LOW TESTOSTERONE
















References [1,2,3]
Primary hypogonadism
Cause Risk factors/Symptoms/Other
Klinefelter's syndrome
  • 1 in 600 births
  • Small, firm testes or undescended testes
  • Underdeveloped genitalia, infertility
  • Reduced body hair, gynecomastia
  • Tall stature, learning disabilities
Undescended testes or ectopic testes
  • Also called cryptorchidism
  • 85% idiopathic
Testicular trauma
  • Blunt trauma
  • Testicular torsion
Orchitis
  • Infections (ex. mumps)
Cancer treatment
  • Alkylating chemotherapeutic agents (ex. cyclophosphamide)
  • Radiation
Varicocele
  • Possible cause
Defects of steroid biosynthesis
  • 17,20 desmolase defect
  • 17β-hydroxysteroid dehydrogenase defect
Y-chromosome defects
  • Microdeletions
  • 46, XX male syndrome (1 in 10,000 - 20,000 births)
  • 47,XYY syndrome (1 in 2,000 births)
Noonan syndrome
  • Cryptorchidism, short stature, short neck
  • Deep philtrum, wide-spaced eyes, heart defects
LH receptor mutations
  • 1 in 20,000 to 1 in 1,000,000 births
  • Leydig cells do not develop


References [1,2,3,28,29]
Secondary hypogonadism
Cause Comments
Unknown
  • Most common
  • Often seen in obese men
  • May be secondary to increased estradiol production in adipose tissue
Hyperprolactinemia
Isolated hypogonadotropic hypogonadism (IHH)
  • GnRH deficiency
Kallmann syndrome
  • 1 in 10,000 to 86,000 births
  • GnRH deficiency and no sense of smell (anosmia)
  • Cryptorchidism, cleft palate, hearing loss
  • Bimanual synkinesis - movements of one hand are mirrored by the other hand
Hypopituitarism
  • Radiation therapy-induced
  • Head trauma
  • Infections (tuberculosis)
  • Infiltrative diseases (hemochromatosis, sarcoidosis, histiocytosis)
  • Vascular insufficiency (stroke)
  • Congenital
Pituitary adenomas
  • Both hormone-secreting and inactive
  • Visual field defects may be present (mass effect)
Prader-Willi syndrome
  • 1 in 10,000 births
  • Congenital disturbance of GnRH
  • Chronic overeating, underdeveloped genitals
  • Mild-to-moderate learning disabilities
Congenital adrenal hypoplasia
with hypogonadotropic hypogonadism
  • 1 in 12,500 births
  • X-chromosome recessive disease
Pasqualini syndrome
  • Isolated LH deficiency
LH or FSH mutations
  • Mutations in the Beta subunit






  • Ranges are based on log hormone concentrations since their distribution is skewed
  • Reference [4]
Average age
of sample		 Average
testosterone level
∼ 95% CI		 Average free
testosterone level
∼ 95% CI
55
(N=1667)		 517 ng/dl
(17.9 nmol/l)
167 - 867 ng/dl
(5.8 - 30 nmol/L)		 11.5 ng/dl
(0.4 nmol.l)
2.9 - 20.1 ng/dl
(0.10 - 0.70 nmol/l)
62
(N=947)		 459 ng/dl
(15.9 nmol/l)
145 - 773 ng/dl
(5.03 - 26.8 nmol/L)		 9.3 ng/dl
(0.32 nmol/l)
3.3 - 15.3 ng/dl
(0.11 - 0.53 nmol/l)
68
(N=584)		 414 ng/dl
(14.4 nmol/l)
94 - 734 ng/dl
(3.3 - 25.5 nmol/L)		 7.1 ng/dl
(0.25 nmol/l)
1.9 - 12.3 ng/dl
(0.066 - 0.43 nmol/l)





  • To convert ng/dl to nmol/l, multiply ng/dl by 0.0347
  • 1CPL labs
  • 2LabCorp®
  • 3PMID 26707506
Total testosterone3 Free testosterone
(calculated)1		 Free testosterone
(equilibrium dialysis)2 		Bioavailable2
231 - 850 ng/dl
(8 - 29.5 nmol/l)		 4.8 - 25 ng/dl 52 - 280 pg/ml
(1.5 - 3.2%)		 40 - 250 ng/dl
(9 - 46% of total)






