnosed either with recurrent cancer after first-line treatment (such as radical prostatectomy or radiation treatment) for local disease or with advanced (incurable) disease at presentation.3 This review provides for the practicing clinician and medical provider not only a systemic overview on the evolution and the oncologic dynamics in patients undergoing traditional ADT, but also the clinical aspects and indications for the emerging new pharmaceutical ADT modalities.

The HypothalamicPituitaryGonadal axis functions as a single system or entity due to direct interaction and feedback (Figure 1). Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is secreted from the hypothalamus by GnRH-expressing neurons and stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the anterior portion of the pituitary gland which then stimulates the gonads for producing estrogen and testosterone. The therapeutic principle of Androgen Deprivation Therapy (ADT) in prostate cancer (PCa) has been established and not changed much over the last 80 years since Charles B. Huggins demonstrated the testosterone dependency of PCa.4 Huggins and Hodges first reported the dramatic clinical effects of suppressing serum testosterone levels (Figure 2) in men with advanced prostate cancer in 1941.5 Following bilateral orchiectomy of eight subjects with prostate cancer, serum acid phosphate levels decreased indicating decreased activity of the cancer. Five subjects with prostate cancer injected with stilbestrol also showed decreased serum levels of acid phosphatase while three subjects injected with testosterone propionate had an increase in serum acid phosphatase levels. For this pioneering work in treatment of advanced and metastatic prostate cancer Huggins was awarded the Nobel Prize for Medicine in 1966.

Figure 1 The hypothalamus-pituitary-testicular axis.

Figure 2 Molecule structure of testosterone.

In 1938 diethylstilbestrol (DES, Figure 3) also known as stilbestrol or stilboestrol, was discovered and then introduced for medical use in 1939.6 DES is an estrogen and it suppresses luteinizing hormone-releasing hormone (LHRH) (Figure 4) production at the level of the hypothalamus. In the past, it was widely used for a variety of indications, including treatment of metastatic prostate cancer (chemical castration) and hormonal support during pregnancy for women with recurrent miscarriage. DES has excellent bioavailability and is well tolerated when taken by mouth.7

Figure 3 Molecule structure of diethylstilbestrol (DES).

Figure 4 Molecule structure of luteinizing hormone-releasing hormone (LHRH).

In 1959 the Veterans Administrative Cooperative Urological Research Group (VACURG) was established which further evolved ADT in the treatment of advanced prostate cancer. The VACURG used prospective randomized clinical trials for investigating the role of monotherapy of estrogen versus combined therapy of orchiectomy plus estrogen in advanced prostate cancer patients.8 The major conclusions were: 1.) A daily dose of 3 mg DES was considered the optimal dose and became the accepted regimen for pharmacologic castration. 2.) A lower DES dose (1 mg) was associated with reduced cardiovascular toxicity but did not reliably achieve castrate levels of testosterone. 3.) No survival advantage of early versus delayed initiation of hormonal therapy in advanced disease. Up to the 1970s DES as hormonal therapy was widely accepted as the treatment for advanced and metastatic prostate cancer. However, its main adverse effects were increased risks of blood clots and cardiovascular events.9

Furthermore, reports in the 1970s revealed that DES caused clear-cell carcinoma of the vagina, a rare tumor in girls and women who had been exposed to this medication in utero. Due to these discoveries and the significant cardiovascular side effects DES essentially disappeared from the pharmaceutical market.10

Both surgical and pharmacologic castration resulted in dramatic palliation of painful bony metastatic lesions, and improved quality of life in prostate cancer patients. In 1971 Schally and associates purified the decapeptide gonadotropin-releasing hormone (LHRH).9 Studies showed that constant exposure to LHRH ultimately suppressed testosterone serum levels by desensitizing pituitary cells through downregulation of the LHRH receptors.11 Modification of the sixth amino acid position of the LHRH molecule was significantly more potent.12 The monthly depot of leuprolide (Figure 5) was the first LHRH agonist granted FDA approval for advanced prostate cancer. In a randomized clinical trial, leuprolide was equivalent to 3 mg of DES in reducing serum testosterone to castrate levels, but with much lower cardiovascular toxicity.13 Ultimately in the 1980s Leuprolide replaced DES and orchiectomy as the preferred approach to androgen deprivation.

Figure 5 Molecule structure of leuprolide.

Over the following decades substitutions at the sixth amino acid position yielded a variety of more LHRH agonists (goserelin, triptorelin, and histrelin), which then also became commercially available in the United States. These LHRH agonists are differentiated by their route of administration (intramuscular injection vs subcutaneous injection vs subcutaneous implant) and frequency of administration (112 months). All these LHRH agonists have similar therapeutic effectiveness in lowering serum testosterone to castrate levels, but also have a similar profile of adverse effects. One study directly compared different LHRH agonists.14 Overall improved survival with triptorelin compared with leuprolide, 97% vs 90.5% at 9 months (P = 0.033). Although not statistically significant, triptorelin seemed to better maintain castrate levels of testosterone over a 9-month interval.

The luteinizing hormone-releasing hormone (LHRH) agonists offered true medical castration but showed clinical issues due to testosterone surge and tumor flare when first administered. The flare phenomenon is attributed to the surge of serum testosterone levels caused by the initial stimulation of LHRH receptors. The introduction of antiandrogens was considered to ease this clinical issue by inhibiting the stimulation effect at the level of the androgen receptor.15 Despite initial expectations, the combined medical therapy of antiandrogens and LHRH agonists did not improve cancer-specific survival. The costs, inconvenience of therapy, added toxicity, and the introduction of the saturation model were considered the main reasons why the combined treatment never became standard of care. A 2017 literature review concluded that there is no evidence of testosterone flare following initiation of an LHRH agonist.16 It was proposed that this is due to the limited ability of androgens to stimulate prostate growthalso known as the saturation model.16 The saturation model, introduced in 2009, showed tumor growth increased when exposed to low levels of androgen, however after reaching a certain threshold, androgens no longer affected tumor growth. In the current literature there is still an ongoing and controversial debate on the validity of this saturation model.17

The introduction of Gonadotropin-releasing hormone (GnRH) antagonists offered a solution for the above mentioned flare phenomenon. This new drug class proved a rapid reduction of serum testosterone to castrate level without the initial testosterone surge and tumor flare. However, the long-term clinical benefits are still debated. A recent meta-analysis study comparing GnRH agonists and antagonists in patients with metastatic prostate cancer, showed that GnRH antagonist use was associated with a lower risk for all-cause mortality and cardiovascular events, respectively. However, this study did not find any significant differences between groups in PSA progression, musculoskeletal events, fractures or serious adverse events such as hepatic failure.18

In summary, ADT has come a long way since its introducing by Huggins for treatment of advanced and metastatic prostate cancer 80 years ago. Whereas surgical ADT via orchiectomy has become obsolete, medical ADT plays still a main role in the repertoire of treatment options for patients with recurrent, progressive and advanced prostate cancer.

LHRH/GnRH agonists, such as leuprorelin/leuprolide, goserelin, and triptorelin, are by far the most commonly utilized forms of ADT in clinical practice in the treatment of PCa, targeting the LHRH/GnRH receptor in the anterior pituitary gland and administered as an intramuscular or subcutaneous injection. They stimulate the receptor, creating a temporary surge in LH and testosterone levels followed by downregulation of the receptor over the next 23 weeks with a subsequent reduction in LH and suppression of testosterone production by the testes.19 They achieve serum testosterone levels below castration (<50 ng/dL) within 46 weeks with a subsequent reduction in the PSA level.20 The most common adverse effects (AE) associated with treatment are hot flashes, fatigue, sexual/erectile dysfunction, testicular atrophy, cognitive decline, increased risk of diabetes and cardiovascular events, and decreased bone mineral density associated with joint disorders and/or osteoporosis that needs to be monitored periodically with bone density scanning.21

LHRH/GnRH antagonists, such as degarelix, abarelix, and relugolix, are newer agents that competitively bind to the LHRH/GnRH receptor, inhibiting downstream LH signaling and suppressing testosterone secretion from the testes. LHRH/GnRH antagonists are not associated with an initial surge of serum testosterone, and castration levels are achieved within 23 days, so they are a good therapeutic option for the initiation of ADT in a newly diagnosed PCa patient.22 While degarelix is only available as a 1-month subcutaneous dose with a higher risk of adverse skin reactions, relugolix is a daily oral agent, although a food effect can reduce exposure by 50%.23 The side effect profile of LHRH/GnRH antagonists is similar to that of LHRH/GnRH agonists although since degarelix reduces FSH more than the LHRH/GnRH agonists (90 vs 50%), these lower levels of FSH may be cardioprotective, especially in men with preexisting cardiovascular disease, and may produce less muscle mass loss.24

Antiandrogens, such as bicalutamide, flutamide, and nilutamide, are some of the oldest drugs that inhibit binding of dihydrotestosterone (DHT) to the androgen receptor (AR).25 Since they do not reduce serum levels of testosterone, they can be considered as monotherapy in nonmetastatic patients who want to preserve libido and avoid the metabolic and sexual side effects of traditional ADT.26 They are, however, less effective than surgical castration or LHRH agonists/antagonists in metastatic prostate cancer (PCa) and are typically utilized concurrently with these agents for dual androgen blockade, especially during initiation of treatment with LHRH agonists to prevent clinical manifestations of testosterone surge within the first month.27 Table 1 summarizes single use versus combined use of ADT drugs and antiandrogens.

Table 1 List of ADT Drugs and Antiandrogens That Can Be Used in Combination

After long-term testosterone suppression, reactivation of AR pathways in some cell populations occur from multiple mechanisms including production of androgens by the adrenal glands and PCa cells themselves, androgen-independent activation of the AR, and AR gene amplification or overexpression.28 In this state, elimination of testosterone production from the testes is no longer sufficient to fully suppress PCa tumor cell growth, and another generation of antiandrogens is available for further testosterone suppression typically below 20 ng/dL.29

Abiraterone (in combination with traditional ADT) reduces androgen production from all sources including the testes, adrenal glands, and PCa cells through selective and irreversible inhibition of the enzyme 17-hydroxylase/C17,20-lyase (CYP17), which can suppress testosterone levels even lower than with traditional LHRH/GnRH agonists alone. In the LATITUDE and STAMPEDE study, the addition of abiraterone acetate and prednisone to standard ADT significantly increased overall survival (OS) and radiographic progression-free survival (PFS) in men with newly diagnosed, metastatic, castration-sensitive PCa.30,31 In the LATITUDE study, OS was significantly longer in the abiraterone acetate plus prednisone group compared to the placebo group (median OS: 53.3 vs 36.5 months) when administered in combination with standard ADT.32 In a meta-analysis of both studies, abiraterone plus prednisone with standard ADT resulted in a 38% risk reduction of death compared to placebo with standard ADT for metastatic hormone-sensitive PCa.33 In addition to the expected AEs associated with testosterone suppression, abiraterone may also produce side effects associated with mineralocorticoid toxicity (ie, hypertension, hypokalemia, and fluid retention) and liver function abnormalities.34 Those patients with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia need to be monitored more closely while on treatment.

Enzalutamide, another third-generation antiandrogen, competitively binds to the AR at the androgen-binding site, inhibiting nuclear translocation and interaction of the AR with chromosomal DNA, which prevents further transcription of tumor-associated Androgen genes. This prevention of AR-dependent transcription causes decreased cell proliferation and induces cell death. Enzalutamide blocks the action of testosterone at the cellular level regardless of where it is derived from and, in conjunction with traditional ADT, can be utilized for newly diagnosed, metastatic, castration-sensitive PCa.35 In the ENZAMET trial, enzalutamide with traditional ADT was associated with significantly longer PFS and OS compared to traditional ADT alone in men with metastatic, hormone-sensitive PCa (3-year OS: 80 vs 72%).36 In addition to the commonly expected AEs for an AR inhibitor, seizures and posterior reversible encephalopathy syndrome have also been seen on rare occasions, likely due to the drug crossing the bloodbrain barrier.37 Seizure occurred in 0.4% of patients receiving treatment, but in patients with predisposing factors, seizures were reported in 2.2% of patients.

