CHAPTER Panhypopituitarism

182 Minal Mohit

INTRODUCTION million. A Spanish study has reported a prevalence of Panhypopituitarism is a condition of inadequate or of 290 and 450 cases per million from absent production of the anterior pituitary hormones. It two cross-sectional surveys in 1992 and 1999, respectively, is frequently the result of other problems that affect the and a corresponding incidence of 60 per million per year. and either reduce or destroy its function MORTALITY or interfere with hypothalamic secretion of the varying Mortality is increased in hypopituitarism. Data from six pituitary-releasing hormones. Hypopituitarism refers epidemiologic studies, comprising patients aged between to the deficiency of one or more pituitary hormones. It 46 and 52 years who were followed for 10 to 13 years, report is associated with increased morbidity and mortality. increased mortality with standardized mortality rates Clinical manifestations are influenced by the cause, (SMRs) from 1.2 to 2.2. The higher mortality arises from severity, and rate of onset of pituitary hormone deficiency. cardiovascular and cerebrovascular disease and appears Adult patients with hypopituitarism receive substitutive to be greater in women (Figure 1). Craniopharyngiomas hormone treatment for growth hormone, secondary carry a worse prognosis than pituitary adenomas, and glucocorticoid, sex steroid, and hormone radiotherapy has been identified as a factor that increases deficiency. mortality. GH deficiency has been implicated as a major EPIDEMIOLOGY contributor to excess mortality in hypopituitarism Limited information is available on the epidemiology because it is the only defect not replaced in the studies of hypopituitarism. A Swedish survey estimates the of hypopituitarism. However, the contribution to overall prevalence of hypopituitarism to be 175 cases per mortality of other risk factors, such as radiotherapy and suboptimal replacement therapies for other hormone deficits, is the subject of ongoing investigation. CAUSES Major causes of hypopituitarism are shown in (Table 1). The most common cause is a pituitary adenoma or treatment with pituitary surgery or radiotherapy. PITUITARY AND HYPOTHALAMIC MASS LESIONS Pituitary microadenomas, though found commonly (1.5% - 27%) at autopsy, are very rarely associated with hypopituitarism and tend to run a benign course. Macroadenomas are less common but are more frequently associated with pituitary hormone deficiencies; some 30% of patients with pituitary macroadenomas have one or more anterior pituitary hormone deficiencies. The causative mechanism of hypopituitarism is compression of the portal vessels in the pituitary stalk, secondary to the expanding tumor mass directly or to increased intrasellar pressure, which explains the potential reversibility of pituitary dysfunction after surgery in some patients. Derangement of central endocrine regulation also occurs with parapituitary space-occupying lesions such as craniopharyngiomas, Rathke’s cleft cysts, arachnoid Fig. 1: Standard mortality rates (SMR) and 95% confidence cysts, chondromas, chordomas, suprasellar meningiomas, intervals (CI) in individual studies on patients with astrocytomas of the optic nerve, and primary tumors of nonmalignant pituitary diseases not associated with excess the third ventricle. adrenocorticotropic hormone (ACTH) or growth hormone (GH) secretion, and in the weighted meta-analysis (bottom PITUITARY SURGERY line). Results are shown for men (open boxes) and The incidence and degree of hypopituitarism after women (black boxes) separately. (From Nielsen EH, Lindholm J, surgery depend on the size of the original tumor, the degree of infiltration, and the experience of the surgeon. Laurberg P. Excess mortality in women with pituitary disease: a There is a possible deterioration of postoperative meta-analysis. Clin Endocrinol 67:693–697, 2007.) ENDOCRINOLOGY 838 is thyroid-stimulating hormone (TSH), followed in order in followed (TSH), hormone thyroid-stimulating is not is invasive.to recoverhormone mostlikely The pituitary tumor the if or imaging, postoperative on found Postoperative improvement ismorelikelyifnotumor function. pituitary recovery of significant with