Exercise-Hypogonadal Male Condition

[Michael Scally MD]

Functional Hypogonadotropic Hypogonadism in Men: Underlying Neuroendocrine Mechanisms and Natural History

Context - A subset of men following completion of puberty subsequently experience functional hypogonadotropic hypogonadism (FHH) secondary to excessive exercise and/or weight loss. This phenomenon is akin to hypothalamic amenorrhea (HA) in women, yet little is known about FHH in men.

Objective - To investigate the neuroendocrine mechanisms, genetics and natural history underlying FHH.

Design - Retrospective study in an academic medical center.

Participants - Healthy post-pubertal men presenting with symptoms of hypogonadism in the setting of excessive exercise (>10 hours/week) or weight loss (>10% of bodyweight). Healthy age-matched men served as controls.

Interventions - Clinical assessment, biochemical/neuroendocrine profiling, body composition, semen analysis, and genetic evaluation of genes known to cause isolated GnRH deficiency.

Main outcome measures - Reproductive hormone levels, endogenous GnRH-induced luteinizing hormone (LH) pulse patterns and rare genetic variants.

Results - Ten men with FHH were compared to 18 age-matched controls. Patients had significantly lower BMI, testosterone, LH and mean LH pulse amplitudes yet normal LH pulse frequency, serum FSH and sperm counts. Some patients exhibited nocturnal, sleep-entrained LH pulses characteristic of early puberty while one FHH subject showed a completely apulsatile LH secretion. Following decreased exercise and weight gain, five FHH men normalized serum T levels and symptoms resolved. Rare missense variants in NSMF (n=1) and CHD7 (n=1) were identified in two FHH men.

Conclusions - FHH is a rare, reversible form of male GnRH deficiency. LH pulse patterns in male FHH are similar to those observed in women with HA. This study expands the spectrum of GnRH deficiency disorders in men.

Dwyer AA, Chavan NR, Lewkowitz-Shpuntoff H, et al. Functional hypogonadotropic hypogonadism in men: Underlying neuroendocrine mechanisms and natural history. 2019. Functional hypogonadotropic hypogonadism in men: Underlying neuroendocrine mechanisms and natural history

 

[Old]

Hackney AC, Hooper DR. Reductions in testosterone are not indicative of exercise performance decrement in male endurance athletes. The Aging Male 2019:1-2. https://doi.org/10.1080/13685538.2019.1574736

Our findings indicate that the participants of an 18 week intensive endurance exercise training program experienced significant (p < 0.001) reductions in resting testosterone (−25 to −45% decrease from pre-training), with some reaching the clinical criteria for androgen deficiency during the training regimen.

Nonetheless, none of the participants displayed any running performance decrement, in fact, the opposite occurred (+18.6% improvement; p < 0.05).

These preliminary findings suggest acute decreases in testosterone in and of itself may not be entirely indicative of a compromised exercise performance potential although elements of reproductive and bone health may still be compromised.

Given what happens to bones of endurance athletes this isn't surprising. Isn't the negative effect of endurance exercise due to the rise of cortisol which has a catabolic effect on bones, joint, etc. ?

And doesn't cortisol reduce testosterone and anabolism? Studies about taking cortisol/prednisone and the effects on testosterone seem to be all over the map. Here is one with report 33% reduction Testosterone levels during systemic and inhaled corticosteroid therapy. - PubMed - NCBI and another one with greater reduction Reduction of Serum Testosterone Levels During Chronic Glucocorticoid Therapy | Annals of Internal Medicine | American College of Physicians


As for 'improved performance of 18.6%', is that not what cortisol would do? Elsewhere posted in the forum is info that too much exercise raises cardiovascular risks (another effect of prolonged elevated cortisol). So much for aerobicmania ...

Here is a general study on exercise and cortisol alterations for difference exercise intensities Exercise and circulating cortisol levels: the intensity threshold effect. - PubMed - NCBI

Note: "once corrections for plasma volume reduction occurred and circadian factors were examined, low intensity exercise [40% VO2max] actually resulted in a reduction in circulating cortisol levels"​

 

[Michael Scally MD]

Wong HK, Hoermann R, Grossmann M. Reversible male hypogonadotropic hypogonadism due to energy deficit. Clinical Endocrinology 2019;0. https://doi.org/10.1111/cen.13973

Context - Calorie restriction and overtraining are increasingly seen in young men who suffer from increasing societal pressure to attain a perceived ideal male body image. The resulting energy deficit can lead to multiple endocrine consequences, including suppression of the male gonadal axis.

