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General Considerations
The anterior pituitary hormones are GH, PRL, ACTH, TSH, LH, and FSH. The hypothalamus synthesizes hormones that regulate anterior pituitary secretion, including corticotropin-releasing hormone (CRH), growth hormone-releasing hormone, gonadotrophin-releasing hormone (GnRH), thyrotropin-releasing hormone, and somatostatin. The hypothalamus also secretes dopamine that inhibits PRL secretion. These hypothalamic regulatory hormones are transported by a portal venous system down the pituitary stalk to the anterior pituitary. The hypothalamus also synthesizes oxytocin and arginine vasopressin (AVP), also known as ADH. Nerves from the hypothalamus carry oxytocin and AVP to the posterior pituitary, where they are stored and released. Hypopituitarism can be caused by either hypothalamic or pituitary dysfunction. Patients with hypopituitarism may have single or multiple hormonal deficiencies.
1. Hypopituitarism with Mass Lesions
Lesion in the sellar or perisellar area may cause hypopituitarism by impingement on the hypothalamus, pituitary stalk, or pituitary.
2. Hypopituitarism Without Mass Lesions
At least one pituitary hormone deficiency develops in 25-30% of survivors of moderate to severe traumatic brain injury and in about 55% of survivors of aneurysmal subarachnoid hemorrhage. Some degree of hypopituitarism, most commonly GH deficiency and hypogonadotropic hypogonadism, occurs in one-third of ischemic stroke patients. Other cases of acquired hypopituitarism can be idiopathic or associated with an empty sella on MRI.
Sheehan syndrome refers to hypopituitarism caused by postpartum pituitary necrosis, usually following severe postpartum uterine hemorrhage. It is usually characterized by postpartum amenorrhea and inability to lactate. The WHO has estimated that over 3 million women suffer from Sheehan syndrome with a yearly mortality of about 100,000 worldwide. Although the incidence of Sheehan syndrome has declined in developed countries with modern obstetric care, it remains a worldwide health problem, particularly in developing countries and among immigrants from those countries. Hypopituitarism in Sheehan syndrome usually occurs gradually over 10-20 years; the diagnosis is typically delayed an average of 9 years. Manifestations in affected women are typically hyponatremia, hypoglycemia, or anemia. In acute Sheehan syndrome, MRI shows an enlarged pituitary with only a thin rim of enhancement with gadolinium. After 1 year, MRI shows atrophy of the pituitary and a partially empty sella.
Functional GH deficiency can occur with normal aging, malnutrition, and CKD. ACTH suppression with functional isolated secondary adrenal insufficiency occurs in patients receiving megesterol acetate, high-dose opioid therapy (15%), and endogenous or exogenous corticosteroids (parenteral, oral, inhaled, or topical). Chemotherapy with bexarotene may cause secondary hypothyroidism and hypopituitarism. Mitotane therapy for adrenocortical carcinoma causes central hypothyroidism.
Functional hypopituitarism can usually be distinguished from other causes of hypopituitarism by considering the clinical setting and by the absence of other pituitary hormone deficiencies.
Clinical Findings
When hypopituitarism is caused by a mass lesion or hypophysitis, patients may have headaches or visual field defects. Nonspecific symptoms, such as fatigue, dizziness and hypotension, confusion, cognitive dysfunction, sexual dysfunction, polydipsia, or cold intolerance, can develop. Other symptoms and signs attributed to specific pituitary hormone deficiencies are described below.
A. Symptoms and Signs
1. Gh (Somatropin) Deficiency
Congenital GH deficiency can present in newborns with hypoglycemia, jaundice, and a small penis and later with short stature in childhood. Laron syndrome is an autosomal recessive disorder that is mainly caused by mutations in the gene that encodes the GH receptor, resulting in GH-resistance and a severe deficiency in serum insulin-like growth factor-1 (IGF-1), resulting in short stature (dwarfism) and characteristic features. Affected individuals have a prominent forehead, depressed nasal bridge, small mandible, and central obesity. They may have recurrent hypoglycemic seizures. They have a reduced risk of diabetes mellitus and cancer, but an increased risk of accidental death. Partial resistance to GH may cause some cases of idiopathic short stature without features of Laron syndrome.
