Fasting, Hormones, and Men’s Sexual Health


Guest Bio 

Mark Holthouse, MD, IFMCP, is board certified from the Loma Linda University School of Medicine, later doing his family practice residency training through the USAF scholarship program at UC Davis Medical Center. Dr. Holthouse began studying integrative medical practice in the early 2000s and by 2006 had become certified by the American Board of Holistic and Integrative Medicine at Scripps in San Diego, California. Being part of the first cohort for certification in functional medicine through IFM in 2013, Mark has been teaching with the IFM faculty ever since. His passion for teaching has led further to his appointment as assistant professor of family medicine at his alma mater, Loma Linda University School of Medicine, where he continues to teach preventive cardiometabolic medicine. Dr. Holthouse has teamed up with other IFM faculty in developing a fellowship to train practitioners already certified in functional medicine in an apprenticeship program, furthering client education in applying functional medicine.? 


Kalea Wattles, ND: On this episode of Pathways to Well-Being, we welcome Dr. Mark Holthouse to discuss male hormone imbalances and how they affect men’s sexual health and function. We’ll explore the potential antecedents and mediators related to male infertility and erectile dysfunction and discuss how dietary interventions, including fasting and aromatase-inhibiting foods, can help naturally bring the body back into balance. Welcome, Dr. Holthouse. We’re thrilled to chat with you today. 

Mark Holthouse, MD: Super excited to be here, you guys. 

Kalea Wattles: And perfect timing, we’re heading into Men’s Health Awareness Month. So this is a great time to talk about some men’s hormonal issues and all the lifestyle factors involved. 

Mark Holthouse: Yes, it is. I’m loving it. 

Kalea Wattles: Well, we know that men’s hormonal issues, they aren’t always widely discussed. I think I’m guilty of this. But a large number of men certainly suffer from some form of hormonal-related dysfunction. To kick off our conversation today, can we discuss some of the factors that might lead to hormonal dysregulation? Specifically low testosterone levels, which is, I know, a real area where you focus on in your practice. What are some of the biggest lifestyle risk factors that might lead to low testosterone? 

Mark Holthouse: Yes, everyone comes in, and they want to know about optimizing their T, especially in this era of regenerative medicine. Everybody’s really wanting kind of their optimal version of themselves, whether it’s cosmetically, from a collagen perspective, or whether it’s internally, from an energetic or a steroidal perspective. I’m always surprised how little knowledge there is on some of the really basic things. People will come in, and they kind of just bypass all of this, right? They don’t really stop to think about the data that’s out there on just getting good restorative sleep with testosterone. And the fact that it’s pulse dosed at night with growth hormone, but only when you’re in these really deep stages of architectural sleep.  

So sleep is huge. I mean, we know we’ve gotta get seven, eight hours for general health. But I get these guys coming in and saying, “Well, I’ve never needed more than five hours, and I seem to be fine.” And I’m like, “Well, you probably aren’t. The data is pretty clear that you’re gonna do better with T if you get better sleep.” And then stress is right there. It’s the elephant in the room right now in our society. Everybody’s either stressed from home or work or both and just what’s going on in the world. And we know… I always say in my practice that there’s a couple things that are kryptonite to testosterone, and one of them is stress, cortisol. The other one is insulin, which we’ll talk a lot about today, I think. And so it’s just some of these basic factors of good quality life, work-life balance, having these basic discussions about sleep, about stress, about your family life, have huge impacts on the actual biochemical levels of this hormone. 

Kalea Wattles: That’s excellent. I read a study recently, I think it was a couple years old, where they had this group of college students, which is the group that I guess they could get to volunteer for this. And they did sleep deprivation studies on these college-aged men. And those who slept less than five hours per night, which they sleep-deprived them to make sure that happened, their testosterone dropped by 10 to 15%, which felt really profound, knowing that we have this population of men out there who are already walking around with lower testosterone and then having sleep deprivation for a variety of reasons. That’s a big deal. 

Mark Holthouse: Right, yeah. And in that study, this 10 to 15%, it didn’t take long to get there. It was the space of a week. 

Kalea Wattles: Exactly. 

Mark Holthouse: Of five hours or less. We saw those drops. And I always joke when I present this formally and say, “Wow, I’m really glad I didn’t know that in residency.” Because I could probably count the number of times I actually got five hours a night on one hand during those four years. But I think when we’re in our 20s and 30s, we have this resilience that we start to slowly lose as we get into our fourth decade, and all of a sudden the things that we were doing earlier, we’re starting to have payback, catch up with us. So yes, that’s a big one. And what’s surprising is how quick it happens, right? It’s not a six-week process of deprived sleep. It’s very rapid. 

