fertility

Chronic stress, appetite suppression, control and metabolic inflexibility.

It was the famous stress scientist Hans Selye who suggested that stress can be a positive or negative force. But how do we know whether we are dealing with stress effectively? There’s a common theme among clients both male and female who have got used to feeling in control of their health by suppressing appetite, symptoms and a false sense of health by perhaps feeling in control. Is this control a false economy? A well-known symptom of stress is a loss of appetite and skipping breakfast, it feels better to perpetuate the production of stress hormones like adrenaline and cortisol to liberate energy from stored fats and stride through the day with their endorphin like qualities. A common theme of females suffering from poly cystic ovary syndrome (PCOS) is chronic irregular eating or over eating in the obese. High stress can be chronic and perceived as the norm. I’ve observed the former in my eldest daughter through under eating as a product of emotional stress

‘For those habituated to high levels of internal stress since early childhood, it is the absence of stress that creates unease, evoking boredom and a sense of meaningless. People may have become addicted to their own stress hormones, adrenaline and cortisol, Hans Selye observed. To such person’s stress feels desirable, while the absence of it feels like something to be avoided.’ Gabor Mate

It should come as no surprise why some studies suggest that short term fasting, and calorific restriction seem to be productive in reversing aspects of inflammation and auto immune disease. When the body is stressed even eating certain foods becomes stressful. Dairy, sugar, fruits, grains all get the blame. I feel better when I don’t eat these some say. I feel better when I don’t eat others say. Is it the food or is it you? Can you be so fragile that eating some fruit for example is enough to send your biology into a tail spin. Eating sugar in excess can be problematic but then so can eating fat or anything in excess.

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A foundation of good health is built upon biological flexibility, potential and far away from equilibrium states.

The inability to utilise carbohydrate is a snapshot of the inflexibility of an individuals’ metabolism and not the carbohydrate. Evolutionary biology has provided efficiency by aerobic metabolism of carbohydrate and fat. The loss of efficient use of carbohydrate/sugar is the hallmark of a loss of function or flexibility and the chronic use of fats as a fuel is problematic due to increased oxidation of these lipids which can damage the aerobic apparatus within the mitochondria. The Randle cycle or glucose fatty acid cycle should allow flexibility between using either fats or carbohydrate as a fuel (Randle, Garland, Hales, & Newsholme, 1963). It’s often the lack of flexibility, decreased oxidation of carbohydrate and perpetual use of fats that damage the energy producing cells. Saturated fats are the preferred fuel of aerobic (oxidative) metabolism but in aggressive metabolism of cancer cells, unsaturated fats are utilised perpetuating the damage, promoting inefficient glycolysis or anaerobic metabolism that creates the acidic state of the cell.

The dogma that persists in nutrition circles is not based on sound reasoning but limited ideas that look at short term studies related to carbohydrate restriction. When a system loses its capacity to regulate sugar, we blame sugar instead of looking at the variety of factors that are responsible for degraded biology, carbohydrate utilisation and insulin responses.

Whether excessive exercise or inadequate nutrition the end result may be similar and its effects are far reaching into metabolism, cardiovascular, sexual and reproductive physiology.

By improving life conditions (in many ways) the hormones of pleasure can have a bigger role in our physiology. I think the experience of pleasure (whatever capacity for pleasure there is) increases the ability to experience pleasure, but I don't offer this with much hope as a therapeutic approach, since I know of people who say that running to exhaustion makes them "feel good" - neither "feeling good" nor "having orgasms" has a clear meaning, at present. Ray Peat

I’m not suggesting that going long periods without eating are necessarily bad, nor if you enjoy running is that bad either. Context is key. If you enjoy running run. If you have the capacity to go long hours without eating, then do that too. However if you have a system that lacks flexibility these actions can be problematic.

Have you ever considered not engaging in intense exercise for a couple of weeks to see how your body really feels?

I think this is a useful test to discover where your biology is really at. It can help determine whether you have been propping up a dysfunctional biology with intense exercise that falsely elevates your body temperature through activation of the sympathetic stress pathway. Slowing down and just focusing on walking and a few stretches shouldn’t feel stressful. Equally an individual who switches to eating regularly every 3 hours or so with the same amount of calories they were previously eating shouldn’t feel stressful. We all have patterns, routines and to the extent that they are effective or not is dictated by the metabolic flexibility that one should have. I’ll also suggest that metabolic flexibility could be analogous to emotional flexibility and mood states. A sign of improvements to metabolic flexibility and flux is return of energy, ability to tolerate exercise, good sleep, libido and emotional responses among other aspects of function. How do you know if it’s working? This diagram suggests what drivers are necessary and how to overcome your unwanted symptoms with the right inputs.

