Full Guideline: Hormonal Replacement in Hypopituitarism in Adults
JCEM | October 2016
Maria Fleseriu (Chair), Ibrahim A. Hashim, Niki Karavitaki, Shlomo Melmed, M. Hassan Murad, Roberto Salvatori, and Mary H. Samuels
The 2016 guideline addresses:
- Diagnosis and evaluation of multiple pituitary hormonal deficiency (hypopituitarism)
- Treating a variety of hormone deficiencies
- Managing interactions between replacement hormones and limiting the risks of over-replacement
- Special circumstances, such as peri- and postoperative care and pregnancy
Hormonal Replacement in Hypopituitarism: An Endocrine Society Clinical Practice Guideline | ENDO 2016
Essential Points
The guideline addresses special circumstances that may affect the treatment of patients with hypopituitarism, including pregnancy care, post-surgical care following pituitary or other operations, treatment in combination with anti-epilepsy medication, and care following pituitary apoplexy—a serious condition that occurs when there is bleeding into the gland or blood flow to it is blocked.
Recommendations from the guideline include:
- Measurements of both free thyroxine and thyroid-stimulating hormone are needed to evaluate central hypothyroidism, a condition where the thyroid gland does not produce enough hormones because it isn’t stimulated by the pituitary gland.
- People who have central hypothyroidism should be treated with levothyroxine in doses sufficient to raise levels of the thyroid hormone free thyroxine to the upper half of the reference range.
- Growth hormone stimulation testing should be used to diagnose patients with suspected growth hormone deficiency.
- People who have proven cases of growth hormone deficiency and no contraindications should be offered growth hormone replacement as a treatment option.
- Premenopausal women who have central hypogonadism, a condition where the sex glands produce minimal amounts or no hormones, can undergo hormone treatment, provided there are no contraindications.
- People producing abnormally large volumes of dilute urine should be tested for central diabetes insipidus—a rare condition that leads to frequent urination—by analyzing the concentration of their blood and urine.
- For patients who have low levels of glucocorticoid hormones, hydrocortisone can be given in a daily single or divided dose.
- All hypopituitarism patients should be instructed to obtain an emergency card, bracelet or necklace warning about the possibility of adrenal insufficiency.
- Patients who are suspected of having an adrenal crisis due to secondary adrenal insufficiency should receive an immediate injection of 50 to 100 milligrams of hydrocortisone.
- People who have central adrenal insufficiency should receive the lowest tolerable dose of hydrocortisone replacement on a long-term basis to reduce the risk of metabolic and cardiovascular disease.
- Accurate and reliable measurements are central to diagnose hypopituitarism and monitoring therapies.
Recommendations
+ 1.0 Diagnosis of hypopituitarism
Central adrenal insufficiency
- 1.1 We suggest measuring serum cortisol levels at 8–9 AM as the first-line test for diagnosing central adrenal insufficiency (AI). (2|⊕⚪⚪⚪)
- 1.2 We recommend against using a random cortisol level to diagnose AI. (1|⊕⊕⚪⚪)
- 1.3 We suggest that a cortisol level <3 μg/dL is indicative of AI and a cortisol level >15 μg/dL likely excludes an AI diagnosis. (2|⊕⚪⚪⚪)
- 1.4 We suggest performing a corticotropin stimulation test when morning cortisol values are between 3 and 15 μg/dL to diagnose AI. Peak cortisol levels <18.1 μg/dL (500 nmol/L) at 30 or 60 minutes indicate AI. (2|⊕⊕⚪⚪)
- 1.5 We suggest that clinicians perform biochemical testing for the hypothalamic-pituitary-adrenal (HPA) axis at least 18–24 hours after the last hydrocortisone (HC) dose or longer for synthetic glucocorticoids (GCs). (2|⊕⊕⚪⚪)
Central hypothyroidism