Kalea Wattles: 

Absolutely, you may have already answered this, but I’ll ask it in another way, just so that we can tie a bow on it. We know that a patient’s age plays a role in how their hormones fluctuate across the lifespan. And we see this decrease in testosterone as we get older. Can you map out for us the ideal lifestyle factors for optimizing men’s health from puberty into those later years? Is it the same things you’ve just talked about: sleep, stress management, managing insulin? 

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Mark Holthouse: Yes. Sleep is huge. We’re learning so much about internal biologic clocks and circadia, not just with cancer risk but of course steroidal biology. In addition to stress management and sleep, probably the biggest two factors that I find myself talking with patients most days is around insulin resistance syndromes. And because of the associative data that we see with low T, we don’t have enough studies that are powerful enough as far as duration or the number of people enrolled in the trials to have causality. But we’ve got incredibly good associative data with epidemiological evidence now. And when we talk about the Australian study of two years duration, which came out last year, pretty impressive how we can see, actually, differences in people treated with low testosterone versus placebo in preventing progression from prediabetes to full on type 2 diabetes. These are earth-shaking concepts when you think about this. We do need longer clinical trials, but I envision a day in the not too distance future where we might be talking about TRT after we’ve done some of these lifestyle things as a therapeutic option, in addition to NAC or berberine or even metformin with some of these folks to prevent problems.  

But as far as primary prevention and just good lifestyle, to answer your question, Kalea, it really is weight loss. It really is maintaining a body composition that maximizes fat free mass and lean muscle and minimizes abdominal obesity. I think that’s probably when you look at the lion’s share of the data, as with hypertension, right? Weight loss and, in particular, fat weight loss is your number one objective toward a natural approach to raising T. Right there with it, though, and associated, it’s hard to tease these two apart, are these Met Syn, these prediabetic, these impaired glucose folks that we see all week long. Those are the number one and two that go hand in hand with good sleep, stress management. Those are my top four.  

If you were to put a fifth one in there, I would say definitely strength training and HIIT, not just going on a stair climber and watching TV and then waking up every few minutes realizing, “Oh, I’m exercising.” No. I mean HIIT, where you’re doing Tabata drills. And not long durations. And not every day. You’re doing that with specific muscle group strength training, whether it’s a group, whether it’s individual, just make sure that they know how to do it and that their form is down so they don’t injure themselves. Because then they’re six month immobile trying to nurse an injury. And most of these are middle-aged guys and they’re trying to act like they’re 20 still, right? And so they damage their shoulders doing military bench press like they did when they were 30 years younger. So the fifth one has gotta be building that composition. And I always say, it’s not from diet that you’re gonna build muscle, it’s from exercise. Along with that, I’ll say, you’re not gonna lose weight necessarily by exercise, that’s more about time-restricted eating and food. We know from data that’s how you’re gonna lose weight, but you can’t Muscle Milk your way into an improved body composition without exercising. 

Kalea Wattles: That was a pretty good sound bite there. We have these Mark Holthouse pillars of healthy testosterone, healthy body composition. And this is the perfect lead in to my next question, because I think we naturally associate low testosterone and erectile dysfunction with older men. But now we’re seeing younger and younger men who are reporting low testosterone, erectile dysfunction. And we see this relationship with prediabetes in this population. So when you have younger guys who are coming into the clinic and they have low T and they have erectile dysfunction, is that a red flag for you to think, “Wow, I really need to focus on metabolic health in this patient as well?” 

Mark Holthouse: Kind of the first thing I look at, right? We know now the most common cause of chronic liver disease in the country is fatty, non-alcoholic fatty liver disease. And there’s this association between fatty liver disease and cardiovascular events, and there’s an association between fatty liver disease and low T and insulin resistance syndrome. So it is truly a syndrome, which continues to grow arms. And that’s the exciting part for me. When they present, you’re looking at fasting insulins, but you don’t even have to go that deep. You can look at their triglycerides to HDL ratio. If it’s over two and a half, regardless of what their uric acid’s doing or their impaired glucose, you already know this person’s metabolically heading toward a prediabetic scenario. And it doesn’t take a lot of effort to just check that GGT box, and now suddenly, okay, this is a person who, whether or not their AST and ALT on their liver is abnormal, they’re showing signs that the liver is in trouble. And there’s this fatty liver disease that occurs from insulin resistance. And now we’re seeing these associations between all three of these scenarios.  