Metabolic inflexibilitY.jpg

Some patience seeking the return of these aspects of function is needed. After all, if you have spent decades constrained by negative symptoms then it may take more than a few weeks or months to fully resolve these patterns. In addition to the foundational work on hormones and chemistry, some people might find a need to address belief systems or require counselling for trauma or emotional grief to help resolve emotional stressors.

 References

Mate, G. (2008). In the realm of hungry ghosts. Close encounters with addiction. Canadian Family Physician.

Randle, P. J., Garland, P. B., Hales, C. N., & Newsholme, E. A. (1963). The glucose fatty-acid cycle its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. The Lancet, 281(7285), 785–789. https://doi.org/10.1016/S0140-6736(63)91500-9

Peat, R. (1997). From PMS to Menopause: Female Hormones in context.

Selye, H. (1987). Stress without distress. In Society, stress, and disease, Vol. 5: Old age. (pp. 257–262). http://doi.org/10.1080/00228958.1983.10517713

 

Is testosterone replacement therapy necessary?

In a world where it is increasingly normal to be convinced that we fall into a risk classification, need a treatment and can convince our doctor accordingly, negating any experience that he or she might have. The marketeers and economists that run pharmaceutical companies are doing a great job of increasing profits. Before we keep looking for the next wonder treatment we should take stock of what food and exercise can do.

Testosterone can be increased by some very simple strategies such as:

  1. Having adequate liver and vitamin A in the diet to assist in the conversion of cholesterol to pregnenolone - the base hormone responsible for production of testosterone and other androgens.

  2. Ensuring that adequate energy and thyroid hormone are available to maintain communication of the hypothalamic- pituitary- (signalling centres for hormone production-brain to testicles) gonadal axis.

  3. Understanding stress, sleep and interactions between excesses of estrogen and their impact on testosterone production.

  4. Less understood but increasingly keeping mobile communication devices out of pockets and bags that are close to reproductive tissue, including females (ovaries, endometrium etc), appears to be a pragmatic approach in the future. Steroid producing tissues have increased production of problematic compounds that may be prone to damage.

Here's some of the technical aspects to the situation that are taken from a recent assignment as part of my masters degree..

Introduction

Testosterone is a hormone found in both males and females but is the major reproductive hormone in men that also has a variety of other beneficial functions for maintaining physical and psychological aspects to health. Testosterone levels may decrease with disease and/or be part of an age related decline of output. The use of testosterone supplementation has increased substantially in recent years counter these states, primarily due to increased marketing as an agent of change for energy, strength, fat loss and sexual function. Whilst its use appears beneficial in some areas, caution has been recommended on the effects of T supplementation use and it’s effects on the cardiovascular system.

 Diagnosis

Testosterone (T) is the most important androgen found in males and produced primarily within the testes, when low it is defined as hypogonadism. Hypogonadism is classified as either primary, derived from the testes or secondary, which involves the hypothalamus, pituitary or derived from illness or disease. A low serum testosterone (<300ng/dL) is suggestive, but not definitive of hypogonadism and measurements of luteinising (LH) and follicle stimulating hormone (FSH) is used to establish a primary or secondary diagnosis (Crawford & Kennedy, 2016). A worry trend is that despite striking increases of testosterone prescription a substantial amount (approximately 29% in this review) of patients often fail to have their levels checked prior to undertaking testosterone replacement therapy (TRT). (Corona G, Rastrelli, Maseroli, Sforza, & Maggi, 2015). Additionally only 45 % had their testosterone levels checked during or post TRT intervention.

Low testosterone and cardiovascular risk

Previous studies have highlighted an increase in all cause mortality associated with low testosterone levels in men (Araujo et al., 2011). Conditions that increase risk of mortality related to low testosterone are increased abdominal obesity, inflammatory biomarkers, dyslipidaemia, diabetes mellitus and metabolic syndrome. However the diagnosis of an isolated low testosterone level should be qualified by ruling out other potential diagnosis such as long-term illness, nutritional deficiencies and other endocrine issues such as subclinical or overt hypothyroidism.

Testosterone supplementation and risks

A number of studies and meta analysis have demonstrated a number of beneficial effects of TRT which extend to increased sexual satisfaction, muscle mass, strength mood and metabolic function (Corona G et al., 2015) (Gagliano-Jucá & Basaria, 2017). However the suggested risk to increased CV adverse events have appeared vague in many studies and previous extrapolations/anecdotes between men having increased levels of testosterone (and therefore increased cardiac risk) and females having less testosterone and more oestrogen were not just problematic but incorrect. Many studies have correlated low testosterone to low biomarkers of health and increased cardiovascular disease (Pastuszak, Kohn, Estis, & Lipshultz, 2017) (Kloner, Carson, Dobs, Kopecky, & Mohler, 2016).

