How Does Time Restricted Eating and Intermittent Fasting Work? Part II

How Does Time Restricted Eating and Intermittent Fasting Work? Part II

Intermittent fasting or IF is a practice involving alternating fasting time and/or calorie restriction with periods of feeding that has proven cellular benefits, metabolic gains and remission or reversal for a variety of symptoms and disease states. Time restricted eating is compressing an eating window to a specific number of hours each day. An example of this would be eating all the day’s food within a 6–8-hour window. 

With the prevalence of obesity and chronic disease impacting our healthspan and quality of life, implementing the practices of intermittent fasting or time restricted eating may prove to be an important lifestyle tool for maintaining health and vitality as we age.

In Part One of this series, I went into detail about how intermittent fasting and time restricted eating works along with the long list of health benefits that have been linked to these lifestyle tools. In today’s article, Part Two takes a more practical view regarding the different ways to structure intermittent fasting and time restricted eating. We will also cover some of the most common questions about the safety and details of these two lifestyle practices. This will essentially be a guide to intermittent fasting and time restricted eating for beginners and experienced fasters alike.

This article covers the following topics:

  • How to intermittent fast
  • How to do time restricted eating
  • Is intermittent fasting and time restricted eating safe?
  • Are these two practices different for men and women?
  • Can you drink coffee or tea?
  • Does intermittent fasting and time restricted eating promote weight loss?
  • Can a ketogenic diet be combined with intermittent fasting and time restricted eating?

By the end of this article, you’ll know if intermittent fasting and time restricted eating are for you and how to get started.

Time restricted eating meal plan hours – 16:8, 18:6, and 20:4

There are many ways to implement a time restricted eating and/or intermittent fasting plan. Let’s look at some of the most popular schedules for time restricted eating and intermittent fasting.

Type of time restricted eating or intermittent fastingExplanationSample scheduleWhat to eat in your windowTips
Time restricted feeding (TRF)Fast for 16 hours overnight and condense meals into an 8-hour windowFinish dinner by 8 pm then fast until 12 pm the next dayRegular dietMay be practiced daily or a few times per week
Time restricted feeding 18:6 (TRF)Fast for 18 hours overnight and condense meals into a 6-hour eating windowFinish dinner by 6 pm and fast until 12 pm the next dayRegular dietMay be practiced daily or a few times per week
Time restricted feeding 20:4 (TRF)Fast for 20 hours overnight and condense meals into a 4-hour eating windowFinish dinner by 6 pm and fast until 2 pm the next dayRegular dietMay be challenging to meet nutrient needs if practiced daily
One Meal A Day (OMAD)Eat only one meal per day and fast for 23 hoursEat between 12 pm and 1pm each dayRegular dietMay be challenging to meet nutrient needs if practiced daily 
Alternate Day Fasting (ADF)24-hour fast every other dayFor example Monday – Fast Tuesday – Eat Wednesday – Fast Thursday – Eat  Regular dietSafe for several months, long-term challenges (1)
5:2 fasting (periodic fasting)24-hour fast 2 days per weekMonday, Tuesday – Eat Wednesday – Fast Thursday, Friday – Eat Saturday – Fast Sunday – EatRegular diet 
Fasting-Mimicking Diet (FMD)5 days of plant-based dietMay be practiced monthly for between 3 and 6 monthsPlant-based diet of 800 to 1000 calories per dayFood available through Prolon or Whole Food FMD program, available through the Hoffman Centre

With so many options, it may be challenging to determine how to start time restricted feeding or intermittent fasting. For example, do you just dive in or do you ease into it more slowly? I recommend starting with either time restricted feeding (TRF) or with the fasting-mimicking diet. (FMD). With that experience, you can then work with your provider or myself to determine if you’d benefit from other practices.

TRF may begin with a simple 12:12 schedule, meaning that you begin fasting overnight and then eat your regular diet within a twelve-hour eating window. For many people this isn’t that much different from their typical pattern, although they may have to be aware of any tendencies for late night snacking. A fast from 8 pm until breakfast at 8 am the following day is a good schedule to start with. Once you have this under your belt, you can expand your fasting window, in increments if needed, to a fourteen-hour fast with a ten-hour eating window. You can then potentially lengthen this to include a fast of sixteen hours or longer.

The fasting-mimicking diet (FMD) is a five-day program, typically practiced once per month for between three and six months, and then one time every 3-4 months as a maintenance program. During the five day fast, you follow a plant-based, calorie-restricted diet. The diet is derived from plant sources like vegetables, nuts, seeds, and fruit. The diet relies on plant foods for protein, olives, coconut and nuts and seeds for healthy fats. The diet constituents are carefully chosen by a nutritional expert. There is a commercially available program involving packaged constituents called ProLon.

With calories restricted to approximately between 750 and 1100 per day, with day one containing the most calories. This represents a réduction in calories of around 50 to 60 percent, this diet is designed to mimic molecular and cellular fasting while increasing patient compliance. The stomach sees food, while the cells see fasting. (2, 3)

The fasting mimicking diet has been clinically studied as a therapy for a variety of conditions including autoimmunity, breast cancer, and metabolic disease such as heart disease and diabetes. Extensive studies in mice have been completed, along with a few human clinical trials.

In the most recent randomized controlled trial from 2021, obese women received either a five-day fasting mimicking diet or their typical diet with a calorie deficit of 500 calories each day. This particular study didn’t indicate a difference in weight between the two groups, but the women following the fasting-mimicking plan showed reduced insulin resistance and improved appetite regulating hormones, along with preserved muscle mass and metabolic rate. (4)

At the Hoffman Centre, Justine leads a whole food fasting-mimicking program which I’ve personally undertaken three times and seen the dramatic results. An additional benefit to this structure is the group dialogue component and support provided throughout the process.

Learn more about this program here

It’s important to note that many fasting trends such as juice fasting don’t have the same benefits and may even have risks. Prolonged fasting of more than two days without food may contribute to electrolyte imbalances, dizziness, exhaustion, and other symptoms, making compliance quite challenging. Both time restricted feeding and the fasting-mimicking diet offer the benefits of fasting with intermittent fasting rules that are easy to follow.

Frequently asked questions

Let’s dive into some of the most common questions that I’m asked about intermittent fasting and time restricted eating, who it’s recommended for and who it’s not recommended for, along with some details to help you feel more confident moving forward.

Are intermittent fasting and time restricted eating safe?

