late-onset hypogonadism

Some men present with symptoms, but they have normal testosterone levels, while others with low testosterone levels have no symptoms. The reasons for this phenomenon are currently unknown.

In their late 40s and early 50s, some men may experience depression, loss of libido, erectile dysfunction, and other physical and emotional symptoms. These symptoms include irritability, loss of muscle mass and reduced ability to exercise, weight gain, lack of energy, difficulty sleeping, and poor concentration. It is important to note that many of these symptoms may arise from a midlife crisis or as the results of a long-term unhealthy lifestyle (smoking, excess drinking, overeating, lack of exercise) and may be best addressed by lifestyle changes, therapy, or antidepressants.

Testosterone levels are well-documented to decline with aging at about 1% per year in both men and women after a certain age; the causes are not well understood.{{cite web|title=Could you have low testosterone?: MedlinePlus Medical Encyclopedia|url=https://medlineplus.gov/ency/patientinstructions/000722.htm|publisher=NIH: Medline Plus|date=September 18, 2014}}{{cite journal|last1=Huhtaniemi|first1=I|title=Late-onset hypogonadism: current concepts and controversies of pathogenesis, diagnosis and treatment.|journal=Asian Journal of Andrology|date=2014|volume=16|issue=2|pages=192–202|pmid=24407185|pmc=3955328|doi=10.4103/1008-682x.122336|doi-access=free}}

As of 2016, the International Society for the Study of the Aging Male defines late-onset hypogonadism as a series of symptoms in older adults related to testosterone deficiency that combines features of both primary and secondary hypogonadism; the European Male Aging Study (a prospective study of ~3000 men){{cite journal|last1=Wu|first1=FC |display-authors=etal |last2=EMAS Study Group|title=Identification of late-onset hypogonadism in middle-aged and elderly men.|journal=The New England Journal of Medicine|date=8 July 2010|volume=363|issue=2|pages=123–35|pmid=20554979|doi=10.1056/NEJMoa0911101|hdl=10044/1/19214|s2cid=15635078 |url=http://spiral.imperial.ac.uk/bitstream/10044/1/19214/2/New%20England%20Journal%20of%20Medicine_363_2_2010.pdf|hdl-access=free}} defined the condition by the presence of at least three sexual symptoms (e.g. reduced libido, reduced spontaneous erections, and erectile dysfunction) and total testosterone concentrations less than 11 nmol/L (3.2 ng/mL) and free testosterone concentrations less than 220 pmol/L (64 pg/mL).

If a person has symptoms of late-onset hypogonadism, testosterone is measured by taking blood in the morning on at least two days; while immunoassays are commonly used, mass spectrometry is more accurate and is becoming more widely available. The meaning of the measurement is different depending on many factors that affect how testosterone is made and how it is carried in the blood. Increased concentrations of proteins that bind testosterone in blood occur if the person is older, has hyperthyroidism or liver disease, or is taking anticonvulsant drugs (which are increasingly used for depression and various neuropathies), and decreased concentrations of proteins that bind testosterone occur if the person is obese, has diabetes, has hypothyroidism, has liver disease, or is taking glucocorticoids or androgens, or progestins. If levels are low, conditions that cause primary and secondary hypogonadism need to be ruled out.{{cite journal|last1=Bhasin|first1=S|last2=Cunningham|first2=GR|last3=Hayes|first3=FJ|last4=Matsumoto|first4=AM|last5=Snyder|first5=PJ|last6=Swerdloff|first6=RS|last7=Montori|first7=VM|last8=Task Force, Endocrine Society|title=Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.|journal=The Journal of Clinical Endocrinology and Metabolism|date=June 2010|volume=95|issue=6|pages=2536–59|pmid=20525905|doi=10.1210/jc.2009-2354|s2cid=20816995|doi-access=}}{{cite journal|last1=Seftel|first1=AD|last2=Kathrins|first2=M|last3=Niederberger|first3=C|title=Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systematic Analysis.|journal=Mayo Clinic Proceedings|date=August 2015|volume=90|issue=8|pages=1104–15|pmid=26205546|doi=10.1016/j.mayocp.2015.06.002|doi-access=free}}