TRT reductionism and treating symptoms

A comprehensive review of the data compiled by Oskui et al (Mesbah Oskui, P., French, W.J., Herring, 2013) described the major CV implications of TRT which can be observed below. The authors draw attention to previously conducted studies, that did not show any relationships between low levels of testosterone and CV risk and suggest that both the subfraction of testosterone (Total T compared to Free T) and method of analysis for CVD were inappropriate and therefore unreliable for inclusion. 

Cardiovascular analysis Studies Major findings Association between T and mortality 8 8/8 studies found relationship between low T and increased all cause and CV mortality. Type 2 DM 6 6/6 studies showed improved insulin sensitivity through HOMA-IR/HgA!c and improved blood glucose Cholesterol 3 2/3 studies found no change to LDL/HDL from TRT Markers of inflammation (primarily C reactive protein CRP) 8 4/8 studies found reduced CRP Intima media thickness 8 8/8 found an inverse relationship between low T and IMT

The above studies reviewed by the authors, established a link between low levels of testosterone and increases in mortality (all cause and CV), insulin sensitivity and increases in intima media thickness that are resolved by TRT. Yet markers for lipids and inflammation markers such as CRP are less convincing. Hypothyroidism is related to low testosterone and hypogonadic states mainly through hypothalamic-pituitary dysfunction. Treatment of hypothyroid and subclinical hypothyroid states also resolves low testosterone and hypogonadic states, decreases intima media thickness, improves insulin sensitivity and decreases lipid levels (Crawford & Kennedy, 2016), (Krassas, Poppe, & Glinoer, 2010),(Donnelly & White, 2000) (Gao, Zhang, Zhang, Yang, & Chen, 2013). Is TRT the correct therapy for many males, given a) the rapid increases in often undiagnosed and prescription and b) when hypogonadic states, that have similar (cardiac) manifestations and are improved beyond the effects of TRT, are resolved with thyroid hormone?

Another factor concerning reliability of the studies used in previous meta analysis is the size to determine true risk between CV adverse events and TRT (Onasanya et al., 2016). The authors suggesting that to achieve a two-sided p value of 0.05 and power of 80% some 17664 participants would need to study to clarify any relationship. Observational data conducted over 5 years suggested that control groups treated with testosterone in short term had a lower mortality (HR 0.88 95 % CI 0:84 - 0.93) than controls (Wallis et al., 2016). From the meta analysis and other studies discussed above both age (>65) and predisposition to existing disease states may indicate the likelihood of adverse CV events when treated with TRT.

Another draw back of meta-analysis is the inclusion of data and bias produced by pharmaceutical companies that may not be adequately reflected or assessed. Much like cardiovascular end point studies being scarce. Testosterone studies that are funded by financial interests are usually in place to validate the benefits of TRT and fail to evaluate CV adverse events as end points. The increased adequate sample size needed to validate the safety and efficacy of this treatment often increase cost and decrease profit margin over time. The many studies that have been conducted so far, show much smaller sample sizes and a wide range of TRT delivery and dosing.

In a recent case crossover analysis that is not included in any current meta analysis, Layton et al (Layton et al., 2018) found a unique association between testosterone injections and short term cardio (and cerebrovascular) events in older men. Increased associations with myocardial infarction and stroke, post testosterone injection showed odds ratio (OR) were increased for all outcomes, OR =1.45 (95%: CI 1.07, 1.98).

Summary

Testosterone replacement does appear to have many positive effects on a number of markers related to cardiovascular health which include sexual performance, increased muscle mass, metabolic health, physical performance and decreasing mortality in a younger population. However, despite the many benefits of TRT the use of this therapy may have significant risk in late onset hypogonadal states, in ages >65 years of age, those susceptible to conditions associated with erythrocytosis and an association with acute cardiac events exists. It remains essential to ensure that not only adequate analysis of hypogonadal states are present but to ascertain if low testosterone levels are merely a symptom of other endocrine disturbances, such as hypothyroidism which has striking similarities to low levels of testosterone.