associated be also may adenomas pituitary for surgery hand, other should be performed promptly aftersurgery.Butonthe function pituitary of assessment and function, pituitary Idiopathic Hemosiderosis (thalassemia) Hemochromatosis Iron-overload states Pituitary abscess Encephalitis Infection Perinatal trauma Head injury Traumatic Midline cerebralandcranialmalformations Developmental Isolated pituitaryhormonedeficiencies Combined pituitaryhormonedeficiencies Genetic (table2) Wegener’s granulomatosis Histiocytosis X Tuberculosis Sarcoidosis Granulomatous disease Subarachnoid hemorrhage Intrasellar carotidarteryaneurysm Pituitary apoplexy Sheehan’s syndrome Vascular Lymphocytic hypophysitis Autoimmune Acute lymphoblasticleukemia Head andneckcancer Brain tumors HP axistumors Radiotherapy Surgery: forHPaxistumors Glioma (hypothalamus,thirdventricle, opticnerve) Craniopharyngioma Pituitary adenoma pituitary (HP)axis Neoplastic: Tumors involvingthehypothalamic- Table 1: ofHypopituitarism Causes within 8weeks aftersurgery. GH. and by adrenocorticotropic hormone (ACTH), gonadotropins, normal after radiotherapy (3750to 4250cGy). Growth hormone following external tumorsinadults. radiotherapy for pituitary hormones to the effects of hormones toexternal theeffects radiotherapy, andthyroid- Follicle-stimulating hormone; LH,luteinizing hormone. (From radiation dose, the earlier GH deficiency occurs. radiation the dose,(Courtesy theearlierGHdeficiency children receiving 27to 32Gy or≥35Gy ofcranialirradiation normal hypothalamic-pituitary-target glandaxesnormal hypothalamic-pituitary-target remaining hormone deficitsdevelop isdosedependent;thehigher before adrenocorticotropic hormone (ACTH) deficiency. FSH,before hormone(ACTH) adrenocorticotropic Fig. probabilities analysis ofinitially indicating 3:Life-table (GH) secretion isthemostsensitive oftheanterior pituitary In two thirds develops ofpatients, gonadotropin deficiency This illustrates that thespeedat whichindividualpituitary Littley MD, SM,Beardwell Shalet CG, etal:Hypopituitarism for abraintumorinrelation to timefrom irradiation (dxt). stimulating secretion isthemostresistant. hormone(TSH) Department of Medical Illustrations, ofMedical WithingtonDepartment Hospital, Fig. 2: The incidenceofgrowth in hormone(GH) deficiency eoey f iutr fnto ocr early, occurs function pituitary of Recovery Q JMed70:145–160,1989.) Manchester, England.) CHAPTER 182 839 GONADOTROPIN DEFICIENCYGONADOTROPIN CLINICAL FEATURES DEFICIENCYGH LYMPHOCYTIC HYPOPHYSITIS APOPLEXY PITUITARY DISEASES GRANULOMATOUS In male patients, the clinical deficiency differ according to features whether the was deficiency of gonadotropin acquired before or after pubertal age. If acquired before pubertal age, clinical examination reveals a small penis, small testes, and eunuchoid proportions (span exceeds a height acquired postpubertally of 5 cm). Hypogonadism Presentation of hypopituitarism can be nonspecific. It is pituitary the of onset of rate and type, degree, by affected hormone deficiency. Local pressure effects or hormonal picture. the clinical hypersecretion may complicate Hypopituitarism arising from an expanding mass lesion evolution or from irradiation produces a characteristic of pituitary failure caused by an initial loss of GH by LH and FSH, and finally by failure secretion, followed symptoms onset of The secretion. TSH and ACTH of is insidious, typically occurring with lethargy, mild fatigue, headaches, disinterest, weight depression. mimicking declining libido—symptoms and gain, low mood, Rarely, anorexia and weight loss may arise from ACTH deficiency and may be mistaken for and lead to extensive mass for occult malignancy. Progressive investigations or visual headaches expansion causes increasingly severe symptoms from chiasmal compression. The symptoms and signs of individual hormone deficiency are listed in 3. Table The features of isolated deficiencies of each axis are described below. Adults with childhood GH or acquired in deficiency, later adult of life, whether have a range metabolic, dating 4. abnormalities Table from body compositional, and functional Lymphocytic Lymphocytic hypophysitis, an immune-mediated diffuse and lymphocytes with pituitary