Apalutamide, another oral, nonsteroidal third-generation antiandrogen that blocks the action of testosterone by blocking the ligand-binding domain of the AR, was also designed to supersede the current androgen pathway inhibitors by overcoming AR-related resistance mechanisms. Like enzalutamide, it blocks androgen-receptor nuclear translocation, inhibits DNA binding, and obstructs AR-mediated transcription. In patients with non-metastatic, castrate-resistant PCa, according to the SPARTAN trial, metastasis-free survival (MFS) and time to symptomatic progression were significantly longer with apalutamide compared with placebo in combination with standard ADT (median MFS was 40.5 months in the apalutamide group versus 16.2 months in the placebo group).38 At median 52-month follow-up, median OS was markedly longer with apalutamide than placebo (73.9 vs 59.9 months).39 In the TITAN trial of patients with metastatic, castration-sensitive PCa, OS and PFS were significantly longer with the addition of apalutamide to standard ADT compared with placebo (OS at 24 months was 82.4% in the apalutamide group versus 73.5% in the placebo group).40 The most common adverse reactions with apalutamide were fatigue, hypertension, rash, and diarrhea.

The second and third generation antiandrogen drugs typically cost more than first-generation ADT drugs such as leuprolide or antiandrogens (bicalutamide) because they are not generic and usually patent-protected.

Surgical removal of both testicles (bilateral orchiectomy) remains a viable option as an alternative to chemical castration to eliminate testicular production of testosterone. Surgical castration may be associated with significantly lower risks of peripheral arterial disease and cardiac-related complications compared to chemical castration.41 Chemical castration, however, has largely replaced bilateral orchiectomy in clinical practice in the treatment of PCa because of the ease of administration, reversibility, and the avoidance of disfiguring surgery with its associated aesthetic and psychological consequences for patients.

ADT is a mainstay second-line treatment of prostate cancer once primary curative treatment, such as radiotherapy or radical prostatectomy, has failed. ADT blocks the HPG axis (for details see chapter 1), upon which testosterone production depends this in turn starves androgen-dependent elements of a tumor. However, patients response to ADT is not uniform. Klotz et al 2015 performed a secondary analysis on data from the PR-7 trial, which had examined intermittent vs continuous ADT. They first excluded all patients who underwent intermittent ADT, then stratified the remaining men into three groups based on their nadir testosterone levels: a) <20ng/dL, b) 2050ng/dL, and c) >50ng/dL. They found that men who reached a nadir level of 2050ng/dL and >50ng/dL were at hazard ratios of 1.62 (95% CI 1.202.18) and 1.90 (95% CI 0.984.70) of developing castrate resistant prostate cancer compared to men who had reached a nadir below 20ng/dL (P<0.015). The same group of researchers also found that the median time to development of CRPC for the three subgroups (<20ng/dL, 2050ng/dL, and >50ng/dL) were 10.0, 7.21, and 3.62 years respectively.42 Morote et al 2007 studied patients with non-metastatic disease who were on ADT either as a primary treatment, or as an adjuvant treatment after radical prostatectomy. They showed that men who had testosterone levels above 50ng/dL after reaching their nadir were at higher risk for androgen-independent progression (defined as 3 consecutive rising PSA levels) (HR 2.8, 95% CI 1.35.9, P<0.008).43

It is a common clinical experience that patients on ADT will develop CRPC at some point in the future, even with low, castrate serum levels of testosterone. Montgomery et al 2008 demonstrated that testosterone levels within the tumor tissue of anorchid men had elevated intra-tumoral testosterone levels (0.74 ng/gm, 95% CI 0.590.89) when compared to tumor tissue samples from untreated eugonadal men (0.23ng/gm, 95% CI 0.030.44, P<0.0001). In addition, tumor tissue from anorchid men also had significantly increased levels of steroidogenic enzymes. The authors concluded that prostate tumors are capable of sustaining themselves through autocrine/paracrine signaling and endogenous androgen production, even when blocking the HPG axis with ADT.44

Adrenal androgens are another source of androgens missed by the central blockade of LHRH. Brendler 1973 reviewed cases of adrenalectomy and hypophysectomy in reactivated prostate cancer after failing castration therapy (nowadays we would call this CRPC). Symptomatic improvement in the adrenalectomy group was 65%, with a similar rate for hypophysectomy patients.45 However, these improvements were short lived, as the prostate cancer in these patients would apparently adapt to a more androgen poor environment. In 1983, Labrie et al revisited the clinical idea of total androgen blockade when studying 87 men with metastatic prostate cancer, some of whom had received previous hormonal therapy and some not. All patients were treated with LHRH and RU-23908, an AR blocker. The results showed that serum prostatic acid phosphatase (PAP) dropped to normal levels in 97% of patients who had not previously received hormonal treatment and had an elevated PAP prior. They also noted positive objective radiologic responses in 100% of treatment-nave patients, with several patients experiencing a complete disappearance of all bone lesions on imaging. They also noted that patients with previous systemic estrogen therapy showed a 55% response with PAP drop and an 80% response on bone imaging, respectively. The authors also found that men who had previously undergone hormonal therapy had a fast diminishing response to total androgen blockade, and they concluded that this clinical phenomenon was likely due to a selection process of tumor cell clones less dependent on systemic testosterone support.46 In 1991, Labrie et al published results of a prospective study based on a similar regimen as described earlier by substituting flumatide for RU-23908. They found that 93% of patients had a positive objective response, with 30% of patients experiencing objective regression of all bone lesions.47 In 1997, Ansari et al conducted a trial in which 100 men with metastatic castrate sensitive prostate cancer were randomized into either orchiectomy alone or orchiectomy plus flutamide. The results showed no significant difference in overall survival at 3 years, with orchiectomy alone at 45.83% and orchiectomy plus flutamide at 48.07%. This pattern held to the 5 year follow-up, with orchiectomy and orchiectomy plus flutamide at 20.83% and 23.07%, respectively.48

The next step forward came with abiraterone, a CPY17 inhibitor. It was first described in 1994 by Barrie et al as one of several novel compounds found to inhibit 17-hydroxylase/C17,20 lyase. When testing several of these compounds on mice, there were significant reductions in the weight of the prostate (50%), seminal vesicles (75%), and testes (25%) (P<0.01 for all).49 The first human trial was done by ODonnell et al in 2004. They tested different doses of abiraterone in men with advanced CRPC who were either still receiving or had received ADT. They found significant reductions in serum testosterone levels in all patients, with no grade III adverse events.50 In 2008, Attard et al performed a Phase I clinical trial of 21 patients who had known mCRPC. They found that 66% of patients experienced a reduction of PSA by 30% or more. In addition, serum testosterone became undetectable in all patients within 8 days of their first dose, and 8/11 patients who had required analgesics at baseline had reduced analgesic requirements after receiving abiraterone.51 There was a further improved response rate reported by Tran et al in 2009 in a phase I/II trial for enzalutamide: 43% of patients had a sustained reduction in PSA by 50% or more.52

The idea of maximum androgen blockade has been a goal for men with metastatic prostate cancer for decades. As mentioned earlier, Brendler described some positive therapeutic results in both patients who had undergone hypophysectomy to inhibit ACTH and thereby adrenal androgens, and in patients who had undergone adrenalectomy for the same reason. However, this success typically came at a high cost. The next step forward on maximum androgen blockade came with Labrie in 1983, when he described the use of both LHRH and a first-generation AR blocker. His results in CRPC were impressive, with many patients experiencing both objective responses on imaging as well as symptomatic relief. Newer anti-androgen pharmaceuticals like abiraterone and enzalutamide have shown impressive objective response rates in prospective and randomized FDA trials, and have evolved to be part of the updated AUA guidelines in the treatment repertoire for asymptomatic and symptomatic mCRPC.

The timing of androgen deprivation therapy (ADT) in the management of recurrent and advanced prostate cancer has been controversial for many years. This is mainly due to a lack of adequate randomized clinical trials comparing early vs delayed ADT in patients with recurrent PSA following failure of local curative treatment. To date the available studies and current guidelines are stating that early use of ADT to be only beneficial in symptomatic patients with recurrent or metastatic disease. The EAU recommends ADT only in symptomatic patients requiring palliative treatment.53 In the following we summarize the current practice guidelines on timing of ADT in patients with recurrent prostate cancer after failing local curative treatment.

Messing et al performed one of the first landmark studies addressing the timing of androgen deprivation therapy (ADT) and its effect on survival in patients with node positive prostate cancer following radical prostatectomy and pelvic lymphadenectomy. This randomized controlled trial enrolled 100 patients between 1988 and 1993 who had previously undergone surgery and had histologically proven nodal metastasis. The patients were randomly assigned to receive either immediate ADT or active surveillance with ADT intervention only given on proven symptomatic recurrences or detection of distant metastasis. This study revealed superiority of immediate ADT compared to delayed ADT: Significantly improved overall survival (hazard ratio 1.84 [95% CI 1.013.35], p=0.04), disease specific survival (4.09 [1.769.49], p=0.0004) and progression free survival (3.42 [1.965.98], p<0.0001). The main points of criticism for this study were the low number of recruited patients and that this study did not involve patients with high-risk local disease without node involvement leading to uncertainty of optimal ADT timing for this category of patients.54 Additionally, this debate emphasized the need for further clinical research on optimal ADT timing in patients with PSA recurrence following local curative treatment.

The EAU/ESTRO/SIOG guidelines for localized prostate cancer state that routine use of ADT should be avoided in nonmetastatic patients with the exception for symptom control. This clinical recommendation is based on the EORTC Trial 30,891 which compared immediate versus deferred ADT in T0-4 N0-2 M0 prostate cancer patients unsuitable for local curative treatment. While this trial did not address PSA recurrence following local curative intervention (i.e RP vs RT), it did, however, provide evidence for the benefit of immediate ADT in patients at increased risk of cancer-specific mortality. This study included patients with high baseline PSA (>50ng/mL) and/or a PSA Doubling Time <12 months. The authors stated that patients not meeting these high-risk inclusion criteria were indeed more likely to die of other causes unrelated to prostate cancer.55

Similar to the European guidelines, the AUA/ASTRO/SUO guidelines do also not recommend early initiation of ADT without proven metastatic disease in patients who have failed maximal local therapy.56 This recommendation is mainly based on the observational study by Garcia-Albeniz et al in 2006 where eligible patients had previously been recruited for the Cancer of the Prostate Strategic Urologic Research Endeavour (CaPSURE). These patients had failed prior local curative treatment and had been treated either with immediate or deferred ADT. The study revealed no survival benefits for immediate ADT vs deferred ADT initiation in patients with recurrent PSA. The adjusted mortality hazard ratio for immediate versus deferred ADT was 0.91 (95% confidence interval (CI), 0.521.60), which would be translated into a similar 5-year survival (difference between groups: 2.0% (95% CI: 10.0 to 5.9%). This suggests that in the absence of randomized control studies early ADT initiation does not provide a major survival benefit compared to deferred ADT therapy.57

Van den Bergh and colleagues performed a systematic literature review to assess the effectiveness of ADT in patients with PSA recurrence following local curative treatment. This meta-analysis found that the benefit of early/immediate ADT for nonmetastatic prostate cancer recurrence remains unproven. The conclusion was that early ADT should be reserved for patients with the highest risk of progression based on PSADT or Gleason Score, but having a long life expectancy. This falls in line with the current standard of care recommendations of the EAU/ESTRO/SIOG and AUA/ASTRO/SUO.58

Overall, currently there is a lack of randomized controlled trials (RCT) assessing the impact of early compared to delayed ADT in the management of recurrent prostate cancer following local curative therapy, which has led to the continued controversial debate on this subject. To date no RCT has addressed or shown the benefit of specific ADT timing in patients with recurrent PSA. Bruchovsky and colleagues proposed the idea of Intermittent Androgen Deprivation Therapy as a means to reduce side effects and improve quality of life. However, further research is needed for clarification of the optimal timing of reexposure of prostate cancer cells to androgens and its impact on delaying androgen resistance, which may also be influenced by early or delayed ADT.59 This situation has led to the clinical practice that early ADT is provided only to symptomatic patients in particular when weighing the long-term risks associated with ADT. Unfortunately, due to the lack of adequate RCTs we still are waiting for clear answers regarding the oncological benefits of early vs delayed ADT in asymptomatic patients with recurrent or advanced prostate cancer.53

Since the 1940s, androgen deprivation therapy (ADT) has been the foundational treatment for prostate cancer. Bilateral orchiectomy, the original form of ADT, is still used worldwide, in particular in the developing world. Medical ADT options are the standard of care when available. It is well documented in the literature that ADT is associated with numerous significant adverse effects which include hot flashes, loss of libido, erectile dysfunction, loss of muscle mass and strength, fatigue, anemia, breast enlargement and tenderness, mood swings, osteoporosis and bone fractures, obesity, cardiovascular disease, insulin resistance and diabetes. Some studies also see ADT associated with cognitive decline and dementia (for details see Chapter 9 of this review).

