Dr. Weeks’ Comment: There is a provocative and humbling comment often attributed to Einstein which reads: “Not only is the universe more complicated than you think, but it is also more complicated than you can imagine”. The same can be said of the complexity of human anatomy, physiology and our health-seeking mechanisms. We are indeed “fearfully and wonderfully made”. Therefore, it is ludicrous for we doctors to claim that we know all we need to know in serving a patient. Yet how rare and refreshing it is to hear an honest doctor respond to a patient’s question with: “I really don’t know.” or “Great question. I will need to research that a bit before I can offer you a meaningful answer.” Humility. So refreshing.
Now I share with you the case of a good man, a 72 years old patient who dutifully took androgen deprivation therapy (ADT) recommended by his oncologist for the treatment of metastatic prostate cancer. ADT, the standard of care for metastatic prostate cancer, is also referred to as “chemical castration” in that it lowers testosterone in men with prostate cancer. (Aside: While I personally suspect that estrogen and not testosterone is the dangerous hormone promoting prostate cancer, it is true that the enzyme aromatase does degrade testosterone to estrogen and therefore there can be a benefit to lowering testosterone. However, Dr Abram Morgentaler, a Harvard trained urologist, makes a strong case for maintaining high levels of testosterone in men with prostate cancer while inhibiting the aromatase enzyme, thereby preventing high levels of estrogen while affording me higher quality of life compared to being chemically castrated).
Now, after being on ADT for a year, this 72 year old man has zero blood levels of testosterone but suffers with a new problem. He has new onset atrial fibrillation, a live-threatening irregular beating of his heart, so his oncologist referred him to a cardiologist who recommended inserting a pacemaker.
This patient may well be yet another victim of “silo syndrome” where neither specialist is thinking through the side-effects which their drug causes to the consternation of a different specialist. In this case, lowering testosterone is the goal of the oncologist but his “success” may well have caused a new equally lethal problem (atrial fibrillation) which challenges the other specialist, the cardiologist.
It is well established that low androgens (testosterone) is a risk factor for heart disease, CVD, i.e. coronary vascular disease. Uptodate, the service accessed by many doctors, makes this clear: https://www.uptodate.com/contents/overview-of-possible-risk-factors-for-cardiovascular-disease?search=testosterone%20and%20a%20fib§ionRank=2&usage_type=default&anchor=H475085&source=machineLearning&selectedTitle=1~150&display_rank=1#H475085
“Systemic conditions – The systemic conditions associated with greater risk of CVD include collagen vascular disease, androgen deficiency, infection, iron overload, obstructive sleep apnea, and being born small for gestational age.”
I wondered whether this 72 year old gentleman were now between a rock and a hard place.
I have always asked the question “Why” in life and this curiosity has taken me on some delightful adventures. My question to the oncologist and the cardiologist was “Given that testosterone build muscles, do you think that his levels of testosterone equaling zero caused by the ADT have weakened his heart muscles so that they cannot beat at the healthy normal rate?” Their answer was “No. Low testosterone only weakens skeletal muscles not heart muscles.” I asked for their reference and they told me that they don’t know the references but reminded me that “everyone” knows this to be true.
Whenever I learn something that “everyone” (but me!) knows, I get more curious.
So, I searched PUBMED (a free medical scientific website – the national library of medicine) and found this paper below which contradicts what “everyone” knows.
This study concludes “Our study indicates that low testosterone levels are associated with increased risk of future atrial fibrillation and/or ischaemic stroke in men, while they are protective in women.”
The second cited study below amplifies this disputed cause and effect process showing that hormones like testosterone DO impact heart muscle:
“The renin–aldosterone–angiotensin system, the activation of which has traditionally been associated with an increased risk of atrial fibrillation and other cardiovascular risk factors, is regulated by sex hormones in many ways. In particular, aldosterone promotes atrial fibrosis and extracellular conduction disturbances, leading to a direct proarrhythmic effect in atrial cells.”
What we learn from these two studies is that not “everyone” agrees with the claim of the oncologist and the cardiologist that levels of testosterone do not affect the heart muscle.
I remember way back in the days I was in medical school where at the bedside during rounds, I noted a problem with a patient and pointed it out to the attending (boss) doctor who blithely discounted my concern. I assumed he knew better, so I followed his advice. The next morning, when we rounded on all our patients, we learned that this particular patient had died during the night due to the factors I had pointed out to the attending. Rather than acknowledge his error and consequent culpability, the attending shrugged his white-coat-clad shoulders and uttered words as haunting today as they were callous then: “Live and learn”. My (unspoken) retort was, “Easy for you to say as you get to live and learn, while the patient died.”
So here’s to you patients continuing to ask good questions like your life depended upon it (it may indeed!) and to us doctors answering them with honesty and humility. May YOU continue to live and learn in your association with your care team!