ED is the most complex discussion in, I think, all of men’s health, simply because it involves every bit of the matrix, every node of imbalance, from psychiatry to neurology to endocrinology to toxicology and hormones, the communication part that we talk about so much. So yes, when they present like this, especially my 20 and 30-year-olds, which I’m seeing more of, I have a real burden for them, because they’re in the prime of their life, they shouldn’t be suffering low libido. I’ve got these guys coming in at 25 and their wives sitting next to them looking at me, kind of with their hands in the air, going, “What’s wrong, is it me? Am I not attractive?” All this stuff starts happening. So it really has far reaching implications.  

But yes, one of the first things we do is we look at things like triglycerides, their basic lipid panels. These are things you don’t need a myeloperoxidase or even an oxidized LDL and these advanced cardiovascular markers to really see when there’s a problem. And they’re easy to address when you deal with functional medicine, because down the hallway, you’ve got your RD. You’ve got your coach that can deal with their mito nutrient, mito-keto plan, their tapping or their Heartmath addressing their sleep, addressing their stress. So yes, that’s one of the first things we go after in these guys is their insulin resistance, their abdominal obesity, and we get them on a lifestyle plan. 

Kalea Wattles: This is where functional medicine really shines. 

Mark Holthouse: It rocks. 

Kalea Wattles: We’re addressing all those nodes of the matrix and all the modifiable lifestyle factors. You mentioned that insulin resistance is one of the risk factors for decreased testosterone levels. And then we know that testosterone in men helps to regulate glucose metabolism. So it seems like there’s some bidirectional communication going on here. When you start treating your patients with the lifestyle factors and improving their insulin sensitivity, do you see testosterone improving even without giving testosterone replacement therapy? 

Mark Holthouse: Absolutely. In fact, we have a shared group medical class that we offer at my practice. Part one is how to raise T au naturel. And that’s what we do. We talk about all of these lifestyle factors, and where I really see it is on the body composition. As they start building more lean muscle, and their percent body fat, in particular their visceral fat on the BIA machines, drops, you see their Ts have this inverse relationship where they start to climb. And it’s not uncommon to see improvements of 40, 50% in both total and sometimes free testosterone as well. And so that’s really empowering, because they came often wanting a prescription. And then when they leave, and after attending our therapeutic lifestyle classes and eliminating things and going through a five R kind of gut rehab repair, because we know that they have low T with metabolic endotoxemia, they’re amazed. They’re like, “Oh my goodness, I don’t have to be on testosterone the rest of my life or Clomid or HCG and some of these other things.” They’re very excited about that. But we see dramatic improvements from, I would say, 30 to 50% increase on average. 

Kalea Wattles: That’s really significant. 

Mark Holthouse: It is. It is the intermittent fasting, time-restricted eating is amazing. The question to be answered is, is it other things that we know time-restricted eating is inducing at a mitochondrial level that’s causing this? Or is it the fat weight loss? Or is it something else? We don’t know where and all of the mechanisms yet, but these are the practices that we can be putting in practice in our clinics every day right now that are free, essentially free to these folks, they don’t have to buy a cuisine, that have these kinds of impact. 

Kalea Wattles: Well, you’ve opened the nutrition door. So now I’m gonna go through it. It’s time. I’m so excited to talk to you about this, because I know that this is, as you’ve mentioned, a real important area where we can engage a collaborative care team and really focus on those lifestyle factors, which are foundational to all the work that we do. And you’ve mentioned a little bit, just a moment ago, about the gut connection. And before we move on, I have to dive in a little bit here, because we know that nutrition can impact hormonal signaling in the gut. And you talked a little bit about intestinal hyperpermeability and how that might be related to systemic inflammation, which affects hormonal health. Can you tell us a little bit about any connections, any talking points, dysbiosis, and how that affects our hormonal health? What’s that gut hormonal connection from your perspective? 

Mark Holthouse: Absolutely. One of the most exciting days of my life, okay, I’m exposing the geekiness about me here, was when I heard Joel Evans talking on the female side of things, saying how lipopolysaccharides on the cell wall of bacteria when they translocate across the gut and induce TNF-alpha and IL-6, these inflammatory cytokines in the systemic circulation drop progesterone in women. And I almost stood up and wanted to jump off the table and say, “Oh my gosh, I’ve just been reading about that happening in men with T.” So yes, you’ve got this connection that is very, very real, especially in overweight and obese men, the gilding theory. And this has really gone beyond a theory now, where you’ve got leaky gut or permeability issues that lead to this translocation of bacterial components that aren’t supposed to be in there causing systemic generalized inflammation with cytokines that both directly inhibit testosterone production at the teste and centrally at the hypothalamic level with gonadotropin-releasing hormone. So I can’t have a conversation anymore with my premenopausal females that are having dysfunctional bleeding or estrogen dominance, or with my guys that are having low T, without talking about gut. And it’s funny, cause they’ll come in and say, “Well, I just came in cause I wanted you to check my hormone levels. I don’t know why we got on the gut conversation and talking about stress and neurotransmitters. How did we get there? Because I came for testosterone and estrogen discussions.” So it’s fun to bring those together. 

