D.

Tanda dan Gejala

Obesity
GH dynamics are impaired in many severely obese patients; all
provocative stimuli, including insulin-induced hypoglycemia, arginine,
levodopa, and glucagon plus propranolol, often fail to provoke
GH secretion. The GH response to GHRH is also impaired
in obesity and improves with weight loss. Obesity is also a common
cause of hypogonadotropic hypogonadism in adult men.
Dia betes Mellitus
Although glucose normally suppresses GH secretion, most individuals
with type 1 diabetes have normal or elevated GH levels
that often do not rise further in response to hypoglycemia or arginine.
Levodopa increases GH in some diabetic patients, and even
CHAPTER 4 Hypothalamus and Pituitary Gland 89
a dopamine infusion (which produces no GH change in nondiabetic
subjects, because it does not cross the blood-brain barrier),
stimulates GH in diabetic patients. Despite the increased GH
secretion in patients with inadequately controlled diabetes, the
GH response to GHRH in insulin-dependent diabetic patients is
similar to that of nondiabetic subjects. IGF-I levels are low in
insulin-deficient diabetes despite the elevated GH levels.
U remi a
Basal levels o f G H , PRL, LH, FSH, TSH, and free cortisol tend
to be elevated, for the most part owing to prolongation of their
plasma half-life. GH may paradoxically increase following glucose

administration and is often hyperresponsive to a hypoglycemic

stimulus. Although the administration ofTRH (protirelin) has no
effect on GH secretion in healthy subjects, the drug may increase
GH in patients with chronic renal failure. The response of PRL to
TRH is blunted and prolonged. Gonadotropin response to synthetic
GnRH usually remains intact. Dexamethasone suppression
of cortisol may be impaired.
Starvation a n d Anorexia Nervosa
GH secretion increases with fasting and malnutrition, and such
conditions may cause a paradoxical increase in GH following glucose
administration. Severe starvation, such as occurs in patients
with anorexia nervosa, may result in low levels of gonadal steroids.
LH and FSH responses to GnRH may be intact despite a state of
functional hypogonadotropic hypogonadism. Cortisol levels may
be increased and fail to suppress adequately with dexamethasone.
PRL and TSH dynamics are usually normal despite a marked
decrease in circulating total thyroid hormones (see Chapter 7).

Depression
Depression may alter the ability of dexamethasone to suppress
plasma cortisol and may elevate cortisol secretion; the response to
insulin-induced hypoglycemia usually remains intact. In addition,
late-evening salivary cortisol levels usually remain normal and are
not elevated as seen in patients with Cushing syndrome. The

ACTH response to CRH is blunted in endogenous depression.

Some depressed patients also have abnormal GH dynamics: TRH
may increase GH, and hypoglycemia or levodopa may fail to
increase GH. These patients may also show blunted TSH
responses to TRH.

GH deficiency-In children, congenital monotropic GH

deficiency may be sporadic or familial. These children, who
may experience fasting hypoglycemia, have a gradual deceleration
in growth velocity after 6 to 1 2 months of age. Diagnosis
must be based on failure of GH responsiveness to provocative
stimuli and the demonstration of normal responsiveness of
other anterior pituitary hormones. Monotropic GH deficiency
and growth retardation have also been observed in children
suffering severe emotional deprivation. This disorder is reversed
by placing the child in a supportive psychosocial milieu. A
more detailed description of GH deficiency and growth failure
is provided in Chapter 6.
1.

ACTH deficiency-Mono tropic ACTH deficiency is rare and

is manifested by the signs and symptoms of adrenocortical
insufficiency. LPH deficiency has also been noted in such
patients. The defect in these patients may be due to primary
failure of the corticotrophs to release ACTH and its related
peptide hormones or may be secondary to impaired secretion
of CRH by the hypothalamus. Most acquired cases of monotropic
ACTH deficiency are presumed to be due to lymphocytic
hypophysitis.
2.

Gonadotropin deficiency-Isolated deficiency of gonadotropins

is not uncommon. Kallmann syndrome initially described
in the 1 940s, is characterized by an isolated defect in GnRH
secretion associated with maldevelopment of the olfactory center
with hyposmia or anosmia; X-linked recessive, autosomal
dominant, and autosomal recessive patterns of inheritance are
seen. Sporadic cases occur, and other neurologic defects such as
color blindness and nerve deafness have been reported. At least
five Kallmann syndrome genes have been identified: KAL l ,
FGFR l , FGFS, PROKR2, and PROK2. KALl mutations are
responsible for the X-linked form of the disease and result in
decreased expression of the extracellular glycoprotein anosmin1 . This in turn interferes with the normal embryonic
development and migration of GnRH-secreting neurons.
Because anterior pituitary function is otherwise intact, young
men with isolated hypogonadotropic hypogonadism develop a
eunuchoid appearance, since testosterone deficiency results in
failure of epiphysial closure (see Chapter 1 2) . In women, a
state of hypogonadotropic hypogonadism manifested by oligomenorrhea
or amenorrhea often accompanies weight loss,
emotional or physical stress, and athletic training. Anorexia
nervosa and marked obesity both result in hypothalamic dysfunction
3.

and impaired gonadotropin secretion. Hypothalamic

hypogonadism has also been observed in overtrained male
athletes. Sickle cell anemia also causes hypogonadotropic
hypogonadism due to hypothalamic dysfunction and results in
delayed puberty. Clomiphene treatment has been effective in
some cases. Isolated gonadotropin deficiency may also be seen
in the polyglandular autoimmune syndrome; this deficiency is
related to selective pituitary gonadotrope failure from autoimmune
hypophysitis. Other chronic illnesses (eg, poorly controlled
diabetes, malnutrition) may result in gonadotropin
deficiency. Isolated deficiencies of both LH and FSH without
an obvious cause such as those described have been reported
but are rare. In addition, acquired partial gonadotropin deficiency
may occur in middle-aged men. The cause and exact
frequency of this disorder are unknown.
TSH deficiency-Monotropic TSH deficiency is rare and can
be caused by a reduction in either hypothalamic TRH secretion
(tertiary hypothyroidism) or pituitary TSH secretion
(secondary hypothyroidism) . These defects have reported in
association with gene mutations, empty sella, lymphocytic
hypophysitis, and pituitary rumors. Some patients with chronic
renal failure also appear to have impaired TSH secretion.
4.

5. Prolactin deficiency-PRL deficiency almost always indicates

severe intrinsic pituitary damage, and panhypopituitarism is

usually present. However, isolated PRL deficiency has been
reported after lymphocytic hypophysitis. Deficiencies of TSH
and PRL have been noted in patients with pseudohypoparathyroidism.
Multiple hormone deficiencies isolated from other pituitary
damage-Multiple hormone deficiencies result from
6.

abnormal pituitary development related to abnormalities of the

genes encoding the transcription factors, PIT- 1 (TSH, GH,
and PRL) and PROP- I (TSH, GH, PRL, LH, FSH, and
ACTH).