Due to difficulty and expense of testing, and the ambiguity of the results, screening is not recommended.{{cite journal|last1=Basaria|first1=S|title=Male hypogonadism.|journal=Lancet|date=5 April 2014|volume=383|issue=9924|pages=1250–63|pmid=24119423|doi=10.1016/s0140-6736(13)61126-5|s2cid=30479724}} While some clinical instruments (standard surveys) had been developed as of 2016, their specificity was too low to be useful clinically.

{{See also|Androgen replacement therapy}}

The significance of a decrease in testosterone levels is debated and its treatment with replacement is controversial. The Food and Drug Administration (FDA) stated in 2015 that neither the benefits nor the safety of testosterone have been established in older men with low testosterone levels.{{cite web|url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm436280.htm|title=FDA Cautions About Using Testosterone Products for Low Testosterone Due to Aging; Requires Labeling Change to Inform of Possible Increased Risk of Heart Attack And Stroke|author=Staff|date=3 March 2015|work=FDA|access-date=5 March 2015}}. NEJM Perspective piece: {{cite journal|last1=Nguyen|first1=CP|display-authors=etal|date=20 August 2015|title=Testosterone and "Age-Related Hypogonadism"--FDA Concerns.|journal=The New England Journal of Medicine|volume=373|issue=8|pages=689–91|doi=10.1056/nejmp1506632|pmid=26287846|pmc=8905399 }}. Popular summary: {{cite news|last=Tavernise|first=Sabrina|url=https://www.nytimes.com/2015/03/04/health/drugs-using-testosterone-will-label-heart-risks.html|title=Drugs Using Testosterone Will Label Heart Risks|date=March 3, 2015|work=New York Times|access-date=March 19, 2015}}

Testosterone replacement therapy should only be started if low levels have been confirmed; in the US, this confirmation is not done about 25% of the time, as of 2015. Testosterone levels should also be monitored during therapy.

{{Androgen replacement therapy formulations and dosages used in men}}

{{See also|Testosterone (medication)#Adverse effects}}

Adverse effects of testosterone supplementation may include increased cardiovascular (CV) events (including strokes and heart attacks) and deaths, especially in men over 65 and men with pre-existing heart conditions. The potential for CV risks from testosterone therapy led the FDA to issue a requirement in 2015 that testosterone pharmaceutical labels include warning information about the possibility of an increased risk of heart attacks and stroke. However, the data are mixed, so the European Medicines Agency, the American Association of Clinical Endocrinologists, and the American College of Endocrinology have stated that no consistent evidence shows that testosterone therapy either increases or decreases cardiovascular risk.

Other significant adverse effects of testosterone supplementation include acceleration of pre-existing prostate cancer growth; increased hematocrit, which can require venipuncture to treat; and, exacerbation of sleep apnea.

Adverse effects may also include minor side effects such as acne and oily skin, as well as significant hair loss and/or thinning of the hair, which may be prevented with 5-alpha reductase inhibitors ordinarily used for the treatment of benign prostatic hyperplasia, such as finasteride or dutasteride.{{cite journal|pmc=4212439|title=Adverse effects of testosterone replacement therapy: an update on the evidence and controversy|first1=Anthony|last1=Grech|first2=John|last2=Breck|first3=Joel|last3=Heidelbaugh|date=7 October 2016|journal=Ther Adv Drug Saf|volume=5|issue=5|pages=190–200|doi=10.1177/2042098614548680|pmid=25360240}}

Exogenous testosterone may also cause suppression of spermatogenesis, leading to, in some cases, infertility.

As of 2015, the evidence is inconclusive as to whether testosterone replacement therapy can help with erectile dysfunction in men with late-onset hypogonadism. It appears that testosterone replacement therapy may benefit men with symptoms of frailty who have late-onset hypogonadism.