Intermittent androgen deprivation therapy (iADT) is a cyclic therapy with cessation of ADT (also called treatment holidays by some clinicians) allowing serum androgen recovery. The clinical idea is based on animal studies showing that iADT delayed tumor progression.60 Furthermore, the rationale for iADT is based on balancing drug-related toxicity and oncologic benefits. As continuous ADT (cADT) is associated with substantial side effects, which may increase with duration of therapy, many clinicians consider iADT as an alternative providing reduced morbidity, and thus improved quality of life, with the possible oncological benefit of delaying castration-resistant PCa.

The PR-7 trial, a landmark study, randomized patients for iADT and cADT with biochemical recurrence after either failing primary local treatment or salvage external radiotherapy.61 Eligible patients had PSA levels 3 ng/mL and no evidence for metastatic disease. The overall survival in patients that underwent iADT was 8.8 years compared to 9.1 years in patients that underwent cADT (HR=1.02, 95% CI= 0.861.21) indicating no significant difference. Furthermore, this study showed a non-inferiority P-value of 0.009 for iADT in overall survival. The study also revealed that other causes of death unrelated to PCa were more common in those receiving cADT, leading to the conclusion that intermittent therapy may not only reduce drug-related morbidity, but even mortality associated with cADT toxicity. Furthermore, patients with high-grade disease showed no improved overall cancer-specific survival when receiving cADT.

The ICELAND study published in 2016 is considered one of the main studies on iADT vs cADT in patients with relapsing prostate cancer.62 This prospective study included 102 different locations in 20 European countries and followed more than 700 participants randomized either to iADT or cADT. The authors found no difference in overall survival between the two groups, and they also emphasized the obvious reduced drug cost benefit of iADT over cADT.

The SWOG trial initiated by Dr. Hussain enrolled patients with metastatic, hormone-sensitive disease.63 All patients received an initial 7-month induction course of ADT. Patients with responding PSA levels 4 ng/mL were subsequently randomized to iADT or cADT (770 to iADT and 765 to cADT). The Kaplan-Meier curves were very similar, the hazard ratio was 1.10 with a confidence interval of 0.99 to 1.23. The pre-specified upper boundary of the confidence interval for non-inferiority was 1.20. Therefore, neither superiority nor non-inferiority could be concluded. However, the study data showed improved quality of life outcomes in the iADT arm: Better erectile function, improved bone density, less ischemic and thrombotic events.

A meta-analysis of seven studies with a total of 4810 patients treated with iADT or cADT between the years 2009 and 2015 showed no significant difference regarding cardiovascular events (risk ratio (RR): 0.95; confidence interval (CI) 95%=0.831.08) and thromboembolic events (RR: 1.05; CI 95%=0.851.30). However, iADT was associated with lower cardiovascular-related mortality.64

Another meta-analysis of randomized controlled trials (RCTs) assessed the risks of disease progression, all-cause, and cancer-specific mortality.65 Eight RCTs with 4664 patients were included in this report. It did not find any statistical difference in overall mortality and cancer-specific mortality between iADT and cADT. Again, the authors observed a better quality of life outcome for iADT, and therefore, they concluded that patients should be informed of the potential benefits of iADT.

Dason et al found that iADT was non-inferior to cADT in the primary setting of biochemical recurrence after radiation treatment of non-metastatic local prostate cancer. In the metastatic prostate cancer setting, iADT was also found to be non-inferior to cADT. Additionally, the authors reported that many ADT-related symptoms improved or resolved during the off-cycle with iADT.66

The results of a retrospective Japanese study on PSA recurrence after radical prostatectomy supported the hypothesis that iADT may delay castration-resistance in PCa.67 The iADT group had a significantly higher 5-year non-recurrence rate (92.9% vs 57.9%, p <0.001) and a better 10-year overall survival rate (95.9% vs 84.3%, p = 0.47) than the cADT group.

When summarizing the presented and pooled data, iADT provides better quality of life, whereas cancer-specific mortality shows interchangeable findings for iADT and cADT. Some studies even show improved overall survival for iADT patients likely due to reduced medication-related toxicity. Significantly reduced drug costs are also a strong rationale for iADT. Over more than one decade, iADT has evolved as the first option for patients after failing first-line local treatment in the absence of extensive metastatic disease. Although there are no well-defined recommendations or guidelines, the AUA/ASTRO/SUO website makes the following statement:

if ADT is initiated in the absence of metastatic disease, intermittent ADT may be offered in lieu of continuous ADT. (Conditional Recommendation; Evidence Level: Grade B)68

iADT may be considered after at least 912 months of ADT or until PSA nadir has been reached (in an ideal clinical scenario with PSA < 0.1 ng/mL). The off-treatment period varies depending on PSA monitoring and PSA rising, but also on patients and physicians preference. Again, there are no well-defined recommendations or guidelines at what PSA threshold ADT should be resumed. Some clinicians restart ADT when PSA doubling time (PSADT) is less than 6 months or when serum PSA has reached a level of 610 ng/mL. Some clinicians and medical providers set this threshold even far above 10 ng/mL.

Radiation Therapy (RT) and its part in prostate cancer (PCa) management has continued to evolve as this Technology has improved over time, and research has led to a better understanding of the oncologic disease dynamics. Radiation therapy for prostate cancer consists of targeted energy beams such as External Beam Radiation Therapy (EBRT) or implantable radioactive seeds such as Brachytherapy, which destroy and thus eliminate neoplastic cells. While there are diverse subcategories of radiation-based therapies (such as Intensity Modulated Radiation Therapy, Proton Beam Therapy, and Low/High Dose Rate Implants), the risk and benefits of each as well as other factors such as the patients preference ultimately guide the decision of the selected type of therapy. There are varying degrees of early and late mainly gastrointestinal and genitourinary complications caused by RT which underscore the need for shared decision making between treating physicians and PCa patients.56,69

The current AUA/ASTRO/SUO guidelines for management of advanced prostate cancer recommend primary radiotherapy in combination with ADT as a treatment option for selected patients with hormone sensitive prostate cancer and low volume metastatic disease (mHSPC). This is only a conditional recommendation with Grade C (low) level evidence and is mainly based on two preliminary Phase III trials (HORRAD and STAMPEDE Arm H) showing some benefit of combined therapy in these patients.56 These studies are still ongoing and may provide additional information to guide clinical practice in the upcoming years.

However, the AUA/ASTRO/SUO do not recommend combined therapy on localized, low risk prostate cancer except for the management of prostatic size reduction in selected patients undergoing brachytherapy.69 This recommendation stems from the randomized, phase III trial by Jones et al in 1979 which failed to show any overall survival benefit in low risk prostate cancer patients receiving EBRT with ADT vs EBRT alone; the 10-year overall survival was 64% to 67% (hazard ratio, 1.07; 95% CI, 0.83 to 1.39). In this trial the greatest clinical benefit of combined therapy was seen in the intermediate prostate cancer group: overall survival improved from 54% to 61% (hazard ratio, 1.23; 95% CI, 1.02 to 1.49).70

In the HORRAD trial prostate cancer patients with bone metastasis showed no overall survival benefit with the combination of ADT and Radiation Therapy. This study was a multi-Center randomized controlled trial on primary metastatic prostate cancer (20042014), and 432 patients were randomized to ADT with Radiation Therapy vs ADT alone. The median survival was not statistically different: 45 months (95% confidence interval [CI], 40.449.6) in the ADT plus radiation therapy group, and 43 months (95% CI: 32.653.4) in the control group (p=0.4). The overall survival was also not found different (hazard ratio [HR]: 0.90; 95% CI: 0.701.14; p=0.4).71

In the STAMPEDE phase III trial (Arm H) more than 2000 patients with metastatic prostate cancer on lifelong ADT were randomized to receiving additional radiation therapy. Radiation Therapy did improve failure-free survival (HR 0.76, 95% CI 0.680.84; p<0.0001), but not overall survival (0.92, 0.801.06; p=0.266). However, radiation therapy showed a trend to improve overall survival in those patients with low metastatic burden (73% vs 81% at 3 years).72

Shipley et al performed the landmark trial on the benefits of combining ADT and Salvage Radiation Therapy for post prostatectomy patients with persistent/recurrent PSA. These patients had either pT2 disease with positive surgical margins or pT3 disease without nodal involvement. This double blind, placebo-controlled trial recruited 760 eligible patients between 1998 and 2003 who underwent 24 months of ADT (Bicalumatide) in addition to salvage radiation therapy. This study showed in the ADT plus radiation arm significant higher rates in overall survival, but also decreased incidence of metastasis and cancer-related deaths compared to radiation therapy alone.73

The clinical trial done by Warde et al confirmed the unequivocal benefits of combining ADT and Radiation therapy in the management of nonmetastatic, locally advanced high-risk prostate cancer. This randomized, phase III trial included 1205 patients with high-risk pT2 and pT3/T4 prostate cancer over a 10-year period (19952005) who were randomized either to Radiation Therapy + ADT or ADT alone. The results showed an explicit overall survival benefit when receiving the combination therapy (74% vs 66%).74

Based on current guidelines Low and Intermediate Risk local Prostate Cancer may be treated with EBRT alone.69 However, the still ongoing EORTC 22991 trial with over 800 patients randomized to radiation therapy alone vs radiation therapy plus ADT showed at 7.2 years median follow-up that the radiation therapy plus ADT arm had significantly improved biochemical disease-free survival (DFS) (HR, 0.52; 95% CI, 0.41 to 0.66; P = 0.001) as well as clinical progression free survival (PFS) (HR, 0.63; 95% CI, 0.48 to 0.84; P = 0.001). Overall survival data is still pending. These results suggest an overall benefit with combination therapy in improving biochemical and clinical disease-free survival.75

A meta-analysis by Spratt et al revealed that ADT and radiation treatment sequencing may also be an important aspect. Adjuvant ADT post radiation therapy improved Metastasis Free Survival (MFS) and Progression Free Survival (PFS) compared to Neoadjuvant ADT without increasing long-term toxicity. The authors reviewed two randomized Phase II Trials (Ottawa 0101 and RTOG 9413) in the management of localized prostate cancer, and concluded that delaying radiation therapy to perform neoadjuvant ADT did not lead to additional tumor control or reduced toxicity and may actually be inferior to adjuvant ADT.76

Summarizing the present and available data, it appears that the combined therapy (RT + ADT) is of greatest benefit in patients with high-risk local disease. In addition, some patients with hormone sensitive prostate cancer and low volume metastatic disease may also benefit from combination therapy.

