Testosterone Deficiency: Symptoms and Causes

Testosterone deficiency is a condition in which a man simultaneously exhibits characteristic symptoms/signs (decreased libido and morning erections, fatigue, decreased performance, anemia, decreased bone mineral density, etc.) and documented low total testosterone levels on repeated morning measurements. Important: a "low number" alone without symptoms is usually not an indication for treatment, just as the presence of symptoms without laboratory confirmation is not a diagnosis. [1]

Testosterone fluctuates throughout the day and is sensitive to acute illness, sleep deprivation, etc., so tests should be taken in the morning, on different days, when relatively well. Verification of the diagnosis also includes determination of luteinizing and follicle-stimulating hormones, and sometimes prolactin, thyroid-stimulating hormone, and sex hormone-binding globulin (SHBG) to determine whether the testicular damage is primary or secondary (hypothalamic-pituitary). [2]

Why is this important? Androgen deficiency impairs sexual function, mood, and body composition (more fat, less muscle mass), and contributes to anemia and osteoporosis. However, in some men, decreased testosterone is functionally reversible (obesity, sleep apnea, medications). This dictates the strategy: first correct the reversible causes, then consider hormone therapy. [3]

Finally, safety: Until recently, controversy centered on cardiovascular risk. The large, randomized TRAVERSE trial (NEJM, 2023) showed a non-inferiority rate of major cardiovascular events with testosterone replacement therapy (TRT) compared to placebo in carefully selected men, but identified signals for atrial fibrillation, pulmonary embolism, and acute kidney injury, requiring informed choice and monitoring. [4]

Code according to ICD-10 and ICD-11

In ICD-10, the primary code for male hypogonadism is E29.1 "Testicular hypofunction." For secondary hypogonadism, codes for hypopituitarism (E23.0) and other pituitary/hypothalamic disorders may be used; for hyperprolactinemia, E22.1; and genetic causes (e.g., Klinefelter syndrome) are coded in sections Q98.*. Additional details regarding the etiology may be included in the accompanying documentation. [5]

In ICD-11, male hypogonadism is classified under the section "Disorders of the gonadal system." The most direct node is 5A81.1 "Testicular hypofunction"; if necessary, post-coordination details (etiology, associated conditions) are added. Secondary forms can be coded in the pituitary disorders block, and hyperprolactinemia can be coded separately, with symptomatic nodes (e.g., erectile dysfunction) listed additionally. [6]

Table 1. Example of coding of clinical scenarios

Scenario	ICD-10	ICD-11
Primary hypogonadism (testicular dysfunction)	E29.1	5A81.1
Secondary hypogonadism (hypopituitarism)	E23.0	Pituitary insufficiency nodes (depending on the situation)
Hyperprolactinemia	E22.1	The corresponding node of endocrine disorders
Klinefelter syndrome	Q98.*	Genetic syndromes (by branch)

Epidemiology

The prevalence of testosterone deficiency varies by age group and criteria. With strict laboratory and clinical criteria, symptoms and low testosterone are observed in approximately 2-6% of middle-aged and older men; with more liberal thresholds, the proportion is higher. A significant proportion of the identified "low" values are associated with obesity, metabolic syndrome, and sleep disorders and can normalize with correction. Guidelines emphasize the need to confirm the diagnosis with two morning tests. [7]

The use of TRT in the general population has increased over the past two decades, then stabilized amid tightening indications and monitoring requirements. Large registries show that most patients receive gel forms and short injections, while longer injections and pellets are less common; the choice of form is determined by availability, tolerability, and the patient's target profile. [8]

Reasons

Primary hypogonadism (testicular failure) is damage or dysgenesis of the testes. Causes: history of cryptorchidism, radiation/chemotherapy, trauma/torsion, orchitis (including viral), autoimmune processes, infectious lesions, postoperative changes, genetic syndromes (Klinefelter, etc.). Laboratory findings: low testosterone with high LH/FSH. [9]