anterior the of infiltration plasma cells, occurs predominantly in women and often is first evident in pregnancy or afterdelivery. The classic presentation is peripartum hypopituitarism, often with a pituitary mass and visual failure, whereas in later stages, leaving an empty sella. the gland may atrophy, Pituitary apoplexy is the abrupt destruction of pituitary into the infarction or hemorrhage from tissue that results pituitary, usually into an degree of a variable accompanies headache Severe underlying pituitary tumor. pituitary Consequent palsy. nerve cranial or loss visual hormone deficiencies may develop rapidly. In Sheehan’s severe to secondary occurs infarction pituitary syndrome, circulatory failure. postpartum hemorrhage and ensuing Granulomatous tuberculosis, diseases, and Langerhans affect cell including the histiocytosis, insipidus. hypopituitarism, including diabetes can hypothalamic-pituitary sarcoidosis, axis and cause prolonged stay in the intensive care unit. All patients patients All unit. care intensive in the stay prolonged 3 between hypopituitarism for screening undergo should after injury. 6 months and Hormone Deficiencies Hormone PRL GH, TSH, TSH, GH, LH/FSH, ACTH, PRL TSH, GH, LH/FSH, ADH ACTH, GH, LH/FSH, TSH, PRL GH, PRL GH GH FSH/LH FSH/LH FSH/LH ACTH TSH TSH Gene Defect Gene Pit-1 (POU1F1, GHF1) PROP-1 HESX1 (Rpx) LHX3/LHX4 PITX2 hGH GHRH receptor gene KAL GnRH receptor gene DAX1/AHC TBX19 (Tpit) TSH-β gene TRH receptor gene Combined Isolated Table 2: Genetic Causes Genetic Hypopituitarism of Table 2: RADIOTHERAPY TRAUMATIC BRAIN INJURY BRAIN TRAUMATIC GENETIC CAUSES GENETIC Traumatic brain injury (TBI) cause of is hypopituitarism. an It was first under-appreciated reportedMeta-analysis of in 1918. 19 studies, which included more 1000 than patients, demonstrated of 27.5%. Prevalence hypopituitarism following TBI a pooled prevalence is and 26% in the acute phase is of of decreased to 6.9% among long-term survivors. Risk factors fracture, skull basal include hypopituitarism traumatic of diffuse axonal injury, raised intracranial pressure, and Mutations in genes encoding for the KAL, HESX-1, Prop- 1, and Pit-1transcription factors result one or more anterior pituitary hormones. Mutations in in deficiency of more tend to cause early appearing transcription factors 2). (Table hormone deficiencies extensive Deficiency of one or more anteriorthe hypothalamic-pituitary when pituitaryinvariable almost is hormones axis lies within the fields of radiation. Hypopituitarism radiation therapy in patients who received also develops for nasopharyngeal and primary carcinomas, brain tumors, as well parasellar cranial irradiation for acute prophylactic underwent as in children tumors, who for irradiation (TBI) lymphoblastic leukemia or total body of tumors and other diseases. a variety of an irradiation schedule radiobiological impact The is dependent on the total dose, the number of fractions, follow-up (Figure 2). and the duration and length of to radiation damage sensitive are the most Somatotrophs on a be performed testing should (Figure 3). Endocrine and again at 15 years. basis for at least 10 years yearly ENDOCRINOLOGY 840 results in increased insulin sensitivity and a decrease in childhood, hypoglycemia can occur: Cortisol deficiency secondary of loss sexual particularly, hair occurs. In patients severe ACTH female deficiency, particularly in and disease, Addison’s of hyperpigmentation the to contrast suppression. Examination may reveal pallor of the skin, in can developtherapy adrenalatrophysecondaryto ACTH occult malignancy.Patients onlong-termglucocorticoid weight loss, sometimes mimicking anorexia nervosa or an and anorexia, fatigue, chronic of symptoms chronic progressive with present usually deficiency by ACTH chronic dominated be may profound shock in themost serious form. Patients picture with clinical the apoplexy, pituitary in as abrupt, is onset the If hypopituitarism. of component life-threatening most the is deficiency ACTH remains unless ACTH deficiencyalsoispresent. hair vaginalaxillary and pubic occur; atrophy, dyspareunia and dryness, breast infertility, oligomenorrhea, amenorrhea woman, or adult the In development. hypogonadism