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Replacement therapy: arginine vasopressin (AVP), growth hormone (GH), cortisol, thyroxine, testosterone and estrogen.

Earn Two Contact Hours

This article has been approved for continuing education credit. Objectives are listed below. Test questions follow at the end of the article along with further instructions.

Objectives

1. Explain the indications for hormone replacement therapy. 2. Monitor the patient on hormone replacement for adverse effects of therapy. 3. Teach the patient undergoing hormone replacement appropriate self-care.

Introduction

Replacement therapy is routinely given to treat hormone deficiencies of patients who have had surgery or radiation therapy that damages the hypothalamus or pituitary gland. Underlying causes of hormonal deficiencies include pituitary, brain, nasopharyngeal or metastatic tumor, trauma, infections or infiltrations, and vascular or demyelinating disease affecting the pituitary, nasopharyngeal or hypothalamic areas.[38] For example, among children with suprasellar tumors, approximately 75% will develop a permanent deficiency of arginine vasopressin (AVP) and require replacement therapy.[51] Any child who receives cranial radiation of 18 gray or more is at risk of growth hormone (GH) deficiency. Therefore, GH, pubertal development and the timing of the onset of puberty must be carefully monitored and treated.[7] In adults, tests should be performed annually for at least ten years after radiation therapy because the effects of radiation are delayed. The order of deficiencies that may develop is: GH, gonadotrophins, adrenocorticotropic hormone (ACTH), then thyroid stimulating hormone (TSH); however, in an individual, the sequence is not predictable.[36]

Neuroscience nurses care for patients who may need hormone replacement therapy. This article provides a concise overview of the six hormones that may be replaced AVP, GH, cortisol, thyroxine, testosterone and estrogen. The function of the hormone and symptoms of deficiency as well as the concept of the hypothalamic-pituitary-target gland axis are presented. Replacement therapy and potential problems of over-replacement are discussed. Nursing implications related to replacement therapy focus on dose, route and schedule of medications, cautions and contraindications, drug interactions, as well as patient teaching.[34]

Background

Together, the endocrine glands and nervous system regulate or control nearly all of the body's functions. The location of the pituitary gland, or master gland, at the base of the brain favors this interaction. The pituitary is connected by a thin stalk to the hypothalamus. The hypothalamus controls a number of body functions, including temperature, thirst, hunger, sexual and emotional activity and sleep.[64] The hypothalamus communicates with the rest of the central nervous system and nerves via neurotransmitters or neuroregulators; these are released into the synaptic space between neurons. Endocrine glands, made up of secretory cells, release hormones into the circulation.[61] Immune system peptides also modulate the neuroendocrine circuit; they transmit information from the immune system to the central nervous system.[26]

Hormones released by the hypothalamus are controlled by negative feedback. The following is an example of negative feedback from everyday life: the room temperature falls below a preset level; the thermostat signals the furnace to produce heat; when the room warms to a preset level, the thermostat signals the furnace to shut off. Similarly, the hypothalamus signals the pituitary to produce a particular hormone; this hormone acts, in turn, on a specific target gland to release its hormone. The rising level of the target gland's hormone acts by negative feedback on the hypothalamus which then ceases to produce its hormone.

The pituitary gland consists of two parts; the neurohypophysis is posterior and the adenohypophysis is anterior (Fig 1). The neurohypophysis stores and releases oxytocin and AVP. These hormones are produced by neuroendocrine cells of the hypothalamus which pass through the pituitary stalk to the neurohypophysis. The anterior pituitary not only stores and releases, but also produces the following six hormones: prolactin, GH, ACTH, TSH, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The adenohypophysis releases or halts release of these hormones in response to hypothalamic hormones, which are transported to it via the hypophyseal portal system. The hypothalamic releasing hormones are dopamine, once called prolactin releasing factor (PRF), growth hormone releasing hormone (GHRH); corticotropin releasing hormone (CRH); thyrotropin releasing hormone (TRH); and gonadotropin releasing hormone (GnRH). The hypothalamic inhibitory hormone, which along with GHRH controls GH release, is somatostatin, once called somatotropin release-inhibiting factor (SRIF).[25]

Primary hypopituitarism is due to absent or diminished secretion of hormone(s) by the anterior pituitary gland. This deficiency can result, secondarily, from lack of secretion of hypothalamic releasing hormone(s).

Prolactin supports mammary development during pregnancy.[63] Oxytocin causes release of breast milk and may promote contractions of the uterus during labor. Replacement therapy may be given to women who fail to show normal milk "let-down" (the delayed appearance of milk after a hungry infant begins to nurse from its mother's breast). There is no known function for this peptide in men.[38] Because deficiencies are not thought to impact on health, prolactin and oxytocin are hardly ever replaced.

