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Aug 25

SARMs Before And After Results Real SARM Results And Users Review In 2022 – Outlook India

Whether you search for SARMs results 1 month or results after using them for a few months, we assure you these are some miraculous compounds that are recently proven to be more effective than anabolic steroids. SARMs results popularity has outgrown many bodybuilding supplements and this is because they can help pack on mass, ripped physique, and exhilarating strength in a faster manner.

Checkout Best SARMs Alternatives online that works without any side effects!

In this article, we will talk about the worlds best and most renowned SARMs for Bulking and Cutting. We will also point out multiple SARMs there are for female bodybuilders and those who simply want to lose weight using bodybuilding exercises.

What are SARMs?Recently, many people with no background in scientific studies asking are SARM a drug? This is in fact a fair question because SARMs have infiltrated bodybuilding and somehow managed to replace anabolic steroids.SARMs are actually Selective Androgenic Receptor Modulators, they do resemble to anabolic steroids structure wise but their binding capacity is what makes them different from them. SARMs are unlike steroids in bodybuilding which means they only act on selective receptors without alerting other biological processes in the body.SARMs are less risky than steroids because they do not convert into DHT or Estrogen which is the reason why many male bodybuilders get the side effects. In terms of testosterone suppression, SARMs only cause this phase for a shorter time than steroids which results in prolonged testosterone suppression for bodybuilders.

SARMs Before and After ResultsSome obvious changes/results that you can experience after the intake of SARM are mentioned below. Highlighted Muscle GrowthMost athletes and bodybuilders do take SARMs because they work like a magic for outrageous muscle mass growth. Most of them expect to gain over 30 pounds of lean muscle which they achieved within 4 months time frame, but for this legit SARM supplement with proper prescribed dosage shall be taken into account. For example, regular use of 20mg Ostarine considerably helps with muscle growth which has been experienced by thousands of bodybuilders in the US alone. Weight/Fat lossBest SARMs for fat burning is amongst the top searches on Google and this is because SARMs are capable of incinerating the fat reservoir in the body. Not the healthy fat but the lipids that your body has been storing for years. In recent days, SARMs are more preferred than Clenbuterol a steroid which is used to get rid of extra fat in the body because of less risk associated with Andarine, one of the best SARM for fat loss. Escalated StaminaWhat is the use of SARMs if not for improved stamina and physical power? Nearly every SARM works on physical power and maximized strength which is the demand of every athlete and sportsman. Under the right dosage, SARMs not only amplify the stamina in men and women but also keeps them energetic, focused, and alert throughout the day. Stops Muscle Wasting SyndromeMany bodybuilders during working out with peak performance tend to lose healthy muscle tissues which arent supposed to be this way. This will also accumulate the water content in muscles which gives your arms and chest a flabby appearance. SARMs allocate the muscle and hydro content in a suitable way that will stop muscle wasting. Faster and Superior Recovery against Muscle FatigueStudies have shown that SARMs long-term use makes the body endure the pain and pressure efficiently. SARMs improve the energy production in muscles which also makes them resistant to sprains, injury, and fatigue during the workout or in the outside world.

Bulking SARMS Before and After ResultsHere are the most effective SARMs for bulking in 2022 which are currently being used by bodybuilders and athletes to compliment muscle mass growth.1. Testolone (RAD140)2. Ligandrol (LGD-4033)3. Ibutamoren (MK 677)

Testolone RAD 140 SARM Before and After ResultsTestolone is regarded as one of the latest and potentially active SARM for muscle growth and bulking cycle. RAD 140 is still under many clinical studies and is not been approved by the FDA yet. Bodybuilders like Testolone so much because of the rapid results and it resembles a testosterone steroid.The main use of Testolone RAD140 is in chemotherapy patients whove lost significant muscle mass, this SARM is given to them for rapid recovery by halting the muscle degenerative disorder. Many physicians around the world refer to RAD 140 as an alternative to Testosterone Replacement Therapy (TRT).Speaking of Testolone results, a vast majority of its user reported elevated energy levels and significant improvements in muscle growth. The mechanism hints at escalated protein synthesis which is very beneficial for bulking workouts. Although RAD 140 results take some time occasionally the gains are reportedly permanent and more solid. With the use of RAD140, users tend to feel nauseated and have other symptoms very little.

The best way to take Testolone is by taking it for 60 days straight (if you are looking for 10-20 lbs muscle gain), but it also depends on the dosage of the compounds. For more remarkable results, Testolone is often combined with other SARM for bulking named Ligandrol.

Ligandrol LGD 4033 SARM Before and After ResultsIn 2022, a vast group of bodybuilders prefers Ligandrol for the best-looking body. The SARM is typically run for 12 weeks straight in a 10-20mg per day dosage after which you can expect to achieve 20 pounds of lean mass.First-time Ligandrol LGD 4033 SARM users take it in little dosage i.e. 6-10 mg for 6 weeks which is to experience a very little amount of side effects. As a suitable SARM for bulking cycle, Ligandrol is also being used for improved fat loss, the SARM binds to the androgen receptors located in the adipose tissues which tend to fasten the metabolism and this will lead rapid weight loss.Ligandrol is sometimes compared to Trenbolone because both compounds stimulate the production of trep muscles. Following a calorie-restricted diet and another regular workout, there are many results you can expect while using Ligandrol. Increased energy, sharpened focus, and lean abs are some of them.

