Diseases and Syndromes
Lab: Stimulation tests
Low T4, low 123-Iodine uptake, low FSH, LH, TSH, low urinary 17-ketosteroids and hydroxysteroids, low growth hormone. Prolactin may be elevated in hypothalamic disease. Fasting glucose-low, Plasma sex steroids low.
Etiology of Panhypopituitarism
Acromegaly and Gigantism
Bromocriptine and apomorphine, which in normal subjects stimulates GH causes GH suppression in acromegaly. Most deleterious effects of GH hypersecretion such as bone growth and organomegaly are due to its effects on somatomedins. Insulin resistance however is due to GH. Glucose intolerance follows, overt diabetes and diabetic acidosis, are rare. Half the patients develop hypogonadism possibly due to inhibition of sex-hormone-binding protein SHBG. Gynecomastia and galactorrhea occur in 15% of cases which may be part of MEN type 1 syndrome.
Lab: Glycemia, Glycosuria, hyperphosphatemia and hypercalciuria
Cushing’s Disease (Pituitary)
ACTH-secreting pituitary adenomas. It is the most common cause of primary Cushing’s disease (hypercortisolism). Usually caused by benign pituitary micro-adenomas.
The endocrine abnormalities are:
When thyroid hormone concentrations are low many metabolic processes slow down. Typical presenting symptoms include fatigue, slowing of physical and mental performance, hoarseness, cold intolerance, constipation, dry skin, and coarse hair.
Low concentration of serum T4 and increased level of TSH is common. Chronic lymphocytic thyroiditis (Hashimoto’s) is the most common form (affecting approximately 2% to 4% of the population in the 5th decade) and frequently serum antibodies toward thyroglobulin or thyroid microsomal antigen can be found. When diagnosed, most patients with Hashimoto’s thyroiditis are clinically and biochemically euthyroid. A firm bosselated goiter usually leads to the biochemical confirmation. Stimulation testing is usually not needed in the evaluation of hypothyroidism.
Secondary and tertiary hypothyroidism
These are defined as pituitary TSH deficiency and hypothalamic TRH deficiency, respectively. Secondary hypothyroidism is likely, in the setting of low T4, with inappropriately low serum TSH levels that do not increase after TRH administration. This usually is associated with deficiencies of other anterior pituitary hormones; however, isolated thyrotroph failure has also been reported. Tertiary hypothyroidism is suggested by inappropriately low plasma TSH levels, normal or exaggerated response to exogenous TRH, and imaging evidence of hypothalamic or pituitary stalk disease. Secondary and tertiary hypothyroidism are very rare compared to primary hypothyroidism.
TSH and Hypothalamic Injury
TSH has an alpha and beta subunits. TSH binds to a receptor on thyroid cells increasing production of cAMP in colloid follicles with release of T3 and T4. TRH is its hypothalamic releasing hormone. Regulated by a feedback control of T3 and T4 levels. Cortisol and estrogens also control TSH. Somatostatin inhibits TSH/TRH stimulation. High TSH creates poor thyroid function. Low TSH creates pituitary dysfunction. TRH (protirelin) evaluates hypothalamus-pituitary-thyroid axis. TRH test helps evaluate pituitary-hypothalamic function and distinguish thyroid problems caused in either of these areas. If after giving TRH there is a low TSH response, hypothalamic injury is suspected.
LH and FSH in Disease and Dysfunction
FSH and LH are glycoprotein hormones with two different noncovalently linked subunits. Human chorionic gonadotropin (HCG) is a glycoprotein hormone secreted by the placenta as early as day 9 of pregnancy. Its biologic actions closely parallel those of LH. HCG and the pituitary glycoprotein hormones are composed of two chains, alpha and beta. They have the same alpha subunit. The beta subunit dictates the biologic specificities of each hormone.
LH-releasing hormone is a 10-amino acid peptide. Since it was initially described it has been shown to be the major hypothalamic releasing factor for both LH and FSH and is more appropriately termed gonadotropin-RH (GnRH).
In addition to the known LH (estrogen and progesterone from ovary) and FSH (development of follicle) functions of these hormones on the ovary, these hormones also act on the testicle in the male. LH acts on Leydig cells, and FSH on testicular tubules. GnRH is the hypothalamic releasing hormone for LH and FSH. If testicular tubules are destroyed, FSH increases. Inhibin, another peptide, inhibits FSH.