- 1.6 We recommend measuring serum free T4 (fT4) and TSH to evaluate central hypothyroidism (CH). An fT4 level below the laboratory reference range in conjunction with a low, normal, or mildly elevated TSH in the setting of pituitary disease usually confirms a CH diagnosis. (1|⊕⊕⊕⊕)
- 1.7 In patients with pituitary disease and low-normal fT4 levels suspected to have mild CH, we suggest starting levothyroxine (L-T4) if suggestive symptoms are present or following fT4 levels over time and starting treatment if the fT4 level decreases by 20% or more. (2|⊕⚪⚪⚪)
- 1.8 We suggest against using dynamic TSH-secretion testing to diagnose CH. (2|⊕⊕⊕⚪)
GH deficiency
- 1.9 In patients with suspected GH deficiency (GHD), we recommend GH stimulation testing. Single GH measurements are not helpful. (1|⊕⊕⊕⚪)
- 1.10 We recommend using appropriately controlled body mass index (BMI) cutoffs to assess peak GH values. (1|⊕⊕⚪⚪)
- 1.11 We suggest against biochemical testing for GHD in patients with clear-cut features of GHD and three other documented pituitary hormone deficits. (2|⊕⊕⊕⚪)
Central hypogonadism in males
- 1.12 In males with suspected hypogonadism, we recommend measuring serum T, FSH, and LH to diagnose central hypogonadism. (1|⊕⊕⚪⚪)
- 1.13 We recommend that clinicians perform hormonal testing for central hypogonadism in males in the absence of acute/subacute illness and before 10 AM (after overnight fast) combined with serum prolactin (PRL). (1|⊕⊕⚪⚪)
Central hypogonadism in females
- 1.14 In the presence of oligomenorrhea or amenorrhea, we recommend measuring serum estradiol (E2), FSH, and LH. Clinicians should exclude other causes of menstrual irregularities related to impaired ovulation (hyperprolactinemia, hyperandrogenism, and thyroid disease), particularly if no other pituitary hormone deficits are present. In cases of amenorrhea, clinicians should also exclude pregnancy. (1|⊕⊕⚪⚪)
- 1.15 We suggest against dynamic testing with GnRH, which offers no useful diagnostic information. (2|⊕⊕⚪⚪)
- 1.16 We recommend that in postmenopausal women, the absence of high serum FSH and LH is sufficient for a diagnosis of gonadotrope dysfunction (provided the patient is not on hormonal replacement therapy [HRT]). (1|⊕⊕⊕⚪)
Central diabetes insipidus
- 1.17 We recommend simultaneously measuring serum and urine osmolarity in patients with polyuria (more than 50 mL/kg of body weight/24 hours, 3.5 L/d in a 70-kg person). In the presence of high serum osmolarity (>295 mOsmol/L), urine osmolarity should reach approximately 600 mOsmol/L (urine osmolality/plasma osmolality ratio should be ≥2), whereas urine dipstick should be negative for glucose. (1|⊕⊕⊕⚪)
+ 2.0 Treatment
Hormonal replacement in panhypopituitarism
Glucocorticoid replacement
- 2.1 We recommend using HC, usually 15–20 mg total daily dose in single or divided doses. Patients using divided doses should take the highest dose in the morning at awakening and the second in the afternoon (two-dose regime) or the second and third at lunch and late afternoon, respectively (three-dose regime). (1|⊕⊕⊕⚪)
- 2.2 We suggest using longer-acting GCs in selected cases (eg, nonavailability, poor compliance, convenience). (2|⊕⚪⚪⚪)
- 2.3 We recommend that clinicians teach all patients with AI regarding stress-dose and emergency GC administration and instruct them to obtain an emergency card/bracelet/necklace regarding AI and an emergency kit containing injectable high-dose GC (1|⊕⊕⊕⚪)
- 2.4 We recommend against using fludrocortisone in patients with secondary AI. (1|⊕⊕⊕⚪)
Adrenal crisis
- 2.5 We recommend that clinicians treat patients with suspected adrenal crisis (AC) due to secondary AI with an immediate parenteral injection of 50–100 mg HC. (1|⊕⊕⊕⚪)
Thyroid hormone replacement
- 2.6 We recommend L-T4 in doses sufficient to achieve serum fT4 levels in the mid to upper half of the reference range. Appropriate L-T4 doses in CH average 1.6 μg/kg/d, with dose adjustments based on clinical context, age, and fT4 levels. (1|⊕⊕⊕⚪)