Intermittent fasting and time restricted eating are safe and effective practices for many people. However, it’s important to work with your doctor, especially if you have a medical condition or take any medications. A doctor should look at your medical history, complete a physical exam, and review any laboratory testing. Please however note that your doctor may not be that familiar with these approaches to nutrition nor know the science behind it. Be sure that you are practicing the most well informed kind of patient advocacy and be prepared to educate you doctor on the subject .

While intermittent fasting and time restricted eating might be beneficial in a variety of medical cases, as explained in Part One, there are many cases in which intermittent fasting and time restricted eating are not indicated including:

  • Pregnancy and lactation
  • Anorexia, underweight, or chronic malnutrition
  • Type 1 diabetes or insulin-dependent Type 2 diabetes (as insulin requirements may plummet dramatically requiring a lowering of insulin dosing)
  • Recent stroke or heart attack
  • Pulmonary embolism or deep vein thrombosis
  • Cardiac instability or atrial fibrillation
  • Advanced kidney disease
  • Advanced liver disease
  • Advanced heart disease
  • Porphyria, MCAD
  • Inability to discontinue medications
  • Inability to obtain adequate rest while fasting
  • Active growth, such as with children or adolescents
  • Current fever, cough, or signs of an active infection (5)

Alternatively, if you’re working on any of the following imbalances or disease states, it may be worth discussing intermittent fasting and time restricted eating with your personal doctor or with myself.

  • Excess weight or obesity
  • Elevated cholesterol
  • Elevated blood pressure
  • Cardiovascular disease
  • Metabolic syndrome or type 2 diabetes
  • Lymphoma and other cancers
  • Digestive imbalance, including SIBO
  • Autoimmune disease
  • Dependency or toxicity

Fasting side effects may include fatigue, weakness, headache, dry mouth, menstrual irregularity, memory impairment, muscle pain, constipation, sugar cravings, and brain fog. Be sure to stay well hydrated and avoid strenuous exercise or extreme environments while fasting. Fasting is the ideal time for rest.

Is intermittent fasting and time restricted eating different for men and women?

While much of the initial intermittent fasting research has been conducted on animals and human men, we’re starting to learn more about the unique needs of women when it comes to fasting. Whereas men have similar hormonal patterns from day to day, women’s hormones fluctuate on a monthly cycle and then decline through perimenopause and menopause. You can learn more in my article on hormone replacement therapy.

Women seem to be more sensitive to over-fasting and restricting their food intake too much, too often. They might see imbalances in stress hormones, thyroid hormones, and sex hormones. In extreme cases, too much fasting may lead to amenorrhea or the loss of a woman’s period, especially when percentage body fat drops below a certain percentage. When it comes to intermittent fasting for women, it’s important to note that more fasting isn’t always better. A less-is-more-approach often applies.

And while each woman is different, it’s challenging to provide advice for fasting in women on a worldwide basis. For example, some women with autoimmune disease do very well with implementing intermittent fasting practices, while others might do more poorly. Remember that fasting is a stressor on the body and this can be a good stressor that leads to autophagy, detoxification, and cellular rejuvenation. Yet if the system is already stressed, fasting can sometimes be the straw that breaks the camel’s back. Often, if a woman is exhausted, overwhelmed, and feeling burnt out this isn’t the time to add even more stress.

In a study of obese women, intermittent fasting combined with calorie restriction was shown to reduce weight over a ten-week period. (6) However, many restrictive methods work in the short-term and we may need to learn more about the long-term results of fasting for women.

In another study comparing men and women in a forty-eight-hour fast, it was noted that women tend to accumulate triglycerides in their muscles, while men accumulate these in their livers, although other physiological aspects during the fast were similar. (7) We certainly need more research to further establish the differences related to long-term fasting practices and the different types of intermittent fasting between men and women regarding the potential benefits fasting.

As always with functional medicine, a personalized approach is best. As discussed above, I recommend starting with gentle time restricted feeding or with the fasting-mimicking diet.

Can I drink coffee or tea during fasting hours?

This question about hot drinks usually leads to hot debate! Whether you can drink coffee while intermittent fasting may depend on what works best for you as an individual.

Experts in the fasting field recommend “complete abstinence from all substances except pure water.” (5) Biological fasting is the absence of anything that triggers nutrient-sensing pathways. (3) This certainly means no protein, carbohydrates, or fats, but most likely no vitamins, minerals, or plant compounds either.

While black coffee or tea, doesn’t contain any calories, it does contain caffeine, which can influence the hormones cortisol and insulin. It also contains phytonutrients, the antioxidant compounds that are absorbed and which rely on digestion and metabolism.

So, what can you drink during intermittent fasting? If you want to be a purist, stick to only water during your fasting window then enjoy coffee or tea with your first meal of the day or at any time within your eating window.

After that, you can experiment with plain coffee or tea within your fasting window and see whether it improves, or deters from, your results. Coffee or tea with added fat, such as bulletproof coffee, should be enjoyed during the eating window.

Does intermittent fasting and time restricted eating help with weight loss?

Weight loss is difficult and traditional strategies are largely based on reducing calories and increasing exercise. However, these strategies, especially extreme versions, typically only produce short-term results. Many factors contribute to weight, including hormones, sleep, stress, nutrient levels, toxin exposure, mindset, and so much more. Simply looking at calories doesn’t always address the situation and a short-lived fast may only result in a Band-Aid effect. Yet for some, even a quick boost in hope and confidence that the body can lose stubborn weight can be a catalyst for deeper change. That’s why discussing how to use fasting with a trained professional is key.

Using intermittent fasting and time restricted eating for weight loss might be a solution, or just part of the weight solution, especially for someone who spends the majority of their time in the fed state. Fasting might provide the metabolic balance that will address some of the underlying physiology contributing to weight gain, such as inflammation, elevated insulin, and oxidative stress.

In a review of different types of intermittent fasting, IF produced similar weight loss results to those derived from caloric restriction. 5:2 fasting was similar to restricting daily calories in nine out of eleven studies. In addition, the majority of the weight loss occurred in the first three months before weight hit a plateau and results were similar with different distributions of macronutrients. Time restricted feeding and caloric restriction also seemed similar as far as weight was concerned. (8)

In a long-term study that compared alternate day fasting or ADF with daily calorie restriction in obese adults, weight loss after one year was 6 percent in the ADF group compared to 5.3 percent in the calorie restriction group, so there wasn’t a huge difference. (9)

When examining human studies involving individuals with diabetes, those practicing time restricted feeding as opposed to consuming six small meals per day lost more weight. The studies also showed more results with intermittent fasting in terms of decreasing A1C and blood glucose, which are markers of diabetes, compared to a common recommendation of eating frequent small meals. (10)

The definitive answer to this question regarding the intermittent fasting weight loss diet may not be clear in the science. However, I’ve seen it used successfully in my practice for patients who are good candidates, along with other functional medicine interventions.

