Search Weight Loss Topics:

Page 337«..1020..336337338339..350360..»

Home » Page 337

Shehnaaz Gill, who rose to fame following her stint in the reality show Bigg Boss, has left everyone in awe of her candid nature and impeccable style. Post the show, she stunned her fans with a massive weight-loss transformation that she achieved during the Covid-19 lockdown.

Her weight-loss journey served as fitness goalsto many who were curious to know the secret behind her transformation. To share the same, she recently made an appearance on Shape on You, a fitness show hosted by Bollywood actor Shilpa Shetty.

The 28-year-old revealed that coming out of the Bigg Boss house was a turning point for her. By the time I finished Bigg Boss, the lockdown had started. So, in the lockdown, I thought, Why not do something new? so that when people see me, they will be like, Is that Shehnaaz?'

However, the actor-singer revealed that she didnt resort to a vigorous workout routine or fad diets to reach her goals. She said, It wasnt like I did something different in my diet. I consumed the same diet but reduced my portion size. After waking up, I drink tea and turmeric water. Now I start my day by drinking apple cider vinegar water. For breakfast, I sometimes eat green grams, dosa or a fenugreek paratha. I consume a high-protein breakfast. My 70 per cent focus has been towards my diet

In addition to eating a nutritious diet, she stressed the importance of drinking enough water. I drink a lot of water. To make the water tasty, I add strawberries and cucumber to it and drink it all day. It is also very important for your skin.

While many believe that it is essential to follow a strict diet and hit the gym daily to lose weight, Shehnaaz disagreed. You can lose weight effectively even while staying at home. If you arent allowed to go outside, then walk around in the house, she said.

While she managed to climb up the ladder of success every day in the last couple of years, she hit a personal low after the death of her close friend Sidharth Shukla in September last year. Addressing the trolling she faced when a video of her dancing at a friends party surfaced in December, she said, If I get the chance to laugh, then I will laugh and remain happy. If I feel like celebrating Diwali, I will celebrate it because being happy is very important in life.

Today is the first time I am talking about this and its only because you are asking me to. Otherwise, I dont prefer addressing these questions. Why should I tell anyone about my relationship with Sidharth? I am not answerable to anyone, she added, on speculations about her rumoured relationship with Sidharth.

Sidharth never asked me to stop laughing. In fact, he always wanted to see me happy. So, I will always laugh and continue doing my work because I want to go ahead in my life, the Honsla Rakh star concluded.

For more lifestyle news, follow us on Instagram | Twitter | Facebook and dont miss out on the latest updates!

Go here to see the original:
You can lose weight even while staying at home: Shehnaaz Gill opens up about diet, fitness and mental health - The Indian Express

Read More..

With over 1,000 locations throughout the United States, Smoothie King proves one of the most popular smoothie bars in the country.

The company offers a variety of customizable smoothies, which are grouped into four main categories, including:

However, with their massive menu and huge selection of mix-ins, Smoothie King may overwhelm you with its list of ingredients. You may find it tricky to figure out what to order especially if you have any specific health goals or dietary restrictions to keep in mind.

This article covers 10 of the best Smoothie King smoothies to help you find an option that fits your needs and preferences.

Smoothie King offers a selection of low calorie blends in their Stay Slim line, including the Lean1 Vanilla, which features ingredients like bananas, almonds, and Lean1 Vanilla Protein.

With 240 calories, 21 grams of protein, and 4 grams of fiber per 20-ounce (590-mL) serving, it can be a good choice if youre trying to lose weight (1).

Reducing your appetite and supporting your weight loss, fiber and protein can help keep you feeling full between meals (2, 3).

This classic menu item provides a good mix of carbs and protein, making it a great smoothie to sip on after you hit the gym.

It contains 340 calories, 35 grams of carbs, 27 grams of protein, and 5 grams of fiber in each 20-ounce (590-mL) serving and is made with bananas, almonds, whey protein, and a dairy whey blend (4).

Studies show that pairing whey protein with resistance training can increase your muscle mass and improve your posture (5, 6).