breast hypogonadotropic girl, is associated withprimaryamenorrheaandabsent teenage a In high enoughtomaintainspermatogenesis. remain levels testosterone intratesticular as fertility, and levels andgynecomastiawithpreserved testicularsize testosterone circulating low in result may deficiency LH consequence ofhypogonadotropichypogonadism.Partial general well-being. Azoospermia isanalmostinevitable and libido, function, sexual density, mineral bone mass, youth.” Other effects include a decrease in skeletal muscle “aging the of skin facial wrinkled finely characteristic the to leading of skin, the of thinning loss and hair, body and size, facial testicular in reduction a with associated is ADRENOCORTICOTROPIC HORMONE DEFICIENCY Antidiuretic hormone Prolactin hormone Adrenocorticotropic hormone Thyroid-stimulating Gonadotropins Growth hormone Hormone Deficiency Table 3: Symptoms ofHormone Deficiencies andSigns nocturia, hypotension Polyuria, polydipsia, Failure oflactation pallor, hypoglycemia dizziness onstanding, Weakness, tiredness, skin, weight gain sensitivity tocold,dry energy; constipation; children; decreasein Growth retardationin breast atrophy dyspareunia, infertility, oligomenorrhea In women:amenorrhea/ facial/body hair small softtestes,reduced impotence, infertility, In men:poorlibido/ Hormone Deficiency. 13-6 in thesectionGrowth Please referto Table Symptoms andSigns f rsrain f lotrn scein my e the elderly. be may secretion, presenting feature of aldosterone ACTH deficiency, particularly in the of preservation of because disease Addison’s in than seen although commonly less Hyponatremia, reserves. glycogen hepatic in by the presence of ACTH deficiency, because of the because deficiency, ACTH of presence the by ensue. Thefeatures ofdiabetesinsipidus maybemasked to isunable keep patient up with the fluid the loss, hypotension and If hypovolemia deficiency. (ADH) hormone features ofdiabetesinsipidus resulting from antidiuretic Polydipsia andpolyuria with nocturiaaretheclassic because hypothyroidism, primary some residualTSHsecretionoftenispreserved. in than milder are generally However,symptoms of hypothyroidism. primary symptoms the with keeping in intolerance, cold and constipation, weight, lose to inability weakness, fatigue, occurs late in most pituitary disorders. Symptoms include deficiency (TSH) hormone Thyroid-stimulating density lipoprotein; HDL,high-densitylipoprotein. GH, ANTIDIURETIC HORMONE DEFICIENCY THYROID-STIMULATING HORMONE DEFICIENCY • • • • • Investigations • • • • • • Overweight Signs - - - - - • • • • • Symptoms Table 4: Syndrome ofAdult Growth Hormone Deficiency Growth hormone; Reduced bonemineraldensity Elevated fastinginsulin cholesterol Hyperlipidemia: highLDLcholesterol,lowHDL Low IGF-1(60%ofpatients) patients) Peak GHresponsetohypoglycemia<3 µg/L(all Depressed affect Thin, dryskin Reduced exerciseperformance Poor musculardevelopment Increased adiposity,especiallyabdominal Increased socialisolation Reduced vitalityandenergy Reduced physicalstamina Anxiety Depressed mood Impaired psychologicalwell-being Reduced sweating Reduced strengthandphysicalfitness Reduced musclebulk Increased bodyfat IGF, insulin-like growth factor; LDL, low- CHAPTER 182 841 cortisol concentrations cortisol 57 in association with a serum 4 Following injection of a standard dose of MANAGEMENT Treatment for hypopituitarism can be separated into be separated can hypopituitarismfor Treatment Thyroid-Stimulating Hormone Deficiency Hormone Thyroid-Stimulating with reduced Secondary hypothyroidism is associated concentration of free or total T confirmation Deficiency Hormone Antidiuretic requires first deficiency ADH of diagnosis The than more of excretion the as defined is which polyuria, of 3 L of urine per 24 hours (40 mL/kg/24 hours). The usual first-line investigation is an 8-hour fluid deprivation test. under strict observation be performed test should The because severe fluid and electrolytedepletion can occur. Plasma osmolality, urine volume, measured and hourly osmolarity for are 8 hours, intramuscularly given is (desmopressin) ADH analogue of after which a synthetic In a remeasured. then is urine osmolality The (IM). normal subject, ADH is water secreted is