GH deficiency in adults is often undiagnosed, since maximum height has already been reached and other manifestations are nonspecific. Nonspecific symptoms, varying from mild to severe, include mild to moderate central obesity, reduced physical and mental energy, impaired concentration and memory, and depression. Patients may also have reduced muscle mass, increased LDL cholesterol, and reduced cardiac output with exercise. Chronic GH deficiency leads to osteopenia and an increased risk of fractures. When other more recognizable pituitary hormone deficits are present, there is a high likelihood of concurrent GH deficiency.
2. Gonadotropin Deficiency (Hypogonadotropic Hypogonadism)
In gonadotropin deficiency, insufficiencies of LH and FSH cause hypogonadism and infertility.
Congenital gonadotropin deficiency is characterized by partial or complete lack of pubertal development. Isolated hypogonadal hypogonadism occurs in as many as 1 in 4000 males but is less common in females. About 30% of cases have been linked to genetic variants with variable phenotypic expressions that can be X-linked, autosomal dominant, or autosomal recessive. Patients may have normal or abnormal olfaction (Kallmann syndrome), abnormal genitalia, kidney abnormalities, midline craniofacial defects, neurologic deficits, or musculoskeletal malformations. Some affected women have menarche followed by secondary amenorrhea. Affected boys who survive childhood may present with failure to enter puberty.
The sense of olfaction (smell) is entirely normal, in 58% (normosmic isolated hypogonadotropic hypogonadism), or hyposmic or anosmic in 42% (Kallmann syndrome). Midline craniofacial defects (50%) include cleft lip, high-arched or cleft palate, absent nasal cartilage, dental agenesis, or hypertelorism. Neurologic deficits include cognitive problems, bimanual synkinesis, cerebellar ataxia, oculomotor dysfunction, color blindness, or neurosensory hearing loss. Musculoskeletal malformations include pectus excavatum, syndactyly, clinodactyly, and camptodactyly.
Genetic testing for patients with normosmic, hyposmic, or anosmic isolated hypogonadotropic hypogonadism (Kallmann syndrome) can be prioritized as follows: (1) Patients with synkinesia should be tested for mutations in KAL1. (2) Those with hearing loss should be tested for mutations in CHD7. (3) Patients with dental agenesis or finger abnormalities can be tested for mutations in FGF8/FGFR1. (4) Males with isolated hypogonadotropic hypogonadism and congenital adrenal hypoplasia can be tested for mutations in DAX1/NROB1.
Prader-Willi syndrome presents with cryptorchidism, mental retardation, short stature, hyperflexibility, autonomic dysregulation, cognitive impairment, obesity, hypogonadotropic hypogonadism, or primary hypogonadism.
Acquired gonadotropin deficiency is characterized by the gradual loss of facial, axillary, pubic, and body hair (more prominent in patients who are also hypoadrenal). Men may note diminished libido, erectile dysfunction, muscle atrophy, infertility, and osteopenia. (See Male Hypogonadism.) Women have amenorrhea, infertility, and osteoporosis.
4. Acth Deficiency
Central adrenal insufficiency is caused by ACTH deficiency. There is functional atrophy of the adrenal cortex within 2 weeks of pituitary damage, which results in diminished cortisol. Adrenal mineralocorticoid secretion continues, so manifestations of adrenal insufficiency in hypopituitarism may be less striking than in bilateral adrenal gland destruction (see Primary Adrenal Insufficiency [Addison disease]). Central adrenal insufficiency from pituitary metastases typically presents with nausea, weight loss, and fatigue; these symptoms are often incorrectly attributed to chemotherapy or to the malignancy itself. Patients with partial ACTH deficiency have some cortisol secretion and may not have symptoms until stressed by illness or surgery.