Replacement Therapy

Arginine Vasopressin (AVP)

Arginine Vasopressin (AVP) is also known as antidiuretic hormone (ADH). AVP is the main hormone that regulates water balance in the body. AVP is released by the hypothalamus and travels via the blood to its major target organ, the kidney. The kidney filters blood to eliminate waste products and also absorbs back salts and water. AVP causes the collecting tubules to reabsorb water. Insufficient AVP leads to a condition known as diabetes insipidus. Insipidus means tasteless in Greek.[25] A patient with diabetes insipidus produces large amounts of dilute urine and urinates frequently; also, thirst is intense.[2] Water balance is controlled by several factors; the most important is osmolality.[8] Osmolality of body fluids is directly related to the sodium concentration (Fig 2). If the urine produced is dilute, the osmolality of the blood increases. This increase is sensed by osmoreceptors in the hypothalamus which responds by releasing AVP. In response, the kidney's collecting tubules absorb more water so the effective osmolality of the blood is maintained near a normal range.[62] In central diabetes insipidus, since the kidneys fail to reabsorb water, the osmoreceptors sense dehydration. The intense thirst, followed by drinking of large amounts of water, maintains the blood osmolality.

Patients with AVP deficiency require replacement therapy. A synthetic drug with a very similar chemical structure, 1-desamino-8-D-arginine vasopressin (DDAVP) can be conveniently given as a nasal spray or by injection, if necessary.[29] A transdermal form of DDAVP is currently being investigated in Europe; a small patch of epidermis is removed by a vacuum device to allow efficient permeation.[57] Two other European groups report that oral DDAVP is safe and effective; during long-term follow--up, compared to use of the nasal solution, patients' compliance and quality of life improve significantly.[20,10]

DDAVP should be given subcutaneously if the patient is unable to take intranasal DDAVP, such as after surgery, or if the sinus or nasal anatomy has been disturbed, or if the patient is incapable of being compliant.[11] Water balance must be monitored closely for fluctuations. Urinary output must be monitored and fluids must be replaced to prevent hypernatremia.[67]

Adverse reactions to DDAVP are minimal; headache, nausea, nasal congestion, drowsiness, sweating, facial flushing, shortness of breath, slight elevation of blood pressure and occasional stomach or abdominal cramps are the most common complaints.[39] Water intoxication is the only potentially serious problem of over-replacement; however, when used in children under the age of two years, hyponatremia and seizures are potentially serious adverse effects.[53] Dosing information, nursing implications, and teaching points are presented in Table 1.
Table 1. Vasopressin Replacement[18, 34, 58]

Desmopressin Acetate (DDAVP): a synthetic analog of vasopressin:
 Immediate effect lasts 8-20 hours. Vasopressor and oxytocic
 effects are not noted at usual doses.
Adults: 0.1-0.4 ml intranasal in one or two doses (10 [mu]g once
 or twice a day).
 After surgery, may be given intravenous (IV) or subcutaneous
 (SC), (1-2 [mu]g every 12-24 hours) if unable to take intranasal.
 Concentration of intravenous/subcutaneous dose is approximately
 1/10th of the intranasal dose.
Children: (3 months-12 years) 0.05-0.3 ml intranasal, daily in 1 or
 2 doses.

Nursing Implications
 * Administer with caution to the following patients: Very young
or
elderly patients who may have limited water intake, pregnant or
lactating women, patients with coronary insufficiency or
hypertensive cardiovascular disease, or patients with changes
in nasal mucosa such as scarring, edema, discharge, blockage or
congestion.
 * Monitor intake and output.

Drug Interactions
 * Carbamazepine and chlorpropamide may potentiate effects of
DDAVP.

Patient Teaching
 * Teach possible side effects which include transient headache,
rhinitis, nausea, mild abdominal cramps, slight elevation of
blood pressure and facial flushing. Symptoms disappear with
reduced dose, which patients should not initiate on their own.
 * Teach symptoms of overreplacement which include headache,
abdominal cramps, nausea and facial flushing.
 * Instruct in intranasal administration using tube or spray pump.
Patients with poor vision may require assistance.




Replacement Therapy of Adenohypophyseal Hormones

Growth Hormones

Growth hormone (GH), once called somatotropin, is the single most important hormone for normal growth in a developing child. Without GH, a child retains a juvenile appearance, "baby fat," and may reach only 3 to 4 feet in height. The failure to grow is determined from a growth chart relating age to height. GH accounts for 30-40% of the cells of the pituitary gland where the somatotropes produce and store it. GH affects growth indirectly through its target hormone, a peptide, somatomedin C, which is formed in the liver. Somatomedin C is also called insulin-like growth factor I (IGF-I). Growth occurs at the growth plates on long bones where cartilage is replaced by bone, a process called ossification. GH and somatomedin C together stimulate cartilage to grow and become ossified. Somatomedin C also promotes bone thickening after the growth plates close. GH stimulates calcium uptake from the gut, and boosts bone mineral mass and bone turnover. Like insulin, GH promotes the conversion of glucose to energy. GH balances the body's proportion of protein, particularly muscle, with that of fat and water. In adults, GH maintains muscle strength, cardiac performance and kidney function.[12]

Secretion of GH by the adenohypophysis is under positive and negative feedback control (Fig 3). The hypothalamic growth hormone releasing hormone (GHRH) stimulates the pituitary gland to secrete GH. The GH acts on the liver to produce somatomedin C. In response to feedback control by somatomedin C, the hypothalamus secretes somatostatin. Somatostatin then signals the pituitary gland to halt its secretion of GH. Somatomedin C can also act directly on the pituitary gland to decrease its response to GHRH.[25]

