The Testosterone: Cortisol Ratio - A Tool with Practical Use and Research Potential in Endocrinology

Abstract

Testosterone is a predominantly anabolic hormone whereas cortisol is a catabolic hormone. Measurement of testosterone-cortisol ratio (TCR) can serve as a surrogate for the balance in the anabolic: catabolic states in the body and was studied as a marker in different aspects of sports endocrinology. However, data is limited and conflicting. A comprehensive search using the PubMed and Google Scholar data base was conducted to write a narrative review summarising all available evidences of TCR in endocrinology and their clinical. TCR has been found to be important in predicting overtraining syndrome, timing peak performance in competitive sports in athletes, psychologic stress, social aggressive behaviour and has also been tested as a marker of increased cardiovascular risk. However, there are several controversies regarding its application and a definite threshold has not been established. TCR has many potential applications in clinical endocrine practice but needs further research.

INTRODUCTION

The testosterone-cortisol ratio (TCR) indicates a balance between anabolic and catabolic processes in the body. Testosterone, the primary gonadal hormone in males, is an anabolic hormone. It is known to increase muscle mass and power, stimulate bone health and lead to increased erythropoiesis. However, cortisol being a catabolic hormone works antagonistically with testosterone, inhibiting protein synthesis. If chronically elevated, cortisol can lead to breakdown of proteins including muscle protein, lead to skin thinning, sarcopenia and osteoporosis, apart from other adverse effects like dysglycemia, hypertension, dyslipidaemia, immune dysregulation, and adverse cardiac events.

TCR has been used as a biomarker of physiological stress in athletes during their training phase, during athletic performance, and during recovery and is viewed as a predictor of performance in competitive sports. Its utility has been most prominently established in diagnosing ‘overtraining’. Altered TCR indicates an imbalance between the anabolic and catabolic milieu and monitoring TCR may help improving sports and exercise performance whilst avoiding any deleterious effects from such activity.[1] There are some studies showing the role of TCR assessment in different aspects of sports medicine, however, it has the biological plausibility to be used in many other situations in endocrinology.

CHANGES TO THE TESTOSTERONE-CORTISOL RATIO DURING AND AFTER EXERCISE

Following the onset of physical activity in the morning, there is initial stimulation in the production of both cortisol (C) and testosterone (T).[2,3] However, as exercise progresses, the elevated C levels negatively affect the synthesis of testosterone thus lowering the TCR.[4] The normal circadian variation in T and C shows a progressive rise in the morning till 11 am. Thus, short bouts of acute physical exercise in the morning could lead to the possible generation of a biphasic time profile in the TCR.[5] However, how long this disruption remains during the rest of the day needs exploration in further studies.

Acute responses to exercise

In untrained athletes, both strength and endurance exercises leads to increased total and free T levels after approximately 15–20 min of activity. C also increases in reaction to moderate exercise. These transient hormonal fluctuations with a resultant decrease in TCR of up to 30% decrease in TCR are observed in untrained athletes after the first few days of exercise. In subsequent days of intense exercise, these hormonal changes typically return to normal. This reaction can differ depending upon an athlete’s fitness level. While resistance training could lead to an acute increase in both testosterone and cortisol, in well-trained athletes there is a relative increase in testosterone levels, contributing to muscle growth.[6]

Chronic training adaptations

Chronic exposure to training-induced stress can alter the balance of T and C. In athletes who are well-trained and have adapted to their sport, the TCR stabilizes at a higher level as an effective adaptation to chronic physical stress due to chronic exposure to training sessions.[7,8] However, athletes undergoing excessive training loads with insufficient time to recovery may experience a reduced TCR, signalling a shift towards a more catabolic state that could impair performance and increase the risk of injury.

DETERMINANTS OF THE TESTOSTERONE-CORTISOL RATIO

The ‘rise and fall’ in T, C, or TCR in relation to exercise is complex and depends on multiple factors related to the exercise, including its timing, intensity, duration, and rest periods.