Does intermittent fasting and time restricted eating work while following a ketogenic diet?

Ketogenic diets, time restricted eating, and intermittent fasting are often discussed as going hand in hand. Keto, which is an abbreviation for the ketogenic diet, is a high fat, low carbohydrate eating pattern that in its own way mimics the fasting state through the restriction of dietary glucose. The ketogenic diet, time restricted eating, and intermittent fasting all have the potential to increase ketones in the blood that can be used as fuel by the cells instead of them employing glucose. The ketogenic diet combined with time restricted eating and intermittent fasting may also have similar benefits related to a treatment approach to chronic and metabolic diseases.

To answer the question, yes, intermittent fasting and time restricted eating can be combined with a ketogenic diet. Those following a ketogenic diet that are in a state of ketosis, where the body is efficient at turning fat into ketones and using them as fuel, may have a better experience with fasting and fewer negative side effects. Similarly, those with an existing fasting practice might have an easier time transitioning to a ketogenic diet because their metabolism is already primed to use ketones.

So, while intermittent fasting or time restricted eating combined with a keto diet may certainly be an important dietary approach for some people healing from chronic disease or working to promote longevity, it may be too restrictive for others. This is another reason why working with an experienced practitioner can be so helpful. You can dial in your nutrition plan and then have support adjusting, and even expanding, the diet over time.

We all want to remain healthy and high-functioning as we get older, but it’s about more than living a long time. It’s about improving our quality of life. Intermittent fasting is meant to mimic the balance between feast and famine that humans have always experienced throughout history. Regular feasting is a relatively recent development and this excess time in the fed state may deter us from experiencing all of the important health and longevity benefits that come from fasting. The best part about intermittent fasting is that it makes fasting simple, gentle, and fit into modern life.

To learn more about working with me individually or to join our next group fasting-mimicking diet, please contact my office.

References:

  1. Stekovic S, Hofer SJ, Tripolt N, et al. Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans [published correction appears in Cell Metab. 2020 Apr 7;31(4):878-881]. Cell Metab. 2019;30(3):462-476.e6.
  2. Di Francesco, A., Di Germanio, C., Bernier, M., de Cabo, R. A time to fast. Science. 2018;362(6416),770-775.
  3. Hong, K. Intermittent Fasting and Fasting Mimicking: Clinical Applications. Presentation. University of Southern California.
  4. Sadeghian M, Hosseini SA, Zare Javid A, Ahmadi Angali K, Mashkournia A. Effect of Fasting-Mimicking Diet or Continuous Energy Restriction on Weight Loss, Body Composition, and Appetite-Regulating Hormones Among Metabolically Healthy Women with Obesity: a Randomized Controlled, Parallel Trial [published online ahead of print, 2021 Jan 9]. Obes Surg. 2021;10.1007/s11695-020-05202-y.
  5. Goldhamer, A. Can Fasting Save Your life. TrueNorth Health Center.
  6. Klempel MC, Kroeger CM, Bhutani S, Trepanowski JF, Varady KA. Intermittent fasting combined with calorie restriction is effective for weight loss and cardio-protection in obese women. Nutr J. 2012;11:98. Published 2012 Nov 21.
  7. Browning JD, Baxter J, Satapati S, Burgess SC. The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men. J Lipid Res. 2012;53(3):577-586.
  8. Rynders CA, Thomas EA, Zaman A, Pan Z, Catenacci VA, Melanson EL. Effectiveness of Intermittent Fasting and Time-Restricted Feeding Compared to Continuous Energy Restriction for Weight Loss. Nutrients. 2019;11(10):2442. Published 2019 Oct 14.
  9. Trepanowski JF, Kroeger CM, Barnosky A, et al. Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults: A Randomized Clinical Trial. JAMA Intern Med. 2017;177(7):930-938. doi:10.1001/jamainternmed.2017.0936
  10. Muñoz-Hernández L, Márquez-López Z, Mehta R, Aguilar-Salinas CA. Intermittent Fasting as Part of the Management for T2DM: from Animal Models to Human Clinical Studies. Curr Diab Rep. 2020;20(4):13. Published 2020 Mar 12.

How Does Time Restricted Eating and Intermittent Fasting Work? Part I

How Does Time Restricted Eating and Intermittent Fasting Work? Part I

If you’re interested in living a healthier lifestyle, you’ve probably heard of time restricted eating, or intermittent fasting and the success stories associated with incorporating these practices into your life. Despite living longer these days, the healthspan of many Americans is actually cut short as the average person spends seventeen of their final years living in poor health. This is due to chronic diseases such as diabetes, heart disease, cancer, and Alzheimer’s. In fact, 80 percent of older adults have at least one chronic condition, which is primarily related to their lifestyle.

What if time restricted eating or intermittent fasting could be a solution, one of the tools in the kit, to help combat the underlying factors that contribute to such diseases? Is time restricted eating and intermittent fasting simply a diet trend? Or is there a substantial and credible scientific basis to warrant its therapeutic use?

In this two-part series, we’ll explore these questions, and more.

In Part One we’ll examine the nature of time restricted eating and intermittent fasting, how it works, and the health benefits of both practices.

Part Two will cover methods of fasting and time restricted eating, along with answers to the most commonly asked questions regarding this popular practice.

What are time restricted eating and intermittent fasting?

Time restricted eating, (TRF) and intermittent fasting, also referred to as IF, are often treated as if they are one and the same, but there are actually some major differences between the two.

Time restricted eating involves simply alternating periods of eating with periods of fasting. With TRF, all of your eating is compressed into a 1 -12 hour feeding window. Most hours of the waking day, you’ll spend in a feeding state—say from 8:00 am to 4:00 pm. The other hours, you don’t consume any calories, although you are allowed calorie-less drinks, like water, sparkling water, decaffeinated tea and black coffee. Some people, (known as OMAD’s), eat only one meal a day (OMAD) and fast for 23 hours. 

The term intermittent fasting can be confusing and inaccurate. The term ruffles some researchers feathers because there are many different forms of fasting or restriction. It’s important to distinguish between them. The other problem with the term intermittent fasting is the flexibility around the term “fasting.” Most studies on various intermittent fasting schedules allow up to 700 calories per day on fasting days, while others don’t allow any calories. I want to be very particular about the definitions because I think different forms of fasting and different types of restriction may have different physiologic effects, and by lumping all forms of fasting together, we may dilute such insights.

