Clomid Did Not Raise Testosterone

Clomid Did Not Raise Testosterone

Indian J Urol. 2017 Jul-Sep; 33(3): 236–240.

Testosterone versus clomiphene citrate in managing symptoms of hypogonadism in men

Pranav Dadhich

Scott Department of Urology, Baylor College of Medicine, Houston, USA

Ranjith Ramasamy

¹Department of Urology, University of Miami Miller School of Medicine, Miami, Florida, USA

Jason Scovell

Scott Department of Urology, Baylor College of Medicine, Houston, USA

Nathan Wilken

Scott Department of Urology, Baylor College of Medicine, Houston, USA

Larry Lipshultz

Scott Department of Urology, Baylor College of Medicine, Houston, USA

Received 2016 Nov 16; Accepted 2017 Feb 18.

This article has been cited by other articles in PMC.

Abstract

Introduction:

Both clomiphene citrate (CC) and testosterone supplementation therapy (TST) are effective treatments for men with hypogonadism. We sought to compare changes in symptoms and treatment efficacy in hypogonadal men before and after receiving CC and TST.

Patients and Methods:

52 men who received TST and 23 men who received CC for symptomatic hypogonadism were prospectively followed for change in hormone levels and symptoms after treatment. These men were also compared to eugonadal men who were not on CC or TST during the same period. Comparisons were made between baseline and posttreatment hormone levels and symptoms. Symptoms were evaluated using the androgen deficiency in aging male (ADAM) and quantitative ADAM (qADAM) questionnaires.

Results:

Serum total testosterone increased from pretreatment levels in all men (P < 0.05), regardless of therapy type (TST: 281–541 ng/dL, CC: 235.5–438 ng/dL). Men taking TST reported fewer ADAM symptoms after treatment (5–2, P < 0.05). Similarly, men taking CC reported fewer ADAM symptoms after treatment (3.5–1.5, P < 0.05). Conversely, eugonadal men had similar T levels (352 vs. 364 ng/dL) and hypogonadal symptoms (1.5 vs. 1.4) before and after follow-up. When we evaluated individual symptoms, men treated with TST showed significant increases in qADAM scores in libido, erectile function, and sports performance. However, among the men who received CC, qADAM subscore for libido was lower following treatment (3.75–3.2, P = 0.04), indicating that CC could have an adverse effect on libido in hypogonadal men.

Conclusions:

Both TST and CC are effective medications in treating hypogonadism; however, our study indicates that TST is more effective in raising serum testosterone levels and improving hypogonadal symptoms. CC remains a viable treatment modality for hypogonadal men but its adverse effect on libido warrant further study.

INTRODUCTION

Idiopathic age-related decline in testosterone in adult men is common, currently affecting close to 40% of adult males aged 45 and older.[1] Symptoms associated with decline in testosterone are often assessed using questionnaires such as the androgen deficiency in the aging male (ADAM) and quantitative ADAM (qADAM).[2,3] Lack of energy, erectile dysfunction, diminished libido, and a decrease in concentration are common symptoms in men with testosterone decline.[4,5,6] Although symptoms are a critical part of the definition of clinically relevant hypogonadism, there is a dearth of studies evaluating the effect of testosterone therapy on hypogonadal symptoms.[7]

Clomiphene citrate (CC) is frequently used off-label for the treatment of hypogonadism in men who wish to preserve reproductive function.[8,9] CC is a selective estrogen receptor modulator. Through modulation of estrogen receptors at the hypothalamus and pituitary, CC antagonizes the negative feedback of estradiol, thereby enhancing the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH). Increase in LH subsequently raises serum testosterone levels through its action on Leydig cells in the testis.[10] CC can, theoretically, improve hypogonadal symptoms while maintaining testosterone levels for up to 3 years.[11] As expected, other studies have reported that men receiving CC had an increase in serum levels of testosterone, FSH, and LH.[12]

In a cross-sectional retrospective age-matched analysis, we have previously demonstrated that men receiving testosterone injections had higher serum testosterone levels compared to those taking CC.[11] Nevertheless, both men receiving CC and testosterone injections reported similar baseline hypogonadal symptoms. Our cross-sectional analysis was unable to address whether testosterone supplementation and CC would improve specific hypogonadal symptoms. Therefore, we performed a prospective cohort study comparing hypogonadal symptoms and treatment efficacy in men receiving testosterone supplementation therapy (TST) and CC. A control group of eugonadal men, who did not receive TST or CC, was included to improve the validity of the study.

PATIENTS AND METHODS

After approval from the Institutional Review Board, we assessed hypogonadal symptoms using the ADAM and qADAM questionnaire. The standard ADAM questionnaire consists of ten "yes or no" questions concerning symptoms of androgen deficiency (range 0–10). The qADAM questionnaire builds on the "ADAM" questionnaire using the same ten equally weighted questions from the original document but utilizes a Likert scale of 1–5 to quantify each response rather than a yes or no answer. Through quantification, the magnitude of particular symptoms can be assessed. qADAM scores range from 10 to 50, and higher scores indicate less severe hypogonadal symptoms; however, no particular threshold score is known to accurately diagnose hypogonadism.

Our study group included 52 men on TST and 23 men on CC. All men had two separate values of early morning total serum testosterone <300 ng/dL associated with ≥3 hypogonadal symptoms verified on the ADAM questionnaire. Men who complained of infertility alone were excluded because fertility treatment alone could impair libido and erectile function. We also excluded men with secondary hypogonadism (below normal LH and FSH). Men received CC if they wanted to preserve fertility during treatment of hypogonadal symptoms. The goal of therapy was symptom improvement rather than a target threshold level of testosterone.

During the same study period, 52 eugonadal men who were not receiving TST or CC were included as a control group for comparison. These men underwent hormone estimation and were treated for benign urological conditions such as erectile dysfunction and lower urinary tract symptoms. These eugonadal men were not receiving TST or CC.

Of the men on TST, 27 received testosterone injections and 25 men received testosterone gel. We previously reported hormone levels and symptoms (ADAM questionnaire alone) on the 52 men that received TST.[7] We report the individual subscores on the qADAM questionnaire in men who received TST in this study and compare them to men who received CC during the same period.