Kalea Wattles: Thank you so much for showing us how the functional medicine matrix is all interconnected. We always say that, right? Like, this is all a web and you tug on one part of the web, and there’s this whole downstream effect. So I love the way that we’re always making those connecting points for our patients. As we’re moving into this nutrition and hormone conversation, I wanna talk to you a little bit about aromatase inhibitors and food sources of aromatase inhibitors. Would you mind just giving our listeners, number one, a little refresher on what the aromatase enzyme does and then how you might affect that pathway with lifestyle and nutrition? 

Mark Holthouse: Absolutely, so aromatase, as you guys probably know, it’s found in fat tissue in plentiful supply. But it’s in the skin, it’s in the brain, it’s in many different tissues of the body. And its primary job is to convert testosterone into estrogens. We know that estrogens don’t really ever go backwards to make androgens but that aromatase is causing that arrow to go toward the estrogen direction. The issue is interesting, because a lot of people will come in saying, “I feel low in T.” And really what they need to be asking is, could your lifestyle be metabolizing your existing testosterone away, either to estrogens or another enzyme, five alpha-reductase, toward another form of testosterone, which is really, really highly potent and we only need tiny, tiny little bits of it to be in balance? 

So when I look at aromatase, in particular, we know that things like zinc deficiency, oxidative stress, and deficiencies in things like resveratrol and quercetin and these things from brightly colored plants, when we’re deficient in them, actually can harm our balance and stimulate or upregulate aromatase. In addition to some things like stress, wow, we heard that this morning already, couple times, leptin, insulin, stress, and cortisol, also things like insulin resistance and inflammation. So it’s ironic that the very lifestyle things that we have to address like that, the plants, we kind of take it for granted. We just say, “Eat from the rainbow,” right? And we kind of forget why we say that. But it’s all these phytonutrients and these sterols and these antioxidants that are having these effects at a cell and molecular level that literally are helping enzymatic dynamics, either for or against balancing our hormones.  

So I always look at this discussion as buckets, right? You have things coming in to make testosterone. And we know DHEA is that precursor. And then you have the exit points from testosterone, away from T leading to estradiol and dihydrotestosterone. And all three of those way stations are controlled by different enzymes. But the thing that’s the common thread between the 17,20-lyase that brings things in and the five-alpha-reductase and the aromatase that take things away are this common thread, right? It’s inflammation, it’s hyperinsulinemia, it’s stress. And wow, if you address those three things, you’re gonna make more T and you’re gonna limit how fast it gets metabolized away. So people, when they hear that, they’re like, “Wow, what do I do to affect those enzymes?” And then yeah, you start talking about these magical foods. We talk about resveratrol, and we talk about micronutrients, and we talk about phytonutrients, and then all of a sudden, they go, “Oh, that’s why you want me to eat six to nine servings of plants.” Suddenly it’s, the light comes on. 

Kalea Wattles: Indeed. And isn’t it interesting? I just have to point out that all of these things you’ve just mentioned for helping us maintain our testosterone pool, stress management and reducing inflammation and zinc and quercetin and resveratrol, are the very same things that help us cultivate resiliency in our immune system, like, our bodies know what they’re doing. 

Mark Holthouse: They know what they’re doing. And when you start looking at these patterns, you start seeing where these same chemicals are being used from plants, mostly, but everything in multiple areas of regenerative medicine, in mitochondrial uncoupling, in anti-aging, in steroid health, in cognitive health, it’s endless. But there’s this common repeating theme of a blueprint there. And you’ve got like these players of things that keep showing up. How do you get rid of leptin resistance? Well, it’s kind of the same way that you treat inflammation and insulin resistance. And yeah, it just goes on and on. Anti-aging, you know? 

Kalea Wattles: Yeah, you mentioned aromatase activity in fat cells, which leads me to conclude that if we have a patient who needs fat loss, that’s another way that we can control that conversion of testosterone to estrogen. So I know that one of the ways, strategies you utilize for fat loss is fasting. So I’d love to talk with you a little bit about fasting, because it’s been shown to favorably alter metabolic patterns. And for the sake of our conversation today, we also have some research showing a positive benefit for male libido, male sexual function. Can you talk a little bit about the mechanism of how fasting regimens may support male hormone regulation? 