Featuring a blend of bananas, pineapples, almonds, carrots, spinach, and plant-based protein, the Vegan Pineapple Spinach smoothie is equal parts nutritious and delicious.

It contains 320 calories, 11 grams of protein, and 8 grams of fiber per 20-ounce (590-mL) serving (7).

Though it also contains 41 grams of sugar and 65 grams of carbs, this smoothie can be altered if you remove the apple pineapple juice blend. Try swapping in almond milk or coconut water instead to reduce the amount of sugar.

This hearty smoothie provides you a healthy dose of protein, carbs, and heart-healthy fats, making it a good choice if youre on the go and looking for a quick and easy meal replacement.

In fact, a 20-ounce (590-mL) serving contains 520 calories, 26 grams of fat, 19 grams of protein, 60 grams of carbs, and 7 grams of fiber (8).

Its made with bananas, almond milk, protein powder, peanut butter, cocoa, and an apple juice blend. It also includes Smoothie Kings signature Super Grains Enhancer, which features nutritious ingredients like chia seeds.

Chia seeds have been linked to a long list of benefits and can be a great addition to your diet, thanks to their content of fiber, protein, omega-3 fatty acids, and antioxidants (9).

The Vegan Mango Kale smoothie contains a blend of nutritious, vegan-friendly ingredients including bananas, kale, mangoes, almonds, apple and pineapple juice, and plant-based protein.

It packs quite a punch when it comes to nutrition, with 340 calories, 11 grams of protein, and 6 grams of fiber in a 20-ounce (590-mL) smoothie (10).

Though it is relatively high in carbs, its free of added sugar. You can also opt to reduce the carb content by swapping the fruit juice for lower carb, plant-based alternatives, like almond milk.

There are a variety of low fat selections on the menu at Smoothie King, including Slim-N-Trim Blueberry, which contains wild blueberries, an apple blueberry juice blend, stevia, and a mix of several protein powders.

It contains just 2 grams of fat, including 250 calories and 11 grams of protein per 20-ounce (590-mL) serving (11).

Whats more, it provides 5 grams of fiber, a key nutrient that can support healthy cholesterol levels, increase feelings of fullness, and boost the health of your gut microbiome (12).

Many of the smoothies from Smoothie King are made without gluten, so they can be included on a gluten-free diet, such as the Lean1 Strawberry.

Its very nutritious, containing 200 calories, 19 grams of protein, and 5 grams of fiber per 20-ounce (590-mL) serving (13).

It is also made using just three simple ingredients, including strawberries, stevia, and Lean1 Vanilla Protein, which is gluten-free.

However, note that none of the smoothies from Smoothie King are certified gluten-free and cross-contamination is possible. Therefore, they may not be suitable for people with celiac disease or those who are sensitive to even trace amounts of gluten.

Whether youre following a ketogenic diet or simply trying to cut back on carbs, the Gladiator Vanilla Smoothie is definitely worth a try.

Its one of the lowest carb items on their menu, containing just 3 grams of carbs, 3.5 grams of fat, 230 calories, and 45 grams of protein in a 20-ounce (590-mL) serving (14).

Its made with Gladiator Protein Vanilla, but you can also add two ingredients of your choice.

Consider adding peanut butter to boost the fat content or veggies like spinach, carrots, or kale to increase the nutritional value while keeping the carb count low.

This tasty green smoothie is made with spinach, mango, almonds, and bananas all of which can easily fit into a paleo diet.

It also contains FITAID + Paleo Protein Enhancer, which is used to bump up the amount of protein, B vitamins, and vitamins C and E in your smoothie (15).

A 20-ounce (590-mL) serving provides 400 calories, 29 grams of protein, and 9 grams of fiber. It also contains 41 mg of caffeine to increase your energy levels (16).

Not only does Smoothie King lists all potential allergens for each item on their menu, but they also allow you to customize your order. This proves useful for people with food allergies.

The Veggie Lemon Ginger is free of major allergens and is made from mangoes, pineapples, stevia, spinach, carrots, kale, ginger, and a blend of juices including white grape lemon juice and papaya juice.