Treatment efficacy was evaluated by comparing pre- and post-treatment serum testosterone levels. Pre- and post-treatment values were determined at the same visit that ADAM and qADAM questionnaires were completed. Testosterone and estradiol were measured by radioimmunoassay using the Access^® 2 Immunoassay System. Since there is known time-related variability in serum testosterone concentration in men on testosterone injections, samples were collected during the scheduled patient follow-up visit with no special concern for the timing of the last injection. Variability in levels was obviated by the random nature of the draw and the number of patients surveyed. Data were analyzed using Excel^® and IBM SPSS (IBM SPSS Statistics 21, Armonk, NY, USA). All values are shown as the mean ± standard deviation. The Mann–Whitney test was used to evaluate differences between groups with P ≤ 0.05 considered statistically significant.

RESULTS

Men receiving CC were younger than men taking TST (36 vs. 51, P = 0.01). Testosterone levels increased in men who received CC and TST (CC: 235–438 ng/dL, P < 0.05; TST: 231–541 ng/dL, P < 0.05). As expected, men who received TST had a larger and significant increase (delta) in average serum testosterone (310 ng/dL) compared to men taking CC (233 ng/dL, P = 0.04). Nevertheless, change in estradiol levels were similar between both men who received CC and men who received TST (3.5 ng/dL vs. 3.6 ng/dL, P = 0.87).

Both cohorts who received CC and TST had improvements in hypogonadal symptoms using the ADAM (CC: 3.5 vs. 1.5; TST: 5.0 vs. 2.0, P < 0.05) and qADAM questionnaire (CC: 30.7–32.5; TST: 32–36, P < 0.05). While both men on CC and TST had improvements in hypogonadal symptoms, men on TST experienced greater symptom resolution as measured by qADAM [Table 1]. This increase in qADAM indicates that patients on TST displayed a significant quantifiable improvement in symptoms and experience less severe hypogonadal symptoms than men taking CC. Conversely, eugonadal men had similar T levels (352 vs. 364 ng/dL) and hypogonadal symptoms (1.5 vs. 1.4) before and after follow-up.

Table 1

Comparison of characteristics of men receiving clomiphene citrate versus testosterone supplementation therapy

When we evaluated individual symptoms, men treated with TST showed significant increases in qADAM scores in libido (2.74–3.70, P ≤ 0.001), energy (2.54–3.35, P ≤ 0.001), strength (2.19–3.44, P ≤ 0.001), enjoyment (3.36–3.80, P ≤ 0.001), overall happiness (3.24–3.59, P = 0.011), erectile function (2.62–3.29, P = 0.001), work performance (3.37–3.68, P = 0.035), tendency to fall asleep (2.10–1.65, P = 0.003), and sports performance (2.86–3.20, P = 0.025). There were no differences in qADAM scores between the different TST modalities. Patients receiving CC only showed a significant benefit with respect to sports performance (3.14–3.57, P = 0.035). Remarkably, among the men who received CC, the qADAM subscore for libido was lower following treatment (3.75–3.2, P = 0.04), indicating that CC could have an adverse effect on libido in hypogonadal men. No other subscores on the qADAM demonstrated a significant change in men who received CC [Table 2].

Table 2

Comparison of quantitative androgen deficiency in the aging male scores before and after therapy with clomiphene citrate and testosterone

DISCUSSION

Our study on the effects of TST and CC on patient outcomes (hormone levels and symptoms) has confirmed that both TST and CC are efficacious in treating hypogonadism; however, the magnitude of treatment effect seen in males who received TST was better. Our analysis showed that patients receiving TST achieved greater increases in serum testosterone and better symptom resolution (higher qADAM scores) compared to those who were treated with CC. On further analysis of the qADAM subscores, our study described significant increases in all categories assessed aside from height after treatment with TST, whereas men who received treatment with CC reported improved sports ability but worse libido.

The association between hypogonadal symptoms and serum testosterone levels has been well documented. The previous investigation by the European Male Aging Study group delineated a significant inverse correlation between serum testosterone levels and the presence of poor morning erections, low sexual desire, and erectile dysfunction.[6] Recent retrospective investigation shows that patients treated with either TST or CC reported similar hypogonadal symptoms; on average patients receiving CC, testosterone injections and gels reported total qADAM of 35, 39, and 36, respectively.[11]

The results of this current study show that even though patients prescribed CC had an increase in overall qADAM score, patients reported a significant decrease in libido. The etiology of this CC effect on libido has not been fully elucidated, but it is theorized that modulation of the estrogen receptor could have negative effects on libido. Estrogen, despite widely considered a "female" hormone, remains important to maintain libido in men.[13] However, modulation of the estrogen receptor by CC can impair estrogen's action and subsequently cause impaired sex drive.[13] Although CC is effective in improving overall hypogonadal symptoms, CC appears, in this study, to negatively affect libido. Larger studies are needed to validate the effect of CC on libido.

Although a prospective study design was created to explore the subtle differences of hypogonadal therapy, there are some limitations to the study. The first limitation to address is potential ambiguity regarding the impetus for therapy with CC. Men utilizing CC were younger, reported higher pretreatment libido scores, and used CC to aid with both hypogonadism as well as to preserve fertility rather than treat hypogonadal symptoms alone, thus creating a disconnect between the rationale of TST versus CC treatment. Nevertheless, men with infertility and low testosterone appear to report hypogonadal symptoms similar to men without infertility.[14] The ADAM and qADAM questionnaires are validated for cross-sectional comparison of serum testosterone and hypogonadal symptoms. Since there are no questionnaires that are universally validated to study the change in hypogonadal symptoms, we used ADAM and qADAM questionnaires that are commonly used and easy to administer in clinic.[15] Given the nonparametric nature of the data, power analysis would have been difficult to perform and potentially inaccurate due to reliance on data simulation; however, the utility of this analysis is apparent and will be incorporated in the further analysis. Another limitation and challenge of this study were the lack of an a priori power calculation. However, we anticipate this data will serve as a reference to determine sample size in future work comparing TST and CC for hypogonadal symptoms. Multiple hypothesis testing was not performed at this time due hypothesis-generating nature of the study.

The sample size of patients is not large, often secondary to the intent of the patients, as patients with no desire to preserve fertility tend to prefer TST therapy as they are not as familiar with CC. The study utilizes 2:1 allocation and although not ideal, is acceptable given the nature of the study.

