How to diagnose hypogonadism?

The diagnosis of hypogonadism requires the presence of symptoms and/or signs characteristic of testosterone deficiency, plus low levels of total testosterone or free testosterone.1-7

Symptoms of hypogonadism resemble those of aging; as a consequence, hypogonadism is often overlooked. To prevent this, clinical guidelines have developed diagnostic procedures to confirm hypogonadism in a patient who has symptoms and/or signs of testosterone deficiency. These include symptomatic evaluation, medical history, physical examination and measurement of testosterone levels.

Symptoms of hypogonadism resemble those of aging; as a consequence, hypogonadism is often overlooked. To prevent this, clinical guidelines have developed diagnostic procedures to confirm hypogonadism in a patient who has symptoms and/or signs of testosterone deficiency. These include symptomatic evaluation, medical history, physical examination and measurement of testosterone levels.

Symptomatic evaluation

Evaluation of symptoms that may be related to low testosterone is mandatory for making the diagnosis of hypogonadism. Use of validated symptom questionnaires, such as the Aging Males’ Symptoms (AMS) questionnaire is helpful in daily clinical practice for symptomatic evaluation. The AMS can be used both as part of the diagnosis, and for monitoring of symptomatic improvement during testosterone therapy.

The most common and reliable symptoms of hypogonadism are sexual. These include reduced or absent libido, erectile dysfunction, difficulty achieving orgasm, reduced intensity of orgasm, and reduced sexual sensation in the genital region. Common non-sexual symptoms include fatigue, lack of energy, decreased vitality, inability to perform vigorous activity, depressed mood, irritability, “brain fog” (memory problems, a lack of mental clarity, inability to focus), and decreased motivation. These symptoms may occur singly or in any combination. Decreased libido is one of the primary symptoms of hypogonadism. It may occur, with or without any of these other symptoms or signs, and is strongly suggestive of hypogonadism in men >50 years without obvious other causes, such as relationship issues and stress.

Increased probability of low sexual desire, poor morning erections, erectile dysfunction and reduced physical vigor is seen with testosterone levels below 13 nmol/L (370 ng/dL).8

Medical history

Chronic diseases, such as type 2 diabetes and heart disease, are associated with low testosterone. Furthermore, certain medications, especially opioids,9-12 selective serotonin reuptake inhibitors (SSRIs),13 statins,14-16 and glucocorticoid medications17,18 reduce testosterone levels. Therefore, comorbid conditions must be comprehensively investigated in every patient. Acute illnesses are associated with the development of functional hypogonadism; in patients with acute illness, measurement of testosterone levels should be postponed.

Physical examination

Because obesity is frequently associated with hypogonadism, measuring body weight and height in order to find out BMI, along with measurement of waist circumference, should be done in all men.

Small testicles can also be an indication of a reduced androgen status.

Measurement of testosterone levels

Measurement of total testosterone is mandatory for making the diagnosis of hypogonadism.

Because testosterone levels display a circadian rhythm with highest levels in the morning and lowest in the afternoon,19 it is recommended that total testosterone levels are measured before 11am. However, it must be acknowledged that the literature fails to demonstrate that doing so improves identification of men with hypogonadism who might benefit from treatment, regardless of age.2

  1. Symptomatic men with a total testosterone level of 12.1 nmol/L (350 ng/dL) or below should be treated with testosterone therapy (provided they have no contraindications).
  2. For symptomatic men with borderline low or normal-low testosterone levels, evaluation of free testosterone levels is recommended. This can be done by measuring SHBG levels and using a free testosterone calculator or by measuring free testosterone directly using equilibrium dialysis.
  3. Proposed diagnostic thresholds for free testosterone by calculation or equilibrium dialysis range from 65 - 100 pg/mL (225 - 347pmol/L)or below.2
  4. Symptomatic men with increased LH levels but normal testosterone levels should be considered having hypogonadism.4
  5. A trial of testosterone therapy in symptomatic men with testosterone level above 12.1 nmol/L (350 ng/dL) can be considered.