Intermittent fasting includes the fasting-mimicking diet or FMD, where your intake is restricted to between 750 and 1050 calories (approximately) per day for a five-day period out of the month. This has been shown to mimic some of the physiological benefits of water fasting.

In addition, intermittent fasting also includes alternate day fasting or ADF. With this type of fasting a regular diet is followed for one day followed by a day of fasting. Another option is 5:2, which involves five days of regular eating followed by two fasting days in one week. With each of these methods, the fasting days can feature either a water fast or a calorie-reduced diet.

In contrast, a long-term or prolonged fast is considered more than two days and up to several weeks without food.

As you can see, there are several versions of intermittent fasting in which individuals can engage and that have been explored with scientific research. I’ll cover these in more detail when we discuss an intermittent fasting schedule and how to implement it in Part Two of this series.

How intermittent fasting works

If we take a look back in time to more ancestral or hunter-gatherer ways of eating, feasting was always balanced with famine. There were naturally times of the year when food was abundant and times of the year when food was scarce. The human body has the ability to adapt and thrive in both cases.

With the onset of our modern agricultural system, most of us in the developed world no longer have natural periods of fasting and life is a perpetual feast. We have access to whatever food we desire, grown anywhere in the world, every day. It’s no wonder that rates of obesity are the highest they’ve ever been, leading to inflammation and chronic disease. These days the body’s systems never have an opportunity to rest and reset.

So how exactly does intermittent fasting work? To answer this question, we need to go behind the scenes and into the cell to understand what’s happening on the cellular level, in both the fed state and the fasting state.

When we eat a meal, the body’s system is dedicated to processing food, which places the cell in growth mode. Insulin levels are higher, signaling the cell to grow. More specifically, insulin signals mTOR, meaning mammalian target of rapamycin, which instructs the cell to grow and divide. mTOR also decreases autophagy, the process of cellular recycling, that’s predominant during fasting and important for regular repair and maintenance of the cell. (1)

Autophagy naturally declines with age and decreased autophagy is related to neurodegenerative disease, cardiomyopathy, cancer, metabolic syndrome, suppressed immunity, and signs of aging. Boosting autophagy by means of intermittent fasting methods may help to slow or reverse these changes.

In the fasting state AMPK, or 5’ AMP-activated protein kinase, slows down mTOR. This causes fat breakdown and works to activate autophagy, allowing the body to run on its own stored fuel in the form of fat. AMPK also cleans up and repairs parts of the cell that don’t work, an important process that contributes to healthy aging and preventing diseases such as cancer. (1)

In addition, fasting, intermittent fasting, and calorie restriction down regulates IGF-1, or insulin-like growth factor-1. IGF-1 signaling is important for protein synthesis, as well as blood sugar regulation and growth. Later in life, increased IGF-1 can accelerate the aging process and decreasing it, through methods such as IF or time restricted eating, may increase longevity. Studies in mice indicate that employing different types of intermittent fasting can result in an increased lifespan. (1)

When food is scarce, the body conserves energy by downregulating or decreasing both mTOR and IGF-1, which increases stress resilience and protection on the cellular level. In fact, this can be considered inner rejuvenation, which reduces inflammation and increases autophagy. The results include increased stem cell regeneration and improved immunity, especially during fasts lasting more than a few days or by means of fasting-mimicking. (1)

Decreasing IGF-1 also decreases cellular senescence, in which the cell loses its ability to divide, as measured by telomere length. This process of cellular senescence is caused by underlying factors that produce oxidative stress, changes in the epigenetic gene expression, metabolic dysfunction, and mitochondrial dysfunction and the process is considered irreversible. However, decreasing IGF-1 or mTOR increases sirtuins, via the antiaging molecule NAD+, autophagy, and enables DNA repair. (1)

When the body is in a fed state, cells are highly acetylated so that genes are turned on. This helps cells to survive and proliferate. When these genes are on, the ones that are more related to fat metabolism, stress resistance, and cellular repair are turned down. (1)

This is what happens metabolically throughout a longer fast or a fast-mimicking diet over the course of five days.

  • 12 hours: The body transitions from primarily using glucose as fuel to increasing ketones as the preferred fuel for cells, including cells in the brain. (2) This causes an increase in BDNF, or brain-derived neurotropic factor, which allows for increased brain plasticity and neurogenesis. (1)
  • 18 hours: Ketone levels continue to rise. More ketones lead to a decreased need for glucose and insulin, along with more BDNF.
  • 24 hours: Cells increase autophagy, allowing for recycling and the breakdown of old or broken cellular components. (3)
  • 48 hours: Growth hormone (GH) is five times higher than normal, helping to preserve lean muscle mass, reduce fat, and is important for longevity. (4)
  • 54-72 hours: Insulin sensitivity increases and new stem cells and immune cells form. (5)

In summary, on the cellular level, fasting results in the following:

  • Decreased mTOR
  • Reduced IGF-1
  • Increased AMPK
  • Increased autophagy
  • Greater NAD+ and sirtuins
  • Increased ketones
  • Increased BDNF
  • Increased GH
  • Reduced levels of insulin and blood glucose
  • Decreased cellular senescence
  • Increased fat metabolism
  • Improved resistance to cellular stress
  • Reduced inflammation

Our bodies still need both the fed and fasting state, but in our modern culture the balance strongly favors always being fed. Intentional fasting may be a way to add greater balance to the system by allowing for these natural cellular processes that primarily happen in the fasted state.

Health Benefits of Intermittent Fasting and Time Restrictive Eating

Now that we’ve covered the science of fasting and time restricted eating, the question I’m often asked is whether these practices work in regard to health and longevity. This is an exciting area of study, using a wide variety of animal models, along with increasing numbers of studies in humans, in order to decipher the potential benefits of intermittent fasting and implementing time restricted eating.