Hypogonadal symptoms are subjective, which can complicate patient diagnosis and identify success with treatment. One confounding factor is that patient satisfaction may vary based on psychological perceptions about potential benefits conferred from therapy. Perceptions regarding the type of therapy prescribed could also have impacted patient's expectations. Outcomes could also have been further impacted by preexisting medical comorbidities as these variables were not explicitly factored into the analysis. The difference between follow-up times is different and may suggest differences in patient satisfaction between the two therapies, although this interpretation was not explored in this current study. Because there exists a large number of young men, who present with hypogonadal symptoms but need preservation of fertility, a better understanding about the benefit or lack thereof for alternative treatment options will be important when providing and discussing treatment options for this population.

CONCLUSIONS

Both TST and CC are effective medications in treating hypogonadism; however, our study indicates that TST is more effective in raising serum testosterone levels and improving hypogonadal symptoms. CC remains a viable treatment modality but its adverse effect on libido merits further study.

Footnotes

Financial support and sponsorship: Nil.

Conflicts of interest: There are no conflicts of interest.

REFERENCES

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Clomid Did Not Raise Testosterone

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508437/

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Ling Skincare Vitamin C

Ling Skincare Vitamin C

Researchers in the United Kingdom say a study on eyesight shows diet and environmental factors are more important than genetics in lowering risk of cataracts.

Eating an apple a day may keep the doctor away, but eating oranges might do the same for cataracts.

In a study published today in the journal Ophthalmology, researchers in the United Kingdom said a higher dietary intake of vitamin C might significantly reduce the risk of developing cataracts.

The study, led by scientists at King's College London, is the first to conclude that dietary and environmental factors play a larger role than genetics in the development of cataracts.

"The findings of this study could have significant impact, particularly for the aging population globally by suggesting that simple dietary changes such as increased intake of fruits and vegetables as part of a healthier diet could help protect them from cataracts," Dr. Chris Hammond, professor of ophthalmology at King's College, consultant eye surgeon and lead author of the study, said in a statement.

Read More: What Is a Cataract? »

The researchers estimated genetic factors account for 35 percent of the difference in cataract progression. Environment and lifestyle account for 65 percent.

To study the impact diet has on cataracts, the researchers tracked the progression of the eye condition in 324 pairs of female twins from the United Kingdom.

The scientists examined digital images of the women's eye lenses when they were about 60 years old. They then studied the same type of images 10 years later.

They kept track of the women's intake of vitamins A, B, C, D, and E. They also tracked their intake of copper, manganese, and zinc using a food questionnaire.

The researchers said the women who ingested more vitamin C initially had a 20 percent reduced risk of developing cataracts. After 10 years, that risk had decreased by 33 percent.

The researchers noted that there was little risk reduction in the women who took vitamin supplements. Instead the preventative effects appeared to be obtained only by eating foods rich in vitamin C.

Dr. Ravi D. Goel, an ophthalmologist from New Jersey who is also a clinical instructor at Wills Eye Hospital in Pennsylvania, said the study provides helpful information for patients and doctors.

"These are novel findings for patients going forward," Goel, a spokesperson for the American Academy of Ophthalmology, told Healthline. "This is a helpful tool for patient education."

Read More: Americans Spend Billions on Vitamins and Supplements That Don't Work »

Cataracts occur when the lens of the eye becomes cloudy due to oxidation over a long period of time.

The researchers said the fluids that bathe the eye are rich in vitamin C, which helps stop the lens from oxidizing.

The dietary intake of vitamin C helps prevent cataracts by increasing the amount of this vitamin in the eye fluid.

The researchers added that smoking and diabetes also are risk factors for certain kinds of cataracts, so a balanced diet and healthy lifestyle are important.

"Healthy diets are always an advantage for patients," added Goel.

Goel also said vitamin C has already been shown to help slow the progression of age-related macular degeneration.

This latest information on cataracts adds to vitamin C's attributes. "It helps overall eye health," he said.

The researchers did note that their observational study has its limitations as it only involved women who were aged 60 years and older.

However, the researchers believe the information could also be relevant for male patients.

Cataracts are the leading cause of blindness in the world, affecting about 20 million people, according to statistics from the World Health Organization (WHO). Cataracts also affect 24 million Americans over the age of 40.

The condition can cause blurry vision, glare, poor night vision, and sensitivity to light.

Initially, better lighting and glasses may help ease some of the symptoms, but as cataracts progress surgery is sometimes needed.

Read More: Diabetes and Blurry Vision: What You Need to Know »

Ling Skincare Vitamin C

Source: https://www.healthline.com/health-news/vitamin-c-may-reduce-risk-of-cataracts

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Iv Vitamin C And Cancer

Iv Vitamin C And Cancer

Photo Courtesy: The Good Brigade/DigitalVision/Getty Images

Hepatitis is a condition that causes inflammation of your liver. Currently, there are an estimated 6 million people living with hepatitis in the United States, and more than 50,000 people are diagnosed with this disease every year. There are three primary types of hepatitis, and while their symptoms can be similar, they vary largely in the ways they're transmitted. Learning more about each type of hepatitis can help you better understand the condition as a whole.

Hepatitis A is the most easily transmitted of the three viruses. It affects approximately 2,500 people every year in the United States. It typically spreads through feces-contaminated food or water and is found in the feces of people who have the virus. Hepatitis A causes a short-term, acute sickness that most people heal from without treatment. However, it can cause serious illness in some people. This virus is more common in places with underdeveloped sanitation systems.

While doctors can't treat hepatitis A with medication, people who get this virus can manage its symptoms with fluids, rest and good nutrition. There's also a safe and effective vaccine available to protect you against hepatitis A.

What Is Hepatitis B?

Hepatitis B can occur both acutely (meaning it develops quickly and lasts a short time) and chronically (meaning it develops slowly over time and worsens over months or years). According to the Centers for Disease Control and Prevention, up to 2 million people in the United States are chronically affected with hepatitis B. Hepatitis B can be transmitted through sexual activity and exposure to infected blood. It can also be passed from a parent to their newborn child during birth.

Hepatitis B usually causes short-term discomfort that many people recover from completely after about four to eight weeks. However, it can turn into a chronic condition that lasts for years; this is more likely in older adults. Doctors can treat severe chronic hepatitis B with antiviral medications. However, in most cases, treatments focus on proper hydration and nutrition. There's a safe vaccine available to protect you against hepatitis B, too.

