Male hypogonadism: More than just a low testosterone
ABSTRACTConfronted with a low serum testosterone level, physicians should not jump to the diagnosis of hypogonadism, as confirmation and thorough evaluation are warranted before making the diagnosis or starting therapy. This review discusses how to approach the finding of a low testosterone value, stressing the need to confirm the finding, the underlying pathophysiologic processes, drugs that can be responsible, and the importance of determining whether the cause is primary (testicular) or secondary (hypothalamic-pituitary).
KEY POINTS
- Blood samples for testosterone measurements should be drawn near 8 am.
- A low serum testosterone value should always be confirmed by a reliable reference laboratory.
- The definition of a low testosterone level varies from laboratory to laboratory. In general, values less than 200 or 250 ng/dL are considered low, and values between 250 and 350 ng/dL may be considered borderline low.
- If testosterone is low, determine if the cause is primary (testicular) or secondary (hypothalamic-pituitary).
- Acute illness and treatment with opioids, anabolic steroids, or corticosteroids can result in transient hypogonadism.
CLINICAL FEATURES OF LOW TESTOSTERONE
A history of erectile dysfunction, decreased libido, and fatigue may be seen in patients with low testosterone. However, one must realize that these symptoms—as well as others reported by men with low testosterone, such as depression, difficulty concentrating, irritability, and insomnia—are nonspecific and may be related to other medical conditions.12
Likewise, physical findings such as muscle weakness, reduced body hair, and altered fat distribution (abdominal obesity) are seen in men with low testosterone, but also in those with a number of other medical conditions.
Additional features suggest specific disorders, eg, anosmia in Kallmann syndrome; eunuchoid body habitus, gynecomastia, and small testes in Klinefelter syndrome.
Men with low testosterone may have low bone mineral density or anemia, or both.
Careful examination of the breasts for gynecomastia and the testes for size, consistency, and masses (testicular tumors) helps in formulating a differential diagnosis and in appropriately directing subsequent laboratory evaluation and diagnostic imaging.
LOW TESTOSTERONE: PRIMARY VS SECONDARY
A history of testicular trauma, systemic chemotherapy, or mumps orchitis should direct the physician’s attention to a testicular etiology. On the other hand, darkened or tanned skin (suggesting hemochromatosis), galactorrhea (suggesting hyperprolactinemia), or visual field deficits (suggesting a sellar mass) should direct the physician’s attention toward a pituitary-hypothalamic process.
Once the low testosterone value has been confirmed at least one time near 8 am, one should obtain LH and FSH values to help direct further evaluation in deciphering the etiology (Figure 2). Elevated (hypergonadotropic) values indicate a testicular disorder (primary hypogonadism), whereas low (hypogonadotropic) or normal (normogonadotropic) values point to a pituitary-hypothalamic process (secondary hypogonadism). It should be emphasized that, in the setting of a low testosterone level, LH and FSH values within the normal range are “inappropriately normal” so that further investigation is required.
This evaluation should also include serum prolactin, thyroid-stimulating hormone (TSH, also known as thyrotropin), free thyroxine (T4), and ferritin levels, the latter because hemochromatosis (iron overload) can cause both primary and secondary hypogonadism. If at any time in the evaluation the laboratory results suggest secondary hypogonadism, a full assessment of pituitary function should be undertaken.
Semen analysis is usually reserved for patients presenting with the primary complaint of infertility.
PRIMARY HYPOGONADISM
The patient should be carefully questioned about the age at which his problems began, about pubertal development, and about fertility. Causes of primary hypogonadism include:
- Karyotype abnormalities—Klinefelter syndrome (47, XXY syndrome) is the most common
- Toxin exposure, chemotherapy
- Congenital defects—anorchia, cryptorchidism13
- Orchitis (mumps, autoimmune)
- Testicular trauma or infarction
- Hemochromatosis
- Medications that inhibit androgen biosynthesis, eg, ketoconazole (Nizoral)14
- Increase in temperature of the testicular environment (due to varicocele or a large panniculus).
SECONDARY HYPOGONADISM
Causes of secondary hypogonadism include the following:
Congenital disorders
These disorders are usually diagnosed in childhood or adolescence, often after the patient is brought to the physician because of short stature or pubertal delay.
- Kallmann syndrome (anosmia and GnRH deficiency)15
- GnRH receptor mutation and deficiency16
- Genetic mutations associated with pituitary hormone deficiencies, eg, PROP-1 mutation.17