absorbed normally, throughout and a subsequent the elevation test, of urine osmolality occurs. urine a achieve subjects (normal concentrate to fails urine In diabetes insipidus, the because osmolality) at least twice the plasma osmolality of a lack of ADH; hence, concentrates adequately only after administration Urine plasma osmolality increases. in which the results of a water In cases of desmopressin. deprivation test are inconclusive, ADH measurement is helpful. A definitive diagnosis of ADH deficiency can be established by infusing hypertonic saline for 2 hours to increase plasma osmolality to more than 300 mOsm/kg, with regular 20 to 30 minute blood sampling to estimate ADH. In nephrogenic diabetes plasma osmolality and insipidus, ADH values are above the normal range, reference whereas in cranial diabetes insipidus, values are end of or below the normal reference range. at the lower ACTH level will help distinguish between primary and primary between distinguish will help level ACTH secondary glucocorticoid deficiency:In primary cortisol deficiency(Addison’s disease), the ACTH level the deficiency, glucocorticoid secondary in whereas high, will be normal. or inappropriately will be low ACTH level the response tolerance test The insulin (ITT) evaluates of the HPA axis to the potent stressor of hypoglycemia, and it confirmation of is secondary adrenal failure. generally It is in patients with pituitary reserve test of growth hormone also the the disease. “gold standard” insulin (0.1 unit/kg), intravenous in the TSH concentration below the normal range, analogous to hypogonadism. the biochemical findings in secondary are measured serially. Upon achievement of adequate adequate of achievement Upon serially. measured are hypoglycemia (<2.2 mmol/L), a peak of cortisol between 500 and response 600 nmol/L generally is accepted as adequate. is test sometimes (tetracosactrin) Synacthen short The used as a surrogate test of ACTH deficiency on the basis bolus exogenous an to respond will gland adrenal the that endogenous normal a there is when ACTH synthetic of Although atrophic. and the gland is not ACTH reserve it is a good test of adrenal reserve, In a patient with organic reserve. ACTH test pituitary it does not directly pituitary disease, a normal response to Synacthen does ACTH deficiency. not exclude mild or recent , and the and 8:00AM cortisol level is less than cortisol level AM AM peak GH response to a include the provocative insulin test, tolerance hormone-releasing which growth test and (ITT); clonidine, glucagon, arginine, in combination with (GHRH) alone or hormone arginine or pyridostigmine spontaneous GH secretion, and serum concentrations of GH-regulated proteins (IGF-1) and 1 insulin-like growth factor as such IGF-binding protein-3 (IGFBP-3). ), cortisol, LH, FSH, and testosterone in men, and 4 DYNAMIC TESTING DYNAMIC DIAGNOSIS AND ENDOCRINE EVALUATION ENDOCRINE AND DIAGNOSIS estradiol in women. Baseline blood testing reliably estradiol in women. Baseline blood identifies hypothyroidism, hypogonadism, hypoadrenalism due to pituitary insufficiency. severe and Adrenocorticotropic Hormone DeficiencyAdrenocorticotropic Hormone In normal people, the 6:00 are found between highest plasma cortisol levels lowest before midnight. Plasma cortisol and ACTH and cortisol before midnight. Plasma lowest during physical and emotional concentrations are elevated stress, including acute illness, trauma, surgery, infection, If a 9:00 and starvation. 100 nmol/L, particularly greater level in baseline a whereas likely, an highly is deficiency unwell patient, cortisol assessment dynamic normality; indicates nmol/L 500 than of the hypothalamic-pituitary-adrenal (HPA) axis is not paired plasma A under these circumstances. necessary Adult Gonadotropin Deficiency Gonadotropin Adult In women levels of are clearly postmenopausal premenopausal women, amenorrhea (or less low commonly, age, or oligomenorrhea), in addition undetectable, to gonadotropin low estradiol levels and whereas low in or normal gonadotropin levels, provides evidence sufficient of the diagnosis. In adult men, a similar picture and low or inappropriately of low testosterone levels is seen. normal gonadotropin levels 2. 