Docetaxel, a taxane-based systemic chemotherapy agent, was one of the first additional agents to emerge as a treatment with strong evidence for an overall survival (OS) benefit in patients with metastatic, castrate-sensitive prostate cancer in addition to standard ADT. In the CHAARTED trial, patients with metastatic, hormone-sensitive prostate cancer were randomized to treatment with either traditional ADT alone (which consisted of surgical castration with orchiectomy or medical castration with LHRH agonists such as leuprolide) versus ADT plus docetaxel, which they received as 75 mg/m2 every 21 days for six cycles.77 Median OS was 13.6 months longer (57.6 vs 44.0 months, HR: 0.61) in the ADT plus docetaxel group compared to traditional ADT alone.77 The survival benefit of adding docetaxel to ADT was even more pronounced in high-volume disease (defined as the presence of visceral metastases and/or greater than or equal to four bone lesions with at least one beyond the spine and/or pelvis) with median survival increased by 17.0 months compared to ADT alone (HR: 0.60).77 Additional benefits in the ADT plus docetaxel group included a longer time to the development of castrate-resistant disease, higher rate of decline of the PSA to <0.2 ng/mL at 12 months, and a lower incidence of prostate cancer-related death.77

Another trial called the STAMPEDE trial was published assessing the role of docetaxel in the metastatic hormone-sensitive prostate cancer space.78 When comparing the ADT plus docetaxel group to ADT alone, STAMPEDE again suggested an overall survival benefit with ADT and docetaxel for the subset of patients with metastatic disease (HR: 0.80).78 Patient selection in this trial notably included not only men with metastatic disease (61% of participants), but also patients with node-positive and high-risk localized disease.78

In a meta-analysis performed with the combined data from GETUG-AF15, CHAARTED, and STAMPEDE, men with metastatic castrate-sensitive disease across all three studies had a statistically significant overall survival benefit with the addition of docetaxel to traditional ADT (HR: 0.72).79 The combined data from all three trials yielded an overall 27% risk reduction of death for prostate cancer patients with metastatic disease (HR: 0.73), and a 33% risk reduction of death in high-volume, metastatic, castrate-sensitive prostate cancer patients (HR: 0.67).79

Abiraterone acetate is an androgen biosynthesis inhibitor. Another analysis of the STAMPEDE trial utilized standard ADT alone versus ADT with abiraterone (1000 mg) daily with prednisolone (5 mg daily) to assess its role in men with metastatic, castrate-sensitive prostate cancer, nodal disease, or high-risk localized disease.31 Over a three-year follow-up, overall survival was 83% in the abiraterone plus ADT group vs 76% in the ADT alone group (HR: 0.63).31

In the LATITUDE trial, patients were randomly assigned to ADT alone versus ADT with abiraterone (1000 mg) daily with prednisolone (5 mg daily).30 After a median follow-up of 30.4 months, overall survival was significantly longer in the abiraterone + ADT group than in the ADT alone group (not reached versus 34.7 months, HR: 0.62).30 Progression-free survival was 33.0 months in the abiraterone + ADT group and 14.8 months in the ADT along group (HR: 0.47).30

Enzalutamide is a potent androgen-receptor inhibitor. In the ARCHES trial, 1150 men with metastatic, hormone-sensitive prostate cancer were randomized 1:1 to receive either 160 mg enzalutamide daily plus ADT or ADT plus placebo.80 Sixty-three percent of the study participants had high-volume disease, defined as either visceral metastases or 4 bony metastases with at least one outside the spine/pelvis.80 The risk of radiographic progression or death was significantly reduced with enzalutamide plus ADT compared to placebo plus ADT (HR: 0.39).80 This benefit was similarly seen regardless of disease volume or prior docetaxel chemotherapy. Enzalutamide plus ADT significantly reduced the risk of PSA progression, initiation of new antineoplastic therapy, first symptomatic skeletal-related event, castration resistance, and reduced risk of pain progression compared to ADT with placebo.80

Another contemporary trial evaluating enzalutamide in the metastatic, hormone-sensitive prostate cancer space, ENZAMET, randomized 1125 men with metastatic, castrate-sensitive prostate cancer to treatment with enzalutamide 160 mg daily + ADT versus traditional ADT alone.36 At median follow-up of 34 months, overall survival was improved in the enzalutamide + ADT group compared to the ADT alone group (HR: 0.67).36 Better outcomes with enzalutamide + ADT were also seen in PSA and clinical progression-free survival (HR: 0.39 and 0.40, respectively) compared to ADT alone.36 Enzalutamide was associated with significantly longer progression-free and overall survival than standard care with traditional ADT in men with metastatic, hormone-sensitive prostate cancer.36

Apalutamide is an inhibitor of the ligand-binding domain of the androgen receptor. In the TITAN trial, over 1000 patients with metastatic, castration-sensitive prostate cancer were randomized to receive apalutamide (240 mg per day) with traditional ADT or placebo with ADT.40 A total of 10.7% had received previous docetaxel therapy, 62.7% had high-volume disease, and 37.3% had low-volume disease.40 Progression-free survival at 24 months was 68.2% in the apalutamide with ADT group versus 47.5% in the placebo with ADT group (HR: 0.48).40 Overall survival at 24 months was also greater with apalutamide + ADT than with placebo + ADT (82.4% versus 73.5%, HR: 0.67).40

All four agents (docetaxel, abiraterone, enzalutamide, and apalutamide) have been FDA-approved for the treatment of metastatic, castration-sensitive prostate cancer and are now listed as category 1 recommendations within the NCCN guidelines.81 Treatment choice between agents for metastatic, hormone-sensitive prostate cancer is a challenge, and there is currently no clear consensus on preferential initial selection or sequencing of these agents. There is, however, a moderate degree of uncertainty in the role of chemotherapy in low-volume disease patients.82 Marchioni et al systematically reviewed the literature according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria and found that no treatment was superior to docetaxel in terms of overall survival.83 However, abiraterone (HR: 0.89), enzalutamide (HR: 0.90), and apalutamide (HR: 0.90) showed nonstatistically significant lower overall mortality rates when compared to docetaxel.83 Abiraterone (HR: 0.71), enzalutamide (HR: 0.61), and apalutamide (HR: 0.74) also showed statistically significant lower disease progression rates when compared to docetaxel.83

Despite its effectiveness, nearly all patients on ADT will progress to castrate resistant prostate cancer (CRPC).84 CRPC is defined as biochemical or radiologic progression of disease in spite of castrate level testosterone (<50ng/dL). In the past, ADT was stopped after a cancer became castrate resistant however, Taylor showed in 1993 that there was a survival benefit of 26 months with continued ADT.85 Since then, the AUA has recommended continuing ADT in both metastatic and non-metastatic CRPC.86 In 2015, Merseburger reviewed the rationale for continuing ADT as a backbone of treatment after development of CRPC, and found no trials to this point that compared either abiraterone or enzalutamide with ADT versus without. The SPARE trial done in Germany is comparing abiraterone monotherapy with abiraterone plus ADT however, the final results are still pending. Hen comparing clinical studies Merseburger et al noticed that patients with CRPC who were started on abiraterone with prednisolone benefited from continued ADT, as the LH surge after discontinuing ADT overcame the inhibition of abiraterone. Similarly, they found that there was limited data comparing enzalutamide alone versus enzalutamide with ADT all previously published phase III trials on enzalutamide had continuation of ADT as an inclusion criteria.87

In this context the NCCN guidelines state that androgen receptor activation and autocrine/paracrine androgen synthesis are potential mechanisms of recurrence of prostate cancer during ADT (CRPC), and they recommend continuation of traditional ADT.88 Harris et al 2009 studied mechanisms of androgen persistence in prostate cancer despite ADT they found that prostate cancer cells could bypass castration with multiple mechanisms, including upregulation of the androgen receptor and synthesis of DHT in prostate cancer cells.89 Dai et al 2017 discusses changes to the androgen receptor itself as prostate cancer is treated. The androgen receptor is an intracytoplasmic steroid hormone receptor that functions as a nuclear transcription factor after an androgen binds to its ligand binding domain. In men with prostate cancer treated with ADT, mutations in the androgen receptor are seen in 1030%. On of the most common involves the loss of the ligand binding domain (the target of enzalutamide), which uncouples transcription of the targets of the androgen receptor from its activation by androgens.90 As outlined below, these pathways provide targets for newer hormonal therapies.

For a CRPC to be considered non-metastatic, it must meet the criteria of castrate resistance without radiologic evidence of metastasis on CT or technetium-99m bone scan. Once non-metastatic CRPC (nmCRPC for short) has been confirmed, the next important clinical variable is PSA doubling time (PSADT).

In patients with a PSADT greater than 10 months, the AUA and NCCN recommend continued ADT to maintain castrate level. Serial PSAs should be drawn every 36 months for adequate monitoring PSADT. Additionally, imaging should be obtained every 612 months for re-staging and to rule out development of metastatic disease.

In patients with a PSADT less than 10 months, the AUA and NCCN recommend continued ADT with a non-steroidal anti-androgen such as apalutamide, darolutamide, or enzalutamide. Smith et al 2018 showed a difference in median metastasis-free survival of 40.5 months vs 16.2 months in the apalutamide vs placebo group (P<0 0.001), as well as a significant benefit in time to symptomatic progression, with a hazard ratio of 0.45 (95% CI, 0.320.63 - P<0.001).91 Similar benefits for enzalutamide were shown by Hussain et al in 2018, with a difference in median metastasis free survival of 36.6 months for enzalutamide versus 14.7 months for placebo (P<0.001).92 Fizazi et al 2019 showed a similar benefit for darolutamide, with median metastasis free survival at 40.4 months versus 18.4 months for placebo (hazard ratio 0.41, 95% CI 0.340.50, P<0.001).93 Finally, a review by Mori et al 2020 showed that apalutamide and enzalutamide were more effective than darolutamide in regards to metastasis free survival and PSA-progression free survival, while darolutamide had an overall lower rate of adverse events.94

A patient is considered to have progressed from nmCRPC to metastatic CRPC (mCRPC) when metastatic disease is confirmed on imaging. Depending on previous treatments, the patient may have several options for ADT. Importantly, both the AUA and NCCN recommend continuation of traditional ADT with either GnRH/LHRH agonists or antagonists. Further treatment options depend on prior treatment.

In men with mCRPC without any prior novel hormone therapies (including abiraterone, apalutamide, enzalutamide, or darolutamide) several different treatment options are recommended - these include abiraterone with a steroid, docetaxel, and enzalutamide. Abiraterone is an inhibitor of cytochrome P-450c17, which ultimately manifests in inhibition of 17-hydroxylase and 17,20-lyase. Ryan et al 2013 examined abiraterone with steroid versus placebo in patients with mCRPC on ADT, who had not been previously treated with chemotherapy. Median overall survival was not reached in the abiraterone plus steroid group, while it was 27.2 months in the placebo group (HR 0.75, 95% CI 0.610.93, P<0.01). They also benefit in radiographic progression free survival, with 16.5 months versus 8.3 months in the placebo group (Hazard ratio 0.53, 95% CI 0.450.62, P<0.001).95 De Bono et al 2011 examined the role of abiraterone in mCRPC after treatment with chemotherapy and noted an overall survival of 14.8 months for abiraterone plus prednisolone versus 10.9 months for placebo, with a hazard ratio of 0.66 (95% CI 0.560.79, P<0.001). The same study also noted a benefit to progression free survival according to radiographic imaging, with 5.6 months on abiraterone versus 3.6 months with placebo (HR 0.67, 95% CI 0.590.78, P<0.001).96

Similar results were found with the AR blocker enzalutamide in mCRPC. Beer et al 2014 examined enzalutamide in mCRPC before use of chemotherapy. They showed a benefit in in cancer-specific survival, where 72% on enzalutamide and 65% in the placebo group (Hazard ratio 0.71, 95% CI 0.600.84, P<0.001). Additionally, radiographic progression free survival was 65% in the enzalutamide group versus 14% in the placebo group (Hazard ratio 0.19, 95% CI 0.150.23, P<0.001).97 Scher et al showed similar benefits when enzalutamide was used after receiving chemotherapy for mCRPC, with a difference in survival of 18.4 months for enzalutamide versus 13.6 months for placebo (HR 0.63, 95% CI 0.530.75, P<0.001). The same study showed a benefit in radiographic progression free survival, with 8.3 months versus 2.9 months (HR 0.40, 95% CI 0.350.47, P<0.001).98

The conclusion of the above a data is that ADT is still standard of care in nmCRPC and mCRPC alike, even with the introduction of new modalities.

ADT has been associated with undesirable side effects ranging from musculoskeletal decline to autoimmune disorders. The aim of this narrative is to summarize and update the adverse effects of ADT with studies published within the past 6 years.

