Hypopituitarism

1 What is Hypopituitarism?

Hypopituitarism is a partial or complete loss of anterior function that may result from any lesion that destroys the pituirtary or hypothalamus or that interferes with the delivery of releasing and inhibiting factors to the anterior hypothalamus.

GH and gonadotropins (FSH, LH) are lost early.

2 Symptoms

Signs and symptoms of hypopituitarism vary, depending on which pituitary hormones are deficient and how severe the deficiency is.

The following hormones will appear in the order in which they are lost in hypopituitarism. Gonadotropin deficiency (LH and FSH) can occur in women and lead to

  • ammenorhoea,
  • genital atrophy,
  • infertility,
  • decreased libido,
  • and loss of axillary and pubic hair.

In men, decreased FSH and LH results in

  • impotence,
  • testicular atrophy,
  • infertility,
  • decreased libido
  • and loss of axillary and pubic hair.

GH deficiency occurs next and is not clinically detectable in adults, although it may manifest as fine wrinkles and increased sensitivity to insulin (hypoglycemia). GH deficiency gives an asymptomatic increase in triglyceride levels and a decrease in muscle, bone and heart mass. It also may accelerate atherosclerosis, and it increases fat mass.

GH deficiency in children results in growth failure and short stature.

Thyrotropin(TSH) deficiency results in hypothyroidism with fatigue, weakness, hyperlipedemia, cold intolerance and puffy skin without goiter.

Adrenocorticotopin (ACTH) deficiency occurs last and results in secondary adrenal insufficiency caused by pituitary disease. There is decreased cortisol which results in fatigue, decreased appetite, weight loss, decreased skin and nipple pigment, and decreased response to stress as well as fever, hypotension and hyponatremia. Electrolyte changes like hyperkalemia and salt loss are minimal in secondary adrenal insufficiency because aldosterone production is mainly dependant on the rennin angiotensin system. ACTH deficiency does not result in the salt wasting, hyperkalemia, and death that are associated with aldosterone deficiency.

Symptoms depend on which hormone or hormones are missing

  • ACTH deficiency causing cortisol deficiency: Symptoms include weakness, fatigue, weight loss, abdominal pain, low blood pressure and low serum sodium levels. During a period of severe stress such as infection or surgery, cortisol deficiency may potentially result in coma and death. ACTH also stimulates DHEA secretion from the adrenal cortex.
  • TSH deficiency causing thyroid hormone deficiency: Symptoms include fatigue, weakness, difficulty losing weight, generalized body puffiness, feeling cold, constipation, difficulty with memory and an inability to concentrate. Skin may become dry and the complexion pale. In addition, anemia, high cholesterol levels and liver problems may also occur. Patients with severe or long-term deficiency can appear lethargic. Rarely, severe thyroid hormone deficiency can cause coma, low body temperature, and even death.
  • LH and FSH deficiency in Women: LH and FSH deficiency may cause loss of menstrual cycles, infertility, decrease in sex drive and vaginal dryness and osteoporosis, which can result in a tendency to develop bone fractures. LH and FSH deficiency in Men: LH and FSH deficiency may cause loss of libido (interest in sexual activity), difficulty in achieving and sustaining an erection and infertility due to a low sperm count, and osteoporosis, which can result in a tendency to develop bone fractures.
  • GH deficiency: In children, GH deficiency causes slowing or lack of growth and an increase in body fat. In adults, GH deficiency may cause a decrease in energy and physical activity, change in body composition (increased fat, decreased muscle mass), a tendency toward increased cardiovascular risk factors/diseases and decreased quality of life (including an increased sense of social isolation).
  • PRL deficiency: In the case of PRL deficiency, the mother might not be able to breast feed following delivery.
  • Antidiuretic hormone deficiency: This hormone deficiency results in diabetes insipidus (DI). Symptoms of DI include increased thirst and frequent urination, particularly at night. Pituitary adenomas themselves rarely cause DI unless it occurs after surgery. If DI occurs spontaneously, it usually indicates that some other sort of tumor or inflammation is present in the area.