Secondary hypogonadism (hypothalamic-pituitary) - disturbances in the production of gonadotropin-releasing hormone, LH/FSH, or their regulation. Causes: pituitary tumors, hyperprolactinemia, hypothyroidism, systemic diseases, consequences of traumatic brain injury, obesity and obstructive sleep apnea, chronic stress/diseases, medications (opioids, glucocorticoids, anabolic steroids - "post-cycle" syndrome). Laboratory findings: low testosterone with low/normal LH/FSH. [10]

Functional androgen deficiency is a separate issue in obesity, metabolic syndrome, and OSA; it is often reversible with weight loss and sleep apnea treatment. This is critical: starting TRT "for everyone with borderline T" is a mistake; correct the underlying causes and retest. [11]

Risk factors

Key factors include age, obesity and metabolic syndrome, obstructive sleep apnea, type 2 diabetes, chronic diseases (liver, kidney), and systemic inflammatory conditions. Drug exposure (opioids, corticosteroids, antiandrogens) and the consequences of cancer treatment also make significant contributions. Familial and genetic forms are less common, but important to recognize due to management considerations. [12]

Table 2. Risk factors and what to do about them

Factor	Mechanism	What helps?
Obesity/insulin resistance	Reduction of ZHSPG, suppression of axis	Weight loss, strength training, nutrition
OSA and chronic sleep deprivation	Hypoxic and neurohumoral shifts	Diagnosis/treatment of OSA, sleep hygiene
Opioids, GCS, antiandrogens	Central axis/receptor suppression	Review of therapy, if possible, discontinue
Oncological treatment	Direct injury to testicles/axis	Rehabilitation, consultation with an andrologist
Systemic diseases	Multifactorial mechanisms	Treatment of the underlying disease

Pathogenesis

Testosterone is regulated by the hypothalamus → pituitary → testicular axis. In primary lesions, androgen/inhibin production in the testes decreases, and the pituitary gland compensatorily increases LH/FSH. In secondary forms, pulsatile gonadotropin secretion is impaired, and the stimulus to the testes is weak. In the periphery, YBG and androgen receptor sensitivity are important, so in cases of "borderline total testosterone," the free fraction is assessed. [13]

Obesity reduces IFNG and increases aromatization of testosterone to estradiol, enhancing negative feedback; hypoxia in OSA exacerbates central suppression. Removing the causative factor (weight loss, OSA treatment) can increase testosterone levels without hormones—this is the basic principle of modern management. [14]

Symptoms

The picture consists of sexual and non-specific manifestations. Typical symptoms include decreased libido, less common erectile dysfunction, decreased frequency/quality of morning erections, decreased energy, worsening mood, decreased muscle mass and strength, increased fat mass, anemia, and decreased bone mineral density. No single symptom is specific—the combination of symptoms and laboratory testing is essential. [15]

In young patients, fertility problems (oligospermia, azoospermia) may predominate, while secondary forms may present with hyperprolactinemia (decreased libido, galactorrhea). In older patients, mixed somatic symptoms are more common, where the contribution of androgen deficiency is difficult to separate from other age-related conditions, hence the importance of accurate diagnosis. [16]

Forms and stages

In practice, a distinction is made between primary (testicular) and secondary (central) hypogonadism; overt (symptoms + documented low T) and borderline/questionable (symptoms + T in the "gray zone"). Clinical "staging" is determined by the severity of manifestations (anemia, severe bone loss, depression) and the presence of concomitant pathology, as well as the duration of the condition. [17]

Complications and consequences

Without correction, some patients experience increasing sarcopenia and visceral obesity, worsening mood and cognitive function, and persistent anemia and low bone mass with an increased risk of fractures. In secondary forms, there is a risk of missing a pituitary tumor or hyperprolactinemia. Inappropriate use of TRT can lead to erythrocytosis, edema, and exacerbation/diagnostic "masking" of prostate problems. Therefore, treatment requires proper selection and monitoring. [18]