For replacement therapy, patients are currently receiving recombinant GH produced by biotechnology. This man-made GH is fully biologically active.[45] Prior to recombinant GH, patients with GH deficiency received extracts from human pituitaries. Several patients developed Creutzfeldt-Jakob disease years later.[41] This is a rapidly fatal degenerative neurologic disorder in which a cell-surface protein of neurons is altered; this altered form is known as prion protein.[23] Since 1977, GH has been purified from pituitary glands by a different method. Now, a recombinant form of GH is available, produced in bacteria, which does not cause Creutzfeldt-Jakob disease.[64]

GH requires a subcutaneous injection.[31] An injection pen system (Nordiject) has been developed and is strongly preferred to the conventional syringe for daily doses of GH.[32] Recently, a European group's pharmacokinetics study showed that recombinant GH can be administered intranasally when it is combined with a permeation enhancer for the nasal mucosa, sodium tauro-24,25 dihydrofusidate.[30] To achieve a normal growth rate for bone age, in patients with spontaneous or induced puberty, a 1.5- to 2-fold increase in GH dose may be necessary to accelerate growth rate. Dose is monitored until attainment of a certain target height or fusion of epiphyses [56,31]

In patients whose pituitary gland is intact, a potential alternative to GH would be the hypothalamic hormone GHRH. In clinical tests with GHRH, some patients show dramatic growth, increased levels of somatomedin C in the plasma, and elevation in GH.[5] Another potential future alternative is GHRH-29. The first 29 amino acids of GHRH-29 are the same as those of the naturally occurring GHRH-40 and GHRH-44. Compared to recombinant GH which has 191 amino acids, GHRH-29 will be much less expensive to produce. Since recombinant GH costs the patient approximately $20,000 per year? GHRH-29 is an attractive alternative l More importantly, it will be possible to deliver this smaller molecule via the nasal mucosa.[63] Synthetic somatomedin C is now available. Careful study is required to determine whether these potentially powerful growth factors can replace GH as a treatment for GH deficiency.[14]

Only since 1989, when sufficient GH became available, has GH deficiency been recognized and treated in adults. In clinical trials, replacement therapy partly normalizes the abnormalities in body composition and physical performance and additionally, improves psychosocial well-being.[47,12] However, the FDA has not yet approved GH replacement for adult GH deficiency.

The primary effects of GH overreplacement are acromegaly and gigantism, and the enlargement of skeleton, fingers and toes which characterizes these syndromes. High blood pressure, headache, increased perspiration and weakness may also occur. Patients may develop an antibody to recombinant GH; however, in contrast to other systems, the antibodies usually do not reduce the effectiveness of GH.[66]

In children with radiation-induced GH deficiency secondary to an intracranial malignancy or from prophylactic irradiation of the brain in the treatment of leukemia, there is no proven increase in the risk of having a recurrence or of acquiring another malignancy following GH therapy.[46] Nevertheless, caution should be exercised when GH is given to such children. Before GH therapy is initiated, intracranial lesions must have been inactive for one year and antitumor therapy must have been completed.[4]

Recombinant human GH is a polypeptide composed of 191 amino acids (Somatropin). Somatrem (Protropin) has an extra methionine (metGH).[63] Dosing information, nursing implications and teaching points are presented in Table 2.
Table 2. Growth Hormone Replacement[18, 34, 58]

Somatropin:
(Humatrope): Maximum of 0.06 mg/kg, subcutaneous (SC) or
 intramuscular (IM), 3 times a week
(Nutropin): 0.3 mg/kg total weekly dose, SC injections, daily
Somatrem:
(Protropin) Maximum of 0.1 mg/kg, SC or IM, 3 times a week or
 0.3 mg once a week

Nursing Implications
 * Monitor electrolytes, especially BUN and creatinine for
increased protein synthesis, glucose for insulin resistance,
and alkaline phosphates as a measure of bone growth
pretreatment and periodically.
 * Monitor closely patient who receives both glucocorticoid and GH
replacement. Coordination of medications is necessary to avoid
inhibitory effect on growth.
 * Contraindicated for patients with closed epiphyses (except
in studies for adult patients).
 * Contraindicated for patients with sensitivity to benzyl
alcohol, the preservative, m-cresol or glycerin for
potentially allergic reaction or patients
with active tumors or neoplasia because of potential
growth-promoting effects.
 * Monitor thyroid function periodically for hypothyroidism;
GH replacement may worsen thyroid function in patients with
subclinical thyroid problems.
 * Observe for glucose intolerance; may affect insulin resistance.
 * Observe for limp or complaints of hip or knee pain. Slipped
capital femoral epiphysis may occur.
 * Intracranial hypertension my occur (usually within first 8
weeks of treatment). Observe for papilledema, visual changes,
headache, nausea or vomiting. Dose must be stopped or reduced.

Patient Teaching
 * Teach patient techniques of self administration: Reconstitute
with diluent as directed. Do not shake. Do not inject if
solution is cloudy. Use appropriate length needle to get into
muscle. Use small syringe to assure accurate dose. Use aseptic
technique and rotate injection sites. Follow instructions
regarding stability after reconstitution.
 * Teach patient about possible adverse effects. Infrequently
adults may experience headache, localized muscle pain,
weakness, mild hyperglycemia, glucosuria or mild transient
edema. Most common complaints are joint pain and carpal tunnel
syndrome. Children may experience injection site pain.
 * Teach patients symptoms of overreplacement: hypoglycemia and
then hyperglycemia, joint pain, carpal tunnel syndrome and,
long-term acromegaly.