  • Reference [1,2,3]
Finding Considerations
Delayed or absent sexual development
  • Primary hypogonadism
  • Consider genetic studies for Klinefelter's, etc.
Gynecomastia / galactorrhea
  • Consider hyperprolactinemia
  • Check prolactin
  • MRI to rule out prolactinoma
  • Consider medications that raise prolactin (antipsychotics, metoclopramide, etc.)
Low impact fractures
  • Bone mineral density testing
Visual field defects
  • MRI to look for pituitary mass
Skin hyperpigmentation
  • Consider hemochromatosis
  • Check iron level
  • Diabetes and liver disease are commonly present
Centripetal obesity / moon facies / abdominal striae
  • Consider Cushing's syndrome
















  • Reference [3,30]
Recommendations for monitoring therapy
EAU recommendations
  • Therapy response - assess at 3, 6, and 12 months after initiating therapy and annually thereafter
  • Testosterone level - there is insufficient data to recommend an ideal range. Therapy should restore levels to mid-normal range. Testosterone levels should be checked according to product guidelines. (see testosterone replacement therapies for product-specific recommendations)
  • Hematocrit - obtain baseline level. Monitor at 3, 6, and 12 months after initiating therapy and annually thereafter. Decrease or discontinue therapy if elevated.
  • PSA - obtain baseline PSA and rectal exam. Recheck PSA at 3, 6, and 12 months after initiating therapy and annually thereafter.
  • Bone Mineral Density (BMD) - in men with abnormal BMD, recheck BMD at 6 months and 1 year after starting therapy, and annually thereafter
  • Cardiovascular disease - men with baseline cardiovascular disease should be assessed by a cardiologist before starting therapy and monitored thereafter [3]
Endocrine Society recommendations
  • Therapy response - assess at 3 to 12 months after initiating therapy and annually thereafter
  • Testosterone level - recheck at 3 to 6 months after initiating therapy. Therapy should restore levels to mid-normal range.

    • Therapy-specific recommendations:
      • Testosterone enanthate or cypionate injections - measure serum testosterone concentrations midway between injections. If midinterval testosterone is > 600 ng/dL (24.5 nmol/L) or < 350 ng/dL (14.1 nmol/L), adjust dose or frequency.
      • Transdermal gels - assess testosterone concentrations 2 - 8 hours following the gel application, after the patient has been on treatment for at least 1 week
      • Transdermal patches - assess testosterone concentrations 3 - 12 hours after application
      • Buccal tablet - assess testosterone concentrations immediately before or after application of fresh system
      • Pellets - measure testosterone concentrations at the end of the dosing interval
      • Testosterone undecanoate (Aveed) - measure serum testosterone levels at the end of the dosing interval just prior to the next injection
      • See testosterone replacement therapies for more

  • Hematocrit - obtain baseline level. Recheck at 3 to 6 months after initiating therapy and annually thereafter. If hematocrit is > 54%, stop therapy until decreases to safe level, evaluate patient for hypoxia and sleep apnea, reinitiate therapy at a reduced dose.
  • Bone Mineral Density (BMD) - in men with abnormal BMD, recheck BMD after 1 to 2 years of testosterone therapy
  • PSA - in men 55 - 69 years of age and for men 40 - 69 years of age who are at increased risk for prostate cancer (African Americans or men with first-degree relatives with prostate cancer), perform digital rectal examination and check PSA level before initiating treatment. Check PSA and perform digital rectal examination 3 - 12 months after initiating testosterone treatment, and then in accordance with guidelines for prostate cancer screening depending on the age and race of the patient.