Duration and intensity of exercise

Several studies have shown a significant increase in C with prolonged duration exercise exceeding 120 min but low—moderate levels of C with exercise duration of less than 60-min, irrespective of the intensity.[9,10] T has shown an opposite dual response depending on the duration of the activity, with an increase noted in short bouts (less than 2.5 hour) and reduction in exercises lasting longer than 3 hour.[11]

Degree of training of athletes

The biphasic behaviour of the TCR also depends on the training status of the individuals. In a study, trained runners but not non-runners demonstrated the biphasic profile of TCR in those exercising till 80% heart rate, whereas at the 65% level, neither runners nor non-runners presented the hypothesized biphasic response.[5] This might be due to lower T and higher C response to unaccustomed exercise in the non-runner group during high-intensity exercise.

Gender

T is considered one of the most important factors explaining the performance differences between male and female athletes, which can amount to a 10% to 20% variation in performance outcomes.[12,13] Women have approximately one-tenth of the Τ levels in men, but the response of T to acute physical exercise increases in them too. C change in response to exercise is seen in both genders. In a study that measured C, total-and free T in male and female elite endurance athletes during off-season, early during the competition season and at the end of the competition season, it was seen that while C increased significantly during the competition season in women but not in men, the mean C levels were significantly higher in women than in men.[14] However, T and TCR were similar in both genders. In another study on alteration of TCR in males versus female amateur rowers, it was seen that the TCR demonstrated an association with poorer performance and worse podium results in the race only among female rowers but not in male rowers.[15] Thus, at least in untrained athletes, gender can alter the association of TCR with performance in competitive sports. Thus, gender differences might exist with respect to the effects of TCR in different physiologic conditions; though the exact mechanisms which drive these changes need further studies in this regard.

Estrogen can alter cortisol binding globulin (CBG) levels. The enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) converts cortisone to its active metabolite, cortisol. Estrogen has been found to increase the activity of 11 beta-HSD1 in preadipocytes in women, thus changes in estrogen levels could to some extent affect the levels of cortisol in women during their fertile years.[16] However, there is no data to suggest the role of estrogen: cortisol ratio akin to TCR.

Competition anxiety

Athletes demonstrate distinct alteration in T, C and TCR during ‘training’ and during ‘competition’. In elite athletes, the increase in T is less prominent while C is frequently elevated, and the TCR is decreased in comparison with less trained athletes during competition. In competitive settings, the TCR is influenced to a large extent by pre-competition anxiety levels. A study has shown that official weightlifting competition produced higher salivary cortisol response and, thus, a greater decrease in the salivary TCR than a simulated competition.[17] However, the competitors, who had higher pre-contest salivary cortisol levels were also found to perform better than those with lower levels. Stressful situations can raise salivary cortisol levels to as high as 230% from basal values.[18] Raised catecholamines could be the result of increased cortisol levels by the stimulatory action of cortisol on PNMT enzyme levels. Thus, it might be possible that there is a link between higher cortisol levels and superior performance in performance during official competitions.

Type of sports

A systematic review of several prior studies has shown that the TCR might depend on the type of sports. While playing football generally raises, whereas netball might lead to raised cortisol and lowering of TCR.[19] Increased TCR has been correlated with a better podium position in indoor races. Some studies suggest differences in the predictive value of TCR in indoor and outdoor sports, its value being higher in the indoor race at all considered time-points. Reduced cortisol levels have been observed in athletes before outdoor racing, while testosterone values started to increase at the beginning of ergometer or boat competition, and kept on rising till the end of the race.[20]

Volume of exercise training

Basal TCR can be used to represent the physiological strain arising from exercise training programmes and exhibits an inverse relationship with exercise volume. In elite female weightlifters, a 11-week training period led to 37.0% reduction in training volume and 72.5% increase in basal TCR.[21] Conversely, Wu et al.[22] demonstrated a 54% increase in weight-lifting training volume over 2 weeks along with 60% reduction in the basal TCR. Notably however, weightlifting training for ≥1 year and past exposure to increased training volumes had the potential to attenuate the changes occurring in TCR due to training sessions.[23] Additionally, during extended training periods of varying intensity and volume lasting for 12 to 24 weeks, experienced weightlifters have demonstrated a positive association between increased TCR and maximal voluntary isometric PF and PP.[24] Thus, assessing TCR can provide an effective way to measure acute and chronic adaptive responses to weightlifting training.