Cortisol: Replacement Therapy far ACTH Deficiency

The main role of cortisol is coping with stress.[28] Cortisol is produced by the outer region or cortex of the adrenal glands, which are situated above the kidneys. Aldosterone is another hormone produced by the adrenal cortex; it is called a mineralocorticoid because it maintains the balance between the two salts, sodium and potassium. Cortisol is called a glucocorticoid because it regulates glucose metabolism. It promotes gluconeogenesis, glucose synthesis from simpler compounds. Cortisol controls the conversion of glucose into its storage forms, carbohydrate and glycogen, and influences the body's ability to draw on these fuel reserves for energy.[25] Without adrenal function, weakness, hypoglycemia, malaise, nausea, dizziness, salt craving, abdominal pain and muscular pain may occur.

Both the adrenal cortical hormones aldosterone and cortisol are steroids; they are synthesized from cholesterol. Within the adrenal cortex, ACTH releases cholesterol from its storage form so more becomes available to be made into cortisol. ACTH increases blood flow to the adrenal glands to enhance delivery of hormone to the general circulation. Glucocorticoids are inactivated mainly in the liver; they become unrecognizable to their receptors and more soluble in water so they can be excreted in the urine.

Secretion of cortisol by the adrenal glands is controlled by negative feedback (Fig 4). Corticotropin-releasing hormone (CRH) neurons of the hypothalamus release CRH into the hypophyseal-portal blood vessels. CRH stimulates the adenohypophysis to synthesize pro-opiomelanocortin, the precursor to ACTH.[28] ACTH is secreted into the circulation and stimulates the adrenal cortex to release cortisol. When the concentration of cortisol in blood increases to high values, the CRH neurons in the hypothalamus respond and halt further release. The corticotropes in the anterior pituitary stop further secretion of ACTH until the concentration of cortisol in the blood drops.[25]

Throughout the day the secretion of ACTH and cortisol oscillate with a 24-hour periodicity called circadian rhythm.[49] In the early morning hours just before arousal, the concentration of cortisol is highest; in the evening, it is lowest.[35] Since hydrocortisone can cause stimulation, late evening or night dosing should be avoided to prevent insomnia.[44] Patients should not discontinue therapy on their own. Cards, bracelets or other warning device should be worn or carried with information regarding the patient's condition. Stress increases the need for cortisol, thus CRH secretion increases in response to stress.[24] In patients on replacement therapy, the need for cortisol should be met with supplemental hydrocortisone if stressful situations such as surgery or illness are experienced. An alternative to parenteral hydrocortisone is a rectal preparation which is well absorbed and provides adequate hydrocortisone for up to eight hours.[6]

Glucocorticoids are known for their antiinflammatory effects. They suppress immune and allergic responses, so are used to combat rejection of transplanted tissues. It is worth pointing out to patients that hydrocortisone replacement is not the same as steroid treatment for conditions like rheumatoid arthritis, otherwise, patients may dread but expect the cushingoid effects with which many are often familiar.[54]

In addition to cushingoid fat deposits on the face, neck and trunk, adverse effects of over-replacement are multiple: impaired wound healing, hypertension, headache, bruising, aggravated or precipitated diabetes mellitus, muscle pain, osteoporosis and weakness. Susceptibility to infection may be increased. In children, growth may be retarded. Adults may suffer sexual dysfunction.[55] Dosing information, nursing implications, drug interactions and teaching points are presented in Table 3.
Table 3. Cortisol: Replacement Therapy for ACTH
Deficiency[18, 34, 58]

Prednisolone: 5-7.5 mg per day once, given orally
Hydrocortisone: 20 mg in morning upon awakening, 10 mg at
 4 PM, given orally. May be given IM or IV
 if necessary.

Nursing Implications
 * Dose is based upon individual response. Dose is tapered slowly
to the minimum effective dose for the individual patient.
 * Increased dose is needed with increased stress, such as
physical
illness. Dose my be doubled until well. Often a large loading
dose is given before surgery.
 * Patient is more susceptible to infections. Skin test reactions
may be suppressed. Live vaccines are contraindicated.
 * Use with caution in pregnancy. Mothers who require
corticosteroids should not be breastfeed since corticosteroids
are found in breast milk and may interfere with the growth and
development of the infant.

Drug Interactions
 * Troleandomycin can cause increased steroid blood levels.
 * Phenytoin, phenobarbital, refampin and cholestryramine can
decrease steroid blood levels.
 * Hyrocortisone may cause decreased serum level of salicylates
and decreased effectiveness of anticholinesterases.

Patient Teaching
 * Instruct patient to take medication with food to lessen risk of
gastric irritation.
 * Teach possible adverse effects including increased appetite,
weight gain, indigestion, increased susceptibility to
infections, slow wound healing, fatigue, muscle weakness.
 * Advise patient to notify physician of any of the following:
Cardiac or fluid electrolyte-related problems such as unusual
weight gain, swelling of legs and feet or puffy face.
Gastrointestinal problems such as black or tarry stools,
vomiting of blood, epigastric pain, anorexia, nausea
and vomiting, diarrhea or weight loss. Signs of infection such
as fever, prolonged sore throat, cold or other infections.
Complaints of fatigue, muscle and joint pain, weakness or
dizziness.
 * If unable to take hydrocortisone by mouth, teach self
injection.
Wear medic alert bracelet. Recommend patient keep hyrocortisone
for injection available at all times (ie, at home, on vacation).