Sexual desire in women is partially controlled by the hormone DHEA (which is controlled by ACTH).

DHEA is a weak androgen (a male hormone like testosterone). In men, DHEA is of little functional relevance because much higher levels of the potent male hormone testosterone are present.

However, in women, DHEA deficiency can contribute to impaired quality of life (tiredness, depression) and impaired sexual desire and enjoyment.

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3 Causes

Pituitary adenomas are the most common cause of panhypopituitarism. Large pituitary tumors or cysts, as well as hypothalamic tumors (craniopharyngiomas, meningiomas, gliomas) can lead to hypopituitarism. The mass compresses the gland so it cannot work.

Pituitary apoplexy is a syndrome associated with acute hemorrhagic infarction of a pre-existing pituitary adenomas, and manifests as

  • severe headache,
  • nausea or vomiting,
  • and depression of consciousness.

It is considered an emergency.

Inflammatory diseases can lead to hypopituitarism.

These include granulomatous diseases like

  • sarcoidosis,
  • tuberculosis,
  • syphilis,
  • eosinophilic granuloma,
  • and autoimmune lymphocytic hypophysitis (which is usually associated with other autoimmune diseases such as Hashimoto thyroiditis and gastric atrophy).

Trauma, radiation, surgery, infections and hypoxia may also damage both pituitary and hypothalamus.

Vascular diseases such as Sheehan postpartum necrosis (initial sign being the inability to lactate) and infiltrative diseases like hemochromatosis and amylodosis may induce this state as well.

Stroke also damages these cells. Stroke can cause cranial diabetes insipidus due to damage of hypothalamus and or posterior pituitary.

4 Making a Diagnosis

The first step in diagnosing hypopituitarism is to measure GH, TSH, LH and IGF-1.

To diagnose GH deficiency, the most reliable stimulus for GH secretion is insulin induced hypoglycemia. After injecting 0.1 microns/kg of regular insulin, blood glucose declines to less than 40mg/dl; in normal conditions that will stimulate GH levels to ≥ 10 mg/dl and exclude GH deficiency. Random GH and IGF levels are not sensitive enough to diagnose GH deficiency. This is why a provocative test is used.

Arginine infusion can also stimulate growth hormone release. Measure GH level after infusing arginine. This is less dangerous because it does not lead to hypoglycemia.

To diagnose ACTH deficiency, basal cortisol levels may be preserved (the problem could be only in response to stress). Insulin tolerance test is diagnostic and involves giving 0.05-0.1 U/kg of regular insulin and measuring serum cortisol; plasma cortisol should increase to ≥19 mg/dl.

Metyrapone test: It is used for decreased ACTH production. Metyrapone blocks cortisol production, which should increase ACTH level. A failure of ACTH levels to rise after giving metyrapone would indicate pituitary insufficiency.

Cosyntropin (ACTH) stimulation may give abnormally low cortisol output if pituitary insufficiency has led to adrenal atophy.

To diagnose gonadotropin deficiency in women, measure LH, FSH and estrogen.

In males, gonadotropin deficiency can be diagnosed by measuring LH, FSH and testerone. To diagnose TSH deficiency, measure serum thyroxine(T4) and free triiodothyronine(T3), which are low, with a normal to low TSH.

5 Treatment

Hypopituitarism is treated by replacing the deficient hormones. The goals of treatment are to improve symptoms and to replace the deficient hormone or hormones at a level that is as close to physiologically correct (“mother nature”) as possible.

However, one rule of hormone replacement is that no one dose will suit every patient. Thus, when hormone replacement therapy is prescribed, the patient will need to be seen regularly after starting treatment to assess the effect.