6. Panhypopituitarism
This refers to a deficiency of several or all pituitary hormones. There may be hypogonadotropic hypogonadism (62%), diabetes insipidus (54%), headache (50%), hypothyroidism (48%), ACTH deficiency (47%), GH deficiency (37%), and hyperprolactinemia (36%), which clinicians may mistake for a prolactinoma. Hypopituitarism typically presents in women with amenorrhea. Congenital panhypopituitarism often develops gradually, usually presenting with short stature and growth failure due to GH and TSH deficiency; lack of pubertal development occurs due to deficiencies in FSH and LH. ACTH-cortisol deficiency tends to develop by age 18 years. Patients with long-standing hypopituitarism tend to have dry, pale, fine, wrinkled facial skin and an apathetic countenance.
B. Laboratory Findings
Initially, there may be hyponatremia and hypoglycemia, with secondary hypoadrenalism, hypothyroidism, or GH deficiency. Hyponatremia can be caused by hypothyroidism or hypoadrenalism. Hyperkalemia usually does not occur, since aldosterone production is not affected. Patients with lymphocytic hypophysitis frequently have elevated serum antinuclear or anticytoplasmic antibodies. Patients with hypopituitarism without an established etiology should be screened for hemochromatosis with a serum ferritin or iron and transferrin saturation.
Male hypogonadotropic hypogonadism is diagnosed by drawing blood before 10 AM after an overnight fast in men without an acute or subacute illness. Affected men have a low fasting serum total or free serum testosterone with a low or normal serum LH. A serum PRL is also obtained, since hyperprolactinemia of any cause can result in hypogonadism.
Female hypogonadotropic hypogonadism is suspected in nonpregnant women with amenorrhea or oligomenorrhea, who do not have acute illness, hyperthyroidism, or hyperandrogenism. The serum estradiol is low and the serum FSH is low or normal. In nonpregnant women, a serum PRL is obtained, since hyperprolactinemia of any cause can result in hypogonadism. In postmenopausal women, the absence of an elevated serum FSH (in a woman not taking estrogen replacement) indicates gonadotropin deficiency.
Central hypothyroidism is diagnosed with a low serum free thyroxine (FT4) in the setting of pituitary disease. The serum TSH can be low or normal. Central hypothyroidism can emerge when patients begin GH replacement, so thyroid levels must be monitored in that setting. Patients undergoing pituitary surgery should be assessed for central hypothyroidism preoperatively and again 6 weeks postoperatively.
Central adrenal insufficiency is diagnosed after withholding corticosteroid replacement with hydrocortisone, prednisone, or methylprednisolone for at least 18-24 hours. Blood is drawn at 8-9 AM for baseline plasma ACTH and serum cortisol. A serum cortisol less than 3 mcg/dL (80 nmol/L) usually indicates adrenal insufficiency, whereas AM serum cortisol higher than 15 mcg/dL (400 nmol/L) usually excludes adrenal insufficiency. For AM cortisol levels between 3 and 15 mcg/dL, a cosyntropin test is often required. For the cosyntropin test, patients should hold any corticosteroid replacement for at least 18-24 hours. At 8-9 AM, blood is drawn for serum cortisol, ACTH, and dehydroepiandrosterone (DHEA); then cosyntropin (synthetic ACTH1-24) 0.25 mg is administered intramuscularly or intravenously. Another serum cortisol is obtained 45 minutes after the cosyntropin injection; a stimulated serum cortisol of less than 20 mcg/dL (550 nmol/L) indicates probable adrenal insufficiency. With gradual pituitary damage and early in the course of ACTH deficiency, patients can have a stimulated serum cortisol of 20 mcg/dL or more (550 nmol/L) but a baseline 8 AM serum cortisol of 5 mcg/dL (138 nmol/L) or less, which is suspicious for adrenal insufficiency. The baseline serum ACTH level is low or normal in secondary hypoadrenalism, distinguishing it from primary adrenal disease. Serum DHEA is a proxy for ACTH; levels are usually low in patients with secondary adrenal deficiency, helping confirm the diagnosis. Hyponatremia may occur, especially when ACTH and TSH deficiencies are both present.