Free testosterone calculator icon > Calculate free and bioavailable testosterone

While most guidelines recommend a second testosterone blood test to confirm the first low testosterone value, the clinical vale of this is questionable.20 A notable study showed excellent correlation (r = 0.849) between plasma testosterone level at first sampling and the mean of 7 samples taken subsequently over 1 year.21 It concluded that in middle-aged and elderly men, a single point plasma testosterone measurement reflect fairly reliably the annual mean testosterone level.21 Furthermore, it imposes additional burden on patients and clinicians. Therefore, a single value showing low testosterone in symptomatic men is usually enough to make the diagnosis of hypogonadism.20

Elevated SHBG --> Reduced free testosterone Reduced SHBG --> Elevated free testosterone
Drugs: anticonvulsant, estrogens, thyroid Drugs: GH, glucocorticoids, testosterone,
hormone anabolic androgenic steroids
Hyperthyroidism Hypothyroidism
Hepatic disease Obesity
Aging Acromegaly
Smoking Cushing Disease
AIDS/HIV Insulin resistance (metabolic syndrome or type 2 diabetes)
  Non-alcoholic fatty liver disease (NAFLD)
Nephrotic syndrome

 

Because direct measurement of free testosterone with equilibrium dialysis is expensive, clinical guidelines recommend calculating free testosterone using an online free testosterone calculator.

Calculated free testosterone is obtained by entering measured levels of total testosterone and SHBG into the calculator. A fixed albumin level of 4.3 g/dL is acceptable for most clinical evaluations,31 but for patients who have a marked deviation in albumin levels, measured albumin values should be used.

The impact of various SHBG levels on free testosterone levels for a given total testosterone level can be seen by changing the SHBG level. For example, increasing SHBG from 20 to 60 nmol/L for a total testosterone level of 400 ng/dL reduces free testosterone by nearly half, from 10.5 ng/dL (105 pg/mL) to 5.43 ng/dL (54 pg/mL). Even though these SHBG values are both within the typical normal range, the impact on free testosterone is substantial. A free testosterone level of 10.5 ng/dL (105 pg/mL) would be considered within the normal range by most authorities (65 - 100 pg/mL),1,2 whereas a free testosterone level of 5.43 ng/dL (54 pg/mL) is unequivocally low.

The take home message is that for any given total testosterone level, the free testosterone level will drop by half when the SHBG level increases from the low end of normal (20 nmol/L) to the upper end (60 nmol/L).

Free testosterone calculator

Interpretation of testosterone levels in the diagnosis of hypogonadism

Proper interpretation of testosterone values requires knowledge of the following:

Interpretation of testosterone levels in the diagnosis of hypogonadism

Proper interpretation of testosterone values requires knowledge of the following:

  • The reference (normal) range for testosterone varies widely between laboratories depending on the commercial assay used. Therefore, the same laboratory should be used consistently.
  • There is no universally accepted lower limit of normal testosterone levels. However, most clinical guidelines recommend using the threshold 12.1 nmol/L (350 ng/dL) as a guide for defining low testosterone.1-7

In clinical practice there are men who are highly symptomatic despite having testosterone levels above the recommended thresholds, and who have anecdotally experienced symptom/sign improvement with testosterone therapy.3 Clinicians are advised to use their clinical judgment in the management of such patients.3

Regardless of pre-treatment testosterone levels, the observation of improvements in symptoms and/or signs of testosterone deficiency after the initiation of testosterone therapy may provide confirmation of a diagnosis of hypogonadism.

Supplementary tests

Before starting testosterone therapy, levels of PSA and hematocrit need to be measured, as elevated PSA and hematocrit may be a contraindication for testosterone therapy. Therefore, it makes sense to measure PSA and hematocrit along with total testosterone in the same blood draw.

Depending on the clinical picture, supplementary testing may be recommended, as outlined in the table below.