Calculation and cut-off values

While an absolute value as a threshold couldn’t be established, the use of free Testosterone: Cortisol ratio (FTCR) for the diagnosis of overtraining syndromes have been proposed originally with two approaches: a FTCR lower than 0.35 × 10^-3 calculated using free testosterone (FT) in nanomoles per litre (nmol/L) and cortisol (C) values in micromoles per litre (mmol/L) or a decline in TCR by ≥30% from its previous value is considered as an indicator of insufficient recovery and poor performance in competitive sports.[25] Serial monitoring of TCR is thus necessary in athletes and is considered more accurate predictor for overtraining than a single absolute value cut-off.

Pathophysiologic basis of changes in testosterone-cortisol ratio during exercise

The major form of glucocorticoid in humans is C that is a catabolic hormone released from the adrenal gland in response to any form of stress. Being a ‘catabolic hormone’, its role in breaking down muscle tissue leads to mobilization of energy stores (glucose and fatty acids) for immediate use during intense physical activity. Though vital for metabolic regulation and maintaining homeostasis, prolonged or excessive cortisol release during chronic or intense training can impair recovery and contribute to chronic muscle catabolism. Any form of exercises requiring 60% or more of the maximum oxygen consumption of an individual (V_O2 max) could increase C secretion. Although C levels start to increase during exercise, most of the effects of cortisol occur during the early recovery phase after the exercise bout.

T, an anabolic hormone is mainly produced and secreted by Leydig cells in males. In females, the sources of testosterone include ovary (25%) and adrenals (25%) and peripheral conversion (50%) of circulating androstenedione.[26] In athletes, testosterone primarily enhances muscle protein synthesis, muscle growth, red blood cell production, bone density and overall leads to an increased strength and overall physical performance. During physical exertion, levels of testosterone increase in response to both acute and chronic training sessions.

There is a complex interaction between the hypothalamo-pituitary-adrenal (HPA) and Hypothalamo-Pituitary-Gonadal (HPG) axes and their responses during exercise [Figure 1]. During intense exercise, factors like increased plasma lactate, humoral mediators such as interleukins and angiotensin II are implicated in the activation of the HPA axis by stimulating CRH. Exercise also acts as a non-osmotic stimulus for arginine vasopressin that in turn increases adreno-corticotrophic hormone and HPA activation.[27] Both of these contribute to increasing C levels. However, in those with prolonged periods of intense training exercises, there is release of beta-endorphins from neurons soon after the start of exercise. The primary action of beta-endorphins is analgesia via opioid receptors and mood elevation. It has been seen that the levels of serum beta-endorphin were significantly elevated only during maximum and intense aerobic exercises (80% of consumed oxygen), while they did not change during from light to moderate intensity (20% to 50% of maximum consumed oxygen) did not change substantially.[28] However, another action of beta-endorphin is a an inhibitory effect on GnRH release ultimately attenuating the rise of T during exercise.[29] Thus, in those with prolonged training phases leading to overtraining, following a bout of exercise, the TCR might not be elevated and low TCR is indicative of OTS.

Figure 1.