It is well documented that ADT is associated with decreased bone mineral density (BMD) and an increased risk of developing osteoporosis and bone fractures. In one study, BMD decreased by 2.5%, 4.28%, 5.34%, and 6.16% after 6, 12, 18 and 24 months respectively following initiation of ADT.99 Patients on ADT also had an increased risk for any fracture (HR=1.4, CI=1.281.53), hip fractures (HR= 1.38, CI=1.201.58), and major osteoporotic fractures (HR=1.44, CI 1.281.61).100

Subsequent studies also illustrated the effect of ADT on muscle strength and volume. A 2016 study showed a decrease in self-reported physical functioning in men receiving ADT. Objective measurements of both grip strength and chair rise showed that grip strength was significantly diminished after 12 months of receiving ADT (P=0.01), and chair rise performance was significantly worse at both 6 and 12 months (P=0.02, P=0.003).101 Another study has confirmed differences in muscle volumes, measured by MRI, in patients on ADT. The levator ani muscle volume in men receiving ADT was significantly lower than in men of the control group (P=0.002). These men lost 16% of their initial baseline muscle volume when compared to the control. Patients on ADT had significant muscle loss in the gluteus maximus, iliopsoas, and quadriceps (P=0.017, P=0.013, P=0.031) along with increased intramuscular fat in the gluteus maximus (P=0.003).102

Metabolic syndrome is a set of symptoms that increase the risk of stroke, cardiovascular disease, and type II diabetes mellitus (DM). There is an increased risk of developing DM in prostate cancer patients treated with ADT than patients not treated with ADT (HR=1.49, CI= 1.341.66).103 ADT was also associated with higher risk of complications in patients previously diagnosed with DM. Patients on ADT had a 17% increased risk of developing diabetic retinopathy, 14% higher risk for diabetic neuropathy, and twice as likely to have diabetic amputations.104

In longitudinal cohort study of 190 men undergoing ADT, mean triglycerides (P<0.001), HDL cholesterol (P<0.001), and waist circumference (P<0.001) were significantly increased 6 months and 12 months after initiating ADT.105 Although HDL cholesterol is known to improve cardiovascular Health, an increase in overall cholesterol and triglycerides have negative effects as shown in the next two studies. Patients on ADT were at a higher risk of coronary heart disease and myocardial infarctions (OR=2.07, P<0.01).106 ADT also increased the risk for ischemic stroke (HR= 3.32, CI-1.149.67, P=0.028) when compared to non ADT users.107

The effect of ADT on cognitive function is still controversial. In one study, patients on ADT had more cognitive deficits in language ability, short-term memory, mental flexibility, and inhibitory control (P<0.05) when compared to a control group.108 A literature review and meta-analysis found an increased risk of new dementia onset (of any cause) and Alzheimer disease in patients on ADT (HR=1.21, CI=1.111.33; HR=1.16, CI=1.071.72).109 However, study results are conflicting as another retrospective study using the Taiwan Longitudinal Health Insurance Database in 5340 patients found no significant difference in Alzheimer or Parkinsons disease between patients receiving ADT and patients who did not receive ADT (HR=1.76, CI=0.555.62; HR=1.13, CI=0.582.20).110 When summarizing the reported data, several investigators think that there is a trend of cognitive decline under ADT, but they also agree that further prospective clinical studies are necessary.

A diagnosis of prostate cancer can be devastating patients and their families, and published data has shown that ADT can further increase psychiatric stress, and therefore, its impact must be considered when choosing the best alternative of therapy. The self-reported depression scores were higher in patients on ADT at 12 and 15 months when compared to patients with BPH or post prostatectomy.111 Furthermore, 43.1% of patients on ADT experienced higher incidence of anxiety when compared to control (P<0.001). This study also showed a correlation between longer duration of therapy and higher risk of anxiety (HR= 1.16, CI=2.041.29, P=0.01).112

Androgens can affect hematopoiesis and immunology. Patients on ADT are at increased risk of developing iron deficiency anemia (HR=1.62, CI 1.242.12).113 A retrospective study showed the association between ADT and the risk of developing any hematologic disorder including anemia and hematologic malignancy when compared to patients who underwent radical prostatectomy (HR=1.60, CI=1.291.97; HR 1.98, CI=1.62, 2.42). This associated risk even increased with longer duration of ADT (P<0.001).114

A study in 2016 analyzed the association between ADT and community acquired pneumonia: 62.2% of patients on ADT had respiratory events compared to 54.5% patients who did not receive ADT and 47.8% of patients who underwent one-sided orchiectomy (P<0.001). Patients with more than 11 doses of ADT were at increased risk for developing sinusitis, bronchitis, and pneumonia (HR=1.13; HR=1.26; HR=1.15; all P<0.001).115

The association between ADT and autoimmune diseases apparently depend on the type of disease. Whereas patients on ADT had a 23% increased risk of developing rheumatoid arthritis (HR1.23, CI 1.091.40),116 ADT seems to have a protective role in developing inflammatory bowel diseases: A decreased risk for ulcerative colitis (HR= 0.52, CI= 0.280.99) and Crohns disease (HR=0.38, CI 0.111.37).117

Although ADT is an effective treatment for prostate cancer, it comes with many risks and potentially harmful side effects. Therefore, a detailed risk-benefit discussion should be provided to the patient before initiating this form of treatment.

Bone mineral density (BMD) testing in patients on ADT is underutilized, and many men are unaware how to monitor and maintain good bone health. Clinical investigators have recommended to address patient education on risks of osteoporosis and strategies to improve bone health while on ADT. A 2018 study showed that a bone health pamphlet and support from a bone-health care coordinator resulted in a significantly higher percentage of men undergoing BMD testing when compared to men who underwent usual care (P<0.001). This bone health pamphlet given by the family physician also resulted in a significantly higher percentage of BMD testing (P=0.047).118

Lifestyle modifications including smoking cessation and reduced alcohol intake are recommended for patients on ADT.119 In addition, recent studies have confirmed the benefits of exercise on muscle and bone health for men on ADT. A 2019 study compared BMD in ADT patients who were randomized into immediate exercise and delayed exercise (6 months of usual activity followed by a 6-month exercise program). There was significant preservation of lumbar spine BMD in the immediate exercise group when compared to the delayed exercise group. There were no significant differences in whole body, spine, or hip BMD. Lean mass, appendicular skeletal muscle, and muscle density were preserved in the immediate exercise group after 6 months, while the delayed exercise group recovered after 12 months.120 A 2018 randomized and controlled trial evaluated the effect of home-based exercise intervention on bone-health outcomes. Although there was no difference in bone health, this study showed significantly improved muscle strength in the home-based exercise group when compared to the placebo intervention of stretching exercise.121 Improved muscle strength not only improves vitality in patients on ADT, but may also improve some of the metabolic side effects of ADT. There is some evidence of reduced risks of accidental falls and fractures in patients on ADT when participating in exercising programs, however there is a lack of robust prospective and randomized clinical trials to support this hypothesis.

The National Osteoporosis Foundation recommends a daily calcium intake of 1200 mg and vitamin D supplement of 8001000 IU/d for all men over the age of 50.122 A 2015 study analyzed whether the recommended vitamin D supplementation of 800IU/d increased blood levels of 25-OH vitamin D in patients receiving ADT. Regression analysis showed vitamin D supplementation was associated with increased 25-OH vitamin D serum levels supporting the current recommendation of 800 IU/d for men receiving ADT.123

Two controlled studies have analyzed the effect of zoledronic acid on BMD in patients undergoing ADT. In one study with 32 ADT patients diagnosed with nonmetastatic prostate cancer and osteopenia or osteoporosis received zoledronic acid for 12 months or no treatment. The patients on zoledronic acid treatment were significantly older than the control group and had lower BMD at baseline. BMD of the lumbar spine and hip were significantly increased in the patients on zoledronic acid following 12 months of treatment.124 Similar results were found in a 2-year trial of 76 men showing increased BMD in the lumbar spine and hip when on zoledronic acid versus the control. However, there was no difference in bone microarchitecture measured by high-resolution peripheral quantitative computed tomography indicating that zoledronic acid may slow but does not prevent unbalanced bone modeling.125 These studies have small sample size and inconsistencies in dosing of zoledronic acid, which limit the scientific value, and therefore, larger prospective and randomized clinical trials are needed.

Denosumab, a RANKL inhibitor, has been shown to have similar clinical efficacy when compared to alendronate (Fosamax). One study divided patients into 4 groups: 1) treated with denosumab, 2) treated with alendronate, 3) no treatment, 4) previously treated with alendronate and switched to denosumab. After 1 year, the patients who were treated with denosumab or alendronate had increased bone mass in the lumbar spine and femoral neck when compared to the control. Men treated with denosumab had significantly higher bone mass in the total hip while there was no significant change in men treated with alendronate.126 A subsequent 2017 study on denosumab showed significantly increased bone turnover markers and BMD when compared to alendronate; furthermore, a decreased rate of vertebral fractures were observed.127

Osteonecrosis of the jaw is the most common significant adverse effect of zoledronic acid and denosumab. A retrospective study in 2021 analyzed the incidence of agent-related jaw osteonecrosis in prostate cancer patients: 27.5% developed this feared osteonecrosis of the jaw within 5 years of treatment with a bone-modifying agent.128

Maintaining bone health in prostate cancer patients on ADT is an important clinical aspect as musculoskeletal side effects are common with ADT. The use of vitamin D, calcium, and bone modifying drugs should be properly discussed with patients on ADT in order to protect bone health.

The authors report no conflicts of interest in this work.

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):1029.

2. Ito K. Prostate cancer in Asian men. Nat Rev Urol. 2014;11(4):197212.

3. Connolly RM, Carducci MA, Antonarakis ES. Use of androgen deprivation therapy in prostate cancer: indications and prevalence. Asian J Androl. 2012;14(2):177186.

4. Debruyne F. Hormonal therapy of prostate cancer. Semin Urol Oncol. 2002;20(3 Suppl 1):49.

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Evolution of Androgen Deprivation Therapy | RRU - Dove Medical Press

The herbal supplement, which has been growing in popularity, has helped some people, but researchers said limited trial data only paints a partial picture.

MEMPHIS, Tenn. Health benefits from an herbal supplement grown in Asia and Africa claim to make you smarter, calmer, and less anxious.

Right now, its hard to find in Mid-south health and natural food stores.

Definitely in the last four to six months, it has been a peak herb and a high demand," said Steve Lubin, a retired pharmacist and herbalist in Memphis.

While ashwagandha (ash-wah-gan-duh) has been around for hundreds of years, it has been growing in popularity, recently, thanks to word of mouth and TikTok.

Many TikTok users implied that it helped reduce stress and made them feel happier, and highly recommended the supplement.

Some users also said it improved their sex lives, testosterone levels, sleep patterns, focus, memory, energy levels, and reduced their anxiety.

THE QUESTION

Is the hype behind ashwagandha legit, or is it full of empty promises?

THE SOURCES

Dr. Jeff Mullins, a primary care physician with Methodist Medical Group.

Steve Lubin, an herbalist and retired pharmacist from Good Life Honeysuckle Health foods in Memphis.

THE ANSWER

WHAT WE FOUND

Since these are dietary substances, they are not regulated like medications. So they don't have to prove to anybody, even the FDA or USDA, whether they contain the substance they say they contain or the amount they contain," said Dr. Mullins.

That is also part of the problem of getting a definitive yes or no about the ashwagandha's effectiveness.

Every manufacturer uses a different amount of active ingredients, and the supplement comes in many different forms: powders, capsules, tablets, extracts, roots, and leaves.

Also, how it reacts from person to person varies.

It could affect you more so, one way, than me another way," said Lubin.

While marketed as a supplement that treats a number of conditions including insomnia, aging, anxiety, and more, the National Institutes of Health stated: there is no good scientific evidence to support most of these uses.

Meanwhile, the National Library of Medicine rated ashwagandha's effectiveness as possibly effective for stress.

The six categories of the Natural Medicines Comprehensive Database rates effectiveness using this scale:

Researchers said that there isnt enough reliable information to say whether ashwagandha is helpful for a number of other purposes.

There may be some benefit to taking Aashwaganda or other ancient remedies, but you gotta be careful about what source you get," said Dr. Mullins.

CLINICAL TRIAL DATA

Since 2015 there have been dozens of clinical trials which looked at the effectiveness of the supplement.

In 2015, a randomized study of 57 men between the ages of 18 to 50 found that 300 mg of ashwagandha root extract, twice daily, increased muscle strength, muscle size, and testosterone levels in participants versus those in the placebo group.

A study published in 2015 showed that healthy women given capsules of 300 mg twice daily for eight weeks had improved sexual function.

A 2017 study found that adults given 300 mg of the supplement over eight weeks improved their memory and attention span.

Findings from a study published last year found adults given 300 mg of ashwagandha twice daily for eight weeks increased their endurance.

Findings from a study published in 2019 looked at the fatigue and testosterone levels of 50 healthy but overweight men between the ages of 40 and 70. The men were given ashwagandha for eight weeks.