For patients with signs of secondary adrenal insufficiency (hyponatremia, hypotension, pituitary tumor) but borderline cosyntropin test results, treatment can be instituted empirically and the test repeated at a later date. Insulin tolerance testing and metyrapone testing are usually unnecessary. Patients undergoing pituitary surgery with normal preoperative adrenal function should have an individualized clinical approach to postoperative corticosteroid replacement until ACTH-adrenal function can be retested postoperatively.
Epinephrine deficiency occurs with secondary adrenal insufficiency due to the adrenal medulla lacking the local high concentrations of cortisol that are required to induce the production of the enzyme phenylethanolamine N-methyltransferase (PNMT) that catalyzes the conversion of norepinephrine to epinephrine.
GH deficiency in adults is difficult to diagnose, since GH secretion is normally pulsatile and serum GH levels are normally undetectable for much of the day. Also, adults (particularly men) physiologically tend to produce less GH when they are over age 50 or have abdominal obesity. Therefore, pathologic GH deficiency is often inferred by symptoms of GH deficiency in the presence of pituitary destruction or other pituitary hormone deficiencies. GH deficiency is present in 96% of patients with three or more other pituitary hormone deficiencies and a low serum IGF-1. GH stimulates the production of IGF-1, but the serum IGF-1 level is neither a sensitive (about 50%) nor specific test for GH deficiency in adults. Very low serum IGF-1 levels (less than 84 mcg/L) are usually indicative of GH deficiency but also occur in malnutrition, prolonged fasting, hypothyroidism, uncontrolled diabetes mellitus, and liver failure, as well as with estrogen therapy. A therapeutic trial of GH therapy should be considered for symptomatic patients who have either a serum IGF-1 less than 84 mcg/L or three other pituitary hormone deficiencies. In GH deficiency (but also in most adults over age 40), exercise-stimulated serum GH levels remain at less than 5 ng/mL and usually fail to rise.
Provocative GH stimulation testing to help diagnose adult GH deficiency has a sensitivity of only 66%; however, tests are sometimes indicated or required for insurance coverage of GH therapy. In the absence of a serum IGF-1 level less than 84 mcg/L or multiple other pituitary hormone deficiencies, provocative GH-stimulation testing may be indicated for the following patients: (1) young adult patients who have completed GH therapy for childhood GH deficiency and have achieved maximal linear growth; (2) patients who have a hypothalamic or pituitary tumor or who have received surgery or radiation therapy to these areas; and (3) patients who have had prior head trauma, cerebrovascular accident, or encephalitis. Testing usually entails measuring serum GH following provocative stimuli, including macimorelin or glucagon. The single-dose oral macimorelin GH stimulation test involves the oral administration of macimorelin (a GH secretagogue) to a fasting individual at a dose of 0.5 mg/kg body weight. Blood samples for GH are drawn immediately prior to administration and 45 minutes afterward. This test has an 82% sensitivity and 92% specificity for GH deficiency when the stimulated GH is adjusted for BMI: 6.8 ng/mL for BMI less than 30 and 2.7 ng/mL for BMI greater than 30. The glucagon stimulation test is a practical alternative to traditional provocative GH stimulation testing. It should not be given to patients who are malnourished or who have not eaten for over 48 hours. Glucagon 1.0 mg (or 1.5 mg if weight is more than 200 lb [90 kg]) is administered intramuscularly to patients who have not eaten for 8-9 hours. Serum GH is measured before the injection and every 30 minutes for 4 hours. In patients with GH deficiency, the maximum serum GH is usually less than 3 mcg/L. The test is quite sensitive (95%), but much less specific, mostly due to obesity. Therefore, for overweight individuals or those with obesity (BMI of 25 or more), GH deficiency is considered likely if the stimulated GH is below 1 ng/mL. Side effects are usually mild, but nausea or headache occurs in about 20% of patients. Late hypoglycemia can occur after glucagon, so patients are advised to eat immediately following completion of the test.
