Andropause part 1 - An Introduction

Welcome to the ODX Andropause & Low T Syndrome Series. In this series of posts, the ODX Research team dives into Testosterone with an exploration of andropause and Low T Syndrome in our male patients.

The ODX Male Andropause Series

1. Andropause Part 1 – An Introduction
2. Andropause Part 2 – Biology & Physiology
3. Andropause Part 3 – How to identify it
4. Andropause Part 4 – Lab Assessment and Biomarker Guideposts
5. Andropause Part 5 – Clinical Determination
6. Andropause Part 6 – Lab Reference Ranges
7. Andropause Part 7 – How do we treat and counteract andropause?
8. Andropause Part 8 – Lifestyle approaches to addressing Andropause
9. Andropause Part 9 – Optimal Takeaways
10. Optimal The Podcast – Episode 9: Andropause

Testosterone is a vital hormone both for men and women. But its role is greatly significant among males, as it contributes to their muscle growth, sexual health, and other aspects of health.

 For men, the thought of being low on testosterone feels like a hit to their masculinity. What happens when your patient’s testosterone is low? How can you tell? What can you do to help them boost it?

 The dictionary definition of andropause is “a collection of symptoms, including fatigue and a decrease in libido, experienced by some middle-aged or older men and attributed to a gradual decline in testosterone levels.” [Oxford English Dictionary]

 Technically true andropause is caused by loss of testicular function due to disease, accidents, or therapeutic castration.[i] However, currently the term may be used to reference symptomatic decreases in T that occur later in life.

Andropause may also be referred to as:[ii] [iii] [iv]

• Adult male hypogonadism
• Aging male syndrome (AMS)
• Androgen decline in aging male (ADAM)­
• Low T syndrome
• Late-onset hypogonadism (LOH)
• Male climacteric
• Male senescence
• Partial androgen deficiency in the aging male (PADAM)
• Symptomatic late-onset hypogonadism (SLOH)
• T deficiency syndrome
• Testosterone deficit syndrome
• Viropause

At present, the term low T syndrome is commonly used in online communications and commercial settings. In the published literature, the term late-onset hypogonadism/LOH is often used and refers to an age-related decline in testosterone accompanied by symptoms including a reduction in a general sense of well-being, declining libido, and erectile dysfunction.[v]

Other concurrent symptoms that may affect the quality of life include changes in skin quality, hair loss, mood changes, depression, low energy, memory issues, and loss of physical strength and agility.[vi]

For diagnostic purposes, researchers suggest using a minimum of three sexually related symptoms in conjunction with consistently low serum T.

The European Male Ageing Study (EMAS) specifies diagnostic criteria for LOH as: [vii]

• At least 3 sexually-related symptoms
  • Erectile dysfunction, decreased morning erections, and decreased libido or sexual thoughts
• Reproducibly low serum levels:
  • Total T below 320 ng/dL (11 nmol/L)
  • Free T below 64 pg/mL (220 pmol/L)
• If total T drops below 231 ng/dL (8 nmol/L), LOH is considered “severe.”[viii]

The main causes of low testosterone in LOH:[ix]

• Primary testicular failure
  • Low T, high luteinizing hormone (LH a pituitary hormone that stimulates testosterone production)
• Secondary to hypothalamic-pituitary failure
  • Low T, low or normal LH
  • More common
  • Associated with obesity or chronic disease (metabolic syndrome, diabetes, cardiovascular disease, COPD, frailty)

Testosterone

Testosterone is a steroid androgen hormone synthesized from cholesterol.[x] Circulating testosterone is found in three different forms, mainly: [xi]

~60-70%         Bound tightly to sex hormone binding globulin (SHBG)

~30-40%         Bound loosely to albumin

~2-3%             Free, unbound, active form

 However, research notes that some circulating T is also bound to cortisol-binding globulin (CBG) and orosomucoid, binding proteins that help regulate transport, delivery, and availability of testosterone.[xii]

In LOH, both total and free T levels can decline by ~1% per year, a rate affected by disease state, emotional stress, medication, obesity, and especially expanded waist circumference (abdominal obesity). Free T may have a more pronounced decline due to alterations in SHBG. [xiii]

A 1-2% decline in total serum T translates into an annual decline of ~3.2–3.5 ng/dL (0.110–0.121 nmol/L) after age 30.[xiv]

Prevalence

While the exact prevalence is unknown, some clinical studies suggest hypogonadism may affect ~39% of men 45 years or older using total testosterone (TT) cutoff of less than 300 ng/dL (10.4 nmol/L), a level associated with reduced bone mineral density.[xv]

However, using strict diagnostic criteria, data from the EMAS suggests an overall LOH prevalence of 2.1%, with increased prevalence as BMI and comorbidities increase. Prevalence is expected to change with advancing age:[xvi]

0.1% 40-49 years old

0.6% 50-59 years old

3.2% 60- 69 years old

5.1% 70-79 years old

Additional observations suggest further variations in the prevalence of LOH, especially when diagnostic criteria vary:[xvii]

• Massachusetts Male Aging Study (MMAS)
  • 6% overall prevalence, 18.4% in those over 70 years
• Boston Area Community Health Survey
  • 6% prevalence ages 30-79 years, increased prevalence over age 70
• Baltimore Longitudinal Study of Aging (BLSA)
  • 12% for men in their 50s
  • 20% for men in their 60s
  • 30% for men in their 70s
  • 50% for men in their 80s
• Testosterone trials with cutoff of less than 275 ng/dL (9.5 nmol/L)
  • 8% for men over 65