It often takes time and repeated dose changes to find the optimal dose for each patient. Typically, once the optimal dose is determined, the dose remains adequate for long-term treatment unless other medications are added or the patient’s condition changes in a way that alters the blood levels (e.g., introduction of GH therapy may require an increase in cortisol replacement, whereas pregnancy may require an increase in the dose of thyroid hormone).

Cortisol

On average, cortisol replacement therapy consists of giving approximately 15 mg of cortisol daily in divided doses. Approximately 2/3 of the dose is given in the morning and 1/3 in the late afternoon or evening. Excess cortisol can cause side effects, so it is best to use cortisol replacement in doses that are adequate but not too high.

Some endocrinologists prescribe prednisone instead of cortisol, and the dose of prednisone can be given once or twice a day. Patients with cortisol deficiency must always remember that during periods of stress their bodies may not be able to produce the increased level of cortisol needed. Therefore, patients should always carry a medical or steroid alert card or wear a medical alert bracelet or necklace to inform physicians that they are taking chronic steroid therapy.

If patients have multiple pituitary hormone deficiencies, cortisol should always be the first hormone replaced as medications like thyroid hormone or GH can increase the body’s need for cortisol.

Thyroid hormone

Levothyroxine given daily is the therapy for thyroid hormone deficiency.

  • Most people with hypothyroidism have disease directly in the thyroid gland and are said to have primary hypothyroidism. Patients with primary hypothyroidism have elevated levels of TSH and low levels of thyroid hormone. In this situation, treatment with thyroid hormone causes the level of thyroid hormone to increase and the level of TSH to decrease.
  • Patients with hypothyroidism as a result of pituitary disease are said to have secondary hypothyroidism. Such patients have low levels of both TSH and thyroid hormone. Although treatment with thyroid hormone should increase the level of thyroid hormone in the blood into the normal range, it would not change the level of TSH. Thus, TSH is not used to monitor dosing in patients with secondary hypothyroidism. Instead, the physician has to rely on signs and symptoms and measurement of thyroid hormone in blood.

Sex-related hormones

Women: Premenopausal women who have no menstrual cycles as a result of pituitary disease (secondary hypogonadism) should receive replacement therapy with estrogen and progesterone. Estrogen can be given orally, by patch or by gel. Progesterone equivalent is only required in woman who have an intact uterus. Women who have undergone a hysterectomy can be treated with estrogen alone.

Men: In testosterone-deficient men, testosterone is given by patch, gel or injection either daily (patch or gel) or every 2-4 weeks by intramuscular injection.

GH therapy

GH prescribing practices vary depending upon local customs, national guidelines and insurance coverage. It is important to do tests to prove that patients are indeed GH deficient. Human GH is administered by daily injection. Most pituitary endocrinologists start at relatively low doses to avoid side effects and increase as needed.

DI therapy

Desmopressin is usually given in tablet or spray form (nasal tube or nasal spray). Hospitalized patients may be given desmopressin by injection.

6 Prevention

In most cases, hypopituitarism is not preventable.  Awareness of risk may allow early diagnosis and treatment.

After pituitary surgery, glucocorticoid replacement should be given to avoid undetected hypoadrenalism until deficits of ACTH and other pituitary hormones are excluded about four weeks after surgery.

Following traumatic brain injury or subarachnoid haemorrhage, there is a high risk of hypopituitarism but symptoms are usually masked by the sequelae of brain injury.

Endocrine assessment should be routinely performed, especially following moderate or severe head injury.

7 Alternative and Homeopathic Remedies

Several alternative remedies exist for hypopituitarism.

Strong scientific evidence

Arginine (L-arginine)

L-arginine helps maintain the body's fluid balance (urea, creatinine), and aids in wound healing, hair growth, sperm production (spermatogenesis), blood vessel relaxation (vasodilation), and fights infection. Intravenous arginine can be used for growth hormone reserve evaluation in people with suspected growth hormone deficiencies. Examples of these deficiencies include panhypopituitarism, growth/stature abnormalities, gigantism/acromegaly, or pituitary adenoma.