The study found that testosterone levels improved fatigue, sexual and mental health, but there was no significant difference between the group that received the supplement and the group that received the placebo.

Dr, Mullins cautions though, all of the data from these clinical trials only paints a partial picture.

It seems to me that there have been no real, true clinical trials that have been done. A lot of it is observational," said Mullins.

The authors of the 2019 clinical trial even documented that the sample size of the study - about 50 people - was small.

Researchers also confirmed that other lifestyle changes, like diet and social, were also not looked at.

The study limitations made it difficult to "develop definitive conclusions," per the authors.

While participants in the small, limited clinical trials benefited from the supplement, Dr. Mullins said, "when you are dealing with symptoms like fatigue, stress, sexual potency, focus, mental clarity, these are called subjective symptoms."

"They are based upon how the patient feels," said Dr. Mullins. "They are very prone to what we call the placebo effect."

It's why he cautions talking to your doctor or physician before taking ashwagandha or any herbal supplement - to determine if it's right for you or if it would negatively interact with other medications you might be taking.

See original here:
Yes, ashwagandha could have a positive impact on your physical and mental health - WATN - Local 24

Newlyweds Kyle Canning (played by Chris Milligan) and Roxy Willis (Zima Anderson) are super-excited to head off on their honeymoon on today's episode of Neighbours (6:00pm - see our TV Guide for listings).

Kyle, who is still on the mend after being diagnosed with testicular cancer and his subsequent surgery last year, is determined not to let his new bride, Roxy down in the bedroom.

As soon as the couple arrive at their luxury accommodation, they start to feel frisky!

So Kyle secretly slaps on several extra testosterone patches so he can perform in the bedroom.

Unfortunately, the extra testosterone boost works a bit too well.

And very soon, Kyle has a rather, er, persistent issue to deal with down below!

Zara Selwyn (Freya Van Dyke) is in a whole lot of trouble after just one day at Erinsborough High School.

The building had to be evacutaed and the fire brigade called after Zara deliberately set off the school fire alarm.

Word soon gets back to Zara's mum, Amy Greenwood (Jacinta Stapleton), who is not happy.

Zara's friend Hendrix Greyson (Ben Turland) checks in on her while they are on shift together at Harold's Cafe.

However, rather than cleaning-up her act, Zara is intent on upping her game and causing even more trouble at school!

Amy is determined to make her new fast food truck business a success, after losing her job as manager of The Flamingo Bar.

After what has just happened at Erinsborough High School, Amy reckons she needs to keep a closer eye on her daughter, Zara.

She she offers Zara a job so that they can run the business together.

But as usual, Zara is full of attitude and gets into a shoving match with Amy.

As Zara storms off, she is unaware that Amy has suddenly collapsed to the ground in terrible pain...

Neighbours continues weekdays at 1:45pm and 6:00pm on Channel 5

See the original post:
'Neighbours' spoilers: Kyle Canning has a honeymoon NIGHTMARE! - What To Watch

When you need testosterone treatmentand when you dont

Most men have problems with erections from time to time. But some men have erectile dysfunction, or ED. This is when it is difficult to get or keep an erection thats firm enough for sexual intercourse.

If you have ED, you may think that testosterone treatment will help. Testosterone is a male sex hormone. After age 50, mens levels of testosterone slowly go down and ED becomes more common. But unless you have other symptoms of low testosterone, you should think twice about the treatment. Heres why:

Testosterone treatment has not been shown to improve erections in men with normal testosterone levels. And studies show that it does not help men with low testosterone levels if ED is their only symptom.

ED is almost always caused by low blood flow to the penis. This is a result of other conditions, such as hardening of the arteries, high blood pressure, and high cholesterol. These conditions narrow the blood vessels and reduce blood flow to the penis. Low testosterone may affect the desire for sex, but it rarely causes ED.

Testosterone treatment can cause the body to retain too much fluid. It can also cause acne, an enlarged prostate, and enlarged breasts. Other side effects include lower fertility; an increase in red blood cells; and an increase in sleep apnea symptoms.

Women and children should avoid touching unwashed or unclothed areas of skin where a man has applied testosterone gel. The gel can be transferred through skin contact.

Although available data is conflicting, the Food and Drug Administration (FDA) has concluded that increased cardiovascular risk (problems with the heart and blood vessels) associated with testosterone use is a possibility. The AUA recommends that only FDA-approved medications should be used and a physical evaluation and follow up are important.

Testosterone treatment can be an injection, a gel, or a patch that is put on the skin. All of these are costly. They may cost hundreds of dollars a month, depending on the treatment.

Men who use a testosterone treatment must use it indefinitely to get and keep the full effect.

If youve had trouble having erections for three months, talk to your doctor. He or she will ask about all your symptoms and give you a physical exam. Symptoms of low testosterone can include less of a sex drive, loss of body hair, breast growth, needing to shave less often, a drop in muscle size and strength, and bones that break more easily.

If you have some of these symptoms, your doctor may have you get a blood test to measure your testosterone levels. The blood test should be done more than once. It is best to do it in the morning when testosterone levels are highest.

If the tests show that you have low testosterone levels, your doctor should look for possible causes. For example, the low levels might be caused by a problem in the pituitary glands.

If no other cause is found, you can try testosterone treatment.

This report is for you to use when talking with your health-care provider. It is not a substitute for medical advice and treatment. Use of this report is at your own risk.

2018 ABIM Foundation. Developed in cooperation with the American Urological Association.

Read the original:
Testosterone for Erection Problems | Choosing Wisely

HOLD out your hands - you've probably never realised clues to your personality and health could be right at your very fingertips...

It turns out the length of your fingers can be a sign of how much testosterone - the male sex hormone - you were exposed to in the womb.

2

Testosterone plays a pretty crucial role in a babys development and it also determines how long your index and ring fingers will be as an adult.

But what does all that mean for the kind of person you become?

Tanith Carey reveals how finger length could determine whether

Next time youre on a date, dont look into the other persons eyes - check out their hands instead.

The shorter their index finger in relation to their ring finger, the more likely they are to have been exposed to higher levels of testosterone in the womb, and may be more prone to cheat.

Psychologists from Oxford University and Northumbria University studied 600 men and women in Britain and the US, looking at the link between hand shape and promiscuity.

The study for the journal Biology Letters found people tended to divide into two groups those who are more inclined to stay in relationships and others who want to try lots of partners.

While the scientists couldnt use it to predict everyones fidelity, they found that men and women were generally more likely to cheat if they have slightly longer index fingers (like Tiger Woods appears to have), even though the difference was mere millimetres.

Youd have to look quite hard to notice, says Oxford University Professor Robin Dunbar, who says the differences are "subtle" and "only visible when we look at large groups of people".

"Human behaviour is influenced by many factors, such as the environment and life experience, and what happens in the womb might only have a modest effect on something as complex as sexual relationships," he said.

Women have long been led to believe that checking out a man's shoe size was the best guide to the length of his manhood.

But it turns out we've been looking in the wrong place all along.

According to a study in the Asian Journal of Andrology, men whose ring fingers are longer, in comparison to their index fingers, tend to have bigger penises.

To investigate this link, South Korean doctors measured the index - or pointer finger - on the right hand of 144 male volunteers aged 20 and over.

They also measured the length of each man's ring - or fourth - finger.

Then measured their penises while they were both flaccid and stretched which shows how long they would be when erect.

They found the men who had a small gap between the length of their ring and index digits, like Simon Cowell or Justin Bieber, tended to have bigger penises.

Those with bigger differences, like Donald Trump, tended to be less well-endowed.

And thats not all. In 2014, another study by South Korean researchers found that men with a longer ring finger on their right hand, compared to their right index finger, also had bigger testicles.

If youre a man hoping to seduce a woman with a gorgeous body when you next go out, your chances may have already been decided in the womb.

Men with long ring fingers, like Brad Pitt, are four times more likely to end up with a partner with a combination of a slim waist and prominent chest

Researchers from Polands Jagiellonian University Medical College looked at the hands of 50 young men in long-term relationships and measured the vital statistics of their partners.

They found men with ring fingers longer than their index fingers tended to have partners with classic hourglass figures.

This is possibly because high testosterone levels have also been found to make male faces more symmetrical and attractive to the opposite sex, giving them more chance of attracting a partner with proportions that typically have indicated fertility.

According to the study in the journal Personality and Individual Differences: Our results suggest mens pre-natal environment has an impact on the likelihood of being in a relationship with a more attractive and presumably more fertile woman.

You may go running every day to train for that 5K, but its the length of your fingers that may help decide how long it takes you.

Researchers found young male athletes with long ring fingers compared to their index fingers also had more lung power.

One theory is that higher exposure to testosterone in the womb may boost the development of a baby's lungs for life, improving how well their bodies use oxygen.

In the best runners, they found their ring fingers could measure as much as a centimetre longer than their index fingers.

A similar effect has been seen in women too.

A separate study of female x-rays in the British Journal of Sports Medicine found that more sportier women also had ring fingers longer than their index fingers.

Let your fingers do the talking

Straighten out your hands, holding your fingers together.

Look for the creases at the base of your index and ring fingers.

If there's more than one crease, measure it from the lowest and mark it with a pen.

Next, measure your finger in millimetres from the mark to the tip.

Divide the index finger length by the ring finger length.

A short ratio is about 0.976 while a long digit ratio is around 0.99.

In most women, the ring and index finger tend to be more similar in length.

However, in men it varies more.

If you want a clue as to whether a man is destined to be a high earner, check out his mitts.

For a study in the Proceedings of the National Academy of Sciences, researchers measured the right hands of 44 male stock market traders, some who earned up to 4 million in the city.

Over 20 months, they found the traders with longer ring fingers made 11 times more than those with shorter ring fingers.

Researchers believe that due to a higher exposure to testosterone, they were more confident, happier taking risks and had quicker reaction times.

When you look on a menu, are you the type to opt for a burger and fries, rather than a salad?

While you may think youre being led by your stomach, your choice may actually be down to your finger length.

Researchers at Scandinavia's University of Agder, looked at the food choices of 216 men and women for study in the journal Food Quality and Preference.

They found those with only a small difference in size between their ring and index fingers, like pizza-loving Hunger Games star Jennifer Lawrence, were more likely to reach for stodgy and meaty foods when their tummies were rumbling.

Scientists believe the group with longer ring fingers may have been influenced by ads promoting masculine food products on television, which may particularly appeal to both men and women with higher testosterone levels.

For an early clue as to whether your child will be good at maths, check their fingers.

The hormones in the womb which help make a child good at maths can also make a child's ring finger longer than their index finger, according to University of Bath researchers.

According to study author Dr Mark Brosnan, a childs digit ratio is pretty much set by the time they reach Year 2.

In a study published in the British Journal of Psychology, researchers compared photocopies of the hands of 75 six and seven-year-olds and measured the length of their index and ring fingers on both hands.

They then compared their results in Maths and English tests and found the kids with longer ring fingers whod had more exposure to testosterone in the womb - were better at Maths than English.

Kids who had shorter ring fingers, in comparison to their index fingers - were better at language than maths.

Testosterone is thought to encourage the development of spatial and math skills, while slowing development in the brain's left hemisphere, the part of the brain that deals with language.

Brosnan said: Finger length is by no means a measure of intelligence or ability, but added that a child's finger length might show if a child has a leaning towards maths.

Men with longer ring fingers have a lower risk of dying from Covid and are more likely to get milder symptoms if they do catch it.

The difference may only be a matter of millimetres, but according to research by Swansea University, men with longer finger lengths are likely to have been exposed to more testosterone in the womb, which helps protect organs from the virus.

So if his index finger length divided by the ring finger length is longer 0.99 plus rather than shorter around 0.97 - you may have extra protection.

This is believed to help because testosterone may increase the number of ACE-2 receptors proteins on the surface of cells - in the lungs, which seem to reduce the damage the virus can cause.

However women's finger lengths don't seem to affect their death rates, according to the study, published in the journal Early Human Development.

2

Original post:
From relationships to the size of your manhood what your finger length says about YOU... - The Sun

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Late last week I had an experience thats both completely normal and fundamentally absurd. It was thisI spent a ridiculous amount of time agonizing over the wording of a simple Twitter thread. I struggled to use exactly the right words to express what should be a completely normal and reasonable point.