Ibutamoren MK 677 SARM Before and After ResultsNot always a SARM but MK 677 sometimes referred to as Growth Hormone Secretagogue which produces growth hormone and protein in the body. In dire need of supplements, bodybuilders occasionally take Somatropin steroids for HGH stimulation but Ibutamoren is replacing the steroids as we know. Thats because very few side effects are associated with Ligandrol than Somatropin.Ibutamoren MK 677 SARM is the ideal compound for power-lifters who dont take no for an answer when it comes to showing their full body potential. You can also observe increased fertility while consuming Ibutamoren.In the latest reviews about Ibutamoren SARM, it was concluded that it may not be too much helpful to prevent muscle soreness and injury. It can shorten the muscle healing time but thats nothing compared to what Testolone RAD 140 does.In addition, the growth hormone stimulator like MK 677 aids peaceful and sound sleep which is another useful gimmick for muscle recovery. Ibutamoren users reportedly take a brief amount of sleep but they wake up feeling energetic and fresh like they have been sleeping for a day. You can experience the same Ibutamoren result but the condition is to take it in the evening. Stacking Ibutamoren is easy with other SARMs and the surprising part about the compound is there are no need for Post Cycle Therapy. In fact, some users take MK 677 SARM as a part of their PCT which is to replenish the dropped testosterone and HGH levels.Cutting SARM Before and After ResultsBest SARMs for Cutting in 2022 are reviewed by the experts on the reddit forum and other notable platforms online. Some of these SARMs are perplexedly made but the science justifies the results.

Cardarine Before and After ResultsMany reviews about Cardarine GW-501516 SARM say its not a proper SARM but rather a PPAR receptor agonist. The function of such molecules is to provide the fat-burning effects to the body by burning fats and not glucose entirely. The fat cells fulfill the energy demands more efficiently than glucose does and by this, we mean better muscle definition and improved stamina ahead.Cardarine is used by exceptional types of bodybuilders who want to build an ethos out of themselves. GW 501516 tells us about the eradication of stubborn fat from the belly, only 15mg daily dosage for 8 weeks is sufficient for the desired results. You can see at the end of the first month that your body begins to react to strenuous workouts and that it also loses around 5% of body fats.Most people in 2022 are looking for a supplement that can help them shrink their love handles, after spending a sedentary lifestyle most of us get determined to the workout that only stays for a few days. SARMs like Cardarine is the name of the game when you keep wanting to be dedicated and punctual to the workout without any compunction for laters.

Ostarine Before and After ResultsAn athletic physique means you will develop cuts as well as muscle mass which is a pleasant sight for the viewers. With the help of the Ostarine cycle, many users reportedly gained over 8 pounds of lean muscle mass but they also get immense energy levels that help them with fat eradication.Ostarine cycle results in improved bone density, and insulin resistance and it does not interfere with the hormonal system. Many steroids and SARMs end up disturbing the levels of Testosterone, Progesterone, Growth Hormones, and Estrogen but Ostarine is exempted from all those nasty side effects.Ostarine is considered the mildest SARM which means its also safer than most bodybuilding SARMs available in 2022. So many clinical trials are already done on Ostarine and its awaiting FDA approval, there are fewer side effects than any other SARMs. You can take Ostarine in conjunction with RAD 140 Testolone or Ligandrol but you have to be punctual during the workout sessions.

Stenabolic SR9009 SARM Before and After ResultsStenabolic SARM is an ideal SARM for every type of body whether endomorphs or ectomorphs, the SARM is greatest in fat eradiation while replacing them with healthy muscle mass. Recently, the SR9009 Stenabolic cycle has taken a new turn in which bodybuilders are taking it as a weight loss supplement.Stenabolic is indeed a REV-ERB agonist which means it manages and regulates a special type of protein called REV-ERB. This protein is located throughout the body, especially in the muscle tissue, upon activation the regulation of fat metabolism and energy generation takes place and this turns the user into a more energetic, result-oriented, and literally a beast in the gym.Stenabolic is the best SARM for females in order to accomplish their weight loss goals. Different men and women athletes are getting fond of gene expression effects of Stenabolic which seems to increase the mitochondrial energy in each muscle cell. Mitochondria are frequently referred to as the "powerhouses" of cells because they produce most of the cell's energy. Therefore, by increasing the number of mitochondria in muscle cells, Stenabolic SR9009 may help a woman's muscles to produce more energy and become stronger.

Conclusion - Are SARMs Before and After Results Real?You have the liberty to not believe what they say about mere bodybuilding supplements, but SARMs or steroids are not just any other bodybuilding supplements. It took years of research and critical studies to define them and make them available in the consumer market. Just like the SARMs results, SARM side effects are also real which takes a heavy toll on the body at times.To avoid such outcomes, you may start with the minimum dosage of any SARM that you have chosen, also make sure to stick with a healthy diet plan and workout session which gets the most out of the SARMs before and after results.(Disclaimer : The above is a sponsored post, the views expressed are those of the sponsor/author and do not represent the stand and views of Outlook editorial.)

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SARMs Before And After Results Real SARM Results And Users Review In 2022 - Outlook India


Jun 10

Explained: Testosterone deficiency & the safety of replacement therapy – The Indian Express

Hypogonadism is a condition caused by the deficiency of the male sex hormone, testosterone, and a new study in Lancet Health Longevity looks at the short- to medium-term safety of testosterone treatment. Analysis of data from more than 3,400 patients with hypogonadism from 17 clinical trials found little evidence that testosterone treatment increases the risk of cardiovascular events such as arrhythmia, heart attack, and stroke, in the short to medium terms.