- 2.7 We suggest against treating CH with levotriiodothyronine (L-T3), thyroid extracts, or other formulations of thyroid hormones. (2|⊕⊕⚪⚪)
- 2.8 We recommend against using serum TSH levels to adjust thyroid replacement dosing in patients with CH. (1|⊕⊕⊕⚪)
Testosterone replacement
- 2.9 We suggest T replacement for adult males with central hypogonadism and no contraindications in order to prevent anemia related to T deficiency; reduce fat mass; and improve bone mineral density (BMD), libido, sexual function, energy levels, sense of well-being, and muscle mass and strength. (2|⊕⊕⚪⚪)
Estrogen replacement in premenopausal women
- 2.10 We recommend gonadal hormone treatment in premenopausal women with central hypogonadism, provided there are no contraindications. (1|⊕⊕⊕⚪)
GH replacement therapy
- 2.11 We recommend offering GH replacement to those patients with proven GHD and no contraindications. We recommend a starting dose of 0.2–0.4 mg/d for patients younger than 60 years and 0.1–0.2 mg/d for patients older than 60 years. (1|⊕⊕⊕⚪)
- 2.12 We recommend titrating GH doses and maintaining IGF-1 levels below the upper limit of normal and reducing the dose if side effects manifest. (1|⊕⚪⚪⚪)
- 2.13 We suggest against administering GH to elderly adults with age-adjusted low IGF-1 levels and no history of pituitary or hypothalamic disease. (2|⊕⚪⚪⚪)
- 2.14 We recommend against using GH to enhance athletic performance because this practice is illegal in the United States, has poor scientific or ethical justification, and does not have substantiated efficacy. (Ungraded Good Practice Statement)
Diabetes insipidus
- 2.15 When administering desmopressin (DDAVP) in diabetes insipidus (DI), we suggest individualized therapeutic schedules. Although clinicians should offer therapy to all patients, some patients with partial DI may not be bothered by polyuria and may prefer no treatment. To reduce the risk of hyponatremia, we recommend that clinicians educate all patients receiving DDAVP about the risk of overdosing. Periodically (at least weekly), patients should experience a phase of polyuria during which the effect of the medication has obviously worn off. (Ungraded Good Practice Statement)
- 2.16 In postpituitary surgery DI, we suggest that clinicians should make at least one attempt to discontinue DDAVP during the weeks/months after surgery to determine whether posterior pituitary function has recovered. (Ungraded Good Practice Statement)
- 2.17 In cases of adipsic DI, we suggest careful DDAVP and fluid intake titration that includes frequent weighing and serum sodium level monitoring. (Ungraded Good Practice Statement)
- 2.18 We suggest that all patients with DI wear an emergency bracelet or necklace to inform clinicians of the patient’s health problem if incapacitated. (Ungraded Good Practice Statement)
Interactions between replacement hormones
Glucocorticoids and GH
- 2.19 We suggest testing HPA axis functionality before and after starting GH replacement in patients who are not receiving GC replacement and who have demonstrated apparently normal pituitary-adrenal function. (2|⊕⚪⚪⚪)
Glucocorticoids and thyroid hormone
- 2.20 We suggest evaluating patients with CH for AI before starting L-T4 therapy. If this is not feasible, clinicians should prescribe empiric GC therapy in patients with CH who are starting L-T4 therapy until there is a definitive evaluation for AI. (2|⊕⊕⚪⚪)
Glucocorticoids and estrogen
- 2.21 We suggest that when clinicians assess adrenal reserve or the adequacy of HC replacement, they take into consideration that total serum cortisol level can be elevated due to the effects of estrogen on corticosteroid-binding globulin (CBG). (2|⊕⊕⊕⚪)
GH and thyroid hormones