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References:

1.Araujo, A. B., Dixon, J. M., Suarez, E. a, Murad, M. H., Guey, L. T., & Wittert, G. a. (2011). Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. The Journal of Clinical Endocrinology and Metabolism, 96(10), 3007–19. http://doi.org/10.1210/jc.2011-1137

2.Basaria, S., Davda, M. N., Travison, T. G., Ulloor, J., Singh, R., & Bhasin, S. (2013). Risk Factors Associated with Cardiovascular Events During Testosterone Administration in Older Men with Mobility Limitation. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 68(2), 153–60. http://doi.org/10.1093/gerona/gls138

  1. Corona G, G., Rastrelli, G., Maseroli, E., Sforza, A., & Maggi, M. (2015). Testosterone Replacement Therapy and Cardiovascular Risk: A Review. The World Journal of Men’s Health, 33(3), 130–42. http://doi.org/10.5534/wjmh.2015.33.3.130

  2. Crawford, M., & Kennedy, L. (2016). Testosterone replacement therapy: role of pituitary and thyroid in diagnosis and treatment. Translational Andrology and Urology, 5(6), 850–858. http://doi.org/10.21037/tau.2016.09.01

  3. Donnelly, P., & White, C. (2000). Testicular dysfunction in men with primary hypothyroidism; Reversal of hypogonadotrophic hypogonadism with replacement thyroxine. Clinical Endocrinology, 52(2), 197–201. http://doi.org/10.1046/j.1365-2265.2000.00918.x

  4. Gagliano-Jucá, T., & Basaria, S. (2017). Trials of testosterone replacement reporting cardiovascular adverse events. Asian Journal of Andrology, 19(May), 1–7. http://doi.org/10.4103/aja.aja

  5. Gao, N., Zhang, W., Zhang, Y., Yang, Q., & Chen, S. (2013). Carotid intima-media thickness in patients with subclinical hypothyroidism: A meta-analysis. Atherosclerosis, 227(1), 18–25. http://doi.org/10.1016/j.atherosclerosis.2012.10.070

  6. Kloner, R. A., Carson, C., Dobs, A., Kopecky, S., & Mohler, E. R. (2016). Testosterone and Cardiovascular Disease. Journal of the American College of Cardiology. http://doi.org/10.1016/j.jacc.2015.12.005

  7. Krassas, G. E., Poppe, K., & Glinoer, D. (2010). Thyroid Function and Human Reproductive Health. Endocrine Reviews, 31(5), 702–755. http://doi.org/10.1210/er.2009-0041

  8. Layton, J. B., Li, D., Meier, C. R., Sharpless, J. L., Stürmer, T., & Brookhart, M. A. (2018). Injection testosterone and adverse cardiovascular events: A case-crossover analysis. Clinical Endocrinology. http://doi.org/10.1111/cen.13574

  9. Mesbah Oskui, P., French, W.J., Herring, M. J. et al. (2013). Testosterone and the Cardiovascular System: A comprehensive Review of the Clinical Literature. Journal of the American Heart Association. http://doi.org/10.1161/JAHA.113.000272

  10. Onasanya, O., Iyer, G., Lucas, E., Lin, D., Singh, S., & Alexander, G. C. (2016). Association between exogenous testosterone and cardiovascular events: an overview of systematic reviews. The Lancet Diabetes and Endocrinology. http://doi.org/10.1016/S2213-8587(16)30215-7

  11. Pastuszak, A. W., Kohn, T. P., Estis, J., & Lipshultz, L. I. (2017). Low Plasma Testosterone Is Associated With Elevated Cardiovascular Disease Biomarkers. The Journal of Sexual Medicine, 14(9), 1095–1103. http://doi.org/10.1016/j.jsxm.2017.06.015

  12. Roos, A., Bakker, S. J. L., Links, T. P., Gans, R. O. B., & Wolffenbuttel, B. H. R. (2007). Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects. The Journal of Clinical Endocrinology and Metabolism, 92(2), 491–6. http://doi.org/10.1210/jc.2006-1718

  13. Udovcic, M., Pena, R. H., Patham, B., Tabatabai, L., & Kansara, A. (2017). Hypothyroidism and the Heart. Methodist DeBakey Cardiovascular Journal, 13(2), 55–59. http://doi.org/10.14797/mdcj-13-2-55

  14. Wallis, C. J. D., Lo, K., Lee, Y., Krakowsky, Y., Garbens, A., Satkunasivam, R., … Nam, R. K. (2016). Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study. The Lancet. Diabetes & Endocrinology, 4(6), 498–506. http://doi.org/10.1016/S2213-8587(16)00112-1

  15. Xu, L., Freeman, G., Cowling, B. J., & Schooling, C. M. (2013). Testosterone therapy and cardiovascular events among men: A systematic review and meta-analysis of placebo-controlled randomized trials. BMC Medicine, 11(1). http://doi.org/10.1186/1741-7015-11-108