Testosterone replacement therapy is the standard treatment for hypogonadism, which can cause sexual dysfunction, weakening of bones and muscles, and reduced quality of life. Risk factors include ageing (as testosterone levels decline with age), obesity and diabetes. Contacted via email, Dr Channa Jayasena, Reader in Reproductive Endocrinology, Imperial College London and study author, said that worldwide, 2% of men aged over 40 are affected, and this is growing as the population gets older.

Despite being widely used, the cardiovascular safety of testosterone treatment had so far remained unclear due to inconsistent findings. Most previous clinical studies relied on aggregate data, rather than individual participant data and have not published details of individual adverse events.

Prescribing of testosterone for hypogonadism is increasing globally, but conflicting messages about its safety may have led to many patients not receiving the treatment. Ongoing studies should help to determine the longer-term safety of testosterone but, in the meantime, our results provide much-needed reassurance about its short-to-medium term safety. Our findings could have important implications for the treatment of men with hypogonadism worldwide, lead author Jemma Hudson from the University of Aberdeen said in the report.

Funded by the UK National Institute for Health Research Health Technology Assessment Programme, the study identified 35 eligible clinical trials published since 1992, of which 17 provided individual participant data. None of the studies were from India, Dr Jayasena said.

In the 17 trials, 1,750 participants received testosterone and 1,681 were given a placebo. The average length of testosterone treatment was 9.5 months. The rate of cardiovascular events was not significantly higher for participants receiving testosterone treatment (7.5%) compared to placebo (7.2%). Fewer deaths were reported during testosterone treatment (0.4%) than in the placebo group (0.8%]), but these numbers were too small to establish whether testosterone reduced mortality risk, according to the study authors.

The researchers found that testosterone significantly reduced serum total cholesterol, HDL, and triglycerides compared with placebo.

However, there were no significant differences in LDL, blood pressure, glycaemic parameters, diabetes incidence, and prostate adverse outcomes between the testosterone and placebo groups, according to the report.

The authors have acknowledged some limitations to their study. There was little available data evaluating the cardiovascular safety of testosterone treatment beyond 12 months, and the very small number of deaths recorded during testosterone trials hampered the authors ability to analyse why they occurred. However, the longer-term safety of testosterone treatment is currently being investigated in another clinical trial, Dr Jayasena said.

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Explained: Testosterone deficiency & the safety of replacement therapy - The Indian Express


Jun 10

Testosterone Replacement Therapy Market Research Outlook: 2022, Recent Developments, Growth Opportunities and New Innovations – Digital Journal

The Testosterone Replacement Therapy Market research report provides an in-depth examination of the key factors stimulating market expansion. This report provides statistics on the markets current situation, size, regional analysis, and growth factors. The research report helps gain a truly global perspective of the Testosterone Replacement Therapy industry as it covers 60 geographies worldwide. It also includes important information on financial conditions, growth status, product portfolios, revenue, and gross profit margins, as well as technological and research advances. The Testosterone Replacement Therapy market research focuses on the industrys most significant acquisitions, collaborations, and product launches.

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The primary objective of the report is to educate business owners and assist them in making an astute investment in the market. The study highlights regional and sub-regional insights with corresponding factual and statistical analysis. The Testosterone Replacement Therapy market report will facilitate business owners to comprehend the current trend of the market and make profitable decisions.

Top Listed Company Profiles are:

AbbVie, Endo International, Eli lilly, Pfizer, Actavis (Allergan), Bayer, Novartis, Teva, Mylan, Upsher-Smith

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The Testosterone Replacement Therapy market is segmented as per the type of product, application, and geography. All of the segments of the Testosterone Replacement Therapy market are carefully analyzed based on their market share, CAGR, value and volume growth, and other important factors.The research also looks at the top participants in the market, as well as distributors and the complete industrial chain structure. It also assesses the factors and criteria that may have an impact on market sales growth. The report also constitutes recent development undertaken by key players in the market which includes new product launches, partnerships, mergers, acquisitions, and other latest developments.

Based on Product Type Testosterone Replacement Therapy Market is segmented into

Gels, Injections, Patches, Other

Based on the Application Testosterone Replacement Therapy Market is segmented into

Hospitals, Clinics, Others

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Geographical Analysis Covered:

Regional assessment of the Testosterone Replacement Therapy market has been carried out over six key regions which include North America, Asia-pacific, Europe, Latin America, Middle East, and Africa. Moreover, the report also delivers deep insights on the ongoing research & development activities, revenue, innovative services, the actual status of demand and supply, and pricing strategy. In addition to this, this report also delivers details on consumption figures, export/import supply, and gross margin by region. In short, this report provides a valuable source of guidance and clear direction for the marketer and the part interested in the market.

North America (United States, Canada) Asia Pacific (China, Japan, India, South Korea, Australia, Indonesia, Others) Europe (Germany, France, United Kingdom, Italy, Spain, Russia, Others) Latin America (Brazil, Mexico, Others) The Middle East and Africa

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Testosterone Replacement Therapy Market Research Outlook: 2022, Recent Developments, Growth Opportunities and New Innovations - Digital Journal


Jun 10

Kaplan USMLE Step 1: Woman treated with linear doses of a hormone – American Medical Association

If youre preparing for the United States Medical Licensing Examination (USMLE) Step 1 exam, you might want to know which questions are most often missed by test-prep takers. Check out this example from Kaplan Medical, and read an expert explanation of the answer. Also check outall posts in this series.