- 2.22 We recommend that clinicians monitor euthyroid patients with GHD who begin GH therapy for the risk of developing CH, and if fT4 levels decrease below the reference range, these patients should begin L-T4 therapy. CH patients with GHD who are already receiving L-T4 may require increased L-T4 doses when they begin GH therapy to maintain fT4 levels within target ranges. (1|⊕⊕⚪⚪)
- 2.23 We suggest clinicians treat CH before performing GH stimulation testing because CH may impair the accurate diagnosis of GHD. (2|⊕⊕⚪⚪)
Estrogen and thyroid hormones
- 2.24 In patients with CH requiring changes in estrogen therapy, we recommend monitoring fT4 levels and adjusting L-T4 doses to maintain fT4 levels within target ranges. (1|⊕⊕⊕⚪)
GH and estrogen
- 2.25 We suggest that women on oral estrogen replacement receive higher GH doses compared with eugonadal females or males. (2|⊕⊕⊕⚪)
Glucocorticoids and diabetes insipidus
- 2.26 Because AI may mask the presence of partial DI, we suggest monitoring for the development of DI after starting GC replacement. Conversely, patients with improved DI without an AI diagnosis should undergo AI testing. (2|⊕⚪⚪⚪)
Risk of hormonal over-replacement in hypopituitarism
Bone disease
- 2.27 Clinicians should individually assess GC replacement and avoid over-replacement to reduce the risk of osteoporosis. We suggest low-dose HC replacement because this approach might be associated with increased bone formation and a positive bone-remodeling balance. (2|⊕⊕⚪⚪)
- 2.28 In men with hypopituitarism over-replaced with GC and at risk for fractures, we suggest vertebral fracture assessment (baseline plain spinal x-rays or dual-energy x-ray absorptiometry) to identify patients with unsuspected vertebral fractures. (2|⊕⊕⚪⚪)
- 2.29 We suggest clinicians monitor L-T4 replacement, as recommended in previous sections, and avoid over-replacement to reduce the risk of fractures. (2|⊕⊕⚪⚪)
Cardiovascular risks in patients with hypopituitarism on replacement therapy
Glucocorticoid over-replacement
- 2.30 In patients with central AI, we recommend using the lowest tolerable dose of HC replacement to potentially decrease the risks of metabolic and cardiovascular disease. (1|⊕⊕⊕⚪)
Thyroid replacement
- 2.31 To avoid the possible long-term cardiovascular risks of insufficient or excess thyroid hormone treatment, clinicians should adjust L-T4 doses to avoid low or elevated fT4 levels in CH. (Ungraded Good Practice Statement)
+ 3.0 Special circumstances
Cushing’s disease
- 3.1 We recommend GC replacement until full HPA axis recovery after surgically resecting ACTH-secreting tumors. (1|⊕⊕⊕⚪)
- 3.2 After curative surgery for Cushing’s disease, we recommend retesting thyroid and GH axes before starting replacement treatment. (1|⊕○○○)
Prolactinomas
- 3.3 We recommend reassessing all pituitary axes in patients with macroprolactinoma and central hypogonadism who have had successful dopamine agonist treatments. (1|⊕⊕⊕⚪)
GH replacement in cured acromegaly after surgery and/or radiation
- 3.4 We suggest low-dose GH replacement in patients with cured acromegaly and documented GHD in the absence of known contraindications. (2|⊕⚪⚪⚪)
Perioperative management of hypopituitarism
Pituitary surgery
- 3.5 We recommend using stress doses of steroids in AI before surgery and tapered doses after surgery before repeating testing. (1|⊕⊕⊕⚪)
- 3.6 In patients with normal preoperative adrenal function, we suggest an individualized clinical approach for postoperative GC administration until the HPA axis can be evaluated. (2|⊕⊕⚪⚪)
- 3.7 With preoperative CH, we recommend using L-T4 therapy before nonemergency surgery and throughout the perioperative period. (1|⊕⊕⊕⚪)
- 3.8 With intact preoperative thyroid function, we recommend measuring fT4 levels 6–8 weeks postoperatively to assess for CH. (1|⊕⊕⚪⚪)
- 3.9 We suggest that initial therapy for DI utilizes short-acting sc aqueous antidiuretic hormone (ADH), allowing for safer use in the vast majority of cases in whom DI resolves spontaneously. (2|⊕⊕⚪⚪)