Thyroxine and Triiodothyronine: Replacement Therapy for TSH Deficiency

The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are produced by the thyroid gland and act on nearly every organ system in the body. They promote growth and development. Hypothyroidism, or thyroid-deficiency, is characterized by weight gain, mental sluggishness, fatigue, slowness of speech, a puffy face and a yellowish tint of the skin. If thyroid deficiency occurs neonatally or in childhood, mental retardation occurs and growth is retarded; the resulting malformation of facial bones characterizes juvenile hypothyroidism or cretinism. Thyroid hormone deficiency is directly related to decreased oxygen consumption, which is correlated with reduced energy metabolism and body heat production. The resulting decreased tolerance to cold is a classic sign of hypothyroidism.

Glucose metabolism, its absorption from the digestive tract, its formation from simpler substances and its conversion from storage forms, are all lessened in hypothyroidism. In the skin, accumulation of a characteristic mucus-like protein which absorbs water causes the edema or swelling that gives the name myxedema to hypothyroidism.[17]

The synthesis and secretion of T4 and T3 by the thyroid gland are controlled by modified negative feedback (Fig 5). The hypothalamus releases the tripeptide hormone, thyrotropin-releasing hormone (TRH). The TRH stimulates the pituitary to secrete thyroid stimulating hormone (TSH) or thyrotropin. TSH, in turn, activates the thyroid gland to make and release T4 and T3. The circulating thyroid hormones exert negative feedback effects on the pituitary by decreasing the number of receptors for TRH on the pituitary thyrotrope cells. In turn, the pituitary secretes less TSH.

TSH is secreted by the pituitary in a circadian fashion. The serum TSH concentration is highest in the evening or early morning and lowest mid to late afternoon.[25] Upon TSH stimulation, the thyroid gland's cells concentrate iodine. The iodine becomes activated and binds to the tyrosines of the thyroglobulin protein. Two tyrosines join to form T4 or T3 within the peptide chain. Then the thyroglobulin is completely degraded to free amino acids, including T4 and T3. The T4 and T3 are released into the blood stream.

Synthetic T4, L-thyroxine, is most commonly used for replacement therapy.[59] Its advantages include stability, uniform potency, relatively low cost, long half-life and lack of allergenic foreign protein. Generic preparations of L-thyroxine may not be bioequivalent to brand products.[17] Several brand-name products are available; among them, Levothroid and Synthroid, were shown to be therapeutically interchangeable.[3]

Excessive thyroxine results in an increased metabolic state characteristic of hyperthyroidism. Symptoms are heat intolerance, weight loss despite an increased appetite, sweating, diarrhea and frequent bowel movements, tremor, nervousness, irritability and insomnia. Another symptom of excessive replacement is osteoporosis, which is similar to that observed in endogenous hyperthyroidism.[13,21] Dosing information, nursing implications, drug interactions and teaching points are presented in Table 4.
Table 4. L-Thyroxine: Replacement Therapy for TSH
Deficiency[18, 34]

Levothyroxine (T4) (synthetic): Daily doe 0.1 mg, oral. before
breakfast

Nursing Implications:
 * Dose may be decreased in patients with heart disease, diabetes,
or adrenal cortical insufficiency or the elderly.
 * Monitor T4/T3 ratio or serum free T4 in pituitary disease
patients.
 * Monitor for osteoporosis in both pre and post menopausal women
who are on long-term replacement.
 * No danger to fetus if given during pregnancy because thyroid
hormones and mother usually requires the hormones to maintain
lactation.

Drug Interactions
 * Products which contain tartrazie (hydrazine yellow; a yellow
acid dye) may produce a rare allergic (including bronchial
asthma) and should be avoided.
 * Monitor in patients on oral anticoagulants, insulin or oral
hypoglycemics, or cholestryramine.

Patient Teaching
 * Instruct patient not to discontinue medication unless physician
directs.
 * Instruct patient to avoid generics and older preparations. Do
not change brands. Doses are not always equipment.
 * Teach patient to notify physician for symptoms of
overreplacement which include the following: Headache,
nervousness, excessive sweating, heat intolerance, chest pain,
increased pulse rate, or palpitations. Dose may need to be
reduced or stopped temporarily.




