Androgens in Health and Disease.pdf - E Library

Chapter 16/Androgen Treatment of the Hypogonadal Male 315
decrease SHBG concentrations and, therefore, lower total-T and free-T levels by analog
methods, resulting potentially in a mistaken diagnosis of T deficiency. Conversely,
aging, hyperthyroidism, hepatic cirrhosis, and androgen deficiency increase in SHBG
and raise total-T and free-T levels by analog immunoassays, resulting potentially, in a
mistaken impression of eugonadism.
It is for these reasons that in clinical situations where SHBG levels may be altered or
serum total-T levels are in the low-normal or moderately low range (e.g., 200–350 ng/dL),
free-T or bioavailable (free plus weakly albumin-bound or non-SHBG-bound) assays that
are not affected by changes in SHBG concentrations should be used to confirm androgen
deficiency. These assays include free T by equilibrium dialysis or centrifugation methods,
bioavailable T by the ammonium sulfate precipitation method, or free and bioavailable
T calculated from measurements of total-T and SHBG concentrations (10–14). Unless
SHBG levels are very low (e.g., nephrotic syndrome), total-T levels < 200 ng/dL in men
with clinical manifestations consistent with T deficiency are usually diagnostic of androgen
deficiency.
If the initial serum T level is low, patients should be evaluated for underlying acute
or chronic illnesses, medications, or malnutrition to determine whether transient or
reversible conditions associated with low T levels are present (7). In these situations, a
T level should be repeated after a recent illness is resolved completely, medications that
may lower T are discontinued, and malnutrition is corrected. If these reversible causes
of low T levels are not present or correctable, a serum T level should be repeated together
with serum gonadotropin concentrations (i.e., luteinizing hormone [LH] and folliclestimulating
hormone [FSH] levels). Both because of significant biological and methodological
variability in serum T concentrations, approx 15% of healthy young men may
demonstrate a T level below the normal range in a 24-h period (15). Therefore, before
initiating T treatment, a repeat T level to confirm androgen deficiency is appropriate.
Serum gonadotropin levels should also be obtained prior to starting T therapy in order
to differentiate androgen deficiency resulting from primary testicular disease (primary
hypogonadism) from that resulting from hypothalamic–pituitary dysfunction or disease
(secondary hypogonadism) (2). Gonadotropin levels may be useful in the diagnosis of
primary hypogonadism even in the presence of normal T concentrations. For example,
approx 40% of men with Klinefelter’s syndrome may have total T levels within the normal
range, but all have elevated LH and/or FSH levels. Also, the diagnosis of secondary
hypogonadism has important therapeutic implications. Secondary hypogonadism may be
caused by hypothalamic–pituitary disease that may require therapeutic interventions other
than T treatment alone (e.g., pituitary tumors that may cause local mass effects or be
associated with deficiencies or hypersecretion of other anterior pituitary hormones). In
some instances, treatment of the underlying etiology of hypothalamic–pituitary dysfunction
may correct androgen deficiency (e.g., treatment of Cushing’s syndrome or hyperprolactinemia).
Finally, in men with gonadotropin deficiency, but otherwise normal testis
function, who are interested in fathering children, induction of both androgen and sperm
production and restoration of fertility may be achieved using gonadotropin therapy or, in
men with hypothalamic hypogonadism, pulsatile gonadotropin-releasing hormone (GnRH)
treatment. Therefore, a careful investigation of the etiology of secondary hypogonadism
is needed prior to initiation of T-replacement therapy.
For optimal clinical management of patients, it is important to consider etiological
factors other than androgen deficiency that may contribute as much or more to clinical