TESTIS FAILURE II: SECONDARY (HYPOGONADOTROPIC) HYPOGONADISM
Testicular deficiency due to failure of the anterior pituitary to secrete gonadotropins is termed secondary or hypogonadotropic hypogonadism. The hypothalamus is known to regulate anterior pituitary function, mainly through gonadotropin-releasing hormone (also termed LH-releasing hormone, GnRH or LHRH), a 10–amino acid peptide secreted from neuronal cells in the preoptic and arcuate nuclei. The only known function of GnRH is to stimulate gonadotropin secretion. GnRH has a plasma half-life of approximately 5 to 7 minutes, and it exhibits several types of rhythmicity: seasonal; circadian, resulting in higher testosterone levels during the early morning hours; and pulsatile, with GnRH peaks occurring every 90 to 120 minutes. The importance of the pulsatile GnRH secretory pattern in normal testicular function is aptly demonstrated by the ability of exogenously given GnRH agonists (leuprolide acetate) to stop testicular testosterone production by changing pituitary exposure to GnRH from a cyclic to a constant pattern.
In Kallmann syndrome,
characterized by congenital hypogonadotropic hypogonadism, the GnRH precursor
neurons fail to migrate normally, with a subsequent absence of hypothalamic
GnRH. Affected individuals present with delayed puberty or infertility due to
lack of testosterone production. Because the GnRH neurons comigrate with
olfactory nerves, Kallmann patients may also have anosmia. Causes of acquired
pituitary hypofunction and secondary hypogonadism include severe stress,
malnutrition, diabetes mellitus, chronic opiate use, sickle cell disease, and
intracranial conditions such as prolactinomas, craniopharyngiomas, Rathke cleft
cysts, and trauma. For this reason, pituitary imaging should be undertaken in all
cases of acquired secondary hypogonadism. Notably, not all brain or pituitary
tumors necessarily disturb gonadotropin secretion and result in secondary
hypogonadism.
The clinical picture of
secondary hypogonadism is a similar eunuchoid body morphology as that described
for prepubertal or pubertal primary testicular failure (see Plate 3-16). There
is retarded growth of the external sexual organs, with the penis remaining
small (micropenis) and the scrotum underdeveloped (hypoplastic). The prostate
and seminal vesicles are small but present. The testes vary from infantile to
small adult size, but testicular size does not correlate well with androgen
function, because Leydig cells comprise only 10% to 15% of testicular volume.
Testis biopsies generally reveal infantile seminiferous tubules containing
undifferentiated spermatogonia, Sertoli cells, and Leydig cells. The histologic
picture is essentially that of a prepubertal boy (see Plate 3-4).
There may be a complete
absence of beard and bodily hair, with fine, sparse pubic hair characteristic of
andro- gen deficiency. Baldness is rare with advancing age unless the patient is
treated with androgens. Skin may be smooth, pale, fine in texture, and dry, with
little oiliness; acne rarely develops. The thyroid cartilage may be
inconspicuous, and the voice high pitched. There may also be a striking lack of
muscular development and complaints of extreme fatigability. There may also be
behavioral problems influenced by the adjustment needed due to sexual
immaturity.
The anterior pituitary also
secretes growth hormone in response to hypothalamic growth hormone–releasing hormone, thyroid-stimulating hormone, and adrenocorticotropic hormone
(ACTH). Thus, secondary hypogonadism can be associated with defective growth,
hypothyroidism, and cortisol deficiency. When occurring together, this is
referred to as panhypopituitarism. Boys with panhypopituitarism remain dwarfs,
with greatly decreased height. However, they attain a mature skeletal ratio
without disproportionate extremities or eunuchoid features. Pituitary dwarfs
have infantile faces,
acne-free skin, a lack of
hair development owing to the deficient ACTH, and very low adrenal androgen
levels.
With secondary hypogonadism,
gonadotropin levels are undetectably low in conjunction with low androgens.
This differentiates it from primary hypogonadism. In isolated cases, adrenal
androgens may be sufficient to induce puberty and so the presenting symptom may simply be infertility later in life.
