Male Reproduction Actions of Androgens
Effects of the failure of androgen action
may be best seen in patients with hypogonadotrophic hypogonadism (Fig. 32a).
This is caused by a failure of hypothalamic GnRH secretion or by pituitary
disease resulting in impaired gonadotrophin release and hence low androgen
concentrations (Table 32.1). The clinical features of hypogonadotrophic
hypogonadism depend on the timing of its onset, such that males developing the
condition after puberty present with features of secondary testicular failure
(poor libido, loss of secondary sexual characteristics and subfertility). Prior
to puberty, boys present with delayed or failed puberty or, less commonly, the
condition presents in the neonatal period with cryptorchidism and micropenis
Idiopathic hypogonadotrophic hypogonadism describes those patients in whom
there are no anatomical abnormalities of the hypothalamus and pituitary and no
associated endocrine disorders.
AB presented to the endocrine clinic
at the age of 16 years. He had symptoms of delayed puberty, with absence of
secondary sexual characteristics, but had always been as tall as his friends at
school. On questioning he thought his sense of smell was poor and his parents
confirmed this observation. On examination his height was on the 75th centile
for age but pubertal assessment revealed no evidence of sexual maturation.
Formal testing of the first cranial nerve showed anosmia. Hypogonadotrophic
hypogonadism was confirmed biochemically – LH 0.4 U/L, FSH 0.6 U/L,
testosterone 5.3 nmol/L, prolactin 145 mU/L, TFTs and cortisol were normal. An
MRI scan confirmed a normal pituitary gland and detailed MRI scans of the
hypothalamus revealed abnormalities consistent with Kallman’s syndrome. He was
subsequently treated with gonadotrophins
to induce pubertal
development. Kallman’s syndrome is caused by the failure of
migration of GnRH neurones from the olfactory bulb to the arcuate nucleus of
the hypotha- lamus in early fetal life. Both X-linked and autosomal forms of
the disorder have been described and may be associated with other midline
defects and synkinesia.
Actions of testosterone
The actions of testosterone (Fig. 32b)
are to establish and maintain the function of the male and to maintain libido
in the female. The actions of testosterone can be broadly classified as androgenic
and anabolic.
Brain and spinal cord. In birds and mammals, testosterone sexually
differentiates the fetal brain. The fetal brain contains androgen and estrogen
receptors, which mediate these actions of testosterone. In fetal rats,
testosterone may act to protect neurones from cell death.
In adult male rats, the medial
preoptic nuclei in the brain are larger than in females, but this difference is
eliminated if the males are castrated during the critical period of brain
sexual differentiation. Conversely, if neonatal female rats are injected with
testosterone, they develop a medial preoptic region similar in size to that of
the male. Castration of an adult rat results in the shrinkage of cell bodies
and axons of motor neurones involved in male copulation, and these are restored
in size after androgen replacement. Although no evidence is available about
these actions of testosterone in humans, there is evidence that testosterone
causes changes in the fetal brain during sexual differentiation of the brain at
about 6 weeks.
Behaviour. The precise nature of the influence of testosterone on behaviour is unknown, due in part to the limitations of methods of
study. In humans, there is no apparent relationship between plasma levels of
testosterone and sexual or aggressive behaviour. It seems that behaviour has a
powerful influence on testosterone production, since stress drives it down, as
does depression and threatening behaviour from others. In captive primate
colonies, subordinate males have raised prolactin and very much reduced plasma
levels of testosterone.
Peripheral actions of testosterone
A fundamental role of testosterone,
together with follicle-stimulating hormone (FSH), is the maintenance of
spermatogenesis. It is currently believed that FSH stimulates Sertoli cells to
produce cAMP, which stimulates synthesis of a specific protein,
androgen-binding protein (ABP), which is secreted into the lumen of the
seminiferous tubules. The Sertoli cells also produce the nutrient requirements
of the growing and differentiating spermatozoa. Luteinizing hormone (LH)
stimulates the Leydig cells to produce testosterone, which binds to ABP, and
the complex brings testosterone into close proximity with the developing
spermatocytes. ABP may also function to build up local concentrations of
testosterone and transport the hormone to the epididymis. The Leydig cell also
synthesizes estrogens which bind to ABP, and which are essential for normal
sperma-togenesis. Growth hormone is essential for early division of the
spermatogonia.
Spermatogenesis (Fig. 32c). About 120 million sperm are produced
each day by the young adult human testis. Most are stored in the vas deferens
and the ampulla of the vas deferens, where they can remain and retain their
fertility for at least 1 month. While stored, they are inactive due to several
inhibitory factors, and are activated once in the uterus. In the female
reproductive tract, sperm remain alive for 1 or 2 days at most. Sperm remain
alive in neutral or mildly alkaline environments, but are rapidly killed in strong
acid media. The metabolic activity of sperm increases markedly with increasing
temperature, but this also shortens their life considerably.
Accessory sex organs. Testosterone maintains the functions and
structural integrity of the seminal vesicles and the prostate gland.
The seminal vesicles are essentially secretory, producing many substances,
including large quantities of prostaglandins, fructose and fibrinogen. During
ejaculation, the seminal vesicles contract, ejecting their fluid into that
carrying the spermatozoa. Fructose is an important nutrient for the sperm, and
prostaglandins aid in the movement of sperm by contracting the uterus and
uterine tubes, as well as by reacting with cervical mucus to make it receptive
to sperm. During orgasm and emission, the prostate gland secretes a thin,
alkaline fluid containing a profibrinolysin, a clotting enzyme, calcium,
citrate ions and acidic phosphate. The functions of prostatic fluid are
unknown, but they may serve to create a less acidic environment for the sperm
and increase their motility.
Anabolic actions of testosterone. Testosterone increases basal metabolic rate
through an increase in enzyme and other protein synthesis. Testosterone
produces a 10–15% increase in red blood cell production during puberty, and men
have about 700 000 more red blood cells per millilitre than women. Testosterone
increases muscle mass, despite an apparent absence of androgen receptors in
skeletal muscle. The effect may be due to an inhibition of the normal catabolic
effects of glucocorticoids in muscle.