What Is Hepatitis C?

Photo Courtesy: BSIP/Getty Images

Approximately 4 million people in the United States are affected with hepatitis C. This form of hepatitis causes a chronic illness in over 50% of people who get this type of the virus. It's the least transmissible of the three viruses and can spread through contact with infected blood.

Hepatitis C occurs more commonly in people who engage in intravenous drug use. If you received a blood transfusion before 1992, you should also get tested for hepatitis C if you haven't previously. Hepatitis C can spread through unprotected sexual intercourse, but this is a less common way to transmit it. While there's no vaccine for chronic hepatitis C, treatments that are available today offer a 95% cure rate.

Chronic hepatitis C can significantly affect how your liver works. It can cause cirrhosis, which means that your normal liver tissue is replaced with scar tissue. It can also cause liver cancer. However, there are medications that can help keep this disease in check. Making lifestyle changes, such as reducing or eliminating alcohol from your diet, can also decrease your chances of experiencing complications. In severe cases, hepatitis C may require a liver transplant.

The varying forms of viral hepatitis affect millions of people in the United States. Chronic hepatitis often has few symptoms in its early stages, so recognizing the associated dangers and getting tested if you've been exposed may save your life. Although there are five types of viral hepatitis, only A, B and C are the forms commonly found in the United States.

Resource Links:

"Hepatitis A, B, and C: Learn the Differences," Immunization Action Coalition

"What's the Difference Between Hepatitis A, B and C?," UNC Health Talk

"The ABCs of Hepatitis," Centers for Disease Control and Prevention

"What's the Difference: Hepatitis B vs Hepatitis C?," Hepatitis B Foundation

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A Guide to Vitamin C Serums

leonori/Shutterstock

For 70 years Vitamin C has been one of the biggest weapons in the skin care industry. It's used to make cleansers, moisturizers, lotions, masks, and serums. So what is this powerful vitamin? How can it benefit you? Why should you use serums that contain Vitamin C? We're here to answer all of those burning questions in this complete guide and reveal the many benefits Vitamin C serums offer for your skin.

What Are Vitamin C Serums?

There are many variations of Vitamin C, but the most popular is ascorbic acid, a common ingredient in skincare products. However, all the variations of Vitamin C have anti-inflammatory benefits.

Vitamin C Serums are products that contain a high level of Vitamin C. They're used to treat wrinkles, sagging skin, lighten dark or red spots, prevent breakouts and even your skin tone. Basically, they battle all of those annoying skin issues. There are loads of products out there that claim they'll save your skin, but some can cause damage. Vitamin C is one of the most revered ingredients and conclusive research has shown how effective it can be.

How Are Vitamin C Serums Made?

Well so far we've talked about how incredible Vitamin C is and it sounds like a dream come true doesn't it? It's not all good. In fact, the mighty vitamin is unstable when it's exposed to air and light. Other ingredients need to be used to stabilize it and allow it to deliver amazing results. The serums are combined with ferulic acid and Vitamin E. According to researchers the perfect mixture is 15% Vitamin C with 1% Vitamin E and 0.5% ferulic acid. This makes Vitamin C perform to the best of its abilities, without damaging your skin.

What Does Vitamin C Serum Do for Your Face?

Boosts Collagen Production: Collagen keeps your skin firm and prevents sagging. Environmental factors such as lifestyle choices and pollution can increase the elasticity of your skin, so it's important you try to increase your collagen production.

Hydrates Your Skin: Dry skin is a common issue, but Vitamin C can help to give your skin that much-needed moisture boost. Remember, it doesn't work immediately so you need to keep applying the serum to see results.

Brightens Your Complexion: Dark spots on your skin are caused by the overproduction of melanin. Vitamin C decreases the production and lightens the dark spots to even out your complexion.

Reduces Redness and Inflammation: Conditions such as Rosacea leave many people searching for a magic cure. Vitamin C helps facial redness and inflammation by reducing the appearance of broken capillaries.

Why Should You Be Using Vitamin C Serum?

Don't think Vitamin C serums are just beneficial for your face. They can also shield you from sun damage and reduce stretch marks.

Saves You From The Sun: Prolonged exposure to UV rays can cause long-term damage to your skin. Luckily, Vitamin C is a powerful antioxidant that reduces red sports and prevents sunburn from spreading.

Fades Acne Scars: Acne plagues most of us at some point and we look forward to being free. Most of us get stuck with some scars but Vitamin C helps to fade scars and even out any discoloration.

Reduces Stretch Marks: Yes, Vitamin C serum can even help prevent those unsightly stretch marks by tightening your skin.

Are you ready to change your skin? Add a Vitamin C serum to your beauty regimen and enjoy a glowing complexion.

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High Dose Vitamin C Diabetes

High Dose Vitamin C Diabetes

January 24, 2020, by Lewis Cantley and Jihye Yun

Lewis Cantley received his Ph.D. from Cornell University and did his post-doctoral work at Harvard University. He was formerly a professor in the Departments of Systems Biology and Medicine at Harvard Medical School in Boston. He is current the Meyer Director and Professor of Cancer Biology at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine in New York City. Jihye Yun received her Ph.D. from Johns Hopkins University, School of Medicine under the mentorship of Bert Vogelstein and did her post-doctoral work with Lewis Cantley at Weill Cornell Medicine. She is currently an Assistant Professor and a CPRIT scholar at Baylor College of Medicine in Houston.

The discovery and isolation of vitamin C was one of the most important advances in improving human nutrition. Scurvy, a severe vitamin C deficiency disease characterized by weakness, lethargy, easy bruising and bleeding, was particularly problematic for sailors on long voyages during the 16th century, where access to fresh fruits and vegetables was limited. In fact, scurvy was the leading cause of naval deaths between the 16th and 18th centuries, killing more sailors than all battles, storms and other diseases combined. It wasn't until 1747 that Scottish naval physician James Lind demonstrated that consuming oranges and lemons cured and prevented scurvy. However, it took scientists nearly two more centuries to identify the nature of the curative substance contained in citrus fruits, now commonly known as vitamin C. The search for this elusive substance ended in 1932 when Albert Szent-Gyorgyi, a Hungarian biochemist, isolated and identified a 6-carbon carbohydrate, hexuronic acid, as the anti-scurvy factor. Shortly thereafter, Szent-Gyorgyi renamed it "a-scorbic acid", a reference to its anti-scorbutic properties, and later went on to receive the Nobel Prize in Physiology and Medicine in 1937 for his discoveries.