These can now be measured immunoradiometrically. In females, the presence of normal estrous cycles and normal estradiol are indicative of intact hypothalamic-pituitary-gonadal axis integrity. In males normal levels of testosterone are indicative of normal pituitary function. High LH and FSH in the presence of low gonadal function point to primary gonadal failure. GnRH (gonadorelin) assesses pituitary reserve in cases of gonadal failure. Absence of LH response in the presence of GnRH suggests pituitary dysfunction. Clomiphene blocks estrogen receptors, this causes GnRH release and elevation of LH. A lack of response may point to hypothalamic dysfunction.
Gonadotropin deficiency may be an isolated deficiency or may occur with deficiencies of several pituitary hormones. Although it may be idiopathic, frequently it is due to mass lesions in the hypothalamic-pituitary region. With onset after puberty, these patients present with secondary amenorrhea (amenorrhea occurring in a non-pregnant woman after normal menstrual cycles have been established) in women or impotence in men. When there is associated estrogen deficiency, several other signs and symptoms may be found including atrophy of the breasts, decrease in body hair growth, and premature osteoporosis. Prolonged androgen deficiency in men results in loss of libido, impotence, decrease in growth of facial and body hair, decrease in muscle strength, and loss of "vitality".
Frequently, secondary amenorrhea is temporary and has been termed "functional" or "hypothalamic." Psychotropic drugs can cause secondary amenorrhea and usually is accompanied by increased PRL level. Secondary amenorrhea also may occur with the rapid weight loss associated with anorexia nervosa, stress, or intensive exercise. In these patients, basal GnRH-stimulated LH levels are low.
Isolated GNRH deficiency is the most common finding in idiopathic hypogonadotropic hypogonadism. When associated hyposmia or anosmia is found, the diagnosis of Kallman’s syndrome is suspected, a genetic disorder probably inherited as an X-linked dominant gene with incomplete penetrance. Associated gynecomastia, cryptorchidism, and deafness also may be found. In these patients GNRH stimulation usually results in increases in LH and FSH.
Gonadal failure results in pubertal delay, sexual infantilism, and hypergonadotropism due to lack of negative feedback control. The major causes of primary gonadal failure in boys are Klinefelter’s syndrome, bilateral testicular trauma or congenital anorchia, and Noonan’s syndrome.
Clinical evaluation of secondary amenorrhea: Detailed history, pregnancy test, serum prolactin.
Klinefelter’s syndrome is associated with atrophic testes with hyalinization of the tubules due to a 47,XXY chromosomal anomaly. These patients present with hypogonadism, eunuchoid body proportions, and gynecomastia. The testes may make enough androgens to produce puberty at a normal age but, with time, the androgen levels decrease and gonadotropin levels increase. Noonan’s syndrome presents in boys as Turner’s syndrome does in girls, but is not associated with chromosomal abnormalities. The testes are usually hypoplastic, and cryptorchidism is common.
The most common cause of hypergonadotropic hypogonadism in girls is Turner’s syndrome (45,XO anomaly). This is associated with aplasia or hypoplasia of the ovaries. Autoimmune ovarian failure may occur as part of the polyglandular failure syndrome.
Gonadotropin-producing Pituitary Adenomas
Gonadotropin-secreting pituitary tumors are rare. Excessive secretion of LH and FSH by such a tumor does not result in a phenotypically recognizable endocrine disorder. Most of these tumors are macroadenomas and have been reported to occur in middle-aged men who have apparently normal gonadal function but have vision deficit due to the pituitary tumor mass effect. FSH is the glycoprotein hormone most commonly secreted in excess by these tumors; hypersecretion of intact LH is less common. An increase in alpha subunit level is common with both FSH- and LH- secreting pituitary tumors. As with other types of pituitary tumors, the pathogenesis of gonadotroph cell adenomas is unknown.
Dynamic Function Test
GnRH-stimulation test—Administration of synthetic GNRH results in the release of LH and FSH from pituitary gonadotrophs (Lufkin et al., 1983).
Trans-sphenoidal surgery, radiation, or Ketoconazole (a potent glucocorticoid inhibitor). Metyrapone and/or aminoglutethimide. Mitotane has also been used, it causes adrenal atrophy of fasciculata and reticularis.
Thyrotropin -secreting, Gonadotropin-secreting and Alpha-subunit-secreting.
Updated June 13, 2005