Odds ratios of having LOH increased significantly in the presence of the following:[xviii]

Prostate disease         1.29

Asthma or COPD       1.4

Hyperlipidemia            1.47

Hypertension               1.84

Diabetes                      2.09

Obesity                        2.38

Optimal Takeaways for Andropause / Low T syndrome / LOH Overview

• In some men, testosterone production and availability decrease with advancing age.
• When the decline is associated with sexual symptoms, the phenomenon is described as late onset hypogonadism (LOH)
• Secondary LOH is more likely in those with obesity or chronic metabolic disorders such as diabetes and cardiovascular disease.
• Diagnosis is dependent on repeatedly low serum testosterone coupled with sexual symptoms.
• Prevalence increases with advancing age.
• EMAS criteria for diagnosis of LOH:
  • At least 3 sexually-related symptoms
    • Erectile dysfunction,
    • decreased morning erections, and
    • decreased libido or sexual thoughts

• Reproducibly low serum levels:
  • Total T below 320 ng/dL (11 nmol/L)
  • Free T below 64 pg/mL (220 pmol/L)

NEXT UP: Andropause Part 2 – Biology & Physiology

Research

[i] Singh, Parminder. “Andropause: Current concepts.” Indian journal of endocrinology and metabolism vol. 17,Suppl 3 (2013): S621-9. doi:10.4103/2230-8210.123552

[ii] Rogers, Linda C. "The role of the laboratory in diagnosing andropause (male menopause)." Laboratory Medicine 36.12 (2005): 771-773

[iii] Karakas, Sidika E, and Prasanth Surampudi. “New Biomarkers to Evaluate Hyperandrogenemic Women and Hypogonadal Men.” Advances in clinical chemistry vol. 86 (2018): 71-125. doi:10.1016/bs.acc.2018.06.001 

[iv] Giagulli, Vito Angelo et al. “Critical evaluation of different available guidelines for late-onset hypogonadism.” Andrology vol. 8,6 (2020): 1628-1641. doi:10.1111/andr.12850 

[v] Singh, Parminder. “Andropause: Current concepts.” Indian journal of endocrinology and metabolism vol. 17,Suppl 3 (2013): S621-9. doi:10.4103/2230-8210.123552

[vi] Rogers, Linda C. "The role of the laboratory in diagnosing andropause (male menopause)." Laboratory Medicine 36.12 (2005): 771-773

[vii] Huhtaniemi, Ilpo. “Late-onset hypogonadism: current concepts and controversies of pathogenesis, diagnosis and treatment.” Asian journal of andrology vol. 16,2 (2014): 192-202. doi:10.4103/1008-682X.122336 

[viii] Pye, S R et al. “Late-onset hypogonadism and mortality in aging men.” The Journal of clinical endocrinology and metabolism vol. 99,4 (2014): 1357-66. doi:10.1210/jc.2013-2052 

[ix] Huhtaniemi, Ilpo. “Late-onset hypogonadism: current concepts and controversies of pathogenesis, diagnosis and treatment.” Asian journal of andrology vol. 16,2 (2014): 192-202. doi:10.4103/1008-682X.122336 

[x] Dudek, Piotr et al. “Late-onset hypogonadism.” Przeglad menopauzalny = Menopause review vol. 16,2 (2017): 66-69. doi:10.5114/pm.2017.68595 

[xi] Clapauch, Ruth et al. “Laboratory diagnosis of late-onset male hypogonadism andropause.” Arquivos brasileiros de endocrinologia e metabologia vol. 52,9 (2008): 1430-8. doi:10.1590/s0004-27302008000900005 

[xii] Goldman, Anna L et al. “A Reappraisal of Testosterone's Binding in Circulation: Physiological and Clinical Implications.” Endocrine reviews vol. 38,4 (2017): 302-324. doi:10.1210/er.2017-00025 

[xiii] Singh, Parminder. “Andropause: Current concepts.” Indian journal of endocrinology and metabolism vol. 17,Suppl 3 (2013): S621-9. doi:10.4103/2230-8210.123552

[xiv] Decaroli, Maria Chiara, and Vincenzo Rochira. “Aging and sex hormones in males.” Virulence vol. 8,5 (2017): 545-570. doi:10.1080/21505594.2016.1259053 

[xv] Mulligan, T et al. “Prevalence of hypogonadism in males aged at least 45 years: the HIM study.” International journal of clinical practice vol. 60,7 (2006): 762-9. doi:10.1111/j.1742-1241.2006.00992.x 

[xvi] Wu, Frederick C W et al. “Identification of late-onset hypogonadism in middle-aged and elderly men.” The New England journal of medicine vol. 363,2 (2010): 123-35. doi:10.1056/NEJMoa0911101

[xvii] Karakas, Sidika E, and Prasanth Surampudi. “New Biomarkers to Evaluate Hyperandrogenemic Women and Hypogonadal Men.” Advances in clinical chemistry vol. 86 (2018): 71-125. doi:10.1016/bs.acc.2018.06.001

[xviii] Mulligan, T et al. “Prevalence of hypogonadism in males aged at least 45 years: the HIM study.” International journal of clinical practice vol. 60,7 (2006): 762-9. doi:10.1111/j.1742-1241.2006.00992.x