    • Obtain urology consult for the following:
      • An increase in serum or plasma PSA concentration greater than 1.4 ng/ml within 12 months of initiating treatment
      • PSA > 4 ng/ml
      • Detection of a prostatic abnormality on digital rectal examination
      • Worsening of lower urinary tract symptoms [30]

















Physical function and vitality studies
Testosterone gel vs Placebo in Older Men with Hypogonadism, NEJM (2016) [PubMed abstract]
  • Design: Randomized, placebo-controlled trials (N=790, length = 1 year) in men ≥ 65 years old and testosterone < 275 ng/dl
  • Treatment: Testosterone gel 1% vs Placebo gel for 1 year. Dose was adjusted to keep testosterone within normal range.
  • Primary outcomes: 1. Sexual function 2. 6-minute walking distance 3. Functional Assessment of Chronic Illness Therapy-Fatigue scale
  • Results:
    • Primary outcomes: Testosterone was significantly better for sexual function (p<0.001) but not for 6-min walk test (p=0.20) or functional assessment (p=0.30)
  • Findings: In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment.
TOM trial - Testosterone gel vs Placebo in Older Men with Mobility Limitations, NEJM (2010) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=209, length = 6 months) in men ≥ 65 years old with mobility limitations and testosterone level of 100 - 350 ng/dl
  • Treatment: Testosterone gel 1% vs Placebo gel for 6 months. Dose was adjusted to keep testosterone > 500 ng/dl.
  • Primary outcome: Change from baseline in maximal voluntary muscle strength in a leg-press exercise
  • Results: The trial was stopped early due to higher rate of adverse cardiovascular events in the testosterone group
  • Findings: In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy.

Sexual function
Testosterone gel vs Placebo in Older Men with Hypogonadism, NEJM (2016) [PubMed abstract]
  • Design: Randomized, placebo-controlled trials (N=790, length = 1 year) in men ≥ 65 years old and testosterone < 275 ng/dl
  • Treatment: Testosterone gel 1% vs Placebo gel for 1 year. Dose was adjusted to keep testosterone within normal range.
  • Primary outcomes: 1. Sexual function 2. 6-minute walking distance 3. Functional Assessment of Chronic Illness Therapy-Fatigue scale
  • Results:
    • Primary outcomes: Testosterone was significantly better for sexual function (p<0.001) but not for 6-min walk test (p=0.20) or functional assessment (p=0.30)
  • Findings: In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment.
Testosterone Solution vs Placebo in Men With Ejaculatory Dysfunction and Hypogonadism, J Clin Endocrinol Metab (2015) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=76, length = 16 week) in men with ejaculatory dysfunction and testosterone < 300 ng/dl
  • Treatment: Testosterone solution 60 mg once daily vs Placebo for 16 weeks. Doses were adjusted to keep testosterone in the normal range.
  • Primary outcome: The primary outcome was a change in the score of the three-item Male Sexual Health Questionnaire-Ejaculatory Dysfunction-Short Form (MSHQ-EjD-SF)
  • Results:
    • Primary outcomes: Testosterone +3.1, Placebo +2.5 (p=0.596)
  • Findings: Testosterone replacement was not associated with significant improvement in ejaculatory dysfunction in androgen deficient men.
Intramuscular Testosterone vs Placebo in Men with Type 2 Diabetes and ED, J Clin Endocrinol Metab (2014) [PubMed Abstract]
  • Design: Randomized, placebo-controlled trial (N=88, length = 40 weeks) in men with type 2 diabetes, ED, and testosterone < 346 ng/dl
  • Treatment: Testosterone undecanoate 1000 mg IM at 0,6, and 18 weeks vs Placebo injection
  • Primary outcome: Constitutional symptoms using the aging male symptoms (AMS) score, sexual desire (question 17 AMS score), and erectile function (International Index of Erectile Function-5)
  • Results:
    • Primary outcomes: Mean difference in change in AMS score was -0.9 (p=0.67)
  • Findings: In this trial, testosterone treatment did not substantially improve constitutional or sexual symptoms in obese, aging men with type 2 diabetes with mild to moderate symptoms and modest reduction in testosterone levels typical for the vast majority of such men.