Table: Supplementary laboratory testing in men undergoing evaluation for hypogonadism.3

Laboratory test Indication Clinician response
LH

LH is an appropriate first-line test in conjunction with a repeat testosterone level to determine the etiology of hypogonadism.

A low or low/normal LH level indicates secondary hypogonadism (hypothalamic-pituitary defect), also known as hypogonadotropic hypogonadism.

An elevated LH level indicates primary hypogonadism (testicular defect), also known as hypergonadotropic hypogonadism.

The location of the defect may be an important factor in deciding upon further evaluation of such a patient.

Men with low testosterone and low to low/normal LH, should have prolactin level measured.

Men with low to low/normal LH levels who desire fertility are candidates for the use of SERMs, hCG or AIs in the management of their testosterone deficiency.

Men with very high LH levels (without an obvious cause, such as chemotherapy) may have Klinefelter syndrome, which can be diagnosed using a karyotype.

FSH

Men who are interested in preserving their fertility warrant a baseline FSH prior to the commencement of SERMs, hCG, or AI. The presence of an elevated FSH level suggests abnormal spermatogenesis.

Men with elevated FSH levels should have a semen analysis.

Men with very high FSH levels (without an obvious cause, such as chemotherapy) may have Klinefelter syndrome, which can be diagnosed using a karyotype.

Prolactin

Men with low testosterone level accompanied by a low/ low-normal LH level warrant measurement of serum prolactin to investigate for hyperprolactinemia.

If prolactin is mildly elevated (≤1.5 times the upper limit of normal) a repeat prolactin should be drawn to rule out a spurious elevation.

For persistently elevated prolactin levels referral to an endocrinologist is recommended.

Estradiol

Serum E2 levels should be measured in patients with baseline gynecomastia or breast symptoms.

For men who develop gynecomastia or breast symptoms while on testosterone therapy, measuring a E2 level should also be considered.

For gynecomastia/breast symptoms that develop while on testosterone therapy, a period of monitoring should be considered, as breast symptoms sometimes abate.

If gynecomastia/breast symptoms persist on testosterone therapy and the E2 level is elevated, reduction may be accomplished through dose adjustment of the testosterone therapy if the on-treatment testosterone levels are in the upper range of normal.

If the on-treatment testosterone levels are low/normal, E2 level reduction can be accomplished by the use of AIs.

Pituitary MRI

Men with sustained elevated prolactin levels, very low total testosterone levels (<150 ng/dL) and unexplained failure to produce LH/FSH warrant a pituitary MRI to identify sellar (pituitary adenoma, prolactinoma, infiltrative diseases of the pituitary) or parasellar processes.

The clinician may decide to refer such patients to an endocrinologist prior to ordering an MRI, or may order the MRI first and refer only for abnormalities.

For clinicians experienced in managing prolactinomas, bromocriptine or cabergoline may be prescribed without endocrinolgist input.

Bone Densitometry

Men with testosterone deficiency are at increased risk of bone density loss.

Consideration of a baseline DEXA (dual energy X-ray absorptiometry) scan is warranted, particularly in middle-aged or older men with severe testosterone deficiency or in men with a history low trauma bone fracture.

Results are used to assess baseline bone mineral density, and if abnormal, to follow changes over time (regardless of whether the patient opts for testosterone therapy or not).

Karyotype

A karyotype should be considered in men with unexplained hypergonadotropic hypogonadism.

The most common chromosomal abnormality identified is 47,XXY, also known as KS, although other chromosomal abnormalities can also be found.

For those clinicians inexperienced in managing Klinefelter syndrome, referral to a more experienced clinician is advisable.

 

AI: aromatase inhibitor, E2: estradiol, FSH: follicle-stimulating hormone, hCG: human chorionic gonadotropin, Hg: hemoglobin, Hct: hematocrit, LH: luteinizing hormone, SERM: selective estrogen receptor modulator

Table from: Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline (unabridged). J Urol. 2018;200(2):423-432.

References

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