3. Growth Hormone Deficiency Hormone Growth GH for assessing Three widely accepted approaches secretory status include measuring 1. Endocrine Evaluation with suspected of a patient endocrine assessment The both of measurement involves hypopituitarism usually of Evaluation levels. baseline and stimulated hormone baseline function involves (T prolactin, TSH, thyroxine Imaging higher offers it as choice, of technique scanning the is MRI demonstrate and is able to than CT scanning resolution MRI diameter. in mm 3 as small as microadenomas insights into the morphologic also has provided defects developmental arise from abnormalities that where situations in used is CT the pituitary gland. of MRI is contraindicated, such as when arterial clips or a pacemaker is present. CT has a valuable role in defining for surgery. bone anatomy in preparation consequent hypovolemia and reduced glomerular glomerular reduced and hypovolemia consequent filtration rate. Only when cortisol replacementtherapy is the may commenced polyuria of diabetes and polydipsia be revealed. insipidus ENDOCRINOLOGY 842 and endocrinereplacementtherapyTable 5. disease process the underlying those therapiesdirectedat le oe, n i wmn hn n e. hrfr the Therefore men. in dose ofGHinyoungmenand womenis0.2and starting than women in and ones, older in individuals than in younger secretion isgreater GH symptoms whileavoiding overtreatment. normal hormonal milieu as far as possible, thus improving Endocrine replacement therapyshouldaimtomimic the GROWTH HORMONEGROWTH DEFICIENCY HORMONE REPLACEMENT IN HYPOPITUITARISM Antidiuretic hormone Prolactin hormone Adrenocorticotropic hormone Thyroid-stimulating Gonadotropins (male) Gonadotropins (female) Growth hormone Hormone Deficiency Deficiencies Table 5: EndocrineReplacement Therapy for Hormone 40 µg (individeddoses) doses); intranasal,10- 300-600 µg (individed Desmopressin (DDAVP), Nil evening, to10mgt.i.d. morning, 5mgnoon, Hydrocortisone, 10mg (preferred schedule): Glucocorticoid Thyroxine, 75-200 µg/day every 4-6mo or Implant: 600-800mg or Transdermal: 5-7.5mg mg every 2-3wk testosterone esters):250 Intramuscular (as Testosterone: acetate, 5mg or Medroxyprogesterone transdermal: 7 µg or Levonorgestrel, 250µg, transdermal: 170-250 µg Norethisterone, 0.7-1mg, (examples): PLUS Progesterone 1.25 mg equineestrogens: 0.625- or conjugated transdermal: 25-100 µg Estradiol valerate: 1-2mg, Estrogen: Hormone Deficiency. 13-7 in thesectionGrowth Please referto Table Otherwise) Range (Oral, if Not Stated and TypicalDailyDose Replacement Hormones health, and sexual function, and it is the most appropriate for the maintenance of normal body composition, skeletal In both sexes, sex steroid replacement therapy is important with dualx-rayabsorptiometry andlipidmeasurements. to attention particular quality-of-life questions, assessment of body composition with history, careful and folds, measurements suchaswaist circumferenceandskin anthropometric including examination, physical include an age-adjusted normal range. Clinical monitoring should response, thelevel ofwhich shouldbemaintainedwithin Serum IGF-1 isthemost useful biochemical marker ofGH term safetyandefficacy. preparations ofhumanGHareunderevaluation forlong- guided byclinicalandbiochemicalresponse. Long-acting and individualized, gradual, be should escalation Dose the evening tomimic the greatersecretionofGHatnight. for heavierindividuals in adults. GH is administered in the lackofevidencethatalargerreplacementisrequired variation in absorption and in sensitivity to GH, as well as is notrecommended because oflargeinterindividual day (Table 6). Dose determination basedonbodyweight 0.3 mg/day, respectively, and in older individuals 0.1 mg/ BSL, Blood sugarlevel; IGF-1,insulin-like growthfactor-1. GONADOTROPIN DEFICIENCY Contraindications Dosage considerations Side effects Monitor Adjustments Starting dose Pretherapy Replacement inAdult GHDeficiency Table 6: Treatment Guidelinesfor Growth Hormone (GH) retinopathy hypertension, proliferative Malignancy, intracranial therapy inwomen. transdermal estrogen with oralthan Requirements aregreater than theyoung. Elderly requirelessGH than men. Women requiremoreGH regimens. Avoid weight-based myalgia, paresthesia Edema, arthralgia, quality-of-life measures Weight, bodycomposition, BSL, lipids IGF-1 (dosetitration) 0.01-0.15 mg/day Small monthlyincrement, mg/day forwomen 0.2 mg/dayformenand0.3 IGF-1, BSL,lipids Body composition Pituitary imaging other hormonedeficiencies Adequate replacementof CHAPTER 182 843 ) replacement therapy, as is primary hypothyroidism. 