Testosterone: Replacement Therapy for LH and FSH Deficiency (Male)

Testosterone is the principal hormone produced by the testes. The testes also produce sperm. At puberty, testosterone promotes the development of secondary sexual characteristics and accessory structures that nurture sperm and eject them from the body. Sperm are formed and develop within seminiferous tubules which comprise most of the testes. Testosterone is produced by the interstitial cells of Leydig, which lie between the seminiferous tubules. Testosterone, like cortisol, is a steroid hormone. Testosterone in blood is bound to plasma protein; only 2-3% is present as free hormone. Testosterone is degraded in the liver and excreted from the body in the urine.[25]

Testosterone secretion is regulated by modified feedback control (Fig 6). The hypothalamus releases gonadotropin-releasing hormone (GnRH) in discrete pulses at regular intervals; each pulse lasts only a few minutes. The pituitary gland responds to GnRH by secreting two gonadotropic hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH acts on the immature sperm within the seminiferous tubules so they begin to mature, called spermatogenesis. LH acts on the Leydig cells so the, produce and secrete testosterone; the high concentration of testosterone nurtures the developing sperm. LH and FSH originate in the same pituitary gonadotrope cells. Nevertheless, LH secretion is controlled independently of FSH secretion. Testosterone travels through the circulation to the hypothalamus, where it exerts its negative feedback effect primarily by slowing the frequency of GnRH pulses. The decreased frequency of GnRH pulses decreases the ratio of LH to FSH secreted by the pituitary gonadotropes The feedback inhibitor of FSH is a protein hormone, named inhibin, which is secreted by the testes. Inhibin acts on the pituitary gonadotropes to inhibit FSH secretion.

Unless the patient wants to have children, replacement therapy with testosterone is usually satisfactory.[42] In the adult male, a long-acting preparation can be given intramuscularly every 2-3 weeks. When testosterone is given by mouth the absorption is somewhat irregular and there is risk of liver disease. Delivery of testosterone by skin patches is now available. Although the cost is higher, the main benefit is that a steady level, instead of the peak and trough, of testosterone is maintained. Adequate replacement will maintain beard growth, libido (sex drive) and potency. In boys who are gonadotropin-deficient, replacement therapy with testosterone enanthate should be started at bone age 12-13 to stimulate pubertal development.[56]

If a patient wants to have children and if his pituitary gland is able to produce FSH and LH, the GnRH deficiency can be treated. A pump can be used to deliver GnRH subcutaneously or intravenously; both the volume and interval of GnRH pulses can be controlled.[16] With pulsatile GnRH, usually 18-24 months are required to recapitulate puberty and restore sperm development and serum testosterone to normal. In patients with gonadotropin (FSH and LH) deficiency, fertility can be restored with combined human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG) therapy.[27] Rich in FSH-like gonadotropins, hMG stimulates spermatogenesis. The LH-like effects of hCG promote testosterone production by the Leydig cells. Infertility in men is difficult to treat due to the very long time required (120 days) for the full cycle of sperm maturation and growth. Therefore, fertile men who will have surgery in the pituitary-hypothalamic area are often advised to place sperm in a sperm bank, even if they are not married and do not plan to have children in the near future. Sperm can be kept in good condition for seven years or more in such banks.[38] In addition to sperm banking, other interventions which include sex education, surgical treatments that facilitate sexual function and treatments for erectile dysfunction may be important for achieving sexual rehabilitation.[52]

Over-replacement may result in edema, disturbing sexual drive, nightmares and acne. Nausea, headache, male pattern baldness, rash, increased body hair and gynecomastia may occur. With oral testosterone, hepatotoxicity, polycythemia and increased prostate size are possible adverse effects. Dosing information, nursing implications, drug interactions and teaching points are presented in Table 5.
Table 5. Testosterone: Replacement Therapy for LH
and FSH Deficiency (Male)[18, 34]

Testosterone cipionate or Testosterone enanthate
(long acting form): 250-300 mg in young men and 200-250 mg in older
 men, given IM in gluteal muscle, every 2 to 3
 times a week.
Short acting forms are available but require injections 2 or 3
times a week.
Oral preparations are ineffective, require very high doses and
may have increased risk. A transdermal system is available and use
is increasing. It must be placed daily on scrotal skin. A new
transdermal system allowing chest placement is currently available
and may be used more in the future.

Nursing Implications:
 * Dose and schedule depends on clinical response.
 * Monitoring the following laboratory tests: liver function
tests if an oral preparation is being taken, bone x-rays in
children, CBC in patients receiving high doses (polycythemia
may occur). cholesterol (excess testosterone may raise LDL
and lower HDL), and prostate specific antigen (PSA, testosterone
may stimulate prostate cancer).
 * A prostate evaluation by digital rectal examination should also
be performed at intervals.
 * Contradictions for use of testosterone include the following:
hypersensitivity to drug or history of breast or prostate
cancer.
 * Use cautiously in children due to effects on bone maturation;
rapid fusion of the epiphyses would result in reduced height.

Drug Interactions
 * Adjust dose according to use of anticoagulants.

Patient Teaching
 * Teach patient about possible adverse affects including
gynecomastia, excessive frequency and duration of penile
erections, decreased ejaculatory volume and oligospermia
at high doses.
 * Monitor diabetic patients closely because glucose tolerance
may change.
 * Instruct patient to notify physician of any of the following:
ankle swelling, nausea or vomiting, yellowing of skin or eyes,
unusual bleeding or bruising, penile swelling or pain,
hoarseness, deepening of voice, body hair growth, acne.