Today vitamin C is a popular dietary supplement, and due to improved accessibility to fruits, vegetables and vitamin supplements, disability and death from scurvy are rare. However, it is worth noting that a significant number of people even in developed countries are still vitamin C deficient. For example, approximately 7% of the US population has a plasma vitamin C concentration of less than 11 μM, that is considered scurvy. Vitamin C has many essential functions in our body in addition to its well-known role as an antioxidant. Thus, prolonged periods of sub-optimal vitamin C exposure could have adverse health effects, including an increased susceptibility to a plethora of diseases. In fact, the optimal dosage of vitamin C required to maximize its health benefits has been hotly debated ever since its discovery a century ago. Linus Pauling, a world-renowned chemist and two-time Nobel Prize Laureate, strongly advocated that megadose quantities of vitamin C (above 1 g intake per day) would prevent and treat many illnesses including the common cold and heart diseases. However, mainstream medicine has largely ignored or even ridiculed Pauling's claim. This controversy is still very much alive today.

The controversial history of high-dose vitamin C in cancer treatment

Utilizing high doses of vitamin C as a cancer therapy is no exception to this controversy. Nearly 60 years ago Toronto physician William McCormick observed that cancer patients often presented with severely low levels of vitamin C in their blood and featured scurvy-like symptoms, leading him to postulate that vitamin C might protect against cancer by increasing collagen synthesis. In 1972, extending this theory, Ewan Cameron, a Scottish surgeon, hypothesized that ascorbate could suppress cancer development by inhibiting hyaluronidase, which otherwise weakens the extracellular matrix and enables cancer to metastasize. He began treating terminally ill cancer patients and published a case report of 50 patients in which some of the treated patients benefited from high dose vitamin C.

Encouraged by the result, Cameron teamed up with Linus Pauling to conduct clinical trials involving terminal cancer patients. In 1976, they published a study of 100 patients with terminal cancer treated with ascorbate. Their disease progression and survival rates were compared to 1000 retrospective control patients who were matched with the vitamin C-treated patients regarding age, sex, type of cancer and clinical stage and who were treated by the same physicians in the same hospital, and in the same way except that they did not receive vitamin C. Although the study was not well designed by modern standards, mainly because they lacked the placebo-control group, the results demonstrated that patients treated with vitamin C had improved quality of life and a four-fold increase in their mean survival time. In a follow up study, Cameron and Pauling reported that 22% of vitamin C-treated cancer patients survived for more than one year compared to only 0.4% of control patients. A clinical trial in Japan independently showed a similar result. With these promising outcomes, interest in the potential of vitamin C for cancer therapy grew. However, double-blind randomized clinical trials directed by Charles Moertel of the Mayo Clinic failed to show any positive effects of high dose vitamin C in cancer patients, as reported in two papers in the journal of New England Journal of Medicine. Because the Mayo Clinic's clinical trials were conducted more rigorously, people trusted the Mayo Clinic's data and discredited the Cameron-Pauling trials, dampening the enthusiasm for vitamin C as a cancer therapy.

So why did the Pauling and Mayo Clinic trials have different results? There are at least two crucial differences. First, the Mayo Clinic trials abruptly stopped the ascorbate administration, switching to traditional chemotherapy, when the patient developed signs of tumor progression. Thus, the overall median time of vitamin C treatment under the Mayo Clinic trials was only 2.5 months, while the Pauling and Cameron trials treated patients for the duration of the entire study period or as long as 12 years. Secondly, the Mayo Clinic trials administered 10 g of daily ascorbate to patients only orally, while the Cameron and Pauling trials administered their vitamin C both orally and intravenously. This difference in the two dosage routes proved highly consequential.

Rekindling vitamin C cancer therapy: oral vs intravenous administration

Based on studies pioneered by Mark Levine's group at the NIH in the 2000s, the oral vitamin C doses used in the Mayo Clinic studies would have produced peak plasma concentration of less than 200 μM. In contrast, the same dose given intravenously, as used in the Pauling studies, would produce peak plasma concentrations of nearly 6 mM, more than 25 times higher. When given orally, vitamin C concentration in human plasma is tightly controlled by multiple mechanisms acting together: intestinal absorption, tissue accumulation, renal reabsorption and excretion, and potentially even the rate of utilization. However, when ascorbate is administered intravenously or intraperitoneally the tight controls are bypassed, and pharmacologic millimolar plasma concentrations of vitamin C can easily be achieved. For example, a phase I clinical study revealed that ascorbate concentrations could safely reach 25-30 mM with intravenous infusion of 100 g of vitamin C. In this study, plasma concentrations around 10 mM were sustained for at least 4 hours which, based on preclinical studies, is sufficient to kill cancer cells. Given the fact that cancer patients were only treated with vitamin C orally in the Mayo Clinic studies, the studies do not disprove high dose vitamin C's efficacy as a cancer treatment.

This new knowledge has rekindled interest and spurred new research into the clinical potential of vitamin C. Consequently, over the past decade, there have been an increased number of phase I/II clinical trials and case reports testing the safety and efficacy of high dose vitamin C as a treatment for various cancer patients as a monotherapy or in combinational therapy. We will not discuss these clinical studies as there are already several reviews on the topic. Virtually all studies show improved quality of life for cancer patients by minimizing pain and protecting normal tissues from toxicity caused by chemotherapy. Additionally, vitamin C showed synergistic effects when combined with radiation and standard chemotherapies. Unfortunately, these studies were not designed as large-scale, randomized controlled trials and thus the efficacy of high dose vitamin C therapy remains to be determined.