When to see a doctor

The reason for this is persistent (repeated) symptoms from the above, especially if they are combined: decreased libido/morning erections, fatigue, loss of strength, decreased bone density, and anemia of unknown origin. You should seek immediate medical attention if symptoms indicate an underlying cause (headaches, visual disturbances, nipple discharge, very low testosterone levels). Do not start or buy hormones on your own—a proper diagnosis precedes treatment. [19]

Diagnostics

1. Two morning total testosterone analyses (usually before 10:00 a.m.) on different days, during stable conditions, and, if possible, in the same laboratory. If values are borderline, the FBG is taken into account and free testosterone is calculated. [20]
2. LH, FSH to differentiate between primary and secondary hypogonadism; prolactin, TSH - according to clinical findings; complete blood count (anemia), vitamin D/calcium as indicated. [21]
3. Evaluation factors: body mass index, waist circumference, screening for obstructive sleep apnea, list of medications (opioids, corticosteroids, antiandrogens, anabolic steroids), comorbidity. [22]
4. MRI of the pituitary gland - for "red flags": very low T, hyperprolactinemia, neurological symptoms/visual field defects. Spermogram - if fertility is relevant. [23]

Table 3. Diagnostic thresholds and nuances

Source	Lower limit of total testosterone	Comments
AUA	<300 ng/dL (≈10.4 nmol/L)	Diagnosis: with symptoms + twice low T. [24]
Endocrine Society	≈264 ng/dL (≈9.2 nmol/L)	"Harmonized" boundary; taking into account method and symptoms. [25]
Border zone	264-350/300 ng/dL	Evaluation of free T, search for causes, repeat. [26]

Differential diagnosis

It is important to distinguish true hypogonadism from "mimic" conditions: depression, chronic fatigue syndrome, hypothyroidism, anemia and vitamin D deficiency, drug side effects, and vascular erectile dysfunction, which is often present with normal testosterone. Context and objective tests (e.g., PSG/OSA questionnaires, tonometry, lipid profile) are important. [27]

Table 4. "Similar - not similar"

Symptom/situation	True testosterone deficiency	Alternative
Decreased libido + low morning T twice	Yes, probably.	Depression/stress, CVD with normal T
ED in a man 55+ with metabolic syndrome	There may be a combination	Often vascular ED with normal T
Fatigue, insomnia	Non-specific	OSA, anxiety, hypothyroidism
Infertility	A secondary form is possible	Varicocele, obstruction, genetics

Treatment

1) Correction of reversible causes. For obesity, weight loss (calorie deficit + strength training); for OSA, treatment of sleep apnea and medication review (opioid withdrawal/replacement, if possible, and glucocorticosteroids). In some men, this normalizes testosterone levels and resolves the problem without hormones. [28]

2) Testosterone replacement therapy (TRT) – for symptoms, confirmed low T, and no contraindications. The goal is to bring T to the middle of the reference range and relieve symptoms. Forms:

• Gels/creams - easy to titrate, stable levels; monitor the risk of drug transfer to the skin of loved ones.
• Short injections (cypionate/enanthate every 1-2 weeks) are available, but produce “peaks and troughs” and are more likely to cause erythrocytosis.
• Long-term injections/implantable pellets - less frequent than injections, but more difficult to quickly correct.
• Patches/intranasal forms - according to preference and availability.
• Oral testosterone undecanoate is an option that varies by country/availability. Consult your doctor to determine the appropriate dosage form. [29]

Monitoring of TRT: testosterone (3-6 months after start/correction, then annually) - aim for the middle of the norm; hematocrit (initial, 3-6 months, then annually) - if >54%, reduce the dose/stop, look for hypoxia/OSA; PSA and prostate assessment - according to age/risk (joint decision with the urologist); monitoring of symptoms and side effects (edema, acne, gynecomastia, etc.). [30]