Research has indicated a number of positive clinical benefits related to intermittent fasting and time restricted eating

  • Weight loss
  • Changes in body composition/fat loss
  • Improved insulin sensitivity or decreased insulin resistance
  • Reduced oxidative stress
  • Increased cellular autophagy
  • Stem cell regeneration
  • Optimized neurogenesis
  • Enhanced parasympathetic nervous system response
  • Improved gut motility, which is important for conditions like SIBO
  • Reduced heart rate
  • Reduced blood pressure
  • Improved lipid/cholesterol balance
  • Improved cognitive function
  • Improved detoxification
  • Improved physical performance
  • Improved sleep patterns
  • Improved immunity (1,6,7)

Taken together, all these clinical benefits translate into important applications related to longevity and chronic disease reversal. Intermittent fasting results are clearly beneficial for a variety of disease states and populations, including those with cardiovascular disease, diabetes, obesity, dementia, cancer, depression, and a number of other conditions. (6,7)

Intermittent fasting addresses the metabolic root causes that contribute to disease over time. IF and time restricted eating may be an important lifestyle tool, along with diet, physical activity, and stress reduction, that brings health more into balance.

In Part Two of this series on intermittent fasting, we explore the specifics of the different types of intermittent fasting, along with how to implement an intermittent fasting schedule. We’ll then cover some frequently asked questions on the topic and provide details and guidance to get you started.

If you’re looking for more personalized guidance, or are interested in our whole food fasting-mimicking program available through Justine Stenger and the Hoffman Centre for Integrative and Functional Medicine, please contact us for more information.

References:

  1. Hong, K. Intermittent Fasting and Fasting Mimicking: Science and Molecular Mechanisms. Presentation. University of Southern California.
  2. Anton SD, Moehl K, Donahoo WT, et al. Flipping the Metabolic Switch: Understanding and Applying the Health Benefits of Fasting. Obesity (Silver Spring). 2018;26(2):254-268.
  3. Alirezaei M, Kemball CC, Flynn CT, Wood MR, Whitton JL, Kiosses WB. Short-term fasting induces profound neuronal autophagy. Autophagy. 2010;6(6):702-710.
  4. Hartman ML, Veldhuis JD, Johnson ML, et al. Augmented growth hormone (GH) secretory burst frequency and amplitude mediate enhanced GH secretion during a two-day fast in normal men. J Clin Endocrinol Metab. 1992;74(4):757-765.
  5. Klein S, Sakurai Y, Romijn JA, Carroll RM. Progressive alterations in lipid and glucose metabolism during short-term fasting in young adult men. Am J Physiol. 1993;265(5 Pt 1):E801-E806.
  6. Hong, K. Intermittent Fasting and Fasting Mimicking: Clinical Applications. Presentation. University of Southern California.
  7. Goldhamer, A. Can Fasting Save Your life. TrueNorth Health Center.
  8. Rynders CA, Thomas EA, Zaman A, Pan Z, Catenacci VA, Melanson EL. Effectiveness of Intermittent Fasting and Time-Restricted Feeding Compared to Continuous Energy Restriction for Weight Loss. Nutrients. 2019;11(10):2442. Published 2019 Oct 14.

Patient Questions – HRT and Weight Gain

hormone replacement therapy weight gain

Question 

I’m an active baby boomer who tries to stay in good shape. I walk a lot, go to aerobics twice a week, inline skate in summer, and curl twice a week in the winter. I try to eat healthy food but I’m finding it nearly impossible to lose that excess fat around my waist. My question is, does taking hormonal drugs, such as Premarin and Prometrium, have any effect on trying to lose weight? I’ve tried several times to get completely off the drugs and although I’m only taking half my original dosage, I can’t bear the hot flashes and night sweats without the drugs. I personally believe that I’d be better off without the drugs but I don’t know if it would then be any easier to lose the abdominal fat.

Thank you,
Cathy 

Answer 

Dear Cathy,

Your letter has raised a number of very pertinent questions that every woman that’s approaching menopause should be aware of. 

First of all, we know that the negative conclusions reached by the Women’s Health Initiative study¹ led to 50 percent of women being removed from or voluntarily stopping their hormone replacement therapy. The negative findings were suggestive of an increased risk of heart disease, strokes, breast cancer, and dementia.

However, in later reviews and critiques of the study, many researchers have reversed some of their earlier conclusions. Please see my blog post on this subject, entitled Risks of Hormone Replacement Therapy in Women. The researchers suggest that women become informed regarding the many helpful benefits of hormone replacement therapy, not just about the symptomatic treatment of hot flushes and night sweats. In the journal Fertility and Sterility in December 2005, the authors critiqued the study design and proposed two major reasons why the original authors of the study reached the conclusions that they did². The authors criticized the use of continuous combined estrogen/progestin or estrogen alone as a standard regime to an aging female population with little previous hormonal treatment, who because of their age were naturally predisposed to cardiovascular and cerebrovascular disease. The authors also criticized the use of continuous synthetic progestin or Provera, which is known to have significant side effects and has been linked to increasing rates of breast cancer. There are now over a hundred published studies indicating that estrogen can be safely prescribed to women with a history of breast cancer. The hormone estrogen when prescribed alone, rather than in combination with the synthetic progestin Provera, hasn’t been found to be harmful in any study to date. The hormone combination Prempro was to blame and more specifically, the synthetic progestin, Provera. 

Due to the premature termination of hormone replacement therapy, many women are being exposed to increased risks of osteoporosis and hip fractures, colon cancer, and increased risks of heart disease, strokes, and breast cancer. In the field of anti-aging medicine, we’ve been warning patients of the detrimental effects of synthetic hormones and have strongly suggested that women use bioidentical hormones instead. Restoring one’s hormones to youthful levels seems highly appropriate and is supported by scientific literature. It’s strongly encouraged that you begin to use hormones as soon as possible after menopause. You should also check with your doctor that you have no personal or family history risk factors for hormone replacement therapy before beginning your regime.   

Cathy, bearing this in mind I’d strongly suggest that you continue your hormone replacement therapy, but switch to bioidentical hormones and be sure to reach therapeutic levels. If your doctor prescribes hormones to merely relieve hot flushes and night sweats, and doesn’t reach therapeutic levels with your hormones, you’ll not be protected against the deterioration of your bones, brain, and cardiovascular system. In addition, your risk of colon cancer will increase. 

With regards to the weight issue, it’s well established that Provera, which is synthetic progesterone, can lead to significant weight gain. Sometimes physicians use synthetic progestin in cancer patients suffering from severe wasting to increase their appetite and reverse a condition known as cachexia³. I suggest that you switch to bioidentical progesterone and see if this makes any difference. Prometrium is a reasonable choice but I prefer sublingual slow-release progesterone, which is available from compounding pharmacies. 