Challenges of conducting a randomized controlled trial for vitamin C cancer therapy

There are at least three challenges that have thus far prevented large-scale, randomized controlled trials of vitamin C for cancer therapy. First, vitamin C is not patentable. Therefore, there is no financial incentive for pharmaceutical companies to support vitamin C clinical trials, and those that have been done have largely relied on government grants and small private donations. Second, as discussed above, vitamin C cancer therapy has a long history of controversy. Due to the Mayo clinical studies in the 1980s, many orthodox, mainstream clinicians have a prejudice against vitamin C therapy. Third, although many preclinical studies showed high dose vitamin C could kill cancer cells or retard tumor growth in vivo, vitamin C's mechanisms of action have not been clear, making it hard to predict the pharmacodynamics, the rational design of combinational therapy, and biomarkers for patient stratification. Fortunately, a growing number of recent and rigorous preclinical studies have begun resolving the third challenge, which may also lead to overcoming the first and second barriers. Mechanistic insights into the action of pharmacological vitamin C will generate more explicit scientific hypotheses and allow clinicians to design better trials to investigate those hypotheses, ultimately leading to a definitive answer to the question: can the pharmacological administration of ascorbate benefit cancer patients? Recently, we discussed the potential mechanisms by which vitamin C may act in cancer patients in Nature Reviews Cancer. Here we will highlight one of the mechanisms discovered by our group that relates to Ras protein.

High-dose vitamin C therapy for KRAS/BRAF mutant cancers

More than 80 years ago, the biochemist Otto Warburg observed that cancer cells consume more glucose and produce more lactate even in the presence of ample oxygen as compared with normal cells. This phenomenon, called aerobic glycolysis or the Warburg effect, has been exploited for visualizing tumors in the clinical setting by imaging their uptake of the radiolabeled glucose analog, [18F] fluoro-2-deoxyglucose (FDG), via Positron Emission Tomography (PET). Although the exact mechanism by which glucose reprograming contributes to tumorigenesis remains unclear, numerous genetic and pharmacological studies showed that this metabolic switch can be essential for cancer survival and proliferation. Thus, targeting glycolysis may offer cancer patients a more selective strategy to treat cancer.

More than half of colorectal cancers (CRCs) harbor activating mutations in KRAS or BRAF, yet those cancers are the most refractory to current targeted therapies. Our group and others showed that oncogenic mutations in KRAS or BRAF contribute to the Warburg effect and the addiction to glucose in part by upregulating a glucose transporter, GLUT1, that allows cancer cells to take up glucose efficiently. These data suggest a strategy for targeting KRAS or BRAF mutant cancer by exploiting the selective expression of GLUT1 and the metabolic liability that comes with increased reliance on glycolysis. Indeed, by targeting these unique features in these cancer cells, we recently showed that high dose vitamin C could selectively kill KRAS or BRAF mutant CRC cells.

Interestingly, GLUT1 not only transports glucose but also transports dehydroascorbic acid (DHA), the oxidized form of vitamin C. Subsequently, we observed that CRC cells harboring KRAS or BRAF mutations uniquely increased uptake of DHA via GLUT1 when treated with vitamin C. The increased DHA uptake in mutant cells produced oxidative stress, increasing the level of reactive oxygen species (ROS) in cells because intracellular DHA was rapidly reduced back to vitamin C at the expense of glutathione (GSH), a master antioxidant in cells. In turn, we found that elevated ROS activated poly (ADP-ribose) polymerase (PARP), a DNA repair enzyme, consuming large amounts of cellular NAD+ as its cofactor. The depletion of NAD+ resulted in the inactivation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) because GAPDH requires NAD+ as a cofactor. Inhibiting GAPDH in highly glycolytic KRAS or BRAF mutant cells ultimately led to an energy crisis and cell death not seen in their KRAS and BRAF wild-type counterparts. Finally, we showed that high-dose vitamin C therapy reduced both the number and size of tumors in KRAS or BRAF mutant mice as compared to mice without these mutations, confirming that vitamin C selectively targets KRAS or BRAF mutant tumors in mouse models of colon tumors. In short, ascorbate functions as a "Trojan horse" through its conversion to DHA, and insidiously enters cancer cells via GLUT1 to promote the generation of intracellular ROS, which ultimately kills the cancer cell.

Although our study showed that DHA is the pharmaceutically active agent, reduced ascorbate (not directly DHA) is used for preclinical and clinical anti-cancer studies because ascorbate has a significantly longer plasma half-life than DHA (>60 min vs a few min). Moreover, the reduced ascorbate can be efficiently oxidized to DHA in tumors' extracellular fluids where high level of ROS usually exists. Given that KRAS and BRAF mutations are not only restricted to colorectal cancer, vitamin C may be benefit other types of tumors. For example, 90% of pancreatic cancers and approximately 30% of lung cancers have KRAS mutations. These KRAS mutant tumors also have high GLUT1 expression and are linked to altered glucose metabolism similar to CRC. Therefore, high dose vitamin C may benefit other types of tumors harboring KRAS/BRAF mutations. Based on these results, Weill Cornell Medicine is currently conducting a Phase II clinical trial to examine the effects of intravenous high dose vitamin C in the treatment of KRAS-mutant cancers, and Sun Yat-sen University Cancer Center in China are conducting placebo-controlled, randomized Phase III clinical trials in colorectal cancer patients in combination of chemotherapy.

While KRAS and BRAF mutations are certainly two of the most frequently mutated oncogenes in human cancer, they are not the only mutations known to affect glucose metabolism and sensitivity towards ascorbate therapy. For example, we and others have found that renal cancer cells (RCC) with loss of VHL (Von Hippel-Lindau), a tumor suppressor that destabilizes HIF1A via ubiquination, are significantly sensitive to ascorbate treatment compared to VHL-proficient cells. RCC-VHL null cells have increased HIF1A transcriptional activity, which not only increases GLUT1 expression, but also deregulates many other glycolytic enzymes to induce metabolic reprograming. Additionally, cancers with increased levels of DNA damage, such as those that have been treated with radiation or those with mutations in BRCA genes, are more reliant on DNA repair mediated by PARP. Pharmacologic vitamin C might selectively impair such cancers by depriving them of the NAD+ necessary for PARP activity.

Concluding Remarks

Vitamin C as a cancer therapy has had a controversial past. What has been intriguing are small clinical trials that suggest some responses, but with no clear rationale for why cancers should respond to vitamin C or a path forward for explaining which patients are most likely to respond.  Now a growing number of preclinical studies are showing how high-dose vitamin C might benefit cancer patients. Importantly, these preclinical studies provide a clear rationale and potential biomarkers that may help personalize the therapeutic approach and identify patient populations that are likely to respond to high-dose vitamin C therapy. Since the mechanisms of action of vitamin C are becoming better defined, we can propose vitamin C combinations in a more rational, hypothesis-driven manner. In addition, given the current high financial cost of new cancer drugs, it seems rational to improve the effectiveness of current therapies by studying their clinical interactions with vitamin C. In our view, the implementation of this treatment paradigm could provide benefit to many cancer patients.