It provides 310 calories, 4 grams of protein, and 6 grams of fiber in a 20-ounce (590-mL) serving. It also contains 80 grams of carbs, though this can be lowered by removing some of the juice (17).

Keep in mind that all Smoothie King smoothies are made using the same shared equipment, so they may not be suitable for people with severe food allergies or intolerances. If youre highly sensitive to allergens, you may want to be more cautious.

There are plenty of smoothies available at Smoothie King, making it an easy-to-find option that fits your dietary needs.

Try ordering one of the smoothies above or use the Fuel Finder tool on their website for a list of personalized recommendations tailored to you.

You can also easily customize any of the smoothies on their menu to ramp up the flavor and squeeze more nutrients into your daily diet.

Read the rest here:
10 Best Smoothie King Smoothies: Nutrition and Benefits - Healthline

Read More..

For many of us, it is always a herculean task to knock off stubborn belly fat. Even the body exhaustion that comes with a fever cant really reduce the fat around the belly. Reducing belly fat isnt just about keeping your body in shape, it also helps to keep your cholesterol in check. Excess belly fat can lead to heart problems, type 2 diabetes, cancer etc.

We offer you 5 drinks that will help in reducing belly fat. Add that along with your regular exercise and diet.

Green tea

Green tea is a favourite of those who are trying to lose weight. The antioxidants present in green tea not just remove toxic waste from your body but also help in preventing cancer. Adding green tea not just improves your health and keeps you energized, but is also good for your brain.

Black coffee

It helps in improving your metabolism and burning the fat from your body. Having a cup before a workout helps in burning the calories faster. But make sure to avoid sugar in your coffee as it adds up the calories.

Jeera water

Jeera helps in curbing appetite as well as burning calories effectively. This herb which is a regular feature in Indian curries also aids in digestion. Drinking a glass of lukewarm jeera boiled water after a workout is a very good idea.

Fennel seed water

Soaking a tablespoon of fennel seeds overnight and straining and consuming it the next morning helps not only in weight loss but also in removing toxic waste from our body. It is also good for digestion and acidity.

Ajwain seeds water

After soaking two tbsp of roasted Ajwain seeds overnight, strain and drink it the next morning. It helps in digestion, improves metabolism and also absorbs more vitamins into your body. To avoid gastric issues some people add Ajwain seeds with the chapati dough.

Go here to see the original:
Worried about that your bulging belly? Try these easy beverages to fix that - Onmanorama

Read More..

Apr. 2Food is an essential part of daily life. As essential as it is, a lack of knowledge and ads for particular diets can make nutrition confusing.

King's Daughters Medical Center providers weighed in on how nutrition and food impact not only life, but fitness and sport. Orthopedic surgeon Dr. Brock Johnson shared how food fuels the body for sport and helps in the recovery process.

A group of dietitians responded to questions together in a document submitted to The Daily Independent. Megan M. Cook, Kirstin Anderson and Heather Jenkins contributed to the answers.

Calories, carbs, fat and protein are brought up when discussing healthy eating or the latest diet trend. It's important to know the role each of these play in the body.

"Carbs, fats and protein make up all of the calories in our diet," according to the group of dietitians. "Calories are what the body needs for energy for daily tasks and to survive. Carbs are the body's preferred source of energy. Fats help certain vitamins do their job and provide essential fatty acids. Protein helps maintain muscle mass and promotes wound healing."

The number of calories has a role. "As a general statement, consuming more calories that we burn will cause us to gain weight, and burning more than we take in will cause us to lose weight," Johnson said. "I would point out that not all calories are created equally."

The dietitians and Johnson make it clear that it matters what makes up the calories.

"It is important to focus on the whole picture of nutrition," according to the dietitians. "Three hundred calories from a candy bar versus 300 calories from nuts and seeds will differ in nutrition and macronutrients."

They advise finding foods with the three macronutrients carbs, fats and protein along with vitamins and minerals.

"Calories are simply a measure of how much energy a particular food contains," Johnson said. "The same amount of calories may be obtained by eating a double cheeseburger as eating some carrots. Granted, it would take a lot of carrots."