As some readers may know, after competing for three years as a male swimmer at the University of Pennsylvania (and earning all-Ivy honors) as a male, a transgender swimmer named Lia Thomas is now competing as a female, and dominating the competition. Thomass physical advantage is blatantly obvious. Yes, there are NCAA guidelines mandating testosterone suppressant, but testosterone suppressants dont repeal puberty.

Writing in Swimming World, editor-in-chief Don Lohn describes the problem well:

Despite the hormone suppressants she has taken, in accordance with NCAA guidelines, Thomas male-puberty advantage has not been rolled back an adequate amount. The fact is, for nearly 20 years, she built muscle and benefited from the testosterone naturally produced by her body. That strength does not disappear overnight, nor with a years worth of suppressants. Consequently, Thomas dives into the water with an inherent advantage over those on the surrounding blocks.

So, what was my point and what was my struggle? My point was that it is not invidious discrimination to prohibit a biological male from competing in female sports. Indeed, drawing rational distinctions between biological males and biological females might be necessary to protect equal opportunities for women to enjoy access to athletic opportunities.

As Ive written before, the phrase invidious discrimination is a legal term of art that refers to a classification which is arbitrary, irrational and not reasonably related to a legitimate purpose. Bans on invidious discrimination are legally proper and often necessary. Racial classifications, for example, are virtually always invidious. Sex-based classifications can be invidious as well, but sometimes theyre benign. Sometimes theyre even necessary.

To take an obvious example, segregating bathrooms or showers by race is invidious. By contrast, segregating bathrooms and showers by sex isnt just rational, its prudent.

Theres absolutely such a thing as invidious discrimination against transgender Americansimagine if teachers marked down trans students simply because they were trans, or if employers fired productive employees simply because they were trans. But drawing biological sex-based distinctions in sports not only isnt invidious, it protects women from unfairness.

What was my struggle? I wasnt afraid of cancellation. The Twitter world is full of broadsides against Thomas and the NCAA, and there are legions of right-wing voices who relish taking on this issue, and doing so as contemptuously and snarkily as possible and bask in thunderous applause of their tribe. Besides, thanks to my readers, Im pretty tough to cancel anyway.

No my struggle was simply this: How do I make my point in a way that skeptical and hostile readers will hear it and consider it, rather than simply dismissing it out of hand as the bigoted rantings of a hateful Evangelical? After all, I dont just want to be heard. I want to persuade. I believe what Im saying is true, and I want readers to at least consider my words.

Take transgender rightsor virtually any contentious issueand youll find that there are million different ways that people will not just reject your reasoning but refuse to engage with you at all.

Youre the wrong speaker (who wants to hear from a cishet Evangelical?) You chose the wrong words (did he use the acceptable pronouns? Was his language offensive in any other way?) You have the wrong priorities (American democracy is in peril, and were talking about a single trans swimmer at a single school?)

At any rate, this was my short thread. You can determine whether I made my points in a way that skeptics at least might listen:

Despite that long introduction, this isnt a newsletter about transgender athletes. Its about something much deeper and more consequential. Its about one of the most common and pernicious ways in which we lose the ability to hear the truth. In many ways, its about how we defend ourselves from the truth. Let me introduce you to the process foul.

A process foul is any perceived breach of trust or decorum in the delivery of the message that distracts from the substance of the message. To be crystal clear, Im not remotely arguing that process doesnt matter. Indeed, if youre about to have a tough conversation (say, for example, an intervention) with a person you love, you often obsess about the process, almost to the exclusion of substance.

Do you talk on the phone or gather in person? If in person, where? Who should be in the room? Who should speak first? Who shouldnt speak at all? Indeed, taking exquisite care in the process of communicating difficult truths is an act of love. Were talking to human beings, after all, not factbots who can simply hear a hard word (Dude, you drink too much) and respond accordingly.

Process is so important to persuasion that the persuasion industry is consumed by concepts like manner and method. When I litigated, I didnt just try to master the facts and law of the case, but I practiced my delivery to the judge and the jury. I worried about my ties. I talked to my client about his demeanor on the stand and even while simply sitting at the counsels table.

Why do southern trial lawyers have the most impressive accents in the South? Process, not substance. Its an almost unconscious affectation that says to the jury, Im real. Im you.

The problem, however, should be obvious. Our concerns about process can overwhelm our concerns about truth, and our sense of entitlement about process can completely wall us off from hearingmuch less believingdifficult truths. And once you see the process objections in American politics, you cant unsee them. They dominate our discourse.

In my experience, here are the four most common wrongs that prevent us from hearing and understanding whats right.

Wrong messenger. This is perhaps the easiest and most popular method of discounting uncomfortable information. Once you categorize someone as Never Trump or a warmonger or fake news or then youve put on the bulletproof vest. Nothing that comes out of his or her mouth will penetrate your armor.

Wrong motives. Arguments over, for example, the so-called Evangelical elite often center around motive. We place a condition on truth that says, I will listen to true things only when spoken for the right reasons. After all, why should anyone listen to a grifter? And I definitely shouldnt listen to anyone whos simply trying to curry favor with the left or wants to be accepted by the elite.

And who makes the judgment about motive? How do we have confidence that we can peer into a man or womans heart and know their motivations. I appreciated these words from Thomas Sowell:

Wrong manner. In our populist age, there are few more deadly accusations than condescension or elitism. There are cases where even the assertion of any kind of expertise is virtually self-discrediting.

In far-left spaces, ever-shifting and intolerant language norms can mean that ordinary people can find themselves struggling to even find the right words to discuss contentious topics. Even words like racism are subject to different, evolving meanings, and certain terms of art, like land acknowledgment or BIPOC separate individuals into separate classes of understanding.

Wrong target. This is perhaps the most subtle and versatile of the process fouls. Its how you can still be wrong even when youre right. It encompasses concepts like punching down (people with larger platforms shouldnt take on those with less influence), misplaced priorities (youre squeezing out the gnat and swallowing the camel), and whataboutism (Donald Trump has abused women? What about Bill Clinton? Donald Trump hasnt accepted the results of his election? What about Stacey Abrams?)

The process of communication is laden with reciprocal responsibilities. As a communicator, my job is to do my best to know my audience, to understand them, and to speak in words that I believe theyll hear. In other words, my job isnt to fly over the target, dump my truth bombs like Im a B-52 over Hanoi, and then log off congratulating myself for a job well done.

I especially shouldnt congratulate myself for my bravery when the response is exactly the flak I was told to expector even perhaps hoped to receive.

As a listener, however, I have my own responsibilities. I should do my best to shun the calling of process fouls and listen hard to substance. This is not easy. Some of the most important lessons Ive learned have come from the most unlikely teachers. Some of the harshest words spoken to me have turned out to be the most true.

One way that truth dies is that when we place such exacting preconditions on its delivery into our lives that there is virtually no messenger or message that can penetrate our hearts.

Lets make this lesson a bit personal. Just before Christmas a pastor in my denomination named Kevin DeYoung wrote a piece in a Christian magazine called World called The Temptation of the Jeremiad that gained some traction in my little corner of the world. It was aimed mainly at me and the way in which Ive mounted various critiques of white Evangelical politics and cultural engagement in the age of Trump.

I dont know Kevin, but I have many friends who do. I respect his work a great deal, and so I listen to his critiques carefully. While he agrees with some things I say, these two paragraphs contain his core complaint:

And this is my biggest complaint with the white evangelical jeremiad. It has the same head-shaking you people vibe that prompted the deplorables to embrace Trump in the first place. Its one thing to object to an idea or to a set of propositions. Its another to object to a class of people. Even if French is right, and evangelicals should not have supported (voted for?) Trump and evangelicals should not be skeptical about many of the Covid protocols, there is little sympathy for trying to understand why evangelicals might have behaved in these ways. There is no persuasion, only pique and annoyance.

And:

At the risk of seeming biased toward my own profession, I cant help but notice that the leading voices decrying the moral bankruptcy of white evangelicalism are not pastors but professional writers, academics, and full-time commentators. Given the nature of these vocationsvaluable, honorable vocationsit is easier to produce frequent jeremiads against the church than to produce a positive vision for the church. If your natural rhythm is not the whole counsel of God Sunday after Sunday, but another critique of the church in your inbox on Sunday morning, that should tell you something. The Lord knows there is much to criticize in the church, but I doubt that relentless, unsympathetic, exasperated censure against one specific people is the best way to convince them of your criticisms, let alone build them up in Christ.

These are textbook process fouls. Im the wrong messengernot a pastordelivering the message in the wrong way (with a head-shaking you people vibe). He says that even if Im right there is little sympathy for trying to understand why evangelicals might have behaved in these ways. I write only with pique and annoyance.

But this doesnt mean I should disregard what DeYoung says. If Im trying to communicate things that I believe to be both true and gravely important, and a thoughtful man says Im communicating through pique and annoyance then I need to think very hard about how I write.

In fact, I need to repent of my initial response to this essay. Since I believe he mischaracterized much of my work, my initial response was purely reactionary. I defended myself. But I should have reflected more. I should still reflect. As a communicator, am I failing in my responsibilities? Am I communicating a message that I do not intend?

At the same time, this sentence from DeYoung troubled me greatly: It [my work] has the same head-shaking you people vibe that prompted the deplorables to embrace Trump in the first place.

This is the dark place that an emphasis on process over substance can take you. A distaste for a persons tone should never prompt anyone to embrace a man like Trump. After all, even granting that my tone can be better, is that a reason to embrace a person whose tone is inarguably much worse and whose grasp on the truth is inarguably far more tenuous? Are people placing so many preconditions on critique that theyve effectively walled themselves off from hard truths?

When were communicating, we should care about people, and that means caring about process and truth. We should do our best as fallen and imperfect people to say true things in a careful, compassionate, and persuasive way. But we cannot ever allow often-shifting and sometimes-escalating demands about process to silence the truth.

When were listening, by contrast, we should resist the urge to filter truth through process. Strange messenger? Fine. Heck, even one of Jesuss disciples once tried to reject him by asking, Can anything good come out of Nazareth?

Obscure or tough delivery? That can work. Jesus often spoke in parables that few understood, and his own speech could be incredibly blunt and direct. And what about the prophets? Could they rake a man over the coals? Google the etymology of the word jeremiad, and youll find that answer fast.

Wrong motives? Who cares? And besides, how can I presume to know a persons true motivations?

In a recent Atlantic essay I wrote about our incredibly difficult task. In an age of cruelty, how do we open ourselves to legitimate critique? Heres my answer: The best folks I know have achieved the near impossible. Theyve constructed a thick skin while preserving an open heart. Their defense mechanisms are porous enough to allow fair critiques to penetrate while keeping the bad-faith actors at arms length.

Any other approach and our own heart and mind risk becoming the places where truth goes to die.

One more thing

In the lastest Good Faith podcast, Curtis and I talk about how January 6 helped both of us understand that it was time to grow up. We have to be adults now.

What does that mean? Please listen to the pod to find out.

A personal update

I apologize for the lack of a Tuesday newsletter last week. COVID came to our house, and I caught a breakthrough infection, along with three other members of the family. As the old guy of the bunch, I fared the worst, but it was still never worse than a moderate flu (though with quirky and shifting symptoms!), and we all were on the mend by the end of the week.

Im grateful for the vaccine, and Im grateful to have recovered so quickly. Millions have faced much greater challenges.

One last thing

This is a marvelous hymn and feels right for the first days of a new year that already can feel full of more uncertainty than promise:

Originally posted here:
The Places Where Truth Goes To Die - The Dispatch

In a recent OncView discussion, Aaron Berger, MD, vice president and chief medical officer at Associated Urological Specialists in Chicago, Illinois, shared clinical experiences and perspectives regarding treatments of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).

Clinicians need to be aware of all the treatment options available in this space, as many FDA-approved indications have emerged in the past few years, Berger said.

Thereve been several new options for nonmetastatic castration-resistant prostate cancer to come to market, he noted. The first was enzalutamide [Xtandi] followed shortly thereafter by apalutamide [Erleada], and then most recently darolutamide [Nubeqa]. Weve used all of them in our advanced prostate cancer clinic, and its certainly an improvement over the previous options [such] as first-generation antiandrogen therapies.