Estrogens and Progesterane: Replacement Therapy for LH and FSH Deficiency (Female)

Estrogens (estradiol-17beta and estrone) and progesterone are the principal hormones secreted by the ovary. These hormones are steroids and are derived from cholesterol.[25] Ovarian hormones act on the reproductive tract to prepare it for fulfilling its role in receiving the sperm, fertilization, implantation and development of the embryo. At puberty, estrogens promote growth and development of the breasts, oviducts (fallopian tubes), uterus, vagina and external genitalia. They contribute to the pubertal growth spurt and stimulate the growth plates of the long bones to close. Estrogens circulate in blood tightly bound to a carrier protein. Estradiol and estrone are completely cleared from the blood by a single passage through the liver and are excreted via the kidney.

Secretion of the ovarian hormones, estrogen and progesterone, is controlled by modified negative feedback. The hypothalamus releases gonadotropin-releasing hormone (GnRH) in intermittent pulses. The GnRH stimulates the pituitary gland to secrete the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH stimulates the granulosa cells of the ovarian follicle (Fig 7a); these cells comprise the single layer of cells that surround an ovum. The granulosa cells of the one follicle destined to ovulate secrete estradiol and increase in size and number. The rising estradiol level signals the follicle's readiness to ovulate; the hypothalamus increases secretion of GnRH and the pituitary secretes a massive burst of LH. At ovulation, the follicle ruptures and the ovum is extruded into the abdominal cavity. The ovum enters the funnel-shaped end of the oviduct and is transported to the uterus. Only during this brief transit, about 24 hours, can the ovum be fertilized. The granulosa cells collapse to form a new endocrine structure, the corpus luteum (Fig 7b). In response to LH, the corpus luteum produces progesterone. Progesterone causes the endometrium to become secretory and prepares the uterus for successful implantation and growth of the embryo. It is absolutely required for maintenance of a pregnancy. If conception has not occurred, the corpus luteum regresses and stops producing progesterone; the endo-metrium degenerates, is sloughed into the uterine cavity, and is discharged. This monthly loss of blood is known as menstruation. The ovarian hormones exert feedback effects on the pulses of hypothalamic GnRH; estradiol decreases the amount of GnRH released, whereas, progesterone slows the pulse frequency.

For replacement therapy, synthetic estrogens, which are more potent compared to natural estrogens, are administered orally. Similarly, progestin, a synthetic progesterone, is effective when administered orally.[9] Unless a patient wants to have children, gonadotropin deficiency is satisfactorily managed with steroid hormone replacement therapy alone.[19] One of several estrogenic preparations is given for 25 days of each month and a menstrual period is induced by the administration on days 16 through 25 of progestin. An alternate dosing pattern is estrogen days 1-30 and progestin days 1-13. Because administration of estrogenic hormone increases the risk of endometrial carcinoma, patients with a uterus should take regular progestin treatment to induce menses.[65] Estrogen delivery by skin patches (Estraderm) is now available; this transdermal system offers the advantage of a constant rate of delivery for up to 84 hours after the patch is applied and avoids the hepatic metabolism of oral estrogens.[50] Young women can take birth control pills to regulate menses and replace estrogen.

The advantages of replacement therapy are the maintenance of secondary sex characteristics and sense of well-being, reduced risk of cardiac disease, increased breast size, reduced predisposition to vaginal infections and reduced risk of osteoporosis.

This information regarding estrogen replacement therapy essentially applies also to postmenopausal women.[60] Because of their intact hypothalamus, they may have hot flashes, an annoying symptom. These appear to be synchronous with increased hypothalamic release of GnRH. The GnRH neurons are close to the centers that regulate temperature.[48] Additionally, because their pituitary gland is intact, the concentrations of circulating FSH (>40 IU/L) and LH (>25 IU/L) are high.[43] Replacement therapy with steroid hormones suppresses FSH and LH, normalizes serum estrogen values and reduces menopausal symptoms. Withdrawal bleeding, a disadvantage of replacement therapy, can be eliminated with low-dose continuous estrogen and progestogen regimes.[37]

In patients whose pituitary is intact and who wish to have children, the drug clomiphene is used to induce ovulation in women who are not ovulating. It is given for 5 days after the first day of the menstrual cycle; ovulation takes place 5 to 12 days following the last day of therapy.[38] Clomiphene is a weak estrogen that blocks the negative feedback of estradiol on GnRH and thus enhances FSH and LH release by the pituitary gland.[9] In patients who fail to respond to clomiphene, GnRH can be given. Pulsatile GnRH is administered by a special pump which is worn on a belt; the infusion is delivered either subcutaneously or intravenously.[16] In patients who have potentially functional ovaries and fail to respond to both clomiphene and pulsatile GnRH infusion, an alternative is injections of human menopausal gonadotropin (hMG) followed by injections of human chorionic gonadotropin (hCG) which are given to stimulate ovulation.[22] Gonadotropins isolated from human postmenopausal urine (hMG) have predominantly FSH-like activity and stimulate the ovarian follicle to develop. Recently, clinical application of recombinant human FSH indicated that it contains more bioactivity in the basic fraction than urinary FSH.40 The hMG must be used with hCG which has LH activity. Of placental origin, hCG triggers ovulation of the primed follicle and maintains the corpus luteum. Side effects of hMG/hCG include bloating, abdominal pain, ovarian enlargement, fever and possible shock.[48]

The warning signs of the adverse effects of estrogen can be learned using the word "ACHES" as a memory aid: A: Abdominal pain (severe): may be indicative of a

liver disorder. C: Chest pain (severe), cough, shortness of

breath; may be indicative of pulmonary

embolism or myocardial infarction. H: Headaches (severe), dizziness, weakness,

numbness; may be indicative of stroke. E: Eye problems (vision loss or blurring),

speech problems; may be indicative of retinal

thrombosis or stroke. S: Severe leg pain (calf or thigh); may be

indicative of thrombophlebitis.[48]

Dosing information, nursing implications, drug interactions and teaching points are presented in Table 6.
Table 6. Estrogens and Progesterone: Replacement
Therapy for LH and FSH Deficiency (Female)[18, 34]

Oral Contraceptives may be given to premenopausal women for
estrogen replacement.