Interaction between the hypothalamo-pituitary-adrenal (HPA) and the Hypothalamo-Pituitary-Gonadal (HPG) axes during intense exercise

While the interaction between the HPA axes and HPG axes seem to play the key role in suppression of TCR in OTS, there are some ways in which T, C or TCR are affected in exercise or vice versa. An interesting study on the relationship between T and C in men at rest and after exercise found a negative relationship of total T but positive relationship of free T with C after exercise, though any possibility of the effect of cortisol or of exercise on the levels of the sex hormone binding globulin (SHBG) or the dissociation of free testosterone from SHBG remain unknown. It has been speculated that T and C might regulate Na+ loss due to sweat during exercise by modifying the activity of the cystic-fibrosis-transmembrane-conductance-regulator (CFTR). A study by Sepulveda et al. showed that rate of Na loss in males was proportional to cortisol and TCR irrespective of sweat rate and suggested that cortisol and TCR may influence Na+ loss during exercise.[30]

Use of testosterone-cortisol ratio estimation in sports endocrinology

In sports medicine, studying hormonal responses to exercise and training is important to understand adaptation of the body to physical stress. In this regard, TCR has potential implications for athletic performance, recovery, and overtraining syndromes in sports medicine.

TCR AS A TOOL FOR THE DIAGNOSIS OF OVERTRAINING IN SPORTS

Overtraining syndrome (OTS) is a condition in athletes and other sportspersons that is characterized by prolonged fatigue, decreased performance, and various physiological and psychological symptoms and is often due to inadequate recovery from excessive training. It represents a spectrum disorder from functional overreaching, non-functional overreaching and overtraining with progressive decline in performance seen in the latter two variants.[31,32] As of now, there is still no isolated marker capable of diagnosing training problems and/or overtraining though several indicators have been proposed. For several years, reduced TCR was a hallmark of OTS.[19,31]

In sportspersons with OTS, there is persistently elevated C levels while T fail to rise appropriately or even may drop in response to training.[1] Multiple factors contribute to OTS including a chronic high training volume or intensity that exceeds the body’s ability to recover, inadequate nutrition, insufficient sleep and psychological stress leading to elevated cortisol levels. The high C levels could lead to increased inflammation and immune suppression further hampering the body’s ability to recover to a physiologic state.

Although considered important in the past decades, recently the role of TCR was criticized because it was seen that a ≥30% decline in TCR did not always result in a deterioration of athletic performance. Though there are controversies, the TCR can be used as a marker for OTS. A high TCR would suggest a good rested condition, effective training and predict peak performance period. However, a low TCR might suggest high levels of stress and overtraining syndrome with inadequate recovery and athletes showing symptoms of OTS along with a low TCR, should be monitored and allowed adequate recovery time and their training volume and intensity should be adjusted accordingly.[19,31] Banfi et al.[25] in their study proposed a severity classification system to predict the risk of OTS based on the values of FTCR [Table 1].

Table 1.

Risk classification for overtraining (OTS) based on values of free Testosterone-Cortisol ratio (FTCR)*

FTCR value	Interpretation	Action
>0.8	Normal
0.76–0.8	No risk of OTS
0.71–0.75	Very low risk of OTS
0.66–0.7	Low risk of OTS
0.58–0.65	Slight risk of OTS	Warning
0.51–0.57	Risk of OTS	Re-evaluate training programmes
0.43–0.5	High risk of OTS	Stop training programmes
0.35–0.42	Very high risk of OTS	Stop training programmes and competition
<0.35	Frank overtraining

*Adapted from Banfi G, Dolci A. Free testosterone/cortisol ratio in soccer: usefulness of a categorization of values. Journal of sports medicine and physical fitness. 2006 Dec 1;46(4):611

Role of testosterone-cortisol ratio in deciding the time of training and sports performance