This months stumper

A double-blind study of fertility-enhancing drugs is conducted. A 28-year-old woman is being treated with sequential doses of a hormone which produces a progressive rise in the hormone's plasma level over several days. Initially, the patients plasma levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) decline, but later FSH and LH suddenly and dramatically increase.

Which of the following hormones is she most likely being treated with?

A. Estrogen.

B. Gonadotropin-releasing hormone.

C. Inhibin.

D. Progesterone.

E. Testosterone.

The correct answer is A.

Kaplan Medical explains why

The drug is promoting changes in estrogen levels and estrogen induced FSH and LH levels that would be expected to be occurring during a normal menstrual cycle. Estrogen levels are relatively low at the beginning of the menstrual cycle but rise slowly during the follicular phase.

Estrogen suppresses FSH and LH secretion during the follicular phase through negative feedback inhibition of the hypothalamicpituitaryovarian axis. Once plasma estrogen levels reach a critical threshold (as occurs with the repeated dosing described in this question), and that level is maintained for at least two days, the negative feedback loop changes to a positive feedback loop and a surge in FSH and LH secretion occurs. This sequence occurs at the end of the follicular phase, and the LH surge induces ovulation.

Why the other answers are wrong

Choice B: Gonadotropin-releasing hormone (GnRH) is produced by the hypothalamus and targets gonadotropes in the anterior pituitary. GnRH administration would initially stimulate FSH and LH secretion, but levels of both hormones would then fall due to downregulation of the GnRH receptors. A pulsatile infusion that mimics the normal pattern of GnRH release from the hypothalamus would promote a sustained increase in LH through GnRH receptor upregulation and gonadotroph sensitization.

Choice C: Inhibins are peptide hormones produced by follicular granulosa cells that create a negative feedback control pathway regulating FSH secretion by the anterior pituitary. Inhibins are produced in response to FSH and once released, inhibit FSH secretion. Administration of inhibin would not result in an FSH surge such as that described in the scenario above.

Choice D: Prolonged administration of progesterone inhibits GnRH-induced FSH secretion from the anterior pituitary.

Choice E: Testosterone normally provides the negative feedback for LH and does not directly affect FSH, although very high nonphysiologic levels of testosterone will reduce plasma FSH due to suppression of GnRH release.

Tips to remember

For more prep questions on USMLE Steps 1, 2 and 3, viewother posts in this series.

The AMA selected Kaplan as a preferred provider to support you in reaching your goal of passing the USMLE or COMLEX-USA.AMA members can save 30% on access to additional study resources, such as Kaplans Qbank and High-yield courses. Learn more.

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Kaplan USMLE Step 1: Woman treated with linear doses of a hormone - American Medical Association


Jun 10

Do You Need Hormone Testing? – Health Essentials from Cleveland Clinic

Its probably not an exaggeration to say that every woman on the planet has, at one point or another, heard someone say, Oh, its probably just your hormones. People seem to be inclined to blame just about everything from headaches to hot flashes and all kinds of conditions in between on good old hormones.

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services.Policy

Sometimes itisyour hormones, though. Andhormonal imbalancescan mean more for your health than just a grumpy day or a few zits before your period. So, how can you tell when its hormones and when its something else?

Womens health specialistPelin Batur, MD, talks about a few types of hormonal imbalances commonly seen in women, including symptoms you shouldnt ignore and when to see a medical professional.

To decide whether you need hormone testing (and if so, what kind), your doctor will likely start by asking you lots of questions about your symptoms. This will help them put together the puzzle pieces of what might be going on.

The workflow in my head focuses on three questions, Dr. Batur says. First, do these symptoms sound hormonal? If so, do they sound like theyre related to estrogen, progesterone, testosterone or some other type of hormone? And finally, is it because theyre too low or too high?

Once your doctor has a sense of what might be happening, theyll figure out which tests to (or not to) run.

One symptom that indicates that you may need testing is irregular periods.

If youre having regular menstrual cycles and not having symptoms throughout the month, I dont usually start with lots of estrogen, progesterone or testosterone tests, Dr. Batur says. But if youre experiencing a lot of irregularities in your cycle, Im likely to do more testing.

We have at least 50 different hormones in our body, and very complex symptoms can arise from them, Dr. Batur says. Having too much or too little of certain hormones causes symptoms and issues with your health.

Here are some of the most common hormonal imbalances seen in people assigned female at birth (AFAB).

There are less-common hormonal imbalances, too, likeCushings syndromeandAddisons disease. Only a doctor can help identify which hormonal imbalance youre experiencing and what course of treatment is best.

Heres the thing: Hormonal imbalances can have a lot of symptoms and they can have a lot ofdifferentsymptoms, depending on which ones are at the root of your issues. Those symptoms may seem muddled or initially unrelated, and theyre not always related to hormones at all.

Hormones can cause so many symptoms, but that doesnt mean theyre always the cause of your symptoms, Dr. Batur says, so its really important to be seen by a doctor for an individualized assessment.

Here are some common symptoms of hormonal imbalances in women and what theymight signify.

Weird periods are a key sign of a hormonal imbalance.Irregular menstruationcan be a sign of perimenopause but can have a number of other causes, too, especially if youre not yet nearing menopausal age.

If your menstrual cycles are disrupted or if youre going through menopause, you should definitely come in to be seen and to talk things out, Dr. Batur advises.