The epidemiology is not clear; 20% of men in their 60s and 30% of men in their 70s have low testosterone; around 5% of men between 70 and 79 have both low testosterone and the symptoms, so are diagnosed with late-onset hypogonadism. The UK National Health Service describes it as rare.

Testosterone synthesis involves the hypothalamic-pituitary-gonadal (HPG) axis. As aging occurs both gonadal and hypothalamic-pituitary functions decline.{{Cite journal |last=Golan |first=Ron |last2=Scovell |first2=Jason M. |last3=Ramasamy |first3=Ranjith |date=2015-07-03 |title=Age-related testosterone decline is due to waning of both testicular and hypothalamic-pituitary function |url=http://www.tandfonline.com/doi/full/10.3109/13685538.2015.1052392 |journal=The Aging Male |language=en |volume=18 |issue=3 |pages=201–204 |doi=10.3109/13685538.2015.1052392 |issn=1368-5538 |pmc=4816459}} This reduced secretion of testosterone can be caused by old age which usually results in primary hypogonadism.{{Cite journal |last=Tajar |first=Abdelouahid |last2=Forti |first2=Gianni |last3=O'Neill |first3=Terence W. |last4=Lee |first4=David M. |last5=Silman |first5=Alan J. |last6=Finn |first6=Joseph D. |last7=Bartfai |first7=György |last8=Boonen |first8=Steven |last9=Casanueva |first9=Felipe F. |last10=Giwercman |first10=Aleksander |last11=Han |first11=Thang S. |last12=Kula |first12=Krzysztof |last13=Labrie |first13=Fernand |last14=Lean |first14=Michael E. J. |last15=Pendleton |first15=Neil |date=2010-04-01 |title=Characteristics of Secondary, Primary, and Compensated Hypogonadism in Aging Men: Evidence from the European Male Ageing Study |url=https://academic.oup.com/jcem/article-abstract/95/4/1810/2597149?redirectedFrom=fulltext |journal=The Journal of Clinical Endocrinology & Metabolism |volume=95 |issue=4 |pages=1810–1818 |doi=10.1210/jc.2009-1796 |issn=0021-972X}} The dysfunction of this system is due to degradation of Leydig cells which causes testosterone levels to drop.{{Cite journal |last=RUBENS |first=R. |last2=DHONT |first2=M. |last3=VERMEULEN |first3=A. |date=1974-07-01 |title=Further Studies on Leydig Cell Function in Old Age |url=https://academic.oup.com/jcem/article-abstract/39/1/40/2685431?redirectedFrom=fulltext |journal=The Journal of Clinical Endocrinology & Metabolism |volume=39 |issue=1 |pages=40–45 |doi=10.1210/jcem-39-1-40 |issn=0021-972X}} There have been a number of cellular changes identified that affect the production of testosterone as age increases. Some of these include luteinizing hormone and cAMP production.{{Cite journal |last=Beattie |first=M. C. |last2=Adekola |first2=L. |last3=Papadopoulos |first3=V. |last4=Chen |first4=H. |last5=Zirkin |first5=B. R. |date=2015-08-01 |title=Leydig cell aging and hypogonadism |url=https://www.sciencedirect.com/science/article/abs/pii/S0531556515000765?via=ihub |journal=Experimental Gerontology |series=Proceedings of the Twelfth International Symposium on the Neurobiology and Neuroendocrinology of Aging, Bregenz, Austria July 27–August 1, 2014 |volume=68 |pages=87–91 |doi=10.1016/j.exger.2015.02.014 |issn=0531-5565|pmc=5662440 }} Though it is seen that when secondary hypogonadism occurs it can be linked to obesity and other risk factors rather than old age. When it comes to testosterone deficiency in men who have obesity the issue begins at the gonadotrophin releasing hormone neurons. As a result the hypogonadism that was originally caused by obesity can result in obesity symptoms worsening.{{Cite journal |last=Fernandez |first=Cornelius J. |last2=Chacko |first2=Elias C. |last3=Pappachan |first3=Joseph M. |date=August 2019 |title=Male Obesity-related Secondary Hypogonadism - Pathophysiology, Clinical Implications and Management |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC6785957/ |journal=European Endocrinology |volume=15 |issue=2 |pages=83–90 |doi=10.17925/EE.2019.15.2.83 |issn=1758-3780 |pmc=6785957 |pmid=31616498}}