Mark Holthouse: Yeah, it’s an evolving discussion, because so much of it’s been focused on weight loss, right? We have Valter Longo’s work at USC. We have Stephen Phinney at UC Davis, PhD. Jason Fung, of course, with a lot of his work as a nephrologist, getting frustrated with folks showing up in end-stage kidney disease and realizing that a dietary intensive could prevent a lot of what he’s seeing. I think the most profound piece of this has to do with what I’m really excited about in my kind of latest area of focus, and that is mitochondrial uncoupling and how ketones work. What we got wrong with ketogenic diets and what we thought was why they worked as somehow a preferred source of fuel, when in fact they’re probably more of a signaling molecule to the mitochondria to kind of uncouple, as we call, make heat instead of ATP and anti-oxidize, upregulate our longevity and anti-aging, sirtuin 1 and other genes like this, in addition to kind of taking a break and, “Oh, by the way, let’s stimulate more of us, mitogenesis. Let’s just make a whole bunch more mitochondria while we’re on vacation in our uncoupled states.”  

So when I learned that intermittent fasting, as well as polysterols, phytosterols and plant sterols, polyamines in aged and fermented foods and cheeses and things like this are loaded with these molecules, which uncouple mitochondria, and the red light there being the cold, all these things that are uncoupling, it started to kind of all come together. It’s like, “Okay, where are we making our hormones?” In the cell, you know? And the cholesterol comes into the mitochondria. You’ve got endoplasmic reticulum involved, of course, with packaging, but the intermittent fasting pace became so much more than just a body composition issue where we’re preferentially losing subcutaneous and intra-abdominal fat, which we know is directly related to improving T. But then you throw in this added information that’s coming out regarding uncoupling and how intermittent fasting, time-restricted eating is a signal in our cells to do this. It’s pretty exciting. So the mechanisms are really still being worked out.  

What we do know is that there is this direct association with body composition change. And intermittent fasting does it as well or better than bariatric surgery. We’ve got data to show that, without the side effects and without the cost and the invasiveness, of course. We also know that it is antioxidative. And it has this anti-aging longevity piece. Caloric restriction, in general, with mammals we know stimulates these pathways. But who can calorically restrict long term? And who wants to do chronic calorie restriction? We know from the studies published in the Obesity journal, 2016 on The Biggest Loser show, eight television season premieres, only one person kept their weight off. So we know that limiting calories to a certain degree, a deficit every day, all the time, eventually doesn’t work. We’re just hardwired to drop that BMR and sustain.  

We know that if we restrict everything for a short period of time, as we do with time-restricted eating, the results are profoundly different. So if you look at isocaloric studies in rodents, and now in humans, where we take the same amount of calories per day and we simply put them in a smaller time window over a traditional feeding of three times a day, the results on body composition change and weight loss, and by association improvement in testosterone, are profoundly different. I think mechanistically, it’s the great unknown. We’ve got a few issues coming to light, I think, mitochondrial uncoupling and how that relates to the electron transport chain is probably going to be one of the biggest areas of study as far as membrane physiology. 

Kalea Wattles: Well, every time you speak on this subject at our Hormone Advanced Practice Module, it’s so compelling that people always want to know, “Okay, I wanna use this in the clinic.” What type of patient is a good candidate for a fasting intervention? Are there any subsets of patients for whom fasting is more appropriate than others? 

Mark Holthouse: Really good question. And there’s some great.. YouTube can be scary, these podcasts, but sometimes you get addicted to these things and you see the next one coming up, “Oh, I wanna see that one too.” And at some point, you have to kind of vet these folks. But some of the better presentations that I’ve seen from some nurse practitioners of late really highlight, and I’m gonna just keep, because we’re talking about hormones, I think, premenopausal women, which is right up your alley, one of the things that is kind of like the perfect candidate for time-restricted eating is kind of the, I don’t know, the 25 to 60-year-old male who wants to lose weight. But I would suggest also in women, in particular, post-menopausal. Obviously, skeletally immature kids, there’s some real controversy there, because it’s been a contraindication just like it has been in pregnancy and in breastfeeding, obviously anyone with an eating disorder or active cancer treatment, things like this that are more intuitive.  

What’s really gonna be tough, I think, is our little adolescent kids that are 12, 13-years-old and they’re developing type 2 diabetes and other forms of diabetes, they’re morbidly obese, and yet they’re skeletally immature. I think under medical guidance, there’s definitely a place for that subpopulation. So we have three parts to my intermittent fasting shared group medical class in the clinic. One is just basic. Two is, “Hey, what’s happening? I’m plateaued. This didn’t work like you said it would.” It’s kind of a troubleshooting, part two. Part three is special populations.  