Design - We reviewed the literature, including two unpublished cases.

Results - We identified 23 cases, aged median (range) 20 years (16‐33), with a body mass index of 15.9 kg/m2 (12.5‐20.5). Total testosterone was 3.0 nmol/L (0.6‐21.3), and luteinizing hormone (LH) 1.2 mIU/L (<0.2‐7.5), with 91% of cases demonstrating hypogonadotropic hypogonadism.

Associated findings included evidence of growth hormone resistance (increased growth hormone in 57% and low insulin like growth factor‐1 in 71%), hypercortisolaemia (50%), and a nonthyroidal illness picture (67%).

In cases with longitudinal measurements following weight regain, serum testosterone (n=14) increased from median [interquartile range] 3.2 nmol/L [1.9‐5.1] to 14.3 nmol/L [9.3‐21.2] (p<0.001), and LH (n=8) from 1.2 IU/L [0.8‐1.8] to 3.5 IU/L [3.3‐4.3] (p=0.008).

Conclusions - Hypogonadotropic hypogonadism can occur in the context of energy deprivation in young otherwise healthy men and may be underrecognized. The evidence suggests that gonadal axis suppression and associated hormonal abnormalities represent an adaptive response to increased physiological stress and total body energy deficit.

The pathophysiology likely involves hypothalamic suppression due to dysregulation of leptin, ghrelin and proinflammatory cytokines. The gonadal axis suppression is functional, because it can be reversible with weight gain. Treatment should focus on reversing the existing energy deficit to achieve a healthy body weight, including psychiatric input where required.

 

[Michael Scally MD]

Zekarias K, Shrestha RT. Role of Relative Malnutrition in Exercise Hypogonadal Male Condition. Medicine and science in sports and exercise 2019;51:234-6. Role of Relative Malnutrition in Exercise Hypogonadal Male... : Medicine & Science in Sports & Exercise

OBJECTIVE: Exercise hypogonadal male condition is a well-recognized condition in women but much less understood in men. The aim of this case report is to highlight exercise-induced hypogonadotropic hypogonadism in a male who recovered with lifestyle modifications.

METHODS: We report a case of an adolescent male who developed hypogonadotropic hypogonadism secondary to excessive exercise and malnutrition that was followed up for a year without exogenous testosterone supplementation. Informed consent was obtained from the patient for his information to be used in a manuscript submitted to a journal.

RESULTS: An 18-yr-old adolescent male presented to the clinic with symptoms of fatigue and low endurance, low libido, and lack of morning erections. At the time of his presentation, he was running about 60 miles per week for school cross-country team in addition to cross training with kickboxing. Physical examination was remarkable for low body mass index of 19 kg.m but was otherwise normal. Biochemical workup confirmed hypogonadotropic hypogonadism and a mild pancytopenia. Other pituitary laboratory values and MRI of the brain were unremarkable. Bone marrow biopsy performed for anemia showed features consistent with malnutrition. With a working diagnosis of exercise hypogonadal male condition, he was advised to reduce the frequency and intensity of his exercise and increase calorie intake. Cell counts and testosterone levels normalized, and his symptoms resolved without any further interventions.

CONCLUSION: Significant reversible hypogonadism can develop after intensive and prolonged exercise. One of the mechanisms of hypogonadism in endurance athletes performing intensive exercise could be relative malnutrition. Further studies to evaluate the role of nutrition and body mass index in male endurance athletes presenting with hypogonadism are needed to identify the underlying mechanism of this condition.

 

[Michael Scally MD]

Functional Hypogonadotropic Hypogonadism in Men: Underlying Neuroendocrine Mechanisms and Natural History

Context - After completion of puberty a subset of men experience functional hypogonadotropic hypogonadism (FHH) secondary to excessive exercise or weight loss. This phenomenon is akin to hypothalamic amenorrhea (HA) in women, yet little is known about FHH in men.

Objective - To investigate the neuroendocrine mechanisms, genetics, and natural history underlying FHH.

Design - Retrospective study in an academic medical center.