Story continues

Johnson said foods higher in fiber and higher in protein "can help you feel more full and satiated for longer than processed foods with high fat and carbohydrates."

It all comes down to fueling the body to reach goals.

"As a rule, I generally wouldn't get too caught up in calorie counting," Johnson said. "A well-rounded diet with healthier foods tends to be best. Avoiding processed foods, fast food, sugary and greasy foods is important for meeting fitness and weight loss goals. As with all things, moderation is key."

While the number of calories in and out has a role in fitness and health goals, the dietitians also point to better food choices and adequate nutrition for weight goals.

"Adequate nutrition is important with any weight goal," according to the dietitians. "If you are trying to lose weight, more of your calories should come from lower fat, nutrient-dense foods such as lean proteins, fruits and vegetables."

This should be done in combination with exercise, the said.

"On the other hand, if someone is trying to gain weight, increase calories in high fat, protein-rich foods," according to the dietitians.

Each of the macronutrients of carbohydrates, protein and fats serve an important role in the body's daily function, as well as making and maintaining fitness goals.

"What we put into our bodies is important for what we are able to get out of them," Johnson said. "In general, a well-balanced diet ensuring that you're getting adequate amounts of essential vitamins and minerals is the most important thing. Each food group is important to performance and normal function."

It is beneficial to know the basics of how each type of these macronutrients works to fuel the body based on the type of activity such as running or weightlifting.

"Our bodies utilize different fuel sources depending on the type and duration of exercise we engage in," Johnson said. "Sugars and simple carbs are the quickest and most available energy source."

Carb loading before a run or other similar activity can be a popular piece of advice. Johnson explained the idea behind it, even if flawed.

"Our bodies also store carbohydrates which it may utilize for energy, particularly in lower duration aerobic exercise such as long-distance running," Johnson said. "The effectiveness of 'carb loading' specifically is a bit controversial, but the idea is to ensure that your body has plenty of stored carbohydrates to use as an energy source."

It's not uncommon to see a weightlifter with a protein shake or something similar.

"Protein is an important macronutrient for weight lifters and those looking to put on muscle mass," Johnson said. "It's not necessarily as important as an energy source, but for recovering and building new muscle. As we lift weights, we break down our muscles. It's in the recovery phase that our bodies repair and build up our muscles as an adaptation to greater and greater resistance and loads. It's this repair and recovery that is dependent on protein."

Johnson shared more about recovery and how the macronutrients play into the body's response following physical activity.

"During the recovery phase of training, our bodies need plenty of protein to repair and build muscle," Johnson said. "Carbohydrates are important to replenish spent stores after more strenuous activity. Even fats play a role, particularly in long interval and aerobic training."

Paleo, keto, low-carb and other extremely reductive diets can often have followers of the diets eliminating a substantial portion of one or more of these macronutrients. This can be dangerous for health in many ways, and they aren't sustainable in the long run, according to the dietitians.

They are dangerous and unsustainable because a person is lacking key nutrients from the diet.

"The person is also at risk for developing health conditions such as renal failure, high cholesterol and blood sugar issues," according to the dietitians.

As plant-based diets gain momentum, the dietitians weighed in on the benefits. Primarily relying on plants for food and fuel can reduce the risk for heart disease, lower the risk of diabetes, help maintain a healthy weight and reduce cancer risk, according to the dietitians.

For those who go for fully plant-fueled lives, such as vegetarians and vegans, the dietitians said they should have at least five servings of fruits and vegetables each day and base meals on potatoes, bread, pasta and other starchy vegetables. They choose to add whole grain.

The dietitians also recommend dairy alternatives such as soy or almond milk for vitamin and mineral supplementation.

Food and nutrition don't have a clear one-size-fits-all answer. It is individual. The KDMC dietitians said everyone has a different schedule, lifestyle and eating habits.

"Everyone leads a different life. What works for others may not be suitable for you," according to the dietitians. "Speaking with a dietitian can help determine the most appropriate habits for better health."