So in our part three, we talk about skeletally immature obese kids. We talk about premenopausal females. I think it’s really important that we don’t treat them like we do everyone else, because one of the things that occurs with time-restricted eating is we have these counterregulatory hormones, right? The goal is to lower insulin, because we know the weight is controlled by hormones, and calories kind of have a secondary goal with weight control. We have insulin as the prime villain. And so we know in a post-fed state, when insulin’s high, we cannot bring in peripheral fat stores to the liver to have beta oxidation and burn fat. It just won’t happen. The only mechanism that still occurs in a post-fed high insulin state of burning fat is one that has to do with epinephrine and norepinephrine, which ironically, testosterone has an instrumental role in the peripheral adipocyte. That’s independent of insulin levels. But everything else, whether it’s glucagon, whether it’s cortisol, whether it’s some of these other mechanisms of being able to mobilize peripheral fat, is dependent on where insulin is.  

And so that’s why eating so frequently, especially in our diabetics, is the worst thing we could be telling them to do. What I like to say is that in premenopausal women that are stressed, maybe they’ve got some kids, their cortisol levels are already running high. These counterregulatory hormones that are a player along with lowering insulin with intermittent fasting become important. So counterregulatory, what do I mean? Well, when we go into a fasted state, there is a slight bump in cortisol. We know there’s a slight bump in glucagon, as well as growth hormone. It’s that bump in growth hormone that prevents us from burning, basically, our structural protein. And that’s one of the myths Jason Fung is so famous for busting in his book, that we’re going to lose muscle somehow when we fast or time-restrict in our eating. We just don’t do that because growth hormone compensates for that by promoting fat loss and inhibiting the breakdown of protein as a source of glucogenesis, making new glucose. So the saying is that you’ve gotta have at least 4% body fat or lower before you start dipping into burning structural protein. Which, well, I don’t have any patients at 4% body fat. So I tend not to worry too much about that.  

So in these premenopausal females, what I say in particular is, if you’re in a state of stress, let’s deal with that first. If you’re a single mom who’s gone through some things and has got kids, you’re homeschooling, you’re trying to juggle all these things, the last thing I want to do to them is make their adrenal more stressed by promoting a hyper cortisolemic state, which does what? It promotes inflammation. It promotes belly fat. It does all the things we don’t want to do. So as a general rule, I have them deal with their adrenal, their thyroid, kind of our triage that we do in our module first before getting to some of the other hormone talks, But I will say that it’s that third week of their cycle, the week before menses, think about what women talk about. “I’m craving carbs. I can’t stand him. I don’t know what he did, but I just want to strangle him.” There’s this dysphoria. There’s these things that are preparing the woman’s body for a gestation, pro-gestation, progesterone. The luteal phase is all about the next generation and setting things up. And if we come in there and really aggressively ask them to start a time-restricted eating program, I think that’s a fallacy. And so in my special populations conversation, we have this little caveat of, in your 21st day of your cycle, your third week, really back off a little bit on how rigorous you’re being with your time-restricted eating. Check in with your body. How are you doing mentally? Give yourself some space. That one week out of the four is not gonna derail the benefits you’re gonna get the other three weeks. So there are some subpopulations outside of the hard and fast contraindications with regard to doing this. 

Kalea Wattles: Well, that was a very eloquent way to say this is personalized medicine. 

Mark Holthouse: It is. 

Kalea Wattles: Really, it is. 

Mark Holthouse: It is. 

Kalea Wattles: Now, along those lines in looking at what works for different subtypes, it seems like some folks will get a real benefit from just a 12-hour fast, even, where others see a more benefit from closer to 18 hours. Do you have a way of predicting which people need a longer fast, and what patterns are you using in your practice? 

Mark Holthouse: Yes, your, excellent question. We know that even a 12-hour period of not bumping your insulin has huge benefits. If you go to 14, there’s a little more, 16, a little more. Somewhere between 16 and 18, you’re probably peaking there. I have some people who are just gung ho. And they wanna do what we call OMAD, one meal a day. And I try to just pull that reign back a little bit and assess where they are. The folks that in triaging, who does what, when, that I really am concerned about are my prediabetic patients, right? These are the ones that have what we call a lack of metabolic flexibility. The ability to adapt on the fly between utilizing sugar versus fats as their primary energy source. And as we go to sleep every night, about four hours into things, the glucose supplies are starting to dwindle a little bit, and we’re already doing a little bit of gluconeogenesis from amino acids and from glycerol from fats already every night before the alarm clock even goes off.  

