C h a p t e r
34
Hormone Replacement in Men
Pathophysiology
Testosterone Production
Conversion of cholesterol and steroid hormones occurs in
only three organs: the adrenal cortex, the testis in men, and
the ovary in women. Whereas most endocrine texts discuss
adrenal, ovarian, testicular, placental, and other steroido-
genic processes in a gland-specific fashion, steroidogene-
sis is better understood as a single process that is repeated
in each gland with cell type–specific variations on a single
theme.1 The relative activity of the steroidogenic enzymes
in each of the three organs determines the major secreted
product. This is not absolute, however, and other organs are
capable of secreting small amounts. In pathologic situations
such as a defect in steroidogenesis or a steroid-secreting
tumor, a very abnormal pattern of steroid secretion may be
observed.2
Testosterone is made primarily by the testes. Testosterone
production depends on intact hypothalamus, pituitary gland,
and testicular Leydig cells.3 These Leydig cells make up less
than 10% of the testicular volume and produce 95% of cir-
culating testosterone.4 A small amount of testosterone is also
produced in the adrenal glands and other tissues such as
the fat cells by conversion from adrenal androgens such as
dehydroepiandrosterone (DHEA) and androstenedione into
testosterone.5
Testosterone is produced from the conversion of cho-
lesterol, a 27-carbon molecule, by using enzymes that are
cytochrome P-450 proteins requiring oxygen and reduced
nicotinamide-adenine dinucleotide phosphate (NADPH).
The biosynthetic pathway is largely made up of cleavage of
carbon-carbon bonds and hydroxylation reactions.1 The
first and rate-limiting step in steroidogenesis is the con-
version of cholesterol to pregnenolone, a 21-carbon mol-
ecule, by a single enzyme, P450scc (CYP11A1), but this
enzymatically complex step is subject to multiple regula-
tory mechanisms.6 Chronic quantitative regulation is prin-
cipally at the level of transcription of the CYP11A1 gene
Alicia Stanton, MD
encoding P450scc, which is the enzymatically rate-limiting
step. Acute ­regulation is mediated by the steroidogenic acute
regulatory protein (StAR), which facilitates the rapid influx
of cholesterol into mitochondria, where P450scc resides.1
Cholesterol is converted to pregnenolone, which produces
other possible precursors such as progesterone, 17-alpha
hydroxy-­progesterone, androstenedione, 17-alpha hydroxy-
pregnenolone, DHEA, and androstenediol. These reactions
can be seen in Figure 34-1.
The anterior hypothalamus secretes gonadotropin-
­releasing hormone in a pulsatile fashion. This hormone then
stimulates the pituitary to secrete luteinizing hormone (LH)
in a pulsatile fashion as well. Investigators have established
that steroidogenesis in Leydig cells is mainly regulated by
LH, through the interaction with its receptors coupled to the
adenylate cyclase–cyclic adenosine monophosphate signaling
pathway.6 The LH stimulates the Leydig cells in the testes to
produce testosterone, a 19-carbon corticosteroid. Testosterone
can then be aromatized in adipose tissue to estradiol, an
18-carbon corticosteroid. Testosterone can also be converted,
by 5-alpha-reductase, to dihydrotestosterone (DHT).
Dihydrotestosterone
DHT, one of the two important androgens in boys and men,
is synthesized in the prostate, testes, hair follicles, and adrenal
glands. In men, approximately 5% of testosterone undergoes
5-alpha reduction to form the more potent androgen DHT.
DHT has three times greater affinity for androgen receptors
than does testosterone.7 During embryogenesis, DHT has an
essential role in the formation of the male external genitalia,
and in the adult, DHT acts as the primary androgen in the
prostate and hair follicles.
DHT is generated by reduction of testosterone by the
enzyme 5-alpha-reductase (Fig. 34-2). Two isoenzymes of
5-alpha-reductase have been discovered. Type 1 is pres-
ent in most tissues of the body where 5-alpha-reductase
is expressed and is dominant in sebaceous glands. Type 2
5-alpha-reductase is dominant in genital tissues, ­including
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