Acknowledgements

This work was supported by the US National Institutes of Health (NIH) grant (R35 CA197588), Stand Up to Cancer–American Association for Cancer Research grant (SU2C-AACR-DT22-17), and the Damon Runyon Cancer Research Foundation. Lewis Cantley is a founder and member of the senior advisory boards of Agios Pharmaceuticals and Petra Pharmaceuticals, which are developing novel therapies for cancer. The Cantley laboratory also receives financial support from Petra Pharmaceuticals.

High Dose Vitamin C Diabetes

Source: https://www.cancer.gov/research/key-initiatives/ras/ras-central/blog/2020/yun-cantley-vitamin-c

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Fruits Are Rich In Vitamin C

Photo Courtesy: KARRASTOCK/Moment/Getty Images

Nearly 2 million American adults each year are diagnosed with cancer. If you receive a diagnosis, your schedule can quickly start to fill up with doctor's appointments, medical procedures and pharmacy visits. Creating a checklist of things to do can help keep you busy and feeling more in control. But acknowledging the effects a cancer diagnosis can have on your emotions — and healthily managing those emotions — is almost as important.

Doctors and psychologists now recognize that healing improves after a diagnosis when both our physical and emotional needs are met, says Niki Barr, Ph.D., a psychotherapist at the Center for Cancer and Blood Disorders in Texas, who consults with medical doctors, extended families and caregivers about emotionally coping with a cancer diagnosis.

Learning you have cancer is a stressful experience, and it's important to acknowledge and cope with that stress. Fully understanding how your emotional needs can change after you receive a cancer diagnosis can go a long way in helping you and your family heal. The tips here can help you support your mental health as you navigate your diagnosis and treatment.

Photo Courtesy: burakkarademir/E+/Getty Images

Upon hearing your diagnosis, you might experience grief, fear or even a feeling of denial until some time has passed. "These are all normal and emotionally healthy responses, but it's all too easy to spiral out of control with fear in the beginning," says Barr. Fortunately, these tips can help you manage the anxiety and fear that come along with learning about a cancer diagnosis.

Lessen the Impact of Anxious Thoughts

Start by writing your thoughts down on note cards or in a journal. Identify the first one that's leading you to feel uneasy. For example, you might write down something like "I'm afraid of my hair falling out." Then, move onto the subsequent fear and write it down. That might be something like "People will treat me differently if they see I have cancer."

When you've identified most of your anxious thoughts, go back to the first one and write something new on the card that can help ease your stress. It should be a thought that's confident and empowering. For example, suppose you're worried about your hair falling out. In that case, a positive view could be: "I've been looking forward to getting a new hairstyle anyway." When you're feeling nervous, read the more positive strategies, says Barr.

Work On Your Internal Dialogue

It can also help to defuse all those "What if?" questions you might ask yourself, such as "What if my cancer has spread?" or "What if the treatment doesn't work?" One scary question tends to lead to another and often turns into full-fledged anxiety. Try to focus on those things you have the power to improve on your own. The next time you start asking yourself the what-ifs, substitute the upsetting ideas with this one: "Is this thought helping me or hurting me?" You can also ask, "Is this thought moving me forward or backward?" Your answers might surprise you, and they can help you move away from the thoughts that are holding you back.

Get Grounded

Interrupting periods of anxiety by focusing on small details around you can help you shift your perspective away from negativity and towards the present moment. "Look at the beautiful color of the walls in the room you're in; look at the person you're talking to, the clothes [they're] wearing," Barr suggests. Becoming very present and focused on physical details nearby helps soothe sudden anxious thoughts. Turn your focus towards absorbing the colors, smells, people and each new sound around you. Build those sensations up very clearly in your mind. You can use this technique as a distraction tool the next time you're waiting for a medical procedure or want a diversion from your thoughts.

Meditate to Music

Research shows that 15 to 30 minutes of both guided imagery and soothing tunes can alleviate deep feelings of stress about a cancer diagnosis. The Cancer Treatment Centers of America (CTCA) reviewed 30 clinical cancer trials that analyzed more than 1,890 cancer patients. They found that music therapy can have a beneficial effect on anxiety, pain, mood, quality of life, heart rate, respiratory rate and blood pressure.

The CTCA also offers many classes and therapies to help people relax, reduce stress and improve their quality of life as part of an extensive mind-body medicine program. Many centers provide calming background music during healing therapies.

What Are Your Next Steps?

Photo Courtesy: Peathegee Inc/Getty Images

You have a cancer diagnosis: Now what? Learning how to clear your mind and focus on positive thoughts is a helpful step in the right direction. Here are other soul-soothing strategies you can try.

Start Journaling and Reflecting

Research published in the Journal of Clinical Oncology has shown that expressing your innermost feelings can reduce stress and have a range of other emotional and social benefits. Researchers aren't sure why putting thoughts down on paper is effective. Still, it allows you to process complex emotions and help you chart a way forward, whether you've been diagnosed with cancer or are taking care of someone who has.

Exercise When Possible

Exercising for 2.5 hours per week can help you beat symptoms of depression and fatigue. Among the nation's millions of cancer survivors, there are hints — but not proof yet — that active exercisers may lower their risk of their cancer coming back.

The American College of Sports Medicine hosted a medical panel of cancer specialists to evaluate this exercise evidence. It issued guidelines suggesting that cancer patients and survivors should exercise for about 30 minutes most days of the week. This exercise should be enjoyable to you but also build up a sweat. When patients and their family caregivers exercised together, research found, everyone was more likely to stick with the fitness regimen, boost their physical stamina and experience less emotional strain.

Strengthen Your Social Support System

Connecting with others who've been through this kind of emotional diagnosis already can be a source of comfort and support. Learn more about online communities and your local chapters and support groups that meet up. The American Cancer Society also suggests attending one-on-one professional therapy or its "I Can Cope" online support groups to learn more.

