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.

1. GH deficiency-In children, congenital monotropic GHdeficiency may be sporadic or familial. These children, whomay experience fasting hypoglycemia, have a gradual decelerationin growth velocity after 6 to 1 2 months of age. Diagnosismust be based on failure of GH responsiveness to provocativestimuli and the demonstration of normal responsiveness ofother anterior pituitary hormones. Monotropic GH deficiencyand growth retardation have also been observed in childrensuffering severe emotional deprivation. This disorder is reversedby placing the child in a supportive psychosocial milieu. Amore detailed description of GH deficiency and growth failureis provided in Chapter 6.

2. ACTH deficiency-Mono tropic ACTH deficiency is rare andis manifested by the signs and symptoms of adrenocorticalinsufficiency. LPH deficiency has also been noted in suchpatients. The defect in these patients may be due to primaryfailure of the corticotrophs to release ACTH and its relatedpeptide hormones or may be secondary to impaired secretionof CRH by the hypothalamus. Most acquired cases of monotropicACTH deficiency are presumed to be due to lymphocytichypophysitis.

3. Gonadotropin deficiency-Isolated deficiency of gonadotropinsis not uncommon. Kallmann syndrome initially describedin the 1 940s, is characterized by an isolated defect in GnRHsecretion associated with maldevelopment of the olfactory centerwith hyposmia or anosmia; X-linked recessive, autosomaldominant, and autosomal recessive patterns of inheritance areseen. Sporadic cases occur, and other neurologic defects such ascolor blindness and nerve deafness have been reported. At leastfive Kallmann syndrome genes have been identified: KAL l ,FGFR l , FGFS, PROKR2, and PROK2. KALl mutations areresponsible for the X-linked form of the disease and result indecreased expression of the extracellular glycoprotein anosmin-1 . This in turn interferes with the normal embryonicdevelopment and migration of GnRH-secreting neurons.Because anterior pituitary function is otherwise intact, youngmen with isolated hypogonadotropic hypogonadism develop aeunuchoid appearance, since testosterone deficiency results infailure of epiphysial closure (see Chapter 1 2) . In women, astate of hypogonadotropic hypogonadism manifested by oligomenorrheaor amenorrhea often accompanies weight loss,emotional or physical stress, and athletic training. Anorexianervosa and marked obesity both result in hypothalamic dysfunction

and impaired gonadotropin secretion. Hypothalamichypogonadism has also been observed in overtrained maleathletes. Sickle cell anemia also causes hypogonadotropichypogonadism due to hypothalamic dysfunction and results indelayed puberty. Clomiphene treatment has been effective insome cases. Isolated gonadotropin deficiency may also be seenin the polyglandular autoimmune syndrome; this deficiency isrelated to selective pituitary gonadotrope failure from autoimmunehypophysitis. Other chronic illnesses (eg, poorly controlleddiabetes, malnutrition) may result in gonadotropindeficiency. Isolated deficiencies of both LH and FSH withoutan obvious cause such as those described have been reportedbut are rare. In addition, acquired partial gonadotropin deficiencymay occur in middle-aged men. The cause and exactfrequency of this disorder are unknown.

4. TSH deficiency-Monotropic TSH deficiency is rare and canbe caused by a reduction in either hypothalamic TRH secretion(tertiary hypothyroidism) or pituitary TSH secretion(secondary hypothyroidism) . These defects have reported inassociation with gene mutations, empty sella, lymphocytichypophysitis, and pituitary rumors. Some patients with chronicrenal failure also appear to have impaired TSH secretion.

5. Prolactin deficiency-PRL deficiency almost always indicatessevere intrinsic pituitary damage, and panhypopituitarism isusually present. However, isolated PRL deficiency has beenreported after lymphocytic hypophysitis. Deficiencies of TSHand PRL have been noted in patients with pseudohypoparathyroidism.

6. Multiple hormone deficiencies isolated from other pituitarydamage-Multiple hormone deficiencies result fromabnormal pituitary development related to abnormalities of thegenes encoding the transcription factors, PIT- 1 (TSH, GH,and PRL) and PROP- I (TSH, GH, PRL, LH, FSH, andACTH).