For those looking for personal guidance on diets, supplements, vitamins or other nutritional concerns, the dietitians advise seeing a family doctor for lab work. Following the results, "the physician can come up with a plan of care which can include outpatient appointments with a registered dietician for diet education," according to the dietitians.

"Healthy eating habits can be incorporated into each person's life," the dietitians said.

(606) 326-2654 eporter@dailyindependent.com

Originally posted here:
Progress 2022 -- Food fuels fitness: The basics of nutrition - Yahoo News

Read More..

For 2007s Chapter 27, Jared Leto packed on 67 pounds to play John Lennon assassin Mark David Chapman.

For his Oscar-winning role in Dallas Buyers Club (2013), Leto shed about 30 pounds to play the HIV-positive hustler Rayon.

And now for his new comic book movie Morbius, he put his body through both a dramatic weight loss to play a scientist suffering from a rare blood disease, and just as hefty a weight gain (albeit mostly muscle) after his title character develops superhuman abilities from injecting his body with vampire bat DNA.

I've done a lot of this in films, Leto tells Yahoo Entertainment in a new interview for the third entry in Sony's Spider-Man Universe, explaining that its actually easier for him to lose weight than to gain it and recommending no one intentionally gain 67 pounds in a short period of time like he did.

It's not a fun thing. It's a very hard, bad thing to do to your health and your body, he says.

Losing weight is different because there's something about that restraint that we humans have explored for thousands of years. You know, restriction, meditation as a way to find oneself, as a spiritual part of a spiritual quest. And there's something to that process that is interesting. Gaining, I think is significantly harder, to be honest, especially that amount of weight cause you gain it and you lose it. When you lose weight, your body naturally wants to come back Morbius is kind of the perfect film for me and the things that I'm interested in as an actor, which is big physical challenges [and] emotional challenges.

Jared Leto, Adria Arjona and director Daniel Espinosa on the Morbius set. (Photo: Jay Maidment / Sony Pictures Releasing / Marvel Entertainment / Courtesy Everett Collection)

Whether it was staying in character as the Joker in Suicide Squad or disappearing under prosthetics in House of Gucci to the point that co-star Al Pacino didnt recognize him, Leto has developed a reputation as one of Hollywoods most intensely committed actors. His Morbius collaborators back that up.

I've never experienced that and he stays pretty close to the character the whole time, physically, mentally, emotionally, says Matt Smith, who plays Michael Morbiuss surrogate brother-turned-villain Milo. Once he's in that zone, he's there.

Story continues

Its an honor as a director to work with somebody who's not just committed, but obsessed, says director Daniel Espinosa. That motivates the whole crew to be with somebody who is so immersive at times, it got almost a bit scary cause hes very committed and those transformations, sometimes it looked like they would tear him apart.

It was really interesting to work with someone, agrees Adria Arjona, who plays Morbiuss scientist colleague (and prospective love interest) Martine Bancroft. Like Danny was saying, I think sometimes [it was] very scary. I would see his back and I would see what he had to do with his body physically. And he would spend hours and he would not break character. And I just couldn't imagine being in that position for so many hours. And what that sort of did to his body, it was really impressive, but also terrifying to see.

Morbius is now in theaters. Watch our full interviews with Espinosa and the cast above.

Video produced by Anne Lilburn and edited by John Santo

Watch the trailer:

See more here:
Jared Leto lost and gained weight for 'Morbius,' and commitment was 'terrifying to see' for co-star - Yahoo Entertainment

Read More..

You work various muscles in your body when you do strength training, and depending on your workout plan, you can spend more or less time at the gym. For example, Daily Fitness Info shared how long you work out depends on how many muscles you choose to exercise in a day. Some people have separate days for upper body and lower body workouts, for example, requiring more days at the gym than someone who decides to do a full-body exercise on the same day.

According to Healthline, there are combinations of muscle groups to work out on the same day, which will take less time. If you aren't into an arm day and a leg day, you can choose a full-body workout where you work out every muscle on the same day, and it has its advantages. Bodybuilding.com says choosing a full-body activity will mean you might spend a longer time at the gym that day but not have to go as frequently. Plus, it allows time for your muscles to recover and restore after a workout. Unless you are a Hollywood star, you might not need to workout twice a day after all.