Resource Links:

Find Local Cancer Support Programs | Cancer Support Groups

Strategies Used in Coping With a Cancer Diagnosis Predict Meaning in Life for Survivors

Coping Well with Advanced Cancer: A Serial Qualitative Interview Study with Patients and Family Carers

Coping with cancer

Coping Attitudes of Cancer Patients and Their Caregivers and Quality of Life of Caregivers

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Efficacy Of Vitamin C To Prevent Colds

Efficacy Of Vitamin C To Prevent Colds

Photo Courtesy: KARRASTOCK/Moment/Getty Images

Nearly 2 million American adults each year are diagnosed with cancer. If you receive a diagnosis, your schedule can quickly start to fill up with doctor's appointments, medical procedures and pharmacy visits. Creating a checklist of things to do can help keep you busy and feeling more in control. But acknowledging the effects a cancer diagnosis can have on your emotions — and healthily managing those emotions — is almost as important.

Doctors and psychologists now recognize that healing improves after a diagnosis when both our physical and emotional needs are met, says Niki Barr, Ph.D., a psychotherapist at the Center for Cancer and Blood Disorders in Texas, who consults with medical doctors, extended families and caregivers about emotionally coping with a cancer diagnosis.

Learning you have cancer is a stressful experience, and it's important to acknowledge and cope with that stress. Fully understanding how your emotional needs can change after you receive a cancer diagnosis can go a long way in helping you and your family heal. The tips here can help you support your mental health as you navigate your diagnosis and treatment.

Photo Courtesy: burakkarademir/E+/Getty Images

Upon hearing your diagnosis, you might experience grief, fear or even a feeling of denial until some time has passed. "These are all normal and emotionally healthy responses, but it's all too easy to spiral out of control with fear in the beginning," says Barr. Fortunately, these tips can help you manage the anxiety and fear that come along with learning about a cancer diagnosis.

Lessen the Impact of Anxious Thoughts

Start by writing your thoughts down on note cards or in a journal. Identify the first one that's leading you to feel uneasy. For example, you might write down something like "I'm afraid of my hair falling out." Then, move onto the subsequent fear and write it down. That might be something like "People will treat me differently if they see I have cancer."

When you've identified most of your anxious thoughts, go back to the first one and write something new on the card that can help ease your stress. It should be a thought that's confident and empowering. For example, suppose you're worried about your hair falling out. In that case, a positive view could be: "I've been looking forward to getting a new hairstyle anyway." When you're feeling nervous, read the more positive strategies, says Barr.

Work On Your Internal Dialogue

It can also help to defuse all those "What if?" questions you might ask yourself, such as "What if my cancer has spread?" or "What if the treatment doesn't work?" One scary question tends to lead to another and often turns into full-fledged anxiety. Try to focus on those things you have the power to improve on your own. The next time you start asking yourself the what-ifs, substitute the upsetting ideas with this one: "Is this thought helping me or hurting me?" You can also ask, "Is this thought moving me forward or backward?" Your answers might surprise you, and they can help you move away from the thoughts that are holding you back.

Get Grounded

Interrupting periods of anxiety by focusing on small details around you can help you shift your perspective away from negativity and towards the present moment. "Look at the beautiful color of the walls in the room you're in; look at the person you're talking to, the clothes [they're] wearing," Barr suggests. Becoming very present and focused on physical details nearby helps soothe sudden anxious thoughts. Turn your focus towards absorbing the colors, smells, people and each new sound around you. Build those sensations up very clearly in your mind. You can use this technique as a distraction tool the next time you're waiting for a medical procedure or want a diversion from your thoughts.

Meditate to Music

Research shows that 15 to 30 minutes of both guided imagery and soothing tunes can alleviate deep feelings of stress about a cancer diagnosis. The Cancer Treatment Centers of America (CTCA) reviewed 30 clinical cancer trials that analyzed more than 1,890 cancer patients. They found that music therapy can have a beneficial effect on anxiety, pain, mood, quality of life, heart rate, respiratory rate and blood pressure.

The CTCA also offers many classes and therapies to help people relax, reduce stress and improve their quality of life as part of an extensive mind-body medicine program. Many centers provide calming background music during healing therapies.

What Are Your Next Steps?

Photo Courtesy: Peathegee Inc/Getty Images

You have a cancer diagnosis: Now what? Learning how to clear your mind and focus on positive thoughts is a helpful step in the right direction. Here are other soul-soothing strategies you can try.

Start Journaling and Reflecting

Research published in the Journal of Clinical Oncology has shown that expressing your innermost feelings can reduce stress and have a range of other emotional and social benefits. Researchers aren't sure why putting thoughts down on paper is effective. Still, it allows you to process complex emotions and help you chart a way forward, whether you've been diagnosed with cancer or are taking care of someone who has.

Exercise When Possible

Exercising for 2.5 hours per week can help you beat symptoms of depression and fatigue. Among the nation's millions of cancer survivors, there are hints — but not proof yet — that active exercisers may lower their risk of their cancer coming back.

The American College of Sports Medicine hosted a medical panel of cancer specialists to evaluate this exercise evidence. It issued guidelines suggesting that cancer patients and survivors should exercise for about 30 minutes most days of the week. This exercise should be enjoyable to you but also build up a sweat. When patients and their family caregivers exercised together, research found, everyone was more likely to stick with the fitness regimen, boost their physical stamina and experience less emotional strain.

Strengthen Your Social Support System

Connecting with others who've been through this kind of emotional diagnosis already can be a source of comfort and support. Learn more about online communities and your local chapters and support groups that meet up. The American Cancer Society also suggests attending one-on-one professional therapy or its "I Can Cope" online support groups to learn more.

Resource Links:

Find Local Cancer Support Programs | Cancer Support Groups

Strategies Used in Coping With a Cancer Diagnosis Predict Meaning in Life for Survivors

Coping Well with Advanced Cancer: A Serial Qualitative Interview Study with Patients and Family Carers

Coping with cancer

Coping Attitudes of Cancer Patients and Their Caregivers and Quality of Life of Caregivers

MORE FROM SYMPTOMFIND.COM

Efficacy Of Vitamin C To Prevent Colds

Source: https://www.symptomfind.com/health/tips-coping-with-cancer-diagnosis?utm_content=params%3Ao%3D740013%26ad%3DdirN%26qo%3DserpIndex

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