So in my prediabetic, insulin-resistant crowd that I know is struggling with this flexibility problem, what we do is we usually say, push your breakfast out by no more than an hour over a week or two. If they push it out from seven to eight, eight to nine, nine to ten, so forth, after about five weeks, they’re gonna be out there to about midday for their first meal, where they’re breaking their fast. And we know that that four hours that they’re adding from 12 hours of fasting to 16, all they’re doing is just cranking up the ketones. And we know that as free fatty acids come to the liver, some of them become these magic molecules, these ketones, which are these, we think, now, signaling molecules to uncoupling. So I’m very careful with my prediabetics, people that take, oh, wow… How do you know you have metabolic inflexibility? Well, they’re gonna have glucose, impaired glucose tolerance. They’re gonna have high fast insulins and resistance and these things on their lipid panels, triglycerides to HDL ratio greater than two and a half. But they’re also gonna say, “I get really shaky and tired and sweaty and kinda can’t concentrate around 10 o’clock in the morning unless I eat something. I have my secret stash in my desk.” Boom, that’s a giveaway. These are folks that are overly dependent on glucose as their primary way that their body keeps their serum glucose stable. They’re not very adaptable at grabbing it from glycerol. Grabbing it from proteins. So those are the ones that I’m really cautious about. In those very same people, you can stack the deck with most of your calories for the day in time-restricted eating, either at noon or at dinner, or at breakfast and at dinner. And I prefer for those whose schedules can accommodate it. I could never do this. I’m seeing patients at 10 and at two. But for these prediabetic folks, we know there’s probably a slight advantage if they front load the day with their calories in their time-restricted eating window, so that maybe they’re eating breakfast at seven, having a midday meal at 10:30. And they’re finishing their food for the day by three. And they go all the way around again till 7:00 am. It’s hard for most of us that work to do that. So by default, we end up doing this 16:8 where the eight hours is from one o’clock to seven or so. But I’m really quick to say, 12 is great. If that’s all we can do, that’s incredible. We’ve got data that shows you’re gonna becoming adapted. I hate to say the word “keto-adapted” because it conjures, I think, some old data and ideology. But it is a flexibility issue that they’re gonna develop, whether they do 12 hours of fasting or 16 or 18 a day. 

Kalea Wattles: That’s super helpful. And selfishly, as a clinician, I have to ask, when you’re assessing response to treatment in terms of labs, how often are you repeating lipid panel, fasting insulin, hsCRP to see what’s going on with someone’s metabolic health? 

Mark Holthouse: Yeah, it kind of depends. If they’re a fragile diabetic type 2 already, probably a little bit more frequently. As I’m implementing these things, if they’re insulin requiring, if they’re on antihypertensives, I’m seeing them every few weeks and I’m talking to them, either via my MA or myself, several times a week, as we’re doing this under really close confines. If it’s someone that’s prediabetic, maybe they’re on metformin already, maybe they’re not, where we have a little looser leash, on average, I’m making these changes for the average person who’s presenting, and I’m looking at things, probably no sooner than eight weeks out. And at around eight weeks is when we’re repeating from that baseline bioimpedance test. I want to see at two months what’s going on with body composition. 

So the things I look for are visceral adiposity and percent body fat and percent lean on a BIA. And I’m monitoring very closely, assuming that their thyroid panels were normal at baseline, I’m primarily looking at things like leptin, fasting insulins, and just sometimes a basic lipid panel, cause I wanna see what’s going on with their triglyceride to HDL ratio. You notice I’m not talking a lot about LDL, which is maybe this subject for another day about what I think about LDL and its actual relationship to coronary artery disease. Or is it a case of mistaken blame? So what we look at primarily, though, are those markers of fatty liver, GGT, ALT. Yes, and fasting glucose, insulin, leptin levels, and just basic lipids. I don’t go after Lp-PLA, myeloperoxidase. I’m not looking at the oxidation of LDL with these patients every time. If they have a dramatic dyslipidemia and I’m really concerned about their cardiovascular risk, yes, I’ll throw in things like CIMT for artery aging, coronary artery calcium scores, and things like that to look at their overall cardiovascular risk as we’re dealing with their muscle mass, their weight loss, and their insulin resistance markers. 

Kalea Wattles: That’s really insightful. And it sounds like you’re doing a bioimpedance analysis with most of the patients that come in for your group classes. 