Avoid if allergic to arginine. Avoid with a history of stroke or liver or kidney disease. Avoid if pregnant or breastfeeding. Use cautiously if taking blood-thinners, blood pressure drugs, antidiabetic drugs, or herbs or supplements with similar effects. Blood potassium levels should be monitored. L-arginine may worsen symptoms of sickle cell disease.

Good scientific evidence

Chasteberry

Chasteberry may inhibit prolactin secretion, and thus has been suggested as a potential therapy in hyperprolactinemia, a condition characterized by elevated serum prolactin levels. Although preliminary evidence is promising, additional study is warranted in this area.

Avoid if allergic or hypersensitive to members of the Vitex (Verbenaceae) family or any chasteberry components. When taken in recommended doses, chasteberry appears to be well tolerated with few side effects. Use cautiously in patients taking oral contraceptives or hormone replacement therapy Use cautiously with dopamine agonists or antagonists.

Avoid with hormone sensitive cancers or conditions (like ovarian cancer or breast cancer). Avoid if pregnant, breastfeeding or if undergoing in vitrofertilization.

Probiotics

Probiotics are beneficial bacteria that are sometimes called friendly germs. They help maintain a healthy intestine and aid in digestion. They also help keep harmful bacteria and yeasts in the gut under control. Most probiotics come from food sources, especially cultured milk products. Probiotics can be taken as capsules, tablets, beverages, powders, yogurts, and other foods.

There is evidence that young children (ages 6-36 months) who receive infant formula with Bifidobacteria Bb12 supplementation may achieve faster growth than without supplementation.

Probiotics are generally considered safe and well-tolerated. Avoid if allergic or hypersensitive to probiotics. Use cautiously if lactose intolerant. Caution is advised when using probiotics in neonates born prematurely or with immune deficiency.

Unclear or conflicting scientific evidence

Calcium

Calcium is the most abundant mineral in the human body, and it has several important functions. Growth of very low birth weight infants correlates with calcium intake and retention in the body. It is possible that human milk fortifiers commonly used may not have enough levels of calcium for infants of very low birth weight. Bone mineralization is also lower in very low birth weight infants at theoretical term than infants born at term. Use of a formula containing higher levels of calcium has been suggested for improvement of mineral metabolism in very low birth weight infants.

Avoid if allergic or hypersensitive to calcium or lactose. High doses taken by mouth may cause kidney stones. Avoid with high levels of calcium in the blood, high levels of calcium in urine, high levels of parathyroid hormone, bone tumors, digitalis toxicity, ventricular fibrillation, kidney stones, kidney disease, or sarcoidosis (inflammation of lymph nodes and various other tissues).

Calcium supplements made from dolomite, oyster shells, or bone meal may contain unacceptable levels of lead. Use cautiously with achlorhydria (absence of hydrochloric acid in gastric juices) or irregular heartbeat. Calcium appears to be safe for pregnant or breastfeeding women; talk to a healthcare provider to determine appropriate dosing during pregnancy and breastfeeding.

Copper

Copper is a mineral that occurs naturally in many foods, including vegetables, legumes, nuts, grains, fruits, shellfish, avocado, beef, and animal organs, (e.g. liver and kidney). Severe copper deficiency may slow growth. Adequate intake of micronutrients, including copper and other vitamins may be important for childhood growth promotion as measured by length gains.

Avoid if allergic or hypersensitive to copper. Avoid use of copper supplements during the early phase of recovery from diarrhea. Avoid with hypercupremia, occasionally observed in disease states, including cutaneous leishmaniasis, sickle-cell disease, unipolar depression, breast cancer, epilepsy, measles, Down syndrome, and controlled fibrocalculous pancreatic diabetes (a unique form of secondary diabetes mellitus). Avoid with genetic disorders affecting copper metabolism such as Wilson's disease, Indian childhood cirrhosis, or idiopathic copper toxicosis.