The impact of low levels of testosterone has been previously reported. In 1944, Heller and Myers identified symptoms of what they labeled the "male climacteric" including loss of libido and potency, nervousness, depression, impaired memory, the inability to concentrate, fatigue, insomnia, hot flushes, and sweating. Heller and Myers found that their subjects had lower than normal levels of testosterone, and that symptoms decreased dramatically when patients were given replacement doses of testosterone.{{cite journal|last1=Gabrielsen|first1=JS|last2=Najari|first2=BB|last3=Alukal|first3=JP|last4=Eisenberg|first4=ML|title=Trends in Testosterone Prescription and Public Health Concerns.|journal=The Urologic Clinics of North America|date=May 2016|volume=43|issue=2|pages=261–71|pmid=27132584|doi=10.1016/j.ucl.2016.01.010}}{{cite journal|last1=Heller|first1=CG|last2=Myers|first2=GB|title=The male climacteric, its symptomatology, diagnosis and treatment|journal=Journal of the American Medical Association|date=21 October 1944|volume=126|issue=8|pages=472|doi=10.1001/jama.1944.02850430006003}}

The 1997 book Male Menopause

{{cite book

| last1 = Diamond

| first1 = Jed

| title = Male Menopause

| year = 1997

| url = https://books.google.com/books?id=6Mskf40M1w4C

| edition = reprint

| publisher = Sourcebooks

| publication-date = 1997

| isbn = 9781570711435

| access-date = 7 August 2020

}}

{{cite book |author= Diamond, Jed |title= Male Menopause |publisher= Sourcebooks |location= Naperville, Ill |year= 1998 |isbn= 978-1-57071-397-2 |url= https://archive.org/details/isbn_9781570713972 }} by Jed Diamond, a psychologist with a PhD in international health,

{{cite news

| last1 = James

| first1 = Susan Donaldson

| title = Low-T Syndrome: Another Word for Male Menopause

| url = https://abcnews.go.com/Health/MensHealthNews/story?id=8279787&page=1

| work = ABC News

| publisher = ABC News Internet Ventures

| publication-date = 8 August 2009

| access-date = 7 August 2020

| quote = 'Male menopause is real,' said Jed Diamond, a psychologist and author of a series of books on the topic, including, 'Irritable Male Syndrome.' [...] 'Men are more in denial about this than women,' said Diamond, who has a Ph.D. in international health and a master's degree in social work.

}}

fueled popular interest in the concept of "andropause".{{citation needed|date=August 2020}}

Diamond regards andropause as a change of life in middle-aged men which has hormonal, physical, psychological, interpersonal, social, sexual, and spiritual aspects. Diamond claims that this change occurs in all men, that it may occur as early as age 45 to 50 and more dramatically after the age of 70 in some men, and that women's and men's experiences are somewhat similar phenomena.{{cite book |author =Diamond, Jed |title= Surviving Male Menopause. A Guide for Women and Men |publisher= Sourcebooks |location= Naperville, Ill |year= 2000 |isbn= 978-1-57071-433-7 |url= https://archive.org/details/survivingmalemen00jedd_0 }}{{cite book |author= Tan, Robert S. |title= The andropause mystery: unraveling truths about the male menopause |publisher= AMRED Pub |location= Houston, Tex |year= 2001 |isbn= 978-0-9707061-0-2}} The medical community has rejected the term "andropause" and its supposed parallels with menopause.

{{cite web

|url= https://www.nhs.uk/conditions/male-menopause/

|title= The 'male menopause'

|date= 19 February 2019

|publisher= NHS

|agency= NHS

|access-date= 7 August 2020

|quote= The 'male menopause' (sometimes called the andropause) is an unhelpful term sometimes used in the media.

