Neal Rouzier, MD – Hormones and Beyond 2021 Topics

CVD Update: It’s Not What We’ve Been Taught; It’s so Much More

  • Beta-cell dysfunction leading to insulin resistance
  • LDL-C is not predictive of CVD
  • Inflammation is the cause of IR, CVD, cancer and many other illnesses
  • What’s the Treatment?

CVD update: It’s not what we’ve been taught; it’s so much more. The cholesterol-centric model is out of vogue if statins do not significantly prevent CVD in diabetics, in contrast to non-diabetics. Also, tighter blood sugar control with diabetic medicines worsens CVD events and mortality (see newsletter #1). What are we missing here?

Beta-cell dysfunction leading to insulin resistance increases via inflammation induced by inflammatory cytokines such as IL-1B. If we don’t reduce the inflammation, then we won’t reduce the IR which is the main cause of CVD. How do we reduce inflammation and the beta-cell dysfunction in the pancreas?

LDL-C is not predictive of CVD as we hoped. LDL-particle number and apolipoprotein B are much more predictive of CVD. Statins affect LDL-C but not so much apo-B levels which can be increased by lipids other than LDL-C. Perhaps this accounts for the less than robust ARR of 1-2%. What else can be done to improve the ARR?

Inflammation is the cause of IR, CVD, cancer, and many other illnesses. Monoclonal antibodies against IL-1B have demonstrated benefit in many autoimmune diseases. However, the effect is short lived. What treatment has been proven to reduce all inflammatory cytokines, not just IL-1B, and to a much greater degree, and frequently ignored?

What’s the Secret to Reducing Apo-B Levels?

  • How can we avoid the statin-induced mitochondrial toxicity which diminishes the benefit of statins?
  • The Benefits of statins outweigh the risk? However this is only for CVD
  • What can be added to statins to eliminate this risk?
  • Apoliproprotein B unifies, amplifies, and simplifies conventional lipid markers.
  • “Hypertriglyceridemia (and low HDL) is more common in patients with cardiovascular disease than hypercholesterolemia (JAMA 2019).”

What is the secret to reducing apo-B levels? Dyslipidemia is the first sign of IR that leads to type 2 DM. This dyslipidemic elevation of triglycerides and suppression of HDL results in a significant increase in apo-B which portends an increase in CVD. Statins increase the risk of DM by 20-40%, but IR significantly more so, which raises apo-B levels long before DM is diagnosed. How can we avoid the statin-induced mitochondrial toxicity which diminishes the benefit of statins?

“The benefits of statins outweigh the risks.” However, this is only for CVD. This does not take into consideration the adverse effects of hyperglycemia, inflammation, microvascular disease, and cancer. What can be added to statins to eliminate this risk? These risks, as we will see, can be significant and should not be ignored.

Apolipoprotein B unifies, amplifies, and simplifies conventional lipid markers as to the atherogenic risk attributable to apo-B lipoproteins. Nonetheless, CVD often progresses despite lowering of apo-B levels. In addition to apo-B levels, the amount of time apo-B is at the blood vessel wall, and the efflux rate of oxidized lipids, also determines plaque development and reversal. This mechanism is dependent on HDL level which is suppressed by IR which is worsened by statin mitochondrial toxicity. How can we reverse this harmful cascade and pull apo-B away from the blood vessel wall? How can we limit the time of exposure of apo-B at the blood vessel wall?

“Hypertriglyceridemia (and low HDL) is more common in patients with cardiovascular disease than hypercholesterolemia (JAMA 2019).” And statins make IR dyslipidemia worse, but can also lower apo-B. However, HDL has antioxidant, anti-inflammatory, and anti-atherogenic activity and should be optimized. HDL is responsible for limiting the atherogenesis of the macrophage foam cell as well as removing inflamed foam cells. We must shift our thinking from cholesterol-centric to glucose-centric if we are to improve HDL levels and function.