Mark Holthouse: I am, what I tell them is, “The weight is really deceiving to me,” you know? I say, “I don’t care what you weigh. I wanna know what you’re made of.” And that gets a little smile on their face, and they’re like, “Oh-oh.” And I say, “No, really what I mean is, I don’t care what your weight is, because that doesn’t mean much, even the BMI.” I laugh and say, “It’s really a marker for insurance sales people. It’s an actuarial for insurance companies.” It doesn’t have as much to do with health, because the BMI doesn’t take into account muscle or frame size. And so I get these big football players, they’re like a ball of muscle. And the BMI says they’re obese, every time. And they’ve just learned to kind of blow it off. And I say “You know what? I’m not even gonna look at the BMI. We’re looking at these other things: visceral adiposity. We’re looking at percent body fat.” And that is something we do serially depending on how much cheerleading they need.  

Sometimes we’ll come in once a month while they’re doing this. Some of them will plateau at about month three. So I’m careful to get them in somewhere between that second and third month to make sure that I’ve really helped them work through some of their frustrations. “I’ve got constipation, this thing’s giving me headaches. What about dehydration? What about feeling cold, tired, and hungry?” Which is, that’s the trio that I say, “If those three amigos show up, you have now gone into the realm of decreasing your BMR.” And I can show them that on their thyroid studies, because their reverse T3 goes through the roof. It’s usually transient if they’re doing enough calories per day in their window. If they stay below and they’re eating 500 calories below their BMR, you’ll see that reverse T3 just stay up there. And eventually they give up because they feel so badly. They’re weak, they’re tired, they’re cold, all the symptoms that we know and identify as a low metabolic rate. And that’s what we’re trying to avoid. 

Kalea Wattles: Gosh, Mark, I feel like we need a whole additional hour to talk about all of this stuff. There’s so much to talk about. But for the sake of time, I’m going to ask one more question that I think is really important, because everything that you’ve said today, anyone who’s listening I think understands how important it is to address those modifiable lifestyle factors, the nutrition piece. If someone is new to functional medicine and is thinking, “Wow, I really need to start somewhere,” what’s a piece of advice that you have to get us started if we’re ready to make that debut into the world of initiating these functional medicine, the functional medicine operating system? 

Mark Holthouse: To make it pragmatic, and this sounds like an infomercial, but it’s nice having the IFM Certification, it’s nice having the IFM Membership, because really this is a toolkit issue. I always, in fact, just yesterday I was having this conversation with my medical assistant, I gave her my login credentials to look at my IFM toolkit. And she was scrolling through this thing going, “Oh my goodness, this is a treasure trove.” And I said, “Right, you don’t have to reinvent the wheel. This stuff is all here.” So if I were just starting out and I had an interest in hormone health or cardiometabolic health, the first thing I would do is I would get access to the toolkit so I don’t have to spend my family time branding all of this stuff that my patients are gonna need to hear over and over and over as I go work through my day of patients.  

The second thing I do, I’d invest in a BIA machine. It’s so much more value and so much more information for the patient than just weight and even BMI. To be honest, I can’t do my hormone practice, I can’t do my cardiovascular practice any longer without those two tools. And that sounds maybe funny to some, but that’s where the point I’ve come to. Keeping it simple. Not overthinking what you need to know before starting. Pick a point you’re comfortable with and get really good at talking that point with your patients. They will talk to their neighbors, friends, and family, and you will have a full practice. And what’s better, it ends up being a practice full of the people that have things that you are really becoming good at doing and you love doing. You get to the end of the day and yes, it’s emotionally exhausting, but man, you feel full because you’re doing what you love to do. And each of us in functional medicine gravitates toward the areas naturally that bring us that joy. Do I like talking about biotoxin mold? No, I don’t like talking about detoxing all the time. However, I find myself talking about it a lot in the context of inflammology, right? We’re all inflammologists. And so, yeah, that’s what I would say on my takeaways. 

Kalea Wattles: Very good. Well, thank you so much for your insights today and really helping us understand how hormonal health, gut health, mitochondrial health, our biotransformation mechanisms, it’s all connected. And that’s where the, really the beauty of the functional medicine approach. So really appreciate you being with us today. Was great to chat with you. 

Mark Holthouse: Super fun. Thanks for having me. 

Kalea Wattles: To join the conversation on this topic, visit IFM’s pages on Facebook and Instagram. For more information about functional medicine, visit IFM.org. 

IFM’s Intermittent Fasting: Therapeutic Mechanisms & Clinical Applications course provides an evidence-based overview of several of the fasting methods listed above and outlines potential contraindications and points of personalization for each patient’s unique health needs and goals.