- 3.10 We do not suggest prescheduled DDAVP dosages in the first week postsurgery because of the risk of hyponatremia after transient DI resolves and the risk of syndrome of inappropriate ADH secretion that may occur 7–10 days after surgery. (2|⊕⚪⚪⚪)
- 3.11 We suggest oral or intranasal DDAVP after discharge, with clear instructions that patients should only use the medication if significant polyuria occurs. (2|⊕⚪⚪⚪)
- 3.12 We suggest retesting all pituitary axes starting at 6 weeks after pituitary surgery and then periodically to monitor the development or resolution of pituitary deficiencies. (2|⊕⊕⚪⚪)
Non-pituitary surgery
- 3.13 On the day of surgery, we recommend adjusting GC doses according to the severity of illness and magnitude of the stressor. (1|⊕⊕⊕⚪)
- 3.14 In cases of minor to moderate surgical stress, we suggest 25–75 mg HC per 24 hours (usually for 1–2 days). (2|⊕⊕⚪⚪)
- 3.15 In cases of major surgical stress, we suggest a 100-mg HC per iv injection followed by a continuous iv infusion of 200 mg HC per 24 hours (alternatively 50 mg every 6 hours iv or im). (2|⊕⊕⚪⚪)
Management of hypopituitarism in pregnancy
Glucocorticoids
- 3.16 We suggest using HC as the preferred GC in pregnancy and increasing the dose based on the individual clinical course; higher doses may be required, in particular during the third trimester. (Ungraded Good Practice Statement)
- 3.17 We suggest that pregnant patients with central AI be closely monitored for clinical symptoms and signs of GC over- and under-replacement (eg, normal weight gain, fatigue, postural hypotension or hypertension, hyperglycemia). (Ungraded Good Practice Statement)
- 3.18 We recommend against using dexamethasone in pregnancy because it is not inactivated in the placenta. (1|⊕⊕⚪⚪)
- 3.19 We recommend HC stress dosing during the active phase of labor, similar to that used in major surgical stress. (1|⊕⊕v⚪⚪)
Thyroid
- 3.20 We recommend that clinicians monitor fT4 or total T4 levels every 4–6 weeks for women with CH who become pregnant, and that these women may require increased L-T4 doses to maintain levels within target ranges for pregnancy. (1|⊕⊕⚪⚪)
Desmopressin
- 3.21 In pregnant women with pre-existing DI, we suggest continuing DDAVP during pregnancy and adjusting doses if required. (2|⊕⊕⚪⚪)
Growth hormone
- 3.22 We suggest discontinuing GH replacement during pregnancy because there is no clear evidence yet for efficacy or safety, and the placenta produces GH. (2|⊕⊕⚪⚪)
Management of hypopituitarism in pituitary apoplexy
- 3.23 We recommend testing for acute pituitary insufficiency in all patients with pituitary apoplexy. (1|⊕⊕⊕⚪)
- 3.24 Because acute AI is a major cause of mortality, we recommend GC therapy until a laboratory diagnosis is established and the patient maintains normal pituitary function. (1|⊕⊕⚪⚪)
- 3.25 We recommend that clinicians monitor pituitary axes in pituitary apoplexy patients treated with either surgical decompression or conservative management because hypopituitarism may develop over time. (1|⊕⊕⚪⚪)
Treatment of hypopituitarism in patients receiving antiepileptic medications
- 3.26 We suggest clinicians educate AI patients that are taking nondexamethasone GCs and who start enzyme-inducing antiepileptic drugs (AEDs) about the early signs and symptoms of AI. (2|⊕⊕⚪⚪)
- 3.27 In patients with AI on dexamethasone, we suggest increasing dexamethasone replacement doses if enzyme-induced AEDs are coadministered. (2|⊕⚪⚪⚪)
- 3.28 In CH patients receiving L-T4, we recommend checking fT4 at least 6 weeks after starting an AED and increasing L-T4 doses if fT4 levels decrease below the target range. (1|⊕⊕⚪⚪)
- 3.29 In women who have started estrogen replacement, we suggest evaluating AED levels and adjusting AED doses as required. (2|⊕⊕⚪⚪)
- 3.30 We suggest monitoring DDAVP doses and making further adjustments as needed in patients who are started on AEDs. (2|⊕⊕⚪⚪)