View post:
How Long Should You Actually Work Out At The Gym? - The List

Read More..

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

Read the rest here:
You get 45% more testosterone when you dont masturbate ...

Read More..

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.

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

Read More..

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.

View original post here:
Evolution of Androgen Deprivation Therapy | RRU - Dove Medical Press

Read More..

After quitting meat for ethical, health or environmental reasons, some pet owners want their pets to join them in a plant-only diet. But is it safe to make our carnivorous felines and omnivorous pups give up meat or animal protein altogether?

The short answer is, it's a gray area: It's a possibility for some pets, but not all of them. And it's never recommended to switch your pet to a plant-based diet on your own. Plant-based diets are newer to market and the science is still developing. To make sure your pet gets enough of all the essential nutrients you'll likely need a little help.

Many people who visit Dr. Lindsey Bullen, a North Carolina-based veterinarian and board-certified animal nutritionist, one of about only 100 in the U.S., make this mistake, even though they're often acting with the best intentions. "I think some clients just feel they can do it better," Bullen told Live Science. "But they don't actually know what goes into formulating a diet for their pet."

Related: Are dogs really smiling at us?

Revamping an animal's diet without expert help is often detrimental to the pet's health. Animal proteins that cats and dogs typically eat have a lot of amino acids in a form that's easy for your pet's body to use more than what's usually in plant protein. Pets that don't get enough protein can experience weight loss, muscle loss, weakness, poor digestion and even fluid buildup in their chest or abdomen, according to the Cummings Veterinary Medical Center at Tufts University in Massachusetts.

Cats, in particular, need taurine, an amino acid found in meat protein. In fact, they can't live without it; if taurine is not supplemented properly in a plant-based diet, cats can experience poor neural function, reproductive problems and heart disease, Bullen said. Even the wrong mineral balances in a DIY plant-based pet diet can be a problem. The wrong calcium-to-phosphorus ratio, for instance, can increase the risk of fractures in dogs and cats and also stunt puppy or kitten growth, Bullen said.

But plant-based pet diets can be done. "Vegetarian [diets] can be done safely in both [cats and dogs]," Bullen said. "Vegan can be done safely in dogs but is very difficult in cats." Felines are obligate carnivores, so a lot of their nutritional needs are tied to meat-specific ingredients. As a result, cats need a lot more additives to make a vegan diet complete and balanced.

Bullen even prescribes plant-based diets in certain cases, including for pets that have skin or gastrointestinal food allergies to meat products. (Her own dog has both types of allergies and is on a hydrolyzed soy-based diet.)

If you're planning to switch to a plant-based wet or dry food for your pet, Bullen encouraged consumers to buy from brands that have done digestibility studies, ingredient interaction studies, and feeding trials on their plant-based options. But before you make the leap, it's important to make sure a plant-based diet is a good fit for your animal. An expert, such as a vet or a nutritionist they consult, will first consider the pet's overall well-being, including age, environment and other health issues. If the pet is otherwise healthy, it's likely that a well-formulated plant-based diet could work for them.

If a vegetarian or vegan diet is a safe option, the next step is for a vet or nutritionist to put together a very specific plan. For instance, when Bullen formulates a homemade vegetarian pet diet for a client, she provides a complete list of ingredients, including proportions, explicit cooking guidelines, feeding instructions and monitoring guidelines. She gets specific about every ingredient, including the brand of tofu or the percentage of fat in the cottage cheese.

Bullen encourages owners to take an active role in their pets' nutrition, but she also warns against anthropomorphizing, or giving human traits to animals. "Dogs and cats are vastly different from the human species," she said. "Your goals [for yourself] are great, but we need to keep the pet happy and healthy." Working with an expert is the safest way to meet your goals and your pets' needs.

Originally published on Live Science.

Here is the original post:
Is it safe to feed cats and dogs a vegetarian diet? - Livescience.com

Read More..

Contact Us Today

Page 337«..1020..336337338339..350360..»

Home » Page 337