Low testosterone levels are predictive for incident atrial fibrillation and ischaemic stroke in men, but protective in women – results from the FINRISK study
Tanja Zeller 1 2, Renate B Schnabel 1 2, Sebastian Appelbaum 1, Francisco Ojeda 1, Filip Berisha 1, Benedict Schulte-Steinberg 1, Burkhard-Ekkehart Brueckmann 1, Kari Kuulasmaa 3, Pekka Jousilahti 3, Stefan Blankenberg 1 2, Tarja Palosaari 3, Veikko Salomaa 3, Mahir Karakas 1 2
Eur J Prev Cardiol. 2018 Jul;25(11):1133-1139. doi: 10.1177/2047487318778346.
Background: Atrial fibrillation is the most common serious abnormal heart rhythm, and a frequent cause of ischaemic stroke. Recent experimental studies, mainly in orchiectomised rats, report a relationship between sex hormones and atrial electrophysiology and electroanatomy. We aimed to evaluate whether low testosterone levels are predictive for atrial fibrillation and/or ischaemic stroke in men and women.
Design and methods: The serum total testosterone levels were measured at baseline in a population cohort of 7892 subjects (3876 male, 4016 female), aged 25-74 years, using a commercially available immunoassay. The main outcome measure was atrial fibrillation or ischaemic stroke, whichever came first.
Results: During a median follow-up of 13.8 years, a total of 629 subjects (8.0%) suffered from incident atrial fibrillation ( n = 426) and/or ischemic stroke ( n = 276). Cox regression analyses, adjusted for age (used as time-scale), geographical region, total cholesterol (log), high-density lipoprotein-cholesterol (log), hypertension medication, known diabetes, smoking status, waist-hip-ratio, and time of blood drawn, documented differential predictive value of low sex-specific testosterone levels for atrial fibrillation and/or ischaemic stroke, in men and in women: Increasing levels were associated with lower risk in men (hazard ratio per one nmol/l increase 0.98 (95% confidence interval 0.93-1.00); p = 0.049). On the other hand, increasing testosterone levels were associated with higher risk in women (hazard ratio per one nmol/l increase 1.17 (95% confidence interval 1.02-1.36); p = 0.031).
Conclusion: Our study indicates that low testosterone levels are associated with increased risk of future atrial fibrillation and/or ischaemic stroke in men, while they are protective in women.
and Study #2
Sex differences in atrial fibrillation: The case of testosterone
Federico Guerra, Giuseppe Ciliberti, Alessandro Capucci
European Journal of Preventive Cardiology, Volume 25, Issue 11, 1 July 2018, Pages 1131–1132, https://doi.org/10.1177/2047487318784741 Published: 29 August 2020
In this issue of the European Journal of Preventive Cardiology, Zeller et al.1 delve into the FINRISK97 study to deliver impressive data over a 15-year follow-up period. Their take-home message is simple, yet intriguing: serum testosterone levels and the risk of atrial fibrillation and ischaemic stroke are positively associated in women, but negatively associated in men. More simply, an increase of 1 nmol/L is associated with a 2% reduction of risk in men and a 17% increase of risk in women after correction for the most important cardiovascular risk factors. This finding has a profound (and two-fold) clinical implication.
The paper adds evidence to the idea that low testosterone should be considered as a risk factor for atrial fibrillation and the most dreaded complication, ischaemic stroke.
LASTLY Study #3
Aldosterone promotes atrial fibrillation
Jan-Christian Reil, Mathias Hohl, Simina Selejan, Peter Lipp, Fabian Drautz, Andrey Kazakow, Benedikt M. Münz, Patrick Müller, Paul Steendijk, Gert-Hinrich Reil … Show more
European Heart Journal, Volume 33, Issue 16, August 2012, Pages 2098–2108, https://doi.org/10.1093/eurheartj/ehr266
Published: 04 August 2011.
Hyperaldosteronism is associated with an increased prevalence of atrial fibrillation (AF). However, it is unclear whether this is the consequence of altered haemodynamics or a direct aldosterone effect. It was the aim of the study to demonstrate load-independent effects of aldosterone on atrial structure and electrophysiology.
Neither systolic nor diastolic ventricular function nor atrial pressures were altered in Aldo rats. All Aldo (11/11) showed inducible atrial arrhythmias vs. two of nine controls (P = 0.03). In Aldo, the P-wave duration and the total RA activation time were longer. Prolongation of local conduction times occurred more often in Aldo, whereas the AERP did not differ between both groups. In Aldo, atrial fibroblasts and interstitial collagen were increased, active matrix metalloproteinase 13 was reduced, and atrial myocytes were hypertrophied. The connexin 43 content was unaltered.
Aldosterone causes a substrate for atrial arrhythmias characterized by atrial fibrosis, myocyte hypertrophy, and conduction disturbances. The described model imputes atrial proarrhythmia directly to aldosterone, since ventricular haemodynamics appeared unaltered in this model. This mechanism may have therapeutical impact for primary and secondary prevention of AF.