Both T and cortisol C follow a circadian rhythm, peaking in the morning with slow decline as the day progresses. In the morning, both T and C levels are elevated and counteract the effect of each other on muscle protein synthesis and degradation. The interaction between T and C and their diurnal rhythms is important in athletes, as training timing, sleep quality, and recovery all play a significant role in maintaining an optimal TCR. One study where the authors studied the impact on TCR and morning compared to afternoon high intensity interval training (HIIT) in active men concluded that T levels increased after HIIT in afternoon and there was significant increase in levels of T, C and TCR, suggesting that afternoon time might be best suited for carrying out HIIT.[33] But some other studies suggested that strength training in the morning and afternoon h are equally efficient when aiming for muscle hypertrophy.[34] In a study aimed to evaluate the time-course profile of TCR following an acute episode of physical exercise on trained and non-trained runners, a biphasic time-profile in TCR was seen with short-bout, high intensity exercise exercises like treadmill running in the morning among trained runners.[5] Athletes might test for TCR before and after resistance training and can experience greater hypertrophy and strength gains if the timing of their resistance training protocols are modified dependent on individual TCR response to an exercise at particular times of the day.

Testosterone-cortisol ratio and cardiovascular risk

Low T and low TCR have been associated with an increased risk of coronary artery disease (CAD). Poor sleep quality aggravates the effects of low TCR on CAD.[35] In a study by Lee JM, the highest tertile of the AUC/free testosterone ratio was found to have positive association with carotid bulb IMT and with new onset coronary artery calcification (CAC) between the 15^th and 25^th years. However, there was no association between the tertiles of C or T alone new onset CAC. The authors concluded that the AUC/Free testosterone ratio is associated with a higher risk for atherosclerosis in women and the ratio could be a suitable biomarker of cortisol-linked stress.[36] TCR has been found to be significantly lower in those with severe obstructive sleep apnea (OSA) in comparison to those with moderate OSA and there is a significant correlation between the minimal SpO₂ and apnoea-hypopnea index (AHI) (r = −0.69, P < 0.01), between cortisol and AHI, as well as between cortisol and minimal SpO2.[37] In a study by Beibei Wu et al.,[38] low serum testosterone was negatively associated with stroke in males, while TCR was positively associated with stroke both the genders. One study showed that while the hair T or TCR did not correlate with heart failure severity, TCR was lower in patients requiring heart-failure related hospitalisation.[39] Thus, overall evidences suggest an association of low TCR with adverse cardiovascular risk in adults.

Testosterone-cortisol ratio and social aggression

TCR has also been studied as a possible biomarker for criminally aggressive behaviour. Both T and C can modulate aggressive behaviour. High T have been associated with dominant aggressive behaviour in both sexes, and surprisingly, low C have also been linked to aggressive social tendencies.[40] However, high C have been reported in anxious depression and low mood, non-clinical anxiety and submissive behaviour.[41,42] The dual hormone hypothesis posits that while both cortisol and testosterone have effects on behavioural systems that are implicated in dominance and aggression, such traits associated with high testosterone are more overtly manifested in individuals with low basal cortisol levels.[43]

The hormones also have opposing effects on the sensitivity for punishment and reward dependency. Studies have confirmed reductions in punishment sensitivity and increased reward dependent behaviour after testosterone administration.[44] It is known that psychopaths are not motivated to avoid punishment when reward is pending and low cortisol sets the balance between the punishment sensitivity and reward dependency in a way that is predisposed towards psychopathic behaviour.[45] In non-human species, it has been seen that a combination of high T and low C, or, in other words, high TCR is associated with the most violent behaviour.[42]

In a study, TCR and anger responses were compared in men jailed for Intimate partner violence (IPV) and controls in response to the Trier Social Stress Test. IPV perpetrators had higher TCR than controls, and stress further enhanced the TCR.[46] Another study found greater TCR to be associated with greater aggressive behaviour towards partner, but the TCR–aggression associations became weaker under provoked conditions.[47] Thus higher TCR could serve as a marker to identify men at high risk of reacting violently to their partners.

Another study showed there is differential modulation of risk-taking behaviours by the sex hormone–cortisol ratios in men and women. While high TCR was associated with increased risk-taking behaviour in men, the opposite has been seen in women.[48]

Scope of research on testosterone-cortisol ratio in different aspects of endocrinology

The potential used of TCR in sports and clinical endocrinology based on available evidences are summarised in Table 2. However, there are no practical cut-off values and there is need for further data in this field.