Participants - Healthy postpubertal men presenting with symptoms of hypogonadism in the setting of excessive exercise (>10 hours/week) or weight loss (>10% of body weight). Healthy age-matched men served as controls.

Interventions - Clinical assessment, biochemical and neuroendocrine profiling, body composition, semen analysis, and genetic evaluation of genes known to cause isolated GnRH deficiency.

Main Outcome Measures - Reproductive hormone levels, endogenous GnRH-induced LH pulse patterns, and rare genetic variants.

Results - Ten men with FHH were compared with 18 age-matched controls.

Patients had significantly lower body mass index, testosterone, LH, and mean LH pulse amplitudes yet normal LH pulse frequency, serum FSH, and sperm counts. Some patients exhibited nocturnal, sleep-entrained LH pulses characteristic of early puberty, and one FHH subject showed a completely apulsatile LH secretion.

After decreased exercise and weight gain, five men with men had normalized serum testosterone levels, and symptoms resolved. Rare missense variants in NSMF (n = 1) and CHD7 (n = 1) were identified in two men with FHH.

Conclusions - FHH is a rare, reversible form of male GnRH deficiency. LH pulse patterns in male FHH are similar to those observed in women with HA. This study expands the spectrum of GnRH deficiency disorders in men.

Dwyer AA, Chavan NR, Lewkowitz-Shpuntoff H, et al. Functional Hypogonadotropic Hypogonadism in Men: Underlying Neuroendocrine Mechanisms and Natural History. The Journal of Clinical Endocrinology & Metabolism 2019;104:3403-14. Functional Hypogonadotropic Hypogonadism in Men: Underlying Neuroendocrine Mechanisms and Natural History

 

[Michael Scally MD]

[OA] Exercise, Training, and the Hypothalamic–Pituitary–Gonadal Axis

According to the type and duration, physical exercise may influence positively and negatively the secretion of hormones related to the hypothalamic–pituitary–gonadal axis in males. Indeed, although acute exercise induces a rise in testosterone secretion, chronic, high-load/duration physical exercise reduces the activity of the hypothalamic–pituitary–gonadal axis. This different response of sexual hormones in males to physical exercise and training influences sexual and spermatogenetic functions that might be improved, maintained, or impaired.

Sgrò P. Exercise, training, and the hypothalamic–pituitary–gonadal axis in men. Current Opinion in Endocrine and Metabolic Research 2019;9:86-9. Exercise, training, and the hypothalamic–pituitary–gonadal axis in men - ScienceDirect

 

[Michael Scally MD]

[OA] Hypogonadism in Exercising Males: Dysfunction or Adaptive-Regulatory Adjustment?

For decades researchers have reported men who engaged in intensive exercise training can develop low resting testosterone levels, alterations in their hypothalamic-pituitary-gonadal (HPG) axis, and display hypogonadism.

Recently there is renewed interest in this topic since the International Olympic Committee (IOC) Medical Commission coined the term “Relative Energy Deficiency in Sports” (RED-S) as clinical terminology to address both the female-male occurrences of reproductive system health disruptions associated with exercise.

This IOC Commission action attempted to move beyond the sex-specific terminology of the “Female Athlete Triad” (Triad) and heighten awareness/realization that some athletic men do have reproductive related physiologic disturbances such as lowered sex hormone levels, HPG regulatory axis alterations, and low bone mineral density similar to Triad women.

There are elements in the development and symptomology of exercise-related male hypogonadism that mirror closely that of women experiencing the Triad/RED-S, but evidence also exists that dissimilarities exist between the sexes on this issue.

Our research group postulates that the inconsistency and differences in the male findings in relation to women with Triad/RED-S are not just due to sex dimorphism, but that there are varying forms of exercise-related reproductive disruptions existing in athletic men resulting in them displaying a relative hypogonadism condition.

Specifically, such conditions in men may derive acutely and be associated with low energy availability (Triad/RED-S) or excessive training load (overtraining) and appear transient in nature, and resolve with appropriate clinical interventions. However, manifestations of a more chronic based hypogonadism that persists on a more permanent basis (years) exist and is termed the “Exercise Hypogonadal Male Condition.”

This article presents an up-to-date overview of the various types of acute and chronic relative hypogonadism found in athletic, exercising men and proposes mechanistic models of how these various forms of exercise relative hypogonadism develop.