If a woman comes in complaining of acne, Im concerned about potentially high levels of hormones such as testosterone, Dr. Batur says. We see this in women withpolycystic ovary syndrome. PCOS causes higher levels of male hormones called androgens (including testosterone), which can lead to acne.

If you start to notice differences in your hair whether on your head, face or someplace else, like your arms and legs it could be a sign of a hormone imbalance.

Starting to see chin hairs or a bit of a mustache? Increased testosterone can cause excess hair growth (hirsutism). This can be a symptom of PCOS or menopause, but it has other causes, too.

On the flip side, hormonal imbalances can also cause thinning hair on your head, legs and pubic region.During menopause, a drop in estrogen can lead to slower hair growth, or cause it to fall out more easily.Hypothyroidism and hyperthyroidism can cause hair loss, too. Or your hair loss may be related to something else entirely something nonhormonal.

It can be really complex to figure out, Dr. Batur says. You might assume hair loss is hormonal, but it can be related to high or low thyroid level, low estrogen, high testosterone or something else, like vitamin deficiency or lifestyle stressors.

These symptoms usually indicate that a womans hormones are lower, like the kind of dropping estrogen levels we see in perimenopause or postmenopause, Dr. Batur says. They can alsobe a side effect of some medications and treatments.

Your doctor can help you find ways tomanage your hot flashesso they dont negatively affect your quality of life.

Weight gain can be a symptom of a variety of hormonal imbalances, as well as lifestyle-related factors, so doctors use other clues about your health to get a sense of whats going on.

Difficulty losing weight is a very common problem in the United States, and its often blamed on hormones, Dr. Batur says. Sometimes, its related to high testosterone levels, like with PCOS, and menopause is associated with weight gain, too. But if you have weight gain with regular menstrual cycles, its more likely to be related to something likecortisol, thyroid, insulin or lifestyle habits.

Havent changed your lifestyle habits but have suddenly dropped 15 lbs.? This symptom is often a sign of an overactive thyroid, orhyperthyroidism. When your body produces too much thyroid hormone, your metabolism speeds up, which can cause weight loss along with rapid heartbeat, an intolerance to heat and other symptoms.

Althoughvaginal drynesscan be a sign of a few issues, its one of the most common symptoms of menopause. Your estrogen levels drop during menopause, which can to lead vaginal dryness that causesdiscomfort during sex.

The vagina is quite sensitive to lack of estrogen, Dr. Batur says. About 50% of women have vaginal dryness that may get in the way of intercourse, and it tends to get worse over time.

While its important to advocate for your health, try not to be swayed by broad, overarching claims (looking at you, social media) that insist thateveryoneneeds hormone testing or that every symptom youre experiencing is related to your hormones.

Just because youre experiencing symptoms of a hormonal imbalance doesntmean you haveahormonal imbalance. Nearly every symptom of a hormonal imbalance can have other causes, as well.

Its important to not lump everything together under hormones, and to instead break down each symptom individually, Dr. Batur advises. We have to take a deep dive to make sure were not missing anything, whether its lifestyle factors or another medical condition.

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Do You Need Hormone Testing? - Health Essentials from Cleveland Clinic


Jun 10

What Is Hormone-Replacement Therapy? – POPSUGAR

If you've experienced gender dysphoria the distressing feeling that occurs when your gender identity differs from the one you were assigned at birth you might have considered hormone-replacement therapy. Originally, HRT referred to the process of prescribing sex hormones like estrogen to people going through menopause as a way of treating symptoms such as hot flashes (a practice that has since been the subject of some controversy). But today, the term "HRT" is commonly used to describe "gender affirming hormone therapy" for "individuals who are seeking to alter their secondary sex characteristics for a more 'masculine' or more 'feminine' gender presentation," as defined by Folx, an online health and wellness provider for the LGBTQ+ community. At Folx and other gender-affirming-therapy providers, HRT involves using hormones like estrogen or testosterone to give the body a more traditionally feminine or masculine appearance to match one's gender identity.

While many trans and nonbinary people describe the medicine as life-saving, the process isn't for everyone, nor is it a requirement for trans and nonbinary people. "HRT does not make a trans person trans," stresses TikToker and professional actor Dylan Mulvaney, a trans woman who has been chronicling her self-described girlhood on the app. "If there is a trans person out there, and for whatever reason, they don't think HRT is right for them right now, or ever, we need to see them as such and respect their pronouns as such," Mulvaney adds.

The decision to start HRT is individual and can be complex. Sade Bolger, a Vermont-based activist and public-affairs organizer for Planned Parenthood, started HRT specifically testosterone therapy (or T) in May of 2017. But when he began, the decision was one of uncertainty. "When I did start T, I didn't really actually fully feel like I did know that for certain this is going to be the right thing," Bolger says. "I stepped into T in an explorative way, having seen other people who had gone through that process, and utilized it as a tool for self-discovery and self-exploration."

California-based Mulvaney echoes a similar sentiment: "The initial reason for going on HRT was just to sort of explore what that side to me was." Before beginning HRT, the actor had considered themself nonbinary for about 18 months. "But I always knew that I wanted to be more feminine," she says. "And even while I was nonbinary I knew that I loved the features on a woman, that I would love to have." Even so, she tells POPSUGAR, "I was so nervous to start [HRT] because it really is a huge decision to be potentially altering your body."