The differential diagnosis of GH deficiency is congenital GH resistance with deficiency of IGF-1. At its worst, IGF-1 deficiency results in Laron dwarfism that is completely resistant to GH therapy. The condition responds to therapy with biosynthetic IGF-1 (mecasermin). Side effects include hypoglycemia, lymphoid hyperplasia, weight gain, and coarsening of facial features.
C. Imaging
MRI of the hypothalamus and pituitary is indicated when a mass lesion is suspected, such as men over age 16 with a serum testosterone less than 150 ng/dL and a low (or normal) serum LH, two or more pituitary hormone deficiencies, persistent hyperprolactinemia, or symptoms of a mass (headache, visual field defect). MRI can detect lesions of the pituitary, hypothalamus or pituitary stalk, including pituitary adenoma, lymphocytic hypophysitis, neurosarcoidosis, Langerhans cell histiocytosis, craniopharyngioma, germinoma, astrocytoma, and metastatic malignancy. MRI may show hypoplasia or agenesis of the olfactory bulbs in 75% of cases of Kallmann syndrome and in 8% of patients with normosmic hypogonadotropic hypogonadism. MRI typically shows enlargement of the pituitary gland or pituitary stalk with intense enhancement after gadolinium in lymphocytic hypophysitis. MRI shows pituitary enlargement in 75% of cases of ipilimumab-associated hypophysitis but only 25% of cases of anti-PD-1 agent-induced hypophysitis. MRI is not warranted in cases of functional hypopituitarism associated with severe obesity, drugs, or nutritional disorders.
Differential Diagnosis
The failure to enter puberty may simply reflect a constitutional delay in growth and puberty.
Reversible, second hypothyroidism with suppression of TSH and T4 can be caused by severe illness, hyperthyroxinemia, and administration of triiodothyronine, mitotane, or bexarotene, resulting in temporary central hypothyroidism. Corticosteroids and megestrol reversibly suppress endogenous ACTH and cortisol secretion. High-dose corticosteroid therapy can cause secondary adrenal insufficiency that may persist for many months.
GH deficiency occurs normally with aging and physiologically with obesity (reversible with sufficient weight loss). Very low serum IGF-1 levels can be seen with prolonged fasting, malnutrition, liver failure, hypothyroidism, and uncontrolled diabetes mellitus.
Complications
During a stressful illness, patients with untreated hypoadrenalism may become febrile and comatose and die of hyponatremia and shock.
Rarely, acute hemorrhage may occur in large pituitary tumors, manifested by rapid loss of vision, headache, and evidence of acute pituitary failure (pituitary apoplexy) requiring emergency decompression of the sella. Among patients with craniopharyngiomas, diabetes insipidus is found in 16% preoperatively and in 60% postoperatively. Hyponatremia often presents abruptly during the first 2 weeks following any pituitary surgery. Visual field impairment may occur. Hypothalamic damage may result in morbid obesity as well as cognitive and emotional problems. Conventional radiation therapy for intracranial disorders can result in an increased incidence of small vessel ischemic strokes, second tumors and damaged hypothalamic-pituitary function.
Adults with GH deficiency have experienced an increased cardiovascular morbidity.
Treatment
A. Corticosteroid Replacement
Long-term therapy is initiated with hydrocortisone 10-25 mg orally in the morning and 5-15 mg in the late afternoon. Prednisone or methylprednisolone may also be used; the dosing and timing must be individually tailored. No mineralocorticoid replacement is required. See Corticosteroid Replacement Therapy-Primary Adrenal Insufficiency (Addison Disease) below.