I suggest that you also check your levels of estradiol. If the level’s too high, this may lead to weight gain. The suggested level is between 186-367 pmol/l. I also suggest that you have your blood level taken approximately twenty-four hours after your last estrogen dose, if you’re taking oral estradiol. This will reflect the ‘steady state’ level in your bloodstream. If you’re taking transdermal estrogen cream, you’ll need to do a saliva hormone test to measure estradiol, estriol, and estrone levels to more accurately reflect your levels at the surface of your cell’s receptors. Blood levels of estrogen do not reflect levels of estrogen when given in a transdermal form, a mistake made by many practitioners new to the prescribing bioidentical hormones. You’ll also need to test your urinary metabolites of estradiol to ascertain if you’re making the less harmful metabolites of estradiol, which is known as 2-hydroxyestradiol, as opposed to the potentially more harmful metabolites of estradiol known as 4-hydroxy and 16-hydroxyestradiol.

In a study published by the Oregon Health and Science University, scientists observed a group of forty-six pre- and post-menopausal women. The scientists reached the conclusion that the drop in estrogen levels commonly associated with menopause is linked to an increase in the stress hormone cortisol. This hormone is strongly linked to an increase in abdominal obesity. It was determined that if the women received therapeutic levels of estrogen, cortisol levels decreased and there was a reduction in visceral fat.

In addition, as we age, we lose muscle mass and there’s a corresponding decline in the metabolic rate. As a result, many perimenopausal and menopausal women who continue to eat the same amount of food that they did when they were younger find that with decreasing energy expenditure, they gain weight that’s difficult to lose. Find out if the gym or health clinic closest to you has a bioimpedance machine that can measure your percentage of muscle mass and ask them to track it over time. We routinely measure such biometrics at every visit when patients complain of weight gain or loss. 

Most weight gain during perimenopause and menopause is usually secondary to an increase in appetite. It’s well known that all hormones can significantly increase a person’s appetite. If there’s been rapid weight gain, this is usually due to fluid retention and brief use of a diuretic may be helpful. If your weight gain is gradual, it’s most likely due to an increase in appetite. 

It’s established that hormones have no caloric value. In fact, in a study in 1999⁴, the authors concluded that not only does hormone replacement therapy prevent weight gain, it also favours weight loss by significantly increasing the breakdown of fat after three months of treatment. It also positively influences the insulin/blood sugar response, plasma cholesterol, and energy expenditure.  

In another study published in 2004⁵, the authors determined that hormone replacement therapy in postmenopausal women, along with testosterone replacement therapy in older men, appeared to reduce the degree of central obesity. 

So Cathy, in conclusion I suggest the following:

  • Continue your hormone replacement therapy, but find a doctor who knows how to prescribe bioidentical hormones in therapeutic doses. 
  • Eat a low glycemic paleo autoimmune type diet with a decrease in the total daily dose of calories consumed.
  • Increase the amount of hot, spicy, bitter foods that you consume, as it has been shown in studies of Ayurvedic medicine that these tastes increase one’s metabolism. 
  • Concurrently, decrease your consumption of sweet, sour, and salty foods as these tastes have been shown to increase weight gain. 
  • Exercise five days a week with an exercise regime that includes significant muscle strengthening with large muscle groups, such as those in the legs, to increase your metabolic rate. 
  • Be sure to get a good night’s sleep as this naturally increases your levels of growth hormone, which has also been linked to weight reduction. 

If you’re interested in learning more about how hormone replacement therapy can affect or is affecting your health, then please don’t hesitate to read the other posts on the Hoffman Centre blog or contact my office to set up an appointment.

Resources:

¹JAMA. 2002;288(3) 321-333

²Fert Steril. 2005 Dec; 84 (6): 1589 -601

³Sem Oncol 1991: 18:35-42

⁴Maturitas 1999 Aug 16; 32(3);147 -53

⁵Obesity Review 2004 Nov; 5 (4);197 -216

Male Menopause is No One-Man Band

If all the hormones in the body work together like musical instruments in an orchestra, it means that male menopause is not only about low testosterone. The other players are also out of tune. If you’ve read about “male menopause”, you probably know about testosterone. In fact, in the first edition of Health Intelligence, a lot was explained about this hormone in the article “A moody man with no libido”. Dropping levels of testosterone cause many of the complaints of the typical grumpy man in the grips of a mid-life crisis. Indeed, if the hormones in the body work together like the instruments in an orchestra, testosterone is the strings, while estrogen is the brass section. If the testosterone level fades, estrogen begins to overpower and, before long, the whole orchestra plays out of tune.

So a better overall balance of hormones is required as a man grows older. The thing is, this involves not only testosterone and estrogen, but also all the other hormones. The challenge is noticing the discord when it starts, because the first few bad notes may be subtle and are often blamed on stress or simply getting older.

Sound Check

Men don’t usually come to the doctor’s once complaining about male menopause, also called andropause. The more common scenario is a fifty-something executive, slightly overweight, appearing exhausted and irritable, reluctantly showing up for a check-up. It was his wife, enquiring into her menopausal status the week before, who had mentioned to the doctor, “You know, I think my husband should come and see you. He hasn’t been himself lately. He’s grumpy. He lies down on the couch any chance he can get. He complains of vague aches and pains, and I can’t remember the last time we had sex!”

By asking a few probing questions, the doctor finds out that his symptoms were slower and more insidious in onset than his wife’s but, just as dramatic in their eventual outcome. Men traditionally tend to have a more stoic and fatalistic approach to encroaching signs and symptoms, but as an imbalance in hormone levels typically affects a man’s sexual performance first, this is often what propels him to seek medical attention.

The danger of ignoring all the other signs of declining hormone levels – those – offkey notes of the orchestra getting rusty – is that andropause is not necessarily a harmless, “natural” process. It often comes with major physical and mental changes that, over the long term, can have a dramatic effect on slowly developing diseases. But exactly what do these changes involve and when do they start?

Highs and Lows

Male menopause is a gradual shift in hormonal, physiological and chemical balances that occur in all men between the ages of 40 and 55, although it can occur as early as 35 and as late as 65 (1)

Incidentally, the term “hormone” is derived from the Greek word hormo, which means to set in motion. This is precisely what hormones do. Hormones are involved in almost every biological process, including sexual reproduction, growth, metabolism and your body’s immune response. It’s no wonder that the symptoms of andropause are so varied and widespread. Hormones stimulate, regulate and control the function of various tissues and organs and are manufactured by specialised groups of cells in your glands. These glands, which include the hypothalamus, pituitary, thyroid, adrenals, ovaries and testes, release the hormones into the body as and when they’re needed. But as men grow older, a slow change begins to set in.