Josie Moon, another trans TikToker, also described her decision to start HRT as a tough one. Moon says she didn't know what the word "trans" meant until she was late into high school. The Nashville-based content creator got married at 24 years old, came out to her now-ex-wife as trans about two years into their marriage, and decided to get divorced just before the 2020 COVID lockdown. Through her own research, she discovered that some trans people don't take hormones. When making the choice for herself, she considered how it would affect her. "I was very concerned that even if I went on hormones at 29, it wasn't going to be enough for me to feel comfortable in my body," Moon tells POPSUGAR.

So she gathered more information, reading relevant threads on Reddit and Twitter and speaking to others in the trans community to make sure HRT was the right decision for her. "There's a subreddit called Trans timelines which shows pictures of mostly trans women but also trans men, really trans people in general before and after hormones," Moon says. "And I was like, wow, these people are the same age as me . . . and they look amazing. The results are amazing. So maybe this could work for me too." It had gotten to the point, Moon says, where she was constantly looking at these pictures and "imagining just feeling comfortable in my body and what that would look like." Now, two years on HRT, Moon is happy with her decision to start the therapy. So are Mulvaney and Bolger. "I look at myself in the mirror now and every day I get a little bit closer to finding myself to be a beautiful woman," Mulvaney says. "I think it was through the process of experiencing the changes that came alongside taking T that really kind of confirmed for me that this was what I wanted to do and who I wanted to be on the planet," says Bolger.

If you're still trying to figure out whether HRT is right for you, this explainer will help answer some of your questions, including what to ask your doctor, when to expect changes, and what side effects to be aware of.

Masculinizing or feminizing hormone therapy, also commonly referred to as hormone-replacement therapy or HRT, is a process used to "induce the physical changes in your body" caused by male or female hormones "to promote the matching of your gender identity and body (gender congruence)," per the Mayo Clinic.

Someone transitioning from male to female (MTF) would typically use feminizing hormone therapy and "be given medication to block the action of the hormone testosterone. You'll also be given the hormone estrogen to decrease testosterone production and induce feminine secondary sex characteristics," the Mayo Clinic states. In a female to male (FTM) transition with hormone therapy, "you'll be given the male hormone testosterone, which suppresses your menstrual cycles and decreases the production of estrogen from your ovaries."

The method in which those hormones are administered can vary, says Dave Usman, nurse practitioner at Radiant Health Centers, a California-based LGBTQIA+ Health and HIV care center. "It depends on the comfortability of the individual that's seeking hormone therapy," he says. For those receiving masculinizing HRT through testosterone, there are two options, Usman says. The most common route is injection. "It can be self-administered or office-administered," he says. There's also a topical gel option. For estrogen therapy, there's a pill, injectable, or patch.

Not every hospital or clinic provides gender-affirming healthcare. There are some instances in which medical providers can get exceptions, specifically hospitals and clinics with religious affiliations. It's important to do your research beforehand to ensure that you can get the care you need.

Bolger was referred to an endocrinologist after expressing to his therapist that he was considering HRT. Mulvaney recommends going to a queer health center in your area. "The great part is that they focus primarily on queer trans clients, so they are very in the know as far as treatment plans," she explains. Another good option? An informed-consent clinic, which means that a referral or therapy note is not required to receive care. (Planned Parenthood is an informed-consent clinic.) You can also receive hormone therapy online through services like Folx and Plume.

As far as cost goes, many insurance plans cover hormone therapy. For those who are uninsured or have trouble accessing hormone therapy, health centers like Radiant Health rely on contracted pharmacies that provide the medication at a low out-of-pocket cost for patients. Brands like Folx also offer an HRT care fund which distributes financial resources to an annual grant covering 12 months of hormone-replacement therapy, including prescription medication, unlimited clinical visits and messaging, and labs. Eighty percent of the Folx HRT grants are reserved for BIPOC. Eligibility starts at 18 years old, and you must live in a state where Folx is currently available.

"The first visit is mainly educating the patient, asking questions, and telling them what is expected," Usman says. "And then, once they have all the questions answered, they feel like they're ready, they're mentally and physically ready, that's when we start initiating therapy." That initiation point can be that day or weeks later. It's really about the patient's comfortability level.

Mulvaney first went to get information and ask questions about the process and then was prescribed spironolactone and estradiol. Spironolactone is a testosterone blocker and estradiol is a form of estrogen. "I went for the information, I got it, I got my mind put at ease. And then I started [the hormones] a few weeks later," Mulvaney says. She adds that she started out with a low dosage "because I was still new to it. I was nervous. I just didn't want to throw myself into it too fully quite yet."

One major conversation you should have with your provider, Mulvaney stresses, is about reproductive options, which will change during hormone therapy. Testosterone and estrogen therapy can lower your sperm count or egg production and may permanently change or stop your body's production of eggs and/or sperm altogether. So if someone is planning to undergo hormone therapy and they may want to conceive a child in the future, Usman says it's encouraged to do egg or sperm retrieval or freezing. "I actually didn't start the spironolactone until recently because I wanted to freeze my sperm first," Mulvaney says. "Being in my 20s, I just wanted to keep all my options open for the future and family planning because I don't know what that's going to look like when I'm older." But Bolger adds that not knowing what you want your reproductive options to be is OK, too. They started T when they were 19 years old. "I didn't know what I wanted to do reproduction wise I still don't. I'm 23 now, and I'm still figuring it out." But it's important that you know all of your options and make the decision that's best for you.

Everyone's timeline of changes is different, but Usman says you can start to see small physical changes as early as a month in.

"My first sort of notice was stretch marks on my booty," says Mulvaney. It was an unexpected surprise to her less than three months on HRT, in addition to a smoothing of her face and the loss of muscle mass in the chest. "I never had hard nipples before," Mulvaney says. "And now they are starting to bud."