Hackney AC. Hypogonadism in Exercising Males: Dysfunction or Adaptive-Regulatory Adjustment? Frontiers in Endocrinology 2020;11:11. Hypogonadism in Exercising Males: Dysfunction or Adaptive-Regulatory Adjustment?

 

[Michael Scally MD]

[OA] Reproductive Dysfunction from Exercise Training: The "Exercise-Hypogonadal Male Condition"

The objective of this short review is to discuss how exercise training in men can result in changes in the reproductive system similar to those observed in women who develop athletic amenorrhea or suffer the Female Athlete Triad. Men chronically exposed to training for endurance sports exhibit persistently reduced basal free and total testosterone concentrations without concurrent luteinizing hormone elevations.

These men are deemed to have the "Exercise-Hypogonadal Male Condition" (EHMC). Broadly, dysfunction in the hypothalamic-pituitary-gonadal regulatory axis is associated with either of these states. In women this effect on the axis is linked to the existence of a low energy availability (LEA) state, research in men relative to LEA is ongoing.

The exact physiological mechanism inducing the reduction of testosterone in these men is currently unclear but is postulated to be a dysfunction within the hypothalamic-pituitary-gonadal regulatory axis. The potential exists for the reduced testosterone concentrations within EHMC men to be disruptive and detrimental to some anabolic-androgenic testosterone-dependent physiological processes. Findings, while limited, suggest spermatogenesis problems may exist in some cases; thus, infertility risk in such men is a critical concern.

Present evidence suggests the EHMC condition is limited to men who have been persistently involved in chronic endurance exercise training for an extended period of time, and thus is not a highly prevalent occurrence. Nevertheless, it is critical that endocrinologist and fertility clinicians become more aware of the existence of EHMC as a potential problem-diagnosis in their male patients who exercise.

Lane AR, Magallanes CA, Hackney AC. Reproductive Dysfunction from Exercise Training: The "Exercise-Hypogonadal Male Condition". Arch Med Deporte. 2019;36(5 193):319-322. Reproductive Dysfunction from Exercise Training: The “Exercise-Hypogonadal Male Condition”

 

[Michael Scally MD]

Intensive marathon running: Don’t over do it!
https://www.endocrine-abstracts.org/ea/0070/ea0070aep855.htm

Background: Secondary hypogonadism due to intensive exercise and eating disorders are well documented in females. But there very few reports of secondary hypogonadism due to intensive exercise in male patients.

Case presentation: A 34 year old Caucasian male, presented to our clinic with impaired fertility, lack of libido and increased fatigue. On further enquiry, he mentioned that he had starting running 3–4 yrs. ago, and had been running marathons over the last couple of years since, practicing regularly, runningup to 120 miles/week.

He had lost weight over this period. Moreover, he had become a vegan six months ago, and since then lost another one stone in weight. No history of any anabolic steroids or other hormonal misuse.

On examination, he had adequate secondary sexual characteristics, including male pattern baldness, and testicles were normal in size bilaterally (253 ml). His BMI was 20.

Biochemistry results showed hypogonadotropic hypogonadism (with LH 0.7 IU/l, FSH 3.7 IU/l, Testosterone 1.60 mIU/l). Other hormonal results are normal. (9 am Cortisol 453 nmol/l, Free T4 14 pmol/l, TSH 1.51 mIU/l, Prolactin 273 mu/l). MRI scan of Pituitary was normal. Sperm count showed Oligospermia.

As fertility was the main concern, in view of above results and with history of intensive training (for Marathons) and also recent dietary change, he was advised to reduce his activity levels, recommended to regain some weight and was also referred to a dietician.

At three months review, he had gained 10 kg in weight (and not following Vegan diet) and also reduced the running distance from 120 miles/week to just 40 miles/week and the repeat morning Testosterone has improved to 8.02 nmol/l. After following the same, at 6months review his weight was stable, and still doing only 40 miles/week of running, and the morning Testosterone levels are in normal range at 11. 83 nmol/l.

He had mentioned that his Partner is now pregnant. And his libido and erectile dysfunction have improved as well.

Conclusion: Intensive training for Marathon with dietary restriction have caused hypothalamic hypogonadism in this patient, and changes in exercise intensity and duration and weight gain with appropriate dietary changes, has resolved the Hypothalamic amenorrhoea spontaneously.