The Slow fall

Hormone levels that decline as a man ages are:

  • Testosterone
  • Growth hormone
  • Melatonin
  • Dehydroepiandrosterone (DHEA)
  • Progesterone
  • Pregnenolone
  • Oxytocin

The Gradual Rise

Hormone levels that go up with andropause are:

  • Estrogen
  • Insulin
  • Cortisol

As mentioned before, testosterone is the strings in the ageing man’s orchestra of hormones – when it begins to fade, estrogen takes over. The detrimental effects of this drop in testosterone is summarised below.

Why Low Levels of Testosterone Are Dangerous

Studies have shown that too little testosterone in the ageing man’s blood is linked to:

  • Heart disease (2)
  • Declining memory (3)
  • Anxiety (4)
  • Depression (5)
  • Alzheimer’s disease (6)
  • Diabetes and metabolic syndrome (7)
  • Loss of muscle mass and strength (8)
  • Loss of bone thickness and strength (9)
  • A greater chance of dying from any cause (10)

The fears around testosterone replacement therapy and whether it may cause prostate cancer have also been laid to rest by definitive studies. (11)(12) But what about the effects of all the other fading players in the hormone orchestra?

DHEA

DHEA is a hormone made by the adrenal glands, gonads (testicles and ovaries), brain and skin in both men and women. It also declines with advancing age. By the time we are 70-80 years of age, peak levels of DHEA are only 10-20% of those in young adults (13)

As DHEA is the most important and abundant steroid hormone and the precursor of all other sex hormones, it serves extremely well to help restore many functions in the body. Low levels of DHEA are associated with ageing and most diseases of ageing.

Studies have shown that the dramatic age-related drop in DHEA levels is accompanied by an equally dramatic rise in heart disease.(14) It seems DHEA is incorporated into both HDL “good” cholesterol and LDL “bad” cholesterol and helps to protect both from becoming oxidised – a process that spells trouble for the heart and arteries. As our DHEA levels drop with age, less of this hormone is available to protect our cholesterol and the more at risk we are of developing heart problems.

It’s well known that cortisol, the stress hormone, harms the brain. But DHEA, due to its action in keeping cortisol in check, appears to protect the brain from these damaging effects (15)
Many of the diseases of ageing, such as heart disease, Alzheimer’s, certain cancers, diabetes and osteoporosis, are all linked in one way or another to inflammation. Studies have shown that DHEA is an effective anti-inflammatory and maintaining youthful levels of this hormone as we age may play a key role in protecting us from these in inflammatory diseases (16)

DHEA is also a mood modulator (17) One study showed that supplementing with 50mg of DHEA every night for six months in both men and women, aged 40-70, improved energy levels, quality of sleep, mood and the ability to handle stress (18)

How to Boost your DHEA Levels Naturally:

  • Eat a low-calorie diet containing less than 40g of carbohydrates per day
  • Exercise and meditate
  • Take part in creative, physical activities that reduce stress.

Growth Hormone

A drop in growth hormone (GH) as you grow older can also have a dramatic effect on your sense of well-being. GH has multiple protective roles and is responsible for our major growth spurt during puberty.(19) In adulthood, GH maintains skin, muscle and bone health. With a deficiency of this hormone, signs of ageing are quickly accelerated. Skin wrinkles and sags; fat soon replaces muscle. GH also helps maintain and repair the health of various organs, including the heart, lungs, liver kidneys joints, nerves as well as the brain. As growth hormone activates the calming, regenerative parasympathetic nervous system, a deficiency may result in increased tension, anxiety, depression and a decreasing ability to cope with stress.

From the age of 30 onwards, GH levels decline fairly rapidly, about 1-3% per year. This loss is quickly accelerated if you’re obese. The most efficient way to replace GH is through daily injection, similar to a diabetic insulin injection. Most anti-aging doctors will not treat GH in the first year of restoring optimal hormone levels, as a protein rich diet, adequate sleep and exercise programme, and the replacement of testosterone, progesterone, melatonin and thyroid levels, may increase GH levels by as much as 20-30%. Treatment with GH begins only when all the other hormone levels in the body have been brought back to normal.

How to Boost your GH Levels Naturally:

  • Supplement your diet with amino acids
  • Exercise daily
  • Make sure all the other hormones are at youthful levels
  • Eat a diet rich in proteins
  • Avoid alcohol, sugar, sweets, breads and pasta
  • Lose weight
  • Avoid milk products
  • Avoid sleep deprivation
  • Avoid prolonged stress.

Progesterone

In the third edition of Health Intelligence, we wrote in depth about progesterone replacement therapy for men, who typically produce between 1,5-3mg of this hormone per day. But as men age, progesterone levels fall exponentially. Progesterone is used in the production of cortisol, the stress hormone. So, if a man leads a particularly stressful life, it’s very likely he will have low levels of progesterone. This hormone is vital in keeping the higher levels of estrogen in aging men in check and thus minimising the risk of heart attacks, prostate enlargement and prostate cancer. If a typical dose of progesterone may lower estradiol levels – a cancer-causing form of estrogen – by up to 30%.(20) Progesterone also lowers the hormone responsible for causing hair loss and baldness in men, called dihydrotestosterone (DHT), while reducing water retention and possibly high blood pressure. (21)

How to Boost your Progesterone Levels naturally

  • Eat a diet rich in protein
  • Manage stress daily with stress reduction techniques
  • Supplement with herbs and nutraceuticals, such as Rhodiola rosea, siberian ginseng, liquorice root extract, ashwagandha and vitamins B5 and C.

Melatonin

Melatonin, the sleep hormone, is another hormone on which to keep an eye with advancing age. Signs that you may be deficient include light, restless sleep with many anxious thoughts, easy waking during the night, difficulty falling asleep and falling back asleep once you’re awake, bad dreams or poor dream recall, anxiety at night, depression (especially the winter blues) excessive emotionality and irritability, and restless leg syndrome with increased muscle spasms. You may also have intestinal spasms or cramps. Melatonin has a positive effect on the part of our nervous system involved in rest and relaxation. In particular, melatonin plays a part in slowing the release of adrenalin, so, without enough of it, the body reacts with a fight-or-flight response.(22) Melatonin may also improve your sexual performance, particularly enhancing serenity and relaxation after sex.(23)

Studies have linked a melatonin deficiency to hypertension, artery disease, heartbeat irregularity, obesity, diabetes, osteoporosis, lowered immunity with recurrent infections, breast and prostate cancer, and brain diseases like Parkinson’s and Alzheimer’s disease. Melatonin supplements should be taken at bedtime, either under the tongue or in pill form. It works best when you combine it with vitamin B6 and tryptophan or 5-hydroxytryptophan, which convert to melatonin with the help of vitamin B6. Interestingly, some asthmatics may react negatively to melatonin, so use with care if you‘re an asthma sufferer.(24)

How to Boost your Melatonin Levels Naturally

  • Increase your exposure to morning daylight (use a sunlamp)
  • Make the room pitch black at night, use an eye mask
  • Avoid alcohol and caffeinated drinks
  • Avoid stressful activities
  • Avoid electromagnetic exposures at night such as to cell phones or electrical clocks and radios
  • Wear turquoise coloured glasses 30 minutes before bed.