B. Thyroid Hormone Replacement
Levothyroxine is given to correct hypothyroidism only after the patient is assessed for cortisol deficiency or is already receiving corticosteroids. (See Hypothyroidism.) The typical maintenance dose is about 1.6 mcg/kg body weight, averaging 125 mcg daily with a wide range of 25-300 mcg daily. Because assessment of serum TSH is useless for monitoring patients with hypopituitarism, the optimal replacement dose of levothyroxine is determined clinically by raising or lowering the dose, according to the patient's symptoms and clinical examination. With clinically optimized levothyroxine replacement, serum FT4 levels are usually in the mid to high-normal range. Some patients do not feel clinically euthyroid until they receive levothyroxine in doses at which the serum FT4 levels are mildly elevated; however, serum T3 or FT3 levels should be in the low-normal range. During pregnancy, clinical status and serum FT4 or total T4 levels need to be monitored frequently, since higher doses of levothyroxine are usually required.
C. Sex Hormone and Gonadotropin Hormone Replacement
Hyperprolactinemia-related hypogonadotropic hypogonadism improves or resolves with treatment (see Hyperprolactinemia). Sex hormone replacement may be required. See Male Hypogonadism and Female Hypogonadism.
Adolescents with idiopathic isolated hypogonadotropic hypogonadism, who have received several years of hormone replacement therapy (HRT), may have a trial off hormonal therapy to assess whether spontaneous sexual maturation may have occurred.
Women with panhypopituitarism have profound androgen deficiency caused by the combination of both secondary hypogonadism and adrenal insufficiency. When serum DHEA levels are less than 400 ng/mL, women may also be treated with compounded USP-grade DHEA 25-50 mg/day orally. DHEA therapy tends to increase pubic and axillary hair and may improve libido, alertness, stamina, and overall psychological well-being.
For men with oligospermia, human chorionic gonadotropin (hCG) (equivalent to LH) may be given at a dosage of 1500-3000 units intramuscularly three times weekly and testosterone replacement discontinued. The dose of hCG is adjusted to normalize serum testosterone levels. After 6-12 months of hCG treatment, if the sperm count remains low, hCG injections are continued along with injections of follitropin beta (synthetic recombinant FSH) or urofollitropins (urine-derived FSH). An alternative for patients with an intact pituitary (eg, Kallmann syndrome) is the use of leuprolide (GnRH analog) by intermittent subcutaneous infusion. With treatment, testicular volumes increase within 5-12 months, and some spermatogenesis occurs in most cases. With persistent treatment and the use of intracytoplasmic sperm injection for some cases, the pregnancy success rate is about 70%. Men often feel better during hCG therapy than during testosterone replacement. Therefore, some men may elect to continue hCG therapy long term.
For men with secondary hypogonadism, treatment with hCG achieves serum testosterone levels that are typically higher than with transdermal testosterone therapy and more consistent than intramuscular testosterone therapy. Many men prefer hCG over testosterone replacement, even when fertility is not at issue.
Clomiphene, 25-50 mg/day orally, can sometimes stimulate men's own pituitary gonadotropins (when their pituitary is intact), thereby increasing testosterone and sperm production. For fertility induction in females, ovulation may be induced with clomiphene, 50-100 mg/day orally for 5 days every 2 months. Ovulation induction with FSH and hCG can induce multiple births and should be used only by those experienced with their administration. (See Hypogonadism.)
D. Human Growth Hormone (Hgh) Replacement
Symptomatic adults with GH deficiency may be treated with subcutaneous recombinant human growth hormone (rhGH, somatropin) injections, at a starting dose of 0.2 mg/day (0.6 IU/day), administered three times weekly. The dosage of rhGH is increased every 2-4 weeks by increments of 0.1 mg (0.3 IU) until side effects occur or a sufficient salutary response and a normal serum IGF-1 level are achieved. Lonapegsomatropin (Skytrofa), a long-acting prodrug of rhGH, is available for once-weekly subcutaneous injections for treatment of children with GH deficiency; it is more convenient than daily or alternate-day treatment with somatropin products but more expensive. If the desired effects (eg, improved energy and mentation, reduction in visceral adiposity) are not seen within 3-6 months at maximum tolerated dosage, rhGH therapy is discontinued. Therapy with hGH can bring out central hypothyroidism, so serum FT4 levels require monitoring when beginning hGH therapy.