Atherosclerosis – HDL – Understanding Atherogensis

The inflammation-centric model defines atherosclerosis. “The lowest levels of LDL-C cholesterol are strongly and independently associated with increased risk of cancer and all-cause mortality (Journal of Clinical Medicine 2019).” “This is a paradoxical contradiction to the traditional LDL-C hypothesis of decreasing mortality. We must embrace an inflammatory process that determines health outcomes.” Simply defined, atherosclerosis is a focal inflammatory disease dominated by inflamed macrophages. Uptake of oxidized lipids by macrophages leads to foam cell formation or plaque. How do we reduce the monocyte activation, adhesiveness and inflammation, uptake of oxidized lipids, and increase reverse cholesterol transport (efflux) back to the liver? We must raise HDL. But how do we accomplish that? You must reduce visceral fat and the IR. And how do we accomplish that?

“Multiple studies demonstrate cholesterol lowering with statins does not prevent atherosclerosis progression in diabetics. Despite intensive lipid lowering with statin therapy, diabetic patients still experience disease progression. HDL isolated in diabetic patients is consistently dysfunctional.” Lipid loading in foam cells is prevented by HDL. HDL mediates efflux of oxidized lipids preventing apoptosis and necrosis of foam cells and epithelial cells resulting in plaque regression and stabilization. IR and DM lead to dyslipidemia and low HDL, which accounts for the lack of benefit in cholesterol lowering in diabetics. So, how can we raise HDL levels and improve HDL function? What therapy is utilized by cardiologists to lower visceral fat?

Hyperglycemia leads to disposal of glucose inside fat cells and organs where it is stored as fat. This fat deposition inside beta-cells and the resultant increase in inflammation, results in beta-cell dysfunction (type 2 DM), liver dysfunction (NAFLD), and chronic kidney disease. The pathophysiology involves uptake of glucose into the organs where it is stored as fat, which increases inflammatory cytokines, leading to organ dysfunction. Multiple medicines increase blood glucose levels thereby worsening the disease. The same inflammation affects macrophage foam cells leading to atherosclerosis, even with low apo-B levels. Understanding inflammation-centric and glucose-centric disease models will lead  to a better understanding of atherogenesis and appropriate treatments that lower visceral fat, inflammation, and glucose storage in organs. Increase in glucose metabolism, and fatty acid metabolism via multiple medications, underlies the success in treating these disease models.

Fatty liver disease, chronic kidney disease, CVD, IR and pancreatic dysfunction are all organ damages responding to a systemic metabolic insult and hyperglycemia. We’ll review all the EBM studies demonstrating the various therapies that lower blood sugar via metabolism, lower cholesterol and apo-B, lower all inflammatory cytokines, reverse plaque and CIMT, reverse diabetes, lower CVD events, reverse beta-cell and liver dysfunction, lower visceral fat, and decrease CVD morbidity and mortality, as well as reduce all-cause mortality.

Notch pathway – Statins – CVD

If you have never heard of, or do not understand the Notch pathway, then you will not understand the importance of estradiol in protecting against DM, CVD, inflammation, and cancer. Loss of E2 at menopause leads to endothelial dysfunction, monocyte inflammation, increase in inflammatory cytokines, insulin resistance, dyslipidemia, CVD, and increase in all-cause mortality. Estradiol, via the Notch signaling pathway, protects the endothelium against inflammation and plaque deposition. E2, via the Notch pathway, protects against breast cancer. This research paper is so scientific and will result in you throwing the WHI study in the trash. E2 is not CEE. Notch signaling affects mitochondria, metabolism, AMP-K, endothelial cell dysfunction and dyslipidemia, atherogenesis, proliferation of VSMCs, IR, and cellular metabolism, regulation of white and brown fat, and expression of genes. The benefits of E2, and the harm of estrogen deprivation, are staggering.

Statins increase coronary calcification in every study, but “the benefits outweigh the risks.” However, every study demonstrates that the higher the CAC, the greater the risk for CVD events and CV mortality. If statins increase the risk of IR and diabetes, and IR increases the risk for CVD, then what can we do to eliminate that risk to better protect against CVD? If an increase in CAC portends an increase in CVD, and statins increase CAC, then what can be done to reduce CAC and the risk of CVD? We’ll review all the studies and therapies that reduce CAC, CIMT, and plaque scores.