Pregnenolone

Pregnenolone is made from cholesterol and is the mother of many hormones, including DHEA, testosterone, estradiol, progesterone, cortisol and aldosterone.(25) In addition to functioning as a hormone, it also serves as a brain chemical, or neurotransmitter, in specific areas of the brain responsible for memory. Pregnenolone regulates the flow of calcium through the cell membrane, and this process determines how memory is encoded by our nerve cells. In addition, pregnenolone increases the levels of the neurotransmitter acetylcholine, the brain chemical responsible for creating memories, as well as assisting the main part of the brain that stores memory. (26) The most common complaints of men with pregnenolone deficiency include memory loss and joint pain, as well as dry skin and fatigue. Replacement doses are typically 30mg twice a day for memory loss.

You may choose to use other brain boosting nutraceuticals such as:

  • Acetyl-L -carnitine
  • Vinpocetine
  • Phosphatidylserine, combined with omega-3 fatty acids
  • Phosphatidylcholine
  • DMAE
  • G6PC
  • Huperizine
  • Vitamin D
  • Blueberries.

Oxytocin

Oxytocin, a hormone known to improve social bonding, is made by the pituitary gland in the brain. It helps us fall in love, spurs parenting instincts and intensifies orgasms. Studies have found that similar to women, men report an improved sexual response in all respects when using an oxytocin nasal spray, including stronger feelings of tenderness and closeness with the sexual partner before, during and after sex.(27)

Armed with information about the importance of youthful hormone levels at hand, there is no reason why men of a certain age couldn’t stay completely tuned into the music of life, no matter what their age.

The following Aspects Boosts Oxytocin levels Naturally

  • Romantic love
  • Hugging
  • Soft touching
  • Massage
  • Orgasm
  • Partner support
  • Singing
  • Physical exercise
  • Warm climate
  • Positive environment
  • Reading
  • Positive social contacts
  • Viewing pictures of loved ones
  • Living with others (cohabitation).

References

  1. Jed Diamond. Male Menopause Sourcebook INC. Naperville, IL 1998, 1v
  2. English K, et al. Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms. Eur Heart J. Jun 2000;21(11):890-4
  3. Moffat SD, et al. Longitudinal assessment of free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab. Nov 2002;87(11):5001-7
  4. Cooper MA. Testosterone Replacement Therapy for Anxiety Am J Psychiatry. November 2000;157:1884
  5. Margolese HC, et al. The male menopause and mood: testosterone decline and depression in the aging male–is there a link? J Geriatr Psychiatry Neurol. Summer 2000;13(2):93-101
  6. Gouras GK et al. Testosterone reduces neuronal secretion of Alzheimer’s beta- amyloid peptides. Proc Natl Acad Sci USA. Feb 2000;97(3):1202-5
  7. Laaksonen DE, et al. Testosterone and sex hormone – binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. May 2004;27(5):1036-41
  8. Bhasin S. The dose-dependent effects of testosterone on sexual function and on muscle mass and function. Mayo Clin Proc. Jan 2000;75 Suppl: 70-5
  9. Van Den Beld AW, et al. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density and body composition in elderly men. J Clin Endocrinol Metab. Sep 2000; 85(9):3276-82
  10. Gail A. Low serum testosterone and mortality in older men. J of Clin Endocrin and Metab. Jan 2008;93(1):68-75
  11. Morley JE. Testosterone replacement and the physiologic aspects of aging in men. Mayo Clin Proc. Jan 2000; 75 Suppl: S83-7
  12. Roddam Aw et al. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst. Feb 2008;100(3):170-83
  13. Genazzani Ad, et al. Might DHEA be considered a benefcial replacement therapy in the elderly? Drugs Aging. 2007;24(3):173-85
  14. O’ Donnell AB, et al. The health of normally aging men: The Massachusetts Male Aging Study. Exp Gerontol. Jul 2004;39(7):975-84
  15. Canning MO, et al. Opposing effects of DHEA and dexamethasone on the generation of monocyte-derived dendritic cells. Eur J Endocrinol 2000;143:685-95
  16. Straub RH, et al. Serum Dehydroepiandrosterone (DHEA) and DHEA Sulfate Are Negatively Correlated with Serum Interleukin-6 (IL-6), and DHEA Inhibits IL-6 Secretion from Mononuclear Cells in Man in Vitro: Possible Link between Endocrinosenescence and Immunosenescence. The Journal of Clinical Endocrinology & Metabolism. 1998;83(6):2012-17
  17. Cameron Dr, Braunstein GD. The use of dehydroepiandrosterone therapy in clinical practice. Treat Endocrinol. 2005;4(2):95-114
  18. Morales AJ, et al. Effects of replacement doses of DHEA in men and women of advanced age. J Clin Endo Metab. Jan 1994;78(6):1360-67
  19. Hertoghe T. The Hormone Handbook. International Medical Publications, UK. p54
  20. See reference 13, p247 
  21. See reference 13, p246 
  22. See reference 13, p47
  23. Drago F, Busa L. Acute low doses of melatonin restore full sexual activity in impotent male rats. Brain Res. 2000;878 (1-2):98-104
  24. Sutherland E, et al Elevated serum melatonin is associated with the nocturnal worsening of asthma. Jour Allergy Clin Immunol. 2003;112:513-17
  25. See reference 13, p144
  26. Schumacher M. Neurosteroids in the Hippocampus: Neuronal Plasticity and memory. Stress. Oct 1997;2(1):65-78
  27. Burri A, et al. The acute effects of intranasal oxytocin administration on edocrine and sexual function in males. Psychoneuroendocrinology. Jun 2008;33(5):591-600
  28. Herthoge T. Passion, sex and Long Life: The Incredible Oxytocin Adventure. International Medical Books, Luxemburg. 2009:103