RhGH may be safely administered to pregnant women with hypopituitarism at their usual pregestational dose during the first trimester, tapering the dose during the second trimester, and discontinuing rhGH during the third trimester.
Oral estrogen replacement reduces hepatic IGF-1 production. Therefore, prior to commencing rhGH therapy, oral estrogen should be changed to transdermal or transvaginal estradiol.
Treatment of adult GH deficiency usually improves the patient's overall quality of life, with better emotional sense of well-being, increased muscle mass, and decreased visceral fat and waist circumference. Long-term treatment with rhGH does not appear to affect mortality.
Side effects of rhGH therapy may include peripheral edema, hand stiffness, arthralgias and myalgias, paresthesias, carpal tunnel syndrome, tarsal tunnel syndrome, headache, pseudotumor cerebri, gynecomastia, hypertension, and proliferative retinopathy. Treatment with rhGH can also cause sleep apnea, insomnia, dyspnea, sweating, and fatigue. Side effects are more common in patients who are older, those with higher BMI, and those with adult-onset GH deficiency. Such symptoms usually remit promptly after a sufficient reduction in dosage. Excessive doses of rhGH could cause acromegaly; patients receiving long-term therapy require careful clinical monitoring. Replacement therapy with rhGH does not increase the risk of any malignancy or the regrowth of pituitary or brain neoplasms; serum IGF-1 levels should be kept in the normal range.
GH should not be administered during critical illness, since administration of very high doses of rhGH increased mortality in patients receiving intensive care. There is no proven role for GH replacement for the physiologic GH deficiency that is seen with abdominal obesity or normal aging.
Biosynthetic IGF-1 (mecasermin) is available to treat patients with Laron syndrome, a syndrome of GH resistance.
E. Other Treatment
Selective transsphenoidal surgery is usually performed to resect non-prolactinoma pituitary masses and Rathke cleft cysts that cause local symptoms or hypopituitarism. Such surgery reverses hypopituitarism in a minority of cases. (See Hyperprolactinemia.) Disseminated Langerhans cell histiocytosis may be treated with bisphosphonates to improve bone pain; treatment with 2-chlorodeoxyadenosine (cladribine) has been reported to produce remissions. Patients with lymphocytic hypophysitis have been treated with corticosteroid therapy and other immunosuppressants without much response and without reversing hypopituitarism.
Prognosis
Functionally, most patients with hypopituitarism do well with hormone replacement. Men with infertility who are treated with hCG/FSH or GnRH are likely to resume spermatogenesis if they have had sexual maturation and have descended testicles with a baseline serum inhibin B level over 60 pg/mL. Women under age 40 years with infertility from hypogonadotropic hypogonadism can usually have successful ovulation induction.
Hypopituitarism resulting from a pituitary tumor may be reversible with dopamine agonists for prolactinomas (see Prolactinoma, below) or with careful selective resection of the tumor. Spontaneous recovery from hypopituitarism associated with pituitary stalk thickening has been reported. Patients can also recover from functional hypopituitarism due to excessive exercise or weight loss if they greatly reduce exercise and gain weight; about half of men regain normal serum testosterone levels. Spontaneous reversal of idiopathic isolated hypogonadotropic hypogonadism occurs in about 10% of patients after several years of hormone replacement therapy (HRT). However, hypopituitarism is usually permanent, and long-term HRT is ordinarily required.
Patients with hypopituitarism have an increased mortality risk, particularly women and those in whom diagnosis was made at a younger age, who have a craniopharyngioma, or who required transcranial surgery or radiation therapy. There is also an increased risk of death from infections with adrenal crisis in patients with untreated secondary insufficiency. Some pituitary tumors are locally invasive. Asymptomatic Rathke cleft cysts may not require surgery but do require endocrine, ophthalmic, and scan surveillance.
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