4 THYROID-HORMONE STIMULATING HORMONE DEFICIENCY HORMONE STIMULATING THYROID-HORMONE ADRENOCORTICOTROPIC HORMONE REPLACEMENT HORMONE ADRENOCORTICOTROPIC The normal starting dose in a young patient without evidence of cardiac disease is starting doses are used in the elderly and in patients 1.5 mcg/kg/day. Lower In patients with heart disease. of ischemic with evidence suspected hypopituitarism, thyroxine therapy should Secondary hypothyroidism is (T treated with thyroxine The modern approach to glucocorticoid replacement is The modern approach to glucocorticoid to mimic physiologic levels, ensuring sufficiency during times of acute illness, and to prevent over-replacement, outcomes. metabolic which is associated with adverse replacement must be educated to increase the Patients intercurrent illness of an twofold to threefold in case dose an should wear or when undergoing surgery. Patients should and necklace bracelet or appropriate Medic-alert and taught be issued an IM hydrocortisone pack how of protracted vomiting. to self-administer in the event Hydrocortisone directly replaces the missing hormone. Cortisone acetate is metabolized to cortisol and has a activity. Both onset of action with longer biological slower prednisolone and dexamethasone have longer half-lives, thus allowing daily administration. Generally, the lowest replacement dose tolerated by the patient is preferred (10 to 20 mg/day). Indeed higher serum total concentrations cholesterol, of low-density lipoprotein, triglycerides, with increasing observed circumference were and waist the in a study comparing levels glucocorticoid of doses metabolic phenotypes of patients with growth hormone deficiency treated with different formulations and doses to suit should be divided Doses of glucocorticoids. individual needs. Spermatogenesis Spermatogenesis is unlikely within the first 3 months of 6 for continued is hCG alone with Treatment therapy. months, with regular sperm counts to monitor progress. If adequate spermatogenesis is not achieved, then (hMG) gonadotropin of human menopausal in the form FSH FSH is of dose The added. is FSH recombinant a or not achieved is if adequate spermatogenesis increased therapy. of combination after 6 months alternative The idiopathic hypogonadotropic in patients with regimen hypogonadism and Kallmann’s syndrome SC via a catheter is administered GnRH therapy. GnRH is pulsatile attached to a minipump. This regimen appears therapy in men but gonadotropin over few advantages to offer take up may regimens Both gynecomastia. less may cause adequate spermatogenesis. to achieve to 2 years In women reported after therapy with are up to 80% pregnancy rates with hypogonadotropic pulsatile GnRH or gonadotropins. hypogonadism, Again, the choice gonadotropin therapy and pulsatile therapy lies between of GnRH, but obvious advantages accrue to GnRH therapy function. if the patient has enough residual gonadotroph likely than hMG to result Pulsatile GnRH therapy is more in and development ovulation of a single follicle, thereby hyperstimulation and ovarian for the risks reducing multiple gestation. However, in practice, GnRH therapy may not be practicable, and in more than 50% of women with organic pituitary this method. function is not sufficient to support disease, residual gonadotroph Gonadotropin and Gonadotropin-Releasing Hormone Therapy Hormone and Gonadotropin-Releasing Gonadotropin In the hypogonadotropic hypogonadal patient, fertility with gonadotropin therapy in both be achieved can of therapy lies between The choice men and women. gonadotropin replacement and GnRH. The former is the traditional therapeutic approach; initially, LH “activity” gonadotropin (hCG) by human chorionic is provided administered subcutaneously (SC) or IM at a dose of between 1000 and 2000 IU, two to three times weekly. Androgen