“It is important to note that patients with diabetes typically have lower HDL levels, fewer HDL particles with reduced anti-inflammatory functions, and impaired efflux capacity. Improving the function of HDL will translate to reducing the high level of residual risk of CVD seen after conventional cholesterol lowering therapy and aggressive glucose lowering (Circulation 2020).” We must move beyond the cholesterol-centric model and embrace the glucose-centric and inflammation-centric models of CVD.

Breast Cancer is the Leading Cause of Cancer in Women

  • Do the benefits of endocrine therapy outweigh the risks?
  • How do we prevent the toxicity of breast cancer endocrine therapy?
  • Over 50% of breast cancer patients on endocrine therapy resistance resulting in breast cancer recurrence over time. What is the potential mechanism for failure? Are we increasing the risk?

Breast cancer is the leading cause of cancer in women. Estrogen blockers diminish available estrogen at the cellular level affecting the aging process with increased risks in overall health as uterine cancer, thromboembolic events, osteoporosis and fractures, and musculoskeletal complaints. Estrogen deprivation also increases CAD, stroke, dementia, cognitive impairment, IR and diabetes. Loss of estrogen decreases insulin secretion, increasing obesity, IR, and diabetes. Do the benefits of endocrine therapy for breast cancer outweigh all the risks? Are these risks adequately explained to patients?

AIs increase IR, dyslipidemia, and risk of CVD. There is no benefit in overall survival with prolonged AI therapy in regards to breast cancer.

SERMs can reduce breast cancer recurrence, but meta-analysis revealed no decrease in breast cancer mortality. SERMs increase IR, dyslipidemia, uterine cancer and thromboembolism. Ten years of endocrine therapy with SERMs or AIs led to increased risk of cardiovascular morbidity and mortality. How do we then prevent the toxicity of breast cancer endocrine therapy? Which drug has been consistently shown to decrease breast cancer mortality?

Over 50% of breast cancer patients on endocrine therapy will develop resistance resulting in breast cancer recurrence over time. What is the potential mechanism for this failure? What can we do to prevent this failure? Are we increasing the risk of cancer?

“The most common cause of death in breast cancer survivors is CVD.” Why is this and what can be done to prevent this complication of endocrine therapy for breast cancer?

Even though Obesity and Diabetes Increase CVD and all-cause mortality, there is less awareness that weight gain, obesity, and DM increase the risk of Cancer also.  What else can we offer patients?

  • Increased body mass (BMI) is linked to increased death from every cause including CVD and cancer
  • Statins and Metformin decrease testosterone, what are the metabolic effects of testosterone suppression
  • Are there studies to demonstrate an increased risk of cancer in men with low testosterone levels?
  • Are there studies that demonstrate testosterone therapy reduces BMI, visceral fat, IR and DM?

“Diabetes increased the risk of dying prematurely not only from vascular causes but also from cancer, and from any cause (NEJM 2011).” “A 50-year-old patient dies 6 years earlier than his counterpart without diabetes.” And the reason that we ignore the increased risk of DM from statins, estrogen blockers, and LH-RH agonists is because?

“Even though obesity and diabetes increase CVD and all-cause mortality, there is less awareness that weight gain, obesity, and DM increase the risk of cancer also. A recent review of > 1,000 studies links weight gain, obesity, IR, and DM to 13 cancers (JAMA 2017).” And the reason that we ignore this is because? What else can we offer patients that aren’t successful with diet and exercise?

“But the benefits outweigh the risks!” No, they don’t. “The benefits of maintaining a healthy weight throughout life include prevention of cancer.” And the reason that we ignore all the forgoing studies that demonstrate reduction of body weight, IR, DM, CVD, and cancer with hormone therapy is because? The reason that we ignore or reject our scientific literature is because? We should not wait until we get cancer but rather be proactive.