Cardiovascular disease
Testosterone gel vs Placebo for Coronary Artery Plaque Volume JAMA (2017) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=138, length = 12 months) in men ≥ 65 years old with testosterone level < 275 ng/dl
  • Treatment: Testosterone gel vs Placebo. Dose was adjusted to maintain testosterone in the normal range.
  • Primary outcome: Noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography
  • Results:
    • Primary outcomes: Testosterone was associated with a greater increase (estimated diff 41 mm3, p=0.003)
  • Findings: Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding.
Testosterone gel vs Placebo for Carotid Artery and Coronary Artery Atherosclerosis, JAMA (2015) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=308, length = 3 years) in men ≥ 60 years with testosterone of 100 - 400 ng/dl
  • Treatment: Testosterone gel 75 mg daily vs Placebo gel. Dose was adjusted to maintain testosterone in a range of 500 - 900 ng/dl.
  • Primary outcome: Coprimary outcomes included common carotid artery intima-media thickness and coronary artery calcium
  • Results:
    • Primary outcomes (carotid thickness): Testosterone - 0.012 mm/yr, Placebo - 0.010 mm/yr (p=0.89)
    • Primary outcomes (coronary calcium): Testosterone - 31.4 units/yr, Placebo - 41.4 units/yr (p=0.54)
  • Findings: Among older men with low or low-normal testosterone levels, testosterone administration for 3 years vs placebo did not result in a significant difference in the rates of change in either common carotid artery intima-media thickness or coronary artery calcium nor did it improve overall sexual function or health-related quality of life. Because this trial was only powered to evaluate atherosclerosis progression, these findings should not be interpreted as establishing cardiovascular safety of testosterone use in older men.
Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels, JAMA (2013) [PubMed abstract]
  • Design: Retrospective cohort study (N=8709, length = 3 years) in men with testosterone < 300 ng/dl who underwent coronary angiography in the Veterans Affairs system between 2005 and 2011
  • Exposure: Testosterone therapy vs No testosterone
  • Primary outcome: Primary outcome was a composite of all-cause mortality, MI, and ischemic stroke
  • Findings: Among a cohort of men in the VA health care system who underwent coronary angiography and had a low serum testosterone level, the use of testosterone therapy was associated with increased risk of adverse outcomes. These findings may inform the discussion about the potential risks of testosterone therapy.

Cognitive function
Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment, JAMA (2017) [PubMed abstract]
  • Design: Subgroup analysis of a randomized placebo-controlled trial (N=493, length = 1 year) in men ≥ 65 years old with testosterone < 275 ng/dl
  • Treatment: Testosterone gel vs Placebo gel. Dose was adjusted to maintain testosterone in the normal range.
  • Primary outcome: Mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with age-associated memory impairment
  • Results:
    • Primary outcomes: There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with age-associated memory impairment in the testosterone and placebo groups (adjusted estimated difference, -0.07, 95%CI [-0.92 to 0.79], p=0.88)
  • Findings: Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions

Bone health
Testosterone gel vs Placebo for Bone Mineral Density in Older Men with Hypogonadism, JAMA Intern Med (2017) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=211, length = 1 year) in men ≥ 65 years old with testosterone < 275 ng/dl
  • Treatment: Testosterone gel vs Placebo gel. Dose was adjusted to maintain testosterone in the normal range.
  • Primary outcome: Spine and hip volumetric BMD (vBMD) as determined by quantitative computed tomography at baseline and 12 months. Bone strength estimated by finite element analysis of quantitative computed tomography data.
  • Results:
    • Primary outcome (increase in spine vBMD): Testosterone - 7.5%, Placebo - 0.8% (p<0.001)
  • Findings: Testosterone treatment for 1 year of older men with low testosterone significantly increased volumetric BMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip. A larger, longer trial could determine whether this treatment also reduces fracture risk.

Testosterone measurements
Serum Testosterone (T) Level Variability in T Gel-Treated Older Hypogonadal Men: Treatment Monitoring Implications, J Clin Endocrinol Metab (2015) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=47, length = 24 hours) in men ≥ 65 years old with testosterone < 275 ng/dl
  • Treatment: Testosterone gel vs Placebo gel for 16 weeks. Dose was adjusted to maintain testosterone between 400 - 800 ng/dl.
  • Primary outcome: Variability of serum testosterone 2 hours after the gel application on two outpatient visits and at multiple time points over 24 hours during the inpatient day was measured
  • Results:
    • Ambulatory 2-hour postapplication testosterone levels did not correlate significantly with either 2-hour postapplication serum testosterone or average 24-hour testosterone measured during the inpatient day
  • Findings: Large within-individual variations in serum testosterone after testosterone gel application render ambulatory 2-hour post application testosterone level a poor indicator of average serum testosterone on another day. Our data point out the limitations of dose adjustments based on a single postapplication serum testosterone measurement.