Replacement Androgen of androgen replacement of preparation The choice and patient preference. IM depends on local availability disturbing with associated be can testosterone of injection fluctuations in sexual function, energy level, and mood, concentrations. mirroring the changes in testosterone Transdermal testosterone alternative, are systems, available as patch testosterone or scrotal) or as the recently introduced which systems (nonscrotal are maintain physiologic gel. Both formulations are able to an testosterone profiles in most patients, but skin irritation, the need for scrotal shaving, and drying both of the potential drawbacks of application are some time after gel has undecanoate transdermal systems. Testosterone become available as an intramuscular a 10- to over testosterone levels stable serum achieves injection, which period. This new preparation has essentially 14-week replaced testosterone implants as replacement therapy. be Androgen replacement therapy should always monitored to ensure physiologic mean testosterone result in low trough Suboptimal replacement doses levels. levels, whereas supraphysiologic secondary polycythemia and progression of prostate doses can promote cancer; therefore, regular monitoring of hemoglobin and prostate-specific antigen is recommended. Estrogen Replacement Estrogen In women, this can Progesterone therapy preparations. replacement hormone be provided by all women continuously) in (cyclically or given must be many standard with an intact of uterus unopposed to estrogen prevent on dose The cancer. or endometrial dysfunctional bleeding the the possible endometrium, that effect the not be supraphysiologic (as in of estrogen should is, oral contraceptive pill) unless a clear indication, such as strong patient preference, exists, or a patient with partial gonadotropin deficiency still has occasionalcycles, menstrual along implant, with or gel, a patch, tablet, desire a as for delivered be contraception. can Although estrogen because of reduction of recommended a nonoral route is oral by oxidation fat and (IGF)-1 factor growth insulin-like on study surveillance international an However, estrogen. 315 hypopituitary women taking estrogen replacement demonstrated significant predominance oralof 14%). Women on oral transdermal estrogen use (86% vs. versus estrogen had a significantly greaterwaist/hip ratio after GH treatment, with lower IGF-1 levels at the end of the by women on study period on twice the GH dose received highly route is nonoral a estrogen. Therefore transdermal recommended. form of replacement therapy in patients not desirous of not desirous patients in therapy of replacement form fertility. ENDOCRINOLOGY 844 of T range. Measurement of TSH is unhelpful inthemonitoring 1. fewer hypopituitarypatientsinthefuture. analogues andaGH-receptorantagonistshouldmean use hypopituitarism of medical therapy foracromegalywithsomatostatin greater Furthermore, long-term reduced. significantly of be will incidence the and surgery, centers experienced to replacement ofconventional radiotherapywithstereotactic surgery their prevention. of on restriction focus By also should deficiency GH The modern management ofhypopituitarismand principle a hormone deficiencyinthepracticeofendocrinology. GH, with replacement consistent withthetenetofhormone replacement for have also should evidence of efficacy and safety, adults with GH deficiency treatment of hypopituitary patients.Based on global and Adequate hormone replacementismandatoryinthe appropriate studies. longer-term from confirmation GHdeficiency which to contributes to such excess morbidity and mortality extent awaits The patients. affected Hypopituitarism increasesmorbidityandmortalityin therapy iscommencedorchanged. hyponatremia, and sodium levels should be checked after urine outputiscontrolled.Overdosage carriesariskfor until be startedatlowdoseandincreasedgradually should drug The polyuria. of degree or weight, sex, age, number of in a 10-fold between individuals, with no apparent relation to the recentlyavailable oralform.Dosagesvary asmuch is available and parenteral, intranasal, oral, including It preparations, deficiency. 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