Berger detailed his strategies for therapy selection in this patient population, including insights in baseline patient characteristics, clinical trial data, and toxicity profiles of each novel agent that guide his decisions.

Berger said his first consideration in a patient with nmCRPC is whether they need additional systemic therapy. Age, comorbidities, prostate-specific antigen (PSA) doubling time, and medication adherence are some of the factors that may incline a clinician to treat a patient with a newer antiandrogen medication.

Some of these patients have a lot of other [medical] issues, Berger said. If theyre not excited about another medication or are worried about [adverse] effects, we may just observe them, especially if their [PSA is] rising somewhat slowly.

Ultimately, the treatment goals in this setting are to prevent progression of disease from nonmetastatic to metastatic, as survival rates dramatically decrease in later stages of the disease. Typically, we will check PSA and testosterone levels every 3 months, Berger said. He noted that testosterone less than 50 ng/mL and a PSA doubling of 10 months or less was the threshold for administering medication to patients in clinical trials.

Thats not in the labeling for all these medications. You certainly can use the medication if their doubling time is 11 months or 12 months, but normally its [with a PSA doubling time of] 10 months or less were really focused on, he said.

For imaging in a patient with a significant PSA rise, Berger said he references the RADAR III guidelines, which recommend next-generation imaging techniques for detecting previously metastases (Table 1).

We would certainly consider doing conventional imaging initially, such as a CT scan or bone scan, and if its negative then we would likely continue observation, Berger said. I typically wouldnt wait until PSA is 5, 10, or 20 ng/mL and just keep doing conventional imagingwe would likely move on to doing next-generation imaging studies earlier. Some other factors that might motivate imaging sooner include pain in the back, hips, or legs; urinary symptoms; or obstructions in the kidneys.

Regarding the 3 available next-generation androgen receptor inhibitors that are available to treat patients in this setting, Berger said their mechanisms of action are similar but varying molecular sizes account for the biggest differences reflected in slightly different toxicity profiles.

Darolutamide typically has less in the way of central nervous system effectssuch as fatigue, light headedness, or dizzinessthan what we sometimes may see [with the other agents], Berger said. But mechanistically, they work very similar.

Regarding metastasis-free and overall survival (OS) rates, pivotal clinical trials that led to the approval of these agents reflect similar results. The design of the studies are very similar and the results of the studies are very similar, Berger said. Sometimes theres a reason why you may not use one versus the other, such as if a patient does have significant fatigue or has any other central nervous system issues [such as] gait abnormalities. Potentially, the darolutamide may be a better choice than enzalutamide or the apalutamide. But in my experience, theyre all tolerated pretty well.

Berger then explored data from the phase 3 PROSPER (NCT02003924), ARAMIS (NCT02200614), and SPARTAN (NCT01946204) trials that led to the approvals of enzalutamide, darolutamide, and apalutamide, respectively.

All 3 trials had very similar patient populations with a PSA doubling times of 10 months or less. All the patients had rising PSA that was confirmed on more than 1 occasion and castrate levels of testosterone less than 50 ng/mL, Berger said. They were all looking at metastasis-free survival as the primary end point.

At the initial readout of the SPARTAN trial, metastasis-free survival (MFS) was statistically significantly improved with apalutamide versus the placebo group (HR, 0.28; 95% CI, 0.23-0.36; P < .001).2 Similarly, MFS in PROSPER showed a 71% reduction in the risk of metastasis or death with enzalutamide compared with placebo (HR, 0.29; 95% CI, 0.24-0.35; P < .001).3 In ARAMIS, patients treated with darolutamide derived a significant treatment benefit versus those treated in the placebo group (HR, 0.41; 95% CI, 0.34-0.50; P < .001).4

In subsequent analyses, it is now borne out that they all do result in improvements in overall survival, Berger said. OS results with next-generation agents versus placebo were statistically significant for SPARTAN (HR, 0.78; 95% CI, 0.64-0.96; P = .016),5 PROSPER (HR, 0.73; 95% CI, 0.61-0.89; P = .001),6 and ARAMIS (HR, 0.69; 95% CI, 0.53-0.88; P = .003).7

When discussing toxicity, Berger detailed each in the context of which adverse effects were commonly associated with each agent.

We typically see with enzalutamide fatigue or asthenia. These patients are all on androgen deprivation therapy at baseline [and] they have low testosterone at baseline, which can certainly decrease their overall energy level to start with, Berger said. Adding the enzalutamide in some patients does zap their energy substantially to the point where some dont really feel like they have any motivation and dont want to get out of bed.

For these patients, Berger said a slight dose reduction can have a profound effect on their energy levels. For example, reducing the dosage by 25% or switching a patient from a 4-pill dose to a 3-pill dose may help a patients experience without significant effects on their overall disease outcomes.

With apalutamide, full body rash 2 to 3 months into treatment may occur but often can be managed with oral antihistamines or topical corticosteroids. Rarely, patients have a severe full body rash that requires discontinuation of therapy.

Theres also a slightly higher risk with apalutamide of hypothyroidism, but this is not typically something we screen for routinely, Berger said. Its mainly for those patients who have a history of hypothyroidism and are on medications already for thyroid replacement that well check a thyroid panel along with their PSA and testosterone.

Regarding darolutamide, Berger said its toxicity profile is likely the most favorable of the 3 available agents with its lower rate of fatigue, with most symptoms occurring during treatment.8 The bottom line is to know what to potentially expect and let the patients know what to be on the lookout for, he said.

Berger said comorbid conditions, such as obesity or diabetes, may inform the decision to administer an androgen inhibitor but they do not necessarily preclude a patient from treatment.

If they dont have significant cardiovascular issues and havent had a heart attacks, stroke, or congestive heart failure issues, Im not going to withhold a second-generation androgen inhibitor just because theyre a bit overweight, Berger said.

In fact, the relatively manageable safety profile of these agents means that treatment can be given without many dose adjustments even to patients with renal insufficiencies, he said.

Neurologic issues that may be present, such as unsteadiness, dizziness, or a history of falls should be taken into consideration, Berger said. Then the data would indicate that darolutamide may be a better option [because] there wasnt an increased risk from falls and fractures in the ARAMIS trial.

Regarding unmet needs in the treatment space, Berger said that guidance for prescribers on drug-drug interactions is lacking. There are a lot of medications patients are on, whether its antihypertensives, diabetes medications, or cardiovascular medications, especially the anticoagulants that may have some interactions with these medications. And the guidance, as far as what we can glean from the studies, is not always clear about whats safe and what may not be safe, he said.

Another consideration is whether nmCRPC will continue to be a disease state in the future, as next-generation imaging techniques become more prevalent in the treatment landscape and reveal metastasis in patients who would have been formerly considered nonmetastatic.

When you have a scan that can pick up an area of metastasis at [PSA of] 0.2 to 0.3 ng/mL, it may turn out that these patients are metastatic. All of these studies were done with conventional imaging, Berger said. The big question as far as this entire disease state is, will it still be a disease state 5 years from now?

Overall, Berger said clinicians shouldnt shy away from prescribing these medications to their patients, given their tolerability and ease of administration. I would not be afraid of these medications because you can easily add them into your clinical practice without a lot of trepidation, he said.

1. Crawford ED, Koo PJ, Shore N, et al. A clinicians guide to next generation imaging in patients with advanced prostate cancer (RADAR III). J Urol. 2019;201(4):682-692. doi:10.1016/j.juro.2018.05.164

2. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546

3. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465-2474. doi:10.1056/NEJMoa1800536

4. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671

5. Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in prostate cancer. Eur Urol. 2021;79(1):150-158. doi:10.1016/j.eururo.2020.08.011

6. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382(23):2197-2206. doi:10.1056/NEJMoa2003892

7. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342

8. Gratzke CJ, Fizazi K, Shore ND, et al. Time course profile of adverse events of interest and serious adverse events with darolutamide in the ARAMIS trial. Ann Oncol. 2021;32(suppl 5):S626-S677. doi:10.1016/annonc/annonc702.

Continued here:
Recap: Recent Updates in the Treatment of Nonmetastatic Castration-Resistant Prostate Cancer - Cancer Network

This article was originally published here

Urologiia. 2021 Dec;(6):85-99.

ABSTRACT

OBJECTIVE: Analysis of androgen status in men hospitalized with a moderate COVID-19 and its relationship with the severity of the disease.

MATERIALS AND METHODS: The study included 152 males with a confirmed diagnosis of COVID-19 based on the results of a positive PCR for the SARS-CoV-2 virus and/or computed tomography of the lungs hospitalized at the MSU University Clinic due to the moderate and severe COVID-19. Examination of the level of biochemical blood parameters (CRP, creatinine, urea, glucose, total testosterone (T)); CT of the lungs. To objectify the severity of the clinical symptoms, the NEWS2 distress syndrome severity scales and the original scale for assessing the clinical condition of patients with COVID 19 (SHOCS-COVID) were used.

RESULTS: The median T level in 152 examined patients was 2.14 [1.21; 3.40] ng/ml. In patients with a T level below the median, the CRP level was more than two times higher, and the D-dimer value was almost two times higher than in patients with T level above median. The duration of treatment in the hospital was longer in men with COVID 19 and an initial T level below the median than in patients with T about the median (13 days vs 10.5 days, p=0.003). Low T level was correlated with lung damage by lung CT. After improving the clinical condition, there was a linear increase in the level of T independent of its initial level.

CONCLUSION: Among men with moderate and severe COVID-19, a decreased testosterone level is detected in 46.7% of cases. Patients with low testosterone levels on admission have more severe COVID-19. A significant increase in testosterone level was observed after successful COVID-19 treatment without any special action regarding testosterone level.

PMID:34967512

Read the original post:
Features of a new corOnavirUs infection course and optioNs therapy DEpending on the andRogenic status (FOUNDER): androgenic status in men with...

It has been discovered that Perfect Sting had a positive test back on June 26, 2021, when he was second then placed first in the $148,332 Pennsylvania Sire Stake for harness racing 3-year-old male pacers at The Meadows.

A split sample was also sent to the labs and was found to be also positive for testosterone.

Before this report was published today, Perfect Sting had gone on to be named the Dan Patch Three-Year-old Pacing Colt of the Year and his trainer, Joe Holloway named as the Dan Patch Good Guy Award Winner.

Mr. Holloway has said that he will be appealing the decision.

Here is the ruling found on the USTA website.

HOLLOWAY, JOSEPH J FREEHOLD, NJ YOB 1956Mea on 6/26/2021 FINED: $500FULL 15 DAYS, 1/17/2022 THRU 1/31/2022HORSE DISQUALIFIED PLACED 9, PURSE REDISTRIBUTIONPOSITIVE TEST- POST RACEPA Code Title 7-203.22,401.2 A(1),401.41, 205.33, 205.501 (14).

Sample #376342 was found to contain testosterone at a level of 3765pg/ml, a class 3 violation.

Sample #376342 was provided by #7 Perfect Sting, who was placed 1st through a disqualification, and was trained by Mr. Holloway. A split sample and DNA was requested and confirmed at a level of 3635pg/ml and a match of DNA.

Thus, #7 is disqualified and placed 9th, the purse ($74,166) is ordered to be redistributed, and Mr. Holloway, the trainer of record, is fined $500 and given a 15-day full suspension.

During his suspension, Mr. Holloway is denied the use and privileges of all the grounds sanctioned by the Pennsylvania SHRC.

All horses owned and/or trained by Mr. Holloway may only be transferred through the Judges office at the Meadows.

The fine and purse return must be paid within 10 days of this ruling.

ViewFines and Suspensions for the week of December 31, 2021,as reported to the USTA by racing commissions in the United States.

This bulletinreports actions that have been taken by the USTA and rulings as submitted by the various racing commissions in an abbreviated form; we are not responsible for the accuracy or timeliness of such information. For full ruling text, or if you have questions or concerns about the information found in this report, please contact the racing commission where the ruling was issued.

All reported rulings, current and past, may be found by usingPathway, the USTAs official database. Although there is no charge for this information, aUSTA accountis required.

For a list of archived bulletins, clickhere.

Looking for Canadian Rulings?

Viewrulingsposted at Standardbred Canada. This information is collected and posted by Standardbred Canada. The USTA assumes no liability for errors or omission.

From the USTA and Harnesslink

Excerpt from:
Perfect Sting had positive test; Holloway appealing - Harnesslink

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