Conjugated Estrogens, Oral: Most commonly used estrogen. For
patients with an intact uterus, Premarin 0.625 mg/day for days
1-25; Provera 5 mg/day is added from days 16-25. From days 25-31,
both medications are stopped and withdrawal bleeding occurs. If
the patient does not have an intact uterus, Premarin 0.625 mg,
is given daily on a continuous schedule.

Estradiol Transdermal System: Two dosing systems are available,
one releasing 0.05 mg in 24 hours and the second releasing 0.1
mg in 24 hours. Supplied in calendar packs. Dosing is every 3 days.
Place system on clean dry area of trunk, preferably abdomen but not
waistline. Do not apply to breasts. Rotate sites, with at least one
week rest between use of site. If system falls off, may reapply or
use of site. If system falls off, may reapply or use new system if
necessary.

Estradiol Oral: 1 mg/day oral; Provera 5 mg/day is added for 10
days
for women who have a uterus.

Nursing Implications
 * Contraindicated for patients with breast cancer or other
estrogen dependent cancers, abnormal vaginal bleeding or active
thrombophlebitis.
 * Pretreatment and periodic gynecological examination and
mammogram are required.
 * Estrogens should be administered to lactating mothers only when
clearly needed.

Drug Interactions
 * Decreased serum levels of estradiol with concurrent
administration of barbiturates, phenytoin, rifampin or
with smoking.

Patient Interactions
 * Decreased serum levels of estradiol with concurrent
administration of barbiturates, phenytoin, rifampin or smoking.

Patient Teaching
 * Caution, patient about risks of estrogen use which include
endometrial carcinoma, gallbladder disease and effects similar
to those caused by birth control pills. Effects of birth control
pills include hepatic adenoma, elevated blood pressure,
thromboembolic disease, glucose intolerance, hypercalcemia
and photosensitivity.
 * Advise patient to maintain diary in order to accurately report
her response to the estrogen replacement to her endocrinologist.
 * If the patient has an intact pituitary gland, advise patient to
practice birth control if conception is not desired.
 * Advise that type, dose, schedule and delivery methods of
estrogen can be altered if patient experiences intolerable side
effects.
 * Instruct patient to notify physician of any of the following:
spotting, excessive weight gain, abnormal menstrual flow or
absence of menstrual period once it has been re-established.
Symptoms of high blood pressure, glucose intolerance and
thrombophlebitis (only with birth control pills) should be
reported immediately: These symptoms include pain in calves
or chest, shortness of breath, severe headache, dizziness,
faintness, changes in vision, breast lumps, yellowing skin,
pain, swelling or tenderness in abdomen.




Summary

The importance of the hormone deficiency that is being replaced cannot be overemphasized. AVP or cortisol replacement needs can be acute; effects of GH or thyroid deficiency are more subtle so the patient should be carefully monitored. Although not immediately life threatening, it is critical to replace testosterone and estrogen to reduce the risk of sexual dysfunction, osteoporosis and coronary artery disease (CAD). The replacement drug will need to be taken for life. Neuroscience nurses with an understanding of the mechanisms of action of naturally produced hormones and their impact on the body can teach the patient about managing replacement hormones and possible side effects. The patient can be directed to articles available at local library listed in the bibliography which may help the patient gain a greater understanding of hormones in general. Another valuable resource is a publication, Pituitary Patient Resource Guide, 1st annual North American edition, provided by the Pituitary Tumor Network Association (16350 Ventura Boulevard #231, Encino, California 91436).[15]

Future developments in recombinant DNA technology and drug production will lead to refinements in replacement therapy. Improvement in quality of life should result from these advancements in therapies and increased knowledge about managing these therapies.

Acknowledgements

We thank Kathy Klutsch for preparing the illustrations; Kevin O. Lillehei, MD for encouragement; and Lisa Jensen, RN, BSN, for critical reading of the manuscript.

[Figures 1 to 7b ILLUSTRATION OMITTED]

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Questions or comments about this article may be directed to: Dawn H. Mitchell, PhD, Research Associate, Division of Medical Oncology. University of Colorado Health Sciences Center, 4200 E. Ninth Avenue, B171, Denver, Colorado 80262. Betty Owens, RN, MS, is an instructor in the Division of Neurosurgery at the University of Colorado Health Sciences Center in Denver, Colorado.
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Title Annotation:includes test on replacement therapy
Author:Mitchell, Dawn H.; Owens, Betty
Publication:Journal of Neuroscience Nursing
Date:Jun 1, 1996
Words:8379
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