Cardiovascular safety. In TRAVERSE, in selected patients, TRT did not increase the rate of major cardiovascular events compared with placebo, but a higher rate of AF, PE, and AKI was observed; this requires weighing the risks and individualizing the dosage form, avoiding "supranormal" levels. [31]

3) If fertility is more important than a rapid rise in T. TRT inhibits spermatogenesis, so when planning a pregnancy, stimulators of the own axis are preferable:

• Clomiphene citrate (selective estrogen receptor modulator) - increases LH/FSH and natural testosterone while maintaining/improving spermatogenesis (off-label with observation).
• Human chorionic gonadotropin ± FSH - in case of severe secondary hypogonadism (under the supervision of an andrologist).

Spending time on TRT in this group can delay the achievement of fertility—this is a fundamental fork in the tactic. (Confirmation of these approaches is in the andrology sections of the manuals.) [32]

Table 5. Forms of TRT: pros and cons

Form	Pros	Cons	Who is it suitable for?
Gels/creams	Stable level, flexible dose	Risk of transfer, skin irritation	For those who want fine-tuning
Injections are short	Availability, predictability	Peaks/troughs, erythrocytosis	With good tolerance of injections
Long-term injections/pellets	Rare introduction	It is difficult to change the dose quickly	With a stable dose and control
Patches/intranasal	No injections	More expensive, local reactions	By preference
Oral T-undecanoate	Tablet, without "peaks"	Depends on food intake, availability	Individually

Table 6. Mini-protocol for monitoring on TZT

Parameter	Control deadlines	Goal/Action
Total testosterone	3-6 months → annually	Middle of the reference range
Hematocrit	Initially → 3-6 months → annually	>54% - reduce/stop, evaluate OSA
PSA/prostate	By age/risk	Joint decision with a urologist
Adverse events	Every visit	Edema, acne, AF/PE risk factors

Prevention

Maintaining a healthy weight, regular physical activity (strength training and aerobic exercise), adequate sleep, and treating sleep apnea not only improve well-being but also directly contribute to normalizing the hypothalamic-pituitary-testicular axis. Reviewing medications that suppress the androgen axis (in consultation with a physician) can also be a preventative measure. [33]

Timely diagnosis and correction of endocrine disorders (hypothyroidism, hyperprolactinemia), control of diabetes mellitus and cardiometabolic risk factors are the mainstays of primary prevention of testosterone deficiency and its consequences. [34]

Forecast

With the elimination of reversible causes and appropriate TRT, most patients report improvements in libido, energy, mood, body composition, and bone mineral density. Prognosis depends on the underlying cause (primary/secondary), comorbidities, and adherence to monitoring. In secondary forms, it is important not to miss treatable pituitary conditions. [35]

In the long term, TRT, with strict selection and monitoring, demonstrates acceptable cardiovascular safety (according to TRAVERSE). However, it is important to avoid "supranormal" levels and carefully consider risk factors for arrhythmia and thrombosis. [36]

FAQ

1) Can testosterone be prescribed "symptom-based" if a test result shows low levels once?
No. Two morning confirmations plus a symptomatic assessment are required. This is the principle of all current guidelines. [37]

2) What is considered "low"?
In practice: <300 ng/dL according to the AUA or ≈<264 ng/dL according to the Endocrine Society - along with symptoms. If the levels are borderline, free testosterone is assessed and the underlying causes are sought. [38]

3) Is it true that testosterone is harmful to the heart?
With proper selection and monitoring, TRAVERSE has not shown an increase in major cardiovascular events; however, signals for AF/PE/ARF have been noted, so monitoring is essential. [39]

4) I'm planning a pregnancy – can I use TRT?
No: TRT suppresses spermatogenesis. Clomiphene/hCG and other approaches under the supervision of an andrologist are used to preserve fertility. [40]

5) To what level should testosterone be raised and for how long should treatment be continued?
The goal is the middle of the normal range; the duration is individual, and the effect lasts as long as you receive therapy. The decision to discontinue or reassess is made in consultation with your doctor. [41]