Increased body mass index (BMI) is linked to increased death from every cause including CVD and cancer (The Lancet).” Use of statins is associated significantly with lower total and free testosterone levels (which increases the risk of DM and CVD). Use of metformin reduces levels of total and free testosterone. And the treatment for testosterone suppression by statins and metformin should be? What are the metabolic effects of testosterone suppression? Are there studies and literature demonstrating the increased risk of cancer in men that have low levels of testosterone? Are there studies that demonstrate testosterone therapy reduces BMI, visceral fat, IR, and DM?

“Menopausal estrogen therapy significantly reduces visceral adipose tissue (VAT), BMI, and android fat. (JCEM 2018).” Estrogen, testosterone, and thyroid hormones control metabolism and energy balance leading to increased energy expenditure (JCEM 2016).” Statins allow for plaque progression and calcification. Estradiol, testosterone, and T3 result in plaque reversal and a decrease in CAC. The MOA is due to a decrease in IR, lipids, and inflammation, along with a simultaneous increase in HDL and decrease in inflamed macrophage foam cells. You have to lower the visceral fat!

Testosterone and Risk/Benefit with Prostate Cancer is always a Controversial Topic

  • Low levels of testosterone increase incidence and severity of prostate cancer and high levels are protective.
  • Testosterone is safe and efficacious in prostate cancer survivors
  • Estradiol is as much a male hormone as it is a female hormone

Testosterone and risks/benefits of prostate cancer is always a hot topic. Overwhelming data now support no harm or association of testosterone in the initiation of prostate cancer. On the other hand, a plethora of data indicates that low levels of testosterone portend an increased risk, and high levels demonstrate protection against prostate cancer. Low levels of testosterone increase incidence and severity of prostate cancer, and high levels are protective. High levels of testosterone, as well as testosterone therapy, prevent recurrence of prostate cancer.

Testosterone is safe and efficacious in prostate cancer survivors. There is a significant metabolic component to prostate cancer which can be improved with testosterone therapy. Unfortunately, LH-RH agonist therapy for advanced prostate results in the metabolic syndrome, IR, DM, and CVD morbidity and mortality. These metabolic and CVD perturbations can be eliminated and reversed by estrogen therapy (E2). How can we incorporate this concept into the treatment of prostate cancer? Why isn’t it embraced?

Estradiol is as much a male hormone as it is a female hormone. Testosterone is a pro-hormone that elicits its effects after conversion to DHT and estradiol. There is extensive scientific research, and publications, on the safety and efficacy in treating prostate cancer with estrogen. Estrogen must be used in any situation where prostate cancer is treated by conventional anti-androgen therapy. Unfortunately, most of the urologic world remains oblivious to the harm of endocrine therapy for prostate cancer. The side effects of LH-RH therapy of metabolic and CVD dysfunction can be eliminated by estrogen administration.

Estrogen has the same beneficial effects in men as in women. There is always reluctance to utilize oral E2 because everyone thinks/knows that oral estrogen causes blood clots. Using only transdermal E2 forgoes the CVD benefit of oral E2.

Testosterone has been found to be safe and efficacious in men with prostate cancer that are on active surveillance. High dose testosterone (BAT) has been shown to be effective for metastatic prostate cancer. I have provided literature support for you in case patients or their practitioners are concerned with use in patients with active cancer.

An Overview of the Most Recent Treatments/Therapies for Breast Cancer, Endometrial Cancer, and Ovarian Cancer

An overview of the most recent treatments/therapies for breast cancer, endometrial cancer, ovarian cancer. The oath of medicine is to do no harm. However, often times we don’t realize the harm that we cause by our usual treatments for cancer. “But the benefits outweigh the risks.” No, they don’t.

We also don’t grasp the harm of not using certain hormone therapies. IR and DM increase the risk of many cancers. Many of the medicines we typically prescribe increase BS, IR, and DM. Not replacing and optimizing hormones also increase the risk of breast cancer and prostate cancer which are metabolically driven. We’ll review the literature demonstrating which supplements will prevent IR and metabolic syndrome, treat and prevent obesity, thereby preventing cancer initiation and progression.