For Bolger, the most notable initial changes were voice deepening, peach-fuzz hairs on the lip, and clitoral enlargement, which is commonly referred to as bottom growth. In terms of mood, Bolger says, "My libido pretty greatly increased and stayed kind of intense for the first couple of months into that first year." They also dealt with recurring mood swings. But this was predominantly "just during the period of time where my hormone balance was off because I was transitioning between estrogen and testosterone. And once I kind of plateaued with the T in my body, and that became the main hormone in my body, then all that stuff kind of settled out."

What's important to note is that the mental and emotional changes are just as important to address as the physical ones, and they may hit you sooner. "The first two weeks, I'm not gonna lie, were tough. I didn't feel like myself in some ways. My mind was foggy, I felt very emotional, I had some anxiety," says Mulvaney. These changes ultimately went away, or Mulvaney became accustomed to them. "I think my body learned to accept that this was the new normal and I started to feel like myself again," she says.

Therapy also helped, she adds. "I'm in therapy once a week and I have been with the same therapist for two years, it's changed my whole life and outlook on things." With HRT, you're seeing a doctor every three months or so for check-ins. "But you also need to have a support system in place that can help you with the day-to-day, because it can get pretty overwhelming," says Mulvaney.

Moon agrees that at times, the emotional aspects of HRT can become overwhelming. "When I was younger, I used to say I had three emotions angry, happy, neutral and that was just how it was," says Moon. But in starting HRT, she unlocked a new range of emotions with various depths and layers. "Angry is actually, 'I'm a little bit hungry, but I feel hurt and misunderstood and just sad in general.' And then when I was happy, I'm not just happy or euphoric, it's like, 'I'm excited about this and there's a little bit of joy about this.'" The whole process is "also a little bit bittersweet, because in transitioning, I get to be myself, but I also lost so, so much and had to rebuild," Moon says. "I think emotionally, it took me off guard."

One change that Bolger says he was the most unprepared for is the way others perceive him. "I absolutely took on male privilege," he says. "I noticed that I was being treated differently. The men in the room would shake my hand before they left. I was listened to more. There was more of a platform in a space, people kind of waited for me to have something to say." Emotionally, Bolger says it was "so weird." Because they don't identify as a man, "it was like switching from feeling misgendered on one side to feeling misgendered on the other side." He also says the transition between living the first 18 years experiencing sexism against women only then to be welcomed and respected by sexist men was "not ever in my intentions." There's this layer of complexity for nonbinary individuals, Bolger says, because T or no T, "we live in a society where people assume that you're either a man or a woman."

Another unexpected change? Anecdotally, many people on T have said that it changes their sexual attraction, especially as it pertains to men. Bolger says that being on T hasn't necessarily changed his attraction level to men but rather his comfortability level being with a man. "I felt really uncomfortable being with men, for example, when I was younger, because I knew that that would make people see me as a girl," Bolger says. Being on T changed the way people perceived them and how Bolger perceived himself. Ultimately, "T didn't make me stop loving women. T didn't make me start loving men. T didn't change anything about who I loved or who I f*cked. It changed my comfort, being in those relationships and having those experiences because of how I was feeling and perceiving myself."

Yes. "That's why we screen people initially for their past medical history and family history, because both [hormones] have side effects and adverse effects that can affect their overall health," says Usman. Hormone therapy can aggravate pre-existing depression and anxiety. Other complications include developing diabetes, high cholesterol, high blood pressure, and blood clots. If you're a chronic smoker in particular and you're on estrogen, "there's higher risk of developing blood clots," Usman says. So be sure to be honest about all of your lifestyle habits within that first meeting so that your provider can assess your needs and design a hormone-therapy plan that works best for you.

Bolger, for example, is neurodivergent. "I have ADHD. I sometimes struggle with routine, like hygiene care, because of that," Bolger says, and talking to his provider about that openly was "really important" in figuring out which form of T was right for them. For example, the topical gel has to be applied once a day. "It has to be a part of your routine and for me with my ADHD, that wasn't something that I really thought was going to be plausible," Bolger says. So he went with the weekly injections instead. Even so, Bolger experienced health complications, including ovarian cysts, which were caused by going off schedule on T, a diversion caused by his ADHD. That's why Bolger emphasizes the importance of seeking out a provider who can assess and treat your whole self someone who will be looking our for your mental, physical, and emotional health not just you as a trans person, but you as a whole human, too.

Image Source: Getty Images

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What Is Hormone-Replacement Therapy? - POPSUGAR


Apr 3

You get 45% more testosterone when you dont masturbate …

Theres a lot of rumour and misconception swirling around male abstinence.

Online communities like reddits Nofap group encourage each other to abstain from pornography, claiming to have better sex, more testosterone and increased confidence as a result of this self-imposed masturbation ban. But does an imaginary chastity belt really make you a better man?

(Related: the complete beginner's guide to testosterone)

Researchers from Zhejiang University set out to find out.

The scientists checked the testosterone levels of a group of abstaining men every day for a week. During most of the week, the testosterone fluctuations were minimal at best. However, on day 7, the researchers found that testosterone levels rocketed to a massive 145% of their baseline levels. Thats a lot of T.

Why are people searching for more testosterone? Because your T-levels account for much more than your sex drive.

Testosterone also increases the potential for muscle growth by forcing our body to increase protein synthesis, according to the Journal of Applied Physiology. Low testosterone is also a contributing factor in hair loss, weight gain and decreased bone density.