}}

Compare: {{cite web|last1= Gorski|first1= David|title= "Low T": The triumph of marketing over science « Science-Based Medicine|url= https://www.sciencebasedmedicine.org/low-t-the-triumph-of-marketing-over-science/|publisher= Science-Based Medicine|date= November 25, 2013 | quote = There is a paucity of evidence that 'low T' is the problem that it is advertised to be and even less evidence that testosterone replacement therapy corrects the problems attributed to 'low T.' Before pharmaceutical companies launch big money campaigns to make millions of men 'aware' of low T, they should be required to do what they have to do before introducing a new drug for a new indication: the appropriate large-scale randomized trials to demonstrate that testosterone therapy for otherwise-healthy aging men whose testosterone levels are below the normal range for young men does more good than harm. Right now, we don't have that evidence, and we're not likely to get it from pharmaceutical companies.}}

Thomas Perls and David J. Handelsman, in a 2015 editorial in the Journal of the American Geriatrics Society, say that between the ill-defined nature of the diagnosis and the pressure and advertising from drug companies selling testosterone and human-growth hormone, as well as dietary supplement companies selling all kinds of "boosters" for aging men, the condition is overdiagnosed and overtreated.{{cite journal|last1= Perls|first1= T|last2= Handelsman|first2= DJ|title= Disease mongering of age-associated declines in testosterone and growth hormone levels |journal= Journal of the American Geriatrics Society|date= April 2015|volume= 63|issue= 4|pages= 809–11|pmid= 25809947|doi= 10.1111/jgs.13391|doi-access= free}}

Perls and Handelsman note that in the US, "sales of testosterone increased from $324 million in 2002 to $2 billion in 2012, and the number of testosterone doses prescribed climbed from 100 million in 2007 to half a billion in 2012, not including the additional contributions from compounding pharmacies, Internet, and direct-to-patient clinic sales."

Late-onset hypogonadism is an endocrine condition as well as a result of aging.

The terms "male menopause" and "andropause" are used in the popular media but are misleading, as they imply a sudden change in hormone levels similar to what women experience in menopause.{{cite web|title=Male Menopause|url=http://www.nhs.uk/conditions/Male-menopause/Pages/Introduction.aspx|website=www.nhs.uk|publisher=NHS Choices|date=April 8, 2016|access-date=October 7, 2016|archive-date=October 9, 2016|archive-url=https://web.archive.org/web/20161009181414/http://www.nhs.uk/conditions/Male-menopause/Pages/Introduction.aspx|url-status=dead}} A decrease in libido in men as a result of age is sometimes colloquially referred to as penopause.Gooren, L. J. G. "The age‐related decline of androgen levels in men: clinically significant?." British journal of urology 78.5 (1996): 763-768.

As of 2016, research was necessary to find better ways to measure testosterone and to be better able to understand the measurements in any given person, and to understand why some people with low testosterone do not present with symptoms and some with seemingly adequate levels do present with symptoms. Research was also necessary to better understand the cardiovascular risks of testosterone replacement therapy in older men.

A relationship between late-onset hypogonadism and risk of Alzheimer's disease has been hypothesized, and some small clinical studies have been conducted to investigate the prevention of Alzheimer's disease in men with late-onset hypogonadism; as of 2009, results were inconclusive.{{cite book|last1=Cherrier|first1=MM|title=Testosterone effects on cognition in health and disease.|journal=Frontiers of Hormone Research|date=2009|volume=37|pages=150–62|pmid=19011295|doi=10.1159/000176051|isbn=978-3-8055-8622-1}}

• Androgen deficiency
• Menopause
• European Menopause and Andropause Society

{{Reflist}}

{{Reproductive physiology}}

{{Authority control}}

Category:Endocrinology

Category:Menopause

Category:Middle age

Category:Testosterone

Category:Andrology