Avoid with HIV/AIDS. Use cautiously with water containing copper concentrations greater than 6mg/L. Use cautiously with anemia, arthralgias, or myalgias. Use cautiously if taking oral contraceptives. Use cautiously if at risk for selenium deficiency. The U.S. Recommended Dietary Allowance (RDA) is 1,000 micrograms for pregnant women. The U.S. RDA is 1,300 micrograms for nursing women.

Licorice

Shakuyaku-kanzo-to, an herbal medicine containing licorice has been used for neuroleptic-induced hyperprolactinemia (elevated levels of prolactin). However, additional studies are needed in this area.

Avoid licorice if allergic to licorice, any component of licorice, or any member of the Fabaceae (Leguminosae) plant family. Avoid with congestive heart failure, coronary heart disease, kidney disease, liver disease, fluid retention, high blood pressure, or hormonal abnormalities.

Avoid if taking diuretics. Licorice can cause abnormally low testosterone levels in men or high prolactin or estrogen levels in women. This may make it difficult to become pregnant and may cause menstrual abnormalities.

Qi gong

Qi gong is a type of traditional Chinese medicine (TCM) that is thought to be at least 4,000 years old. It is traditionally used for spiritual enlightenment, medical care, and self-defense. Children are capable of receiving instruction in internal Qi gong as a health promotion activity, and it may have some behavioral benefits. However, it is still unclear whether Qi gong may be beneficial for childhood growth promotion. More research is needed.

Qi gong is generally considered to be safe in most people when learned from a qualified instructor. Use cautiously with psychiatric disorders.

Zinc

Evidence suggests that supplementation with zinc plus iron (but not with zinc alone) may improve linear growth in stunted infants with low hemoglobin.

Zinc is generally considered safe when taken at the recommended dosages. Avoid zinc chloride because evidence of safety and effectiveness are currently lacking. Avoid with kidney disease. Use cautiously if pregnant or breastfeeding.

Traditional or theoretical uses lacking sufficient evidence

Choline

Choline is an essential amino acid that is produced in the body and consumed in the diet. Although choline has been suggested as a potential therapy for childhood growth promotion, human research is currently lacking in this area.

Avoid if allergic/hypersensitive to choline, lecithin, or phosphatidylcholine. Use cautiously with kidney or liver disorders or trimethylaminuria. Use cautiously with a history of depression. If pregnant or breastfeeding it seems generally safe to consume choline within the recommended adequate intake (AI) parameters; supplementation outside of dietary intake is usually not necessary if a healthy diet is consumed.

Creatine

Creatine is naturally made in the human body from amino acids (primarily in the kidneys and liver) and transported in the blood for use by muscles. Although creatine has been suggested as a potential therapy to promote growth, human research is currently lacking in this area.

Avoid if allergic to creatine or if taking diuretics. Use cautiously with asthma, diabetes, gout, kidney disorders, liver or muscle problems, stroke or with a history of these conditions. Avoid dehydration. Avoid if pregnant or breastfeeding.

8 Risks and Complications

There are several risks and complications associated with hypopituitarism, which include:

  • Decreased red cell production
  • Ammenorhea
  • Delayed puberty
  • Low sodium levels
  • Acute confusional states
  • Adrenal cortex insufficiency
  • Alopecia
  • Male infertility
  • Female infertility
  • Low plasma osmolarity

The most serious complication of hypopituitarism results when the reason for the condition is a tumor and the tumor exerts pressure on the optic nerve.

While surgery to excise the tumor is usually successful, there is some danger that the tumor, or the surgery to remove it, will result in blindness.

Other complications usually involve the inability to restore the patient's proper hormonal balance. In such cases, hormone replacement will have to be ongoing.

There is no reason, however, that a patient can't lead a normal life and have a normal life span when taking prescribed hormones long-term.

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