CHAPTER 25The Gonads: Development & Function of the Reproductive System 409also primarily responsible for enlargement of the prostate and
probably of the penis at the time of puberty, as well as for the
facial hair, the acne, and the temporal recession of the hair-
line. On the other hand, the increase in muscle mass and the
development of male sex drive and libido depend primarily
on testosterone rather than DHT (see Clinical Box 25–4).
Testicular Production of Estrogens
Over 80% of the estradiol and 95% of the estrone in the plasma
of adult men is formed by extragonadal and extraadrenal aro-
matization of circulating testosterone and androstenedione.
The remainder comes from the testes. Some of the estradiol in
testicular venous blood comes from the Leydig cells, but some
is also produced by aromatization of androgens in Sertoli cells.
In men, the plasma estradiol level is 20 to 50 pg/mL (73–184
pmol/L) and the total production rate is approximately 50 μg/
d (184 nmol/d). In contrast to the situation in women, estrogen
production moderately increases with advancing age in men.
CONTROL OF TESTICULAR FUNCTION
FSH is tropic for Sertoli cells, and FSH and androgens main-
tain the gametogenic function of the testes. FSH also stimu-
lates the secretion of ABP and inhibin. Inhibin feeds back to
inhibit FSH secretion. LH is tropic for Leydig cells and stimu-
lates the secretion of testosterone, which in turn feeds back to
inhibit LH secretion. Hypothalamic lesions in animals and hy-
pothalamic disease in humans lead to atrophy of the testes and
loss of their function.
Inhibins
Testosterone reduces plasma LH but, except in large doses, it
has no effect on plasma FSH. Plasma FSH is elevated in patients
who have atrophy of the seminiferous tubules but normal levels
of testosterone and LH secretion. These observations led to the
search for inhibin, a factor of testicular origin that inhibits FSH
secretion. There are two inhibins in extracts of testes in men and
in antral fluid from ovarian follicles in women. They are formed
from three polypeptide subunits: a glycosylated α subunit with
a molecular weight of 18,000; and two nonglycosylated β sub-
units, βA and βB, each with a molecular weight of 14,000. The
subunits are formed from precursor proteins (Figure 25–19).
The α subunit combines with βA to form a heterodimer and
with βB to form another heterodimer, with the subunits linked
by disulfide bonds. Both αβA (inhibin A) and αβB (inhibin B)
inhibit FSH secretion by a direct action on the pituitary, though
it now appears that it is inhibin B that is the FSH-regulating in-
hibin in adult men and women. Inhibins are produced by Ser-
toli cells in males and granulosa cells in females.
The heterodimer βAβB and the homodimers βAβA and βBβB
are also formed. They stimulate rather than inhibit FSH secre-
tion and consequently are called activins. Their function in
reproduction is unsettled. However, the inhibins and activins
are members of the TGFβ superfamily of dimeric growth fac-
tors that also includes MIS. Activin receptors have been iden-
tified and belong to the serine/threonine kinase receptor
family. Inhibins and activins are found not only in the gonads
but also in the brain and many other tissues. In the bone mar-
row, activins are involved in the development of white blood
cells. In embryonic life, activins are involved in the formation
of mesoderm. All mice with a targeted deletion of the α-
inhibin subunit gene initially exhibit normal growth but then
develop gonadal stromal tumors, so the gene is a tumor sup-
pressor gene.
In plasma, α 2 -macroglobulin binds activins and inhibins.
In tissues, activins bind to a family of four glycoproteins
called follistatins. Binding of the activins inactivates theirCLINICAL BOX 25–4
Congenital 5α-Reductase Deficiency
Congenital 5α-reductase deficiency, in which the gene for
type 2 5α-reductase is mutated, is common in certain parts
of the Dominican Republic. It produces an interesting form
of male pseudohermaphroditism. Individuals with this syn-
drome are born with male internal genitalia including testes,
but they have female external genitalia and are usually
raised as girls. However, when they reach puberty, LH secre-
tion and circulating testosterone levels are increased. Conse-
quently, they develop male body contours and male libido.
At this point, they usually change their gender identities and
“become boys.” The clitoris enlarges (“penis-at-12 syn-
drome”) to the point that some of the individuals can have
intercourse with women. This enlargement probably occurs
because with the high LH, enough testosterone is produced
to overcome the need for DHT amplification in the genitalia.
5 α-Reductase-inhibiting drugs are now being used clini-
cally to treat benign prostatic hyperplasia, and finasteride,
the most extensively used drug, has its greatest effect on
type 2 5α-reductase.FIGURE 25–19 Inhibin precursor proteins and the various
inhibins and activins that are formed from the carboxyl terminal
regions of these precursors. SS, disulfide bonds.α precursorβA precursorβB precursorS S Inhibin AS SActivins
αα
βAβBS SβA
βAS SβB
βBS SβA
βBInhibin B