Table 2.

Evidence-based roles of the testosterone: Cortisol ratio (TCR) in clinical endocrinology

1. Diagnosis and prevention of overtraining syndrome in athletes

2. Performance monitoring with repeated exercise sessions using serial TCR

3. Timing of resistance training

4. Timing of competitive sports and adjusting training sessions accordingly

5. Predictor of socially aggressive behavior, especially marital aggression

6. Predictor for severity of OSA

7. Predictor for ASCVD risk

Apart from these, there are several other areas in which TCR could be of potential use, but there is dearth of existing evidence and are important avenues for future research in this field.

• TCR in subtyping of obesity: In a study by Chan et al.,[49] it was seen that in obese individuals, while scalp hair cortisol levels increase, scalp hair testosterone levels decrease and the scalp hair TCR had better correlation body mass index (BMI) and waist circumference better than hair cortisol or testosterone than scalp hair cortisol or testosterone alone. Cortisol excess and low testosterone levels are known to be associated with obesity, predominantly central obesity. Additionally, TCR has been correlated with cardiometabolic risk. A potential application of the TCR thus could be to subtype obesity. A low TCR could be a surrogate for central obesity and be potentially used as a marker of more metabolically unhealthy obesity than similar BMI with higher TCR. Individuals with similar BMI might have differential cardiometabolic risk depending on the levels of TCR.

• TCR in late-onset hypogonadism (LOH): Even in presence of clear-cut indications for testosterone therapy in LOH, it is often not given due to fear of adverse events. Although there is no evidence till date, but TCR could be potentially used to assess the risk: benefit ratio of testosterone therapy in elderly men with late-onset hypogonadism (LOH). For the same serum levels of serum testosterone, those with lower TCR might be expected to be at higher risk for adverse effects of testosterone than those with lower cortisol levels and therefore, higher TCR. This could be an important factor to consider prior to starting androgens in elderly men with LOH.

• TCR as a screening tool to evaluate diplomats and top-level employment: Since higher testosterone and lower cortisol levels could be associated with multiple adverse behavioural traits and suboptimal stress-coping mechanisms, TCR might serve as a potential tool to assess the managerial capabilities of top-level posts in companies and diplomats.

Limitations and future directions

The TCR has been criticised as a hormonal tool due its influence by multiple factors such as age, sex, training history, and genetics. Also, other hormones and factors including growth hormone, insulin-like growth factor-1 (IGF-1), and inflammatory cytokines also play key roles in the regulation of muscle function and recovery. Most of the data on cortisol changes with exercise or social aggression or cardiovascular risk comes from salivary rather than serum cortisol. Salivary cortisol is a more sensitive and better marker of endogenous hypercortisolaemia with lesser confounding factors. However, TCR calculation is based on serum levels of cortisol. There is no clear-cut threshold and there is an imminent need for larger and longitudinal studies focussing on TCR to better elucidate its complex interaction with these factors and understand how it relates to performance outcomes, injury risk, and overall well-being.

CONCLUSION

Although the TCR has many limitations and controversies, it does provide valuable insight into hormonal balance between anabolic and catabolic processes in athletes. Rather than considering it as a single tool, interpreting the TCR alongside additional clinical measures, including training load, psychological well-being, and physical health can provide a comprehensive picture of an athlete’s readiness and overall performance and pave a path for personalised exercise prescription.

Author contributions

Author 1 (SM), Author 2 (DD), and author 3 (SB) were involved in in the acquisition of available data from published literature while critically analysing it and formulating the initial draft. Author 4 (SK) formulated the concept and design of this project and), edited the draft incorporating important intellectual content. All the authors approved the final version of the manuscript.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence

Artificial intelligence was not used in any form for analysis or writing of this research article.

Funding Statement

Nil.