Its unclear why it takes exactly 7 days to take effect, but there are safer ways to boost your T. Boston University found that frequent ejaculation is linked to a decreased prostate cancer risk, so building up a backlog may not be the best idea.

Combine our natural testosterone-boosting foods with a big-lifts leg day workout proven to spike your hormones, and youll have all the benefits of abstinence without the irritability.

This content is created and maintained by a third party, and imported onto this page to help users provide their email addresses. You may be able to find more information about this and similar content at piano.io

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You get 45% more testosterone when you dont masturbate ...


Apr 3

Vasectomy: Effect on testosterone levels and sexual function – Medical News Today

Vasectomy is the medical term for male sterilization. It is a medical procedure that involves cutting or sealing the tubes that carry sperm into seminal fluid, or semen. While this procedure permanently prevents the semen from containing any sperm, it does not affect testosterone levels.

People considering a vasectomy may worry that their testosterone levels, libido, and sexual functioning will decrease following the procedure. However, vasectomy has no effect on testosterone levels or sexual function.

Additionally, evidence suggests that people who undergo the procedure may experience improvements in their sex life.

This article asks whether a vasectomy affects testosterone levels, libido, and sexual functioning. We also outline some potential long-term side effects and health risks of vasectomy and clarify some common myths about the procedure.

A vasectomy is a medical procedure that involves cutting or sealing the tubes that carry sperm from the testicles to the penis. This prevents sperm from reaching the seminal fluid, or semen, which a male ejaculates during sex.

Males who have undergone vasectomy will continue to ejaculate semen, but the semen will not contain sperm.

A vasectomy alters the mechanics that make pregnancy possible, but it does not cause biological changes in males. As such, a vasectomy does not affect testosterone levels a 2018 study found that these procedures had no long-term impact on testosterone levels in men.

Hormonal imbalance occurs when the body produces too much or too little of a certain hormone.

No current evidence suggests vasectomies cause hormonal imbalance in males. For example, a 2018 study showed that these procedures do not affect testosterone levels in men.

Some causes of hormonal imbalances in biological males include:

All surgical procedures have the potential to cause side effects, though vasectomies carry a relatively low risk.

Some potential long-term side effects of vasectomy include:

According to a 2021 review, there is no increased risk with vasectomy and the following health conditions:

However, the review concluded that further study with long-term observation is necessary.

In older guidelines, American Urological Association also stated that vasectomy is not a risk factor for:

A person with concerns about the potential short- or long-term side effects of vasectomy can speak with a doctor.

Current evidence does not suggest that vasectomy causes erectile dysfunction or any form of sexual dysfunction.

A 2020 proposed systematic review notes that studies have demonstrated the following improvements in sexual function among males who have undergone a vasectomy:

A vasectomy prevents sperm from entering semen, which a male releases during ejaculation. It does not affect the production of the hormone testosterone, which is responsible for sex drive.

Sperm makes up a very small amount of male ejaculate, so sexual satisfaction should also not decrease.

In fact, according to a 2017 study, biological males who underwent a vasectomy experienced greater sexual satisfaction following the procedure.

In general, medical professionals view vasectomies as relatively low risk procedures. Most people who undergo a vasectomy can:

However, like all procedures, there are risks of short- and long-term side effects.

According to a 2021 review, common short-term side effects include:

The same review notes the following potential long-term complications:

A person considering undergoing a vasectomy may worry about how the procedure will affect their life.

Studies have shown that a persons sex life can actually improve following a vasectomy. Many people who undergo the procedure report increased sexual activity and sexual satisfaction.

However, some people may experience ongoing fears or concerns relating to vasectomy. A 2018 study noted that individuals who have undergone the procedure may benefit from psychological counseling to address these fears and concerns.

There are many rumors surrounding vasectomy, including those relating to the procedure itself, the risks involved, and the changes a vasectomy may bring to a persons life.

Below are some myths and facts associated with vasectomies.

Fact: Recent studies have shown the opposite is true. Most people report having improved libido, and there may also be improved erections and orgasms following the procedure.

Fact: Most people who undergo vasectomy could return to work within 3 days, and most can resume sex and exercise within 12 weeks.

Fact: While vasectomies are the most effective form of birth control, they do not take effect immediately. A couple will need to continue to use other forms of birth control for several months following the procedure and until a doctor confirms the absence of sperm in the semen.

Fact: Though uncommon, a person can have a vasectomy reversal if they change their mind about having children in the future. However, reversals can sometimes fail, so they should only have a vasectomy if they feel confident that they do not want more children.

Vasectomy is a medical procedure that involves cutting or sealing the tubes that carry sperm into semen. The procedure permanently prevents pregnancy.

People considering a vasectomy may worry about the consequences for their sexual function. However, the evidence suggests that vasectomies have no effect on testosterone levels and have a mostly positive effect on sexual function and satisfaction.

Vasectomies also have a low incidence of both short- and long-term health complications, and doctors generally view the procedure as safe and effective in preventing pregnancy.

However, while it is usually possible to reverse a vasectomy, they sometimes fail. As such, a person should only consider a vasectomy if they feel confident that they do not want any further children.

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Vasectomy: Effect on testosterone levels and sexual function - Medical News Today


Apr 3

Evolution of Androgen Deprivation Therapy | RRU – Dove Medical Press

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


Jan 18

Yes, ashwagandha could have a positive impact on your physical and mental health – WATN – Local 24

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.

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



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