Objective:

To formulate clinical practice guidelines for hormonal replacement in hypopituitarism in adults.

Participants:

The participants include an Endocrine Society-appointed Task Force of six experts, a methodologist, and a medical writer. The American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology co-sponsored this guideline.

Evidence:

The Task Force developed this evidence-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies.

Consensus Process:

One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines.

Conclusions:

Using an evidence-based approach, this guideline addresses important clinical issues regarding the evaluation and management of hypopituitarism in adults, including appropriate biochemical assessments, specific therapeutic decisions to decrease the risk of co-morbidities due to hormonal over-replacement or under-replacement, and managing hypopituitarism during pregnancy, pituitary surgery, and other types of surgeries.

1.1 We suggest measuring serum cortisol levels at 89 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 g/dL is indicative of AI and a cortisol level >15 g/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 g/dL to diagnose AI. Peak cortisol levels <18.1 g/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 1824 hours after the last hydrocortisone (HC) dose or longer for synthetic glucocorticoids (GCs). (2|)

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|)

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|)

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|)

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|)

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|)

2.1 We recommend using HC, usually 1520 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|)

2.5 We recommend that clinicians treat patients with suspected adrenal crisis (AC) due to secondary AI with an immediate parenteral injection of 50100 mg HC. (1|)

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 g/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|)

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|)

2.10 We recommend gonadal hormone treatment in premenopausal women with central hypogonadism, provided there are no contraindications. (1|)

2.11 We recommend offering GH replacement to those patients with proven GHD and no contraindications. We recommend a starting dose of 0.20.4 mg/d for patients younger than 60 years and 0.10.2 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)

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 patients health problem if incapacitated. (Ungraded Good Practice Statement)

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|)

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|)

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|)

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|)

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|)

2.25 We suggest that women on oral estrogen replacement receive higher GH doses compared with eugonadal females or males. (2|)

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|)

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|)

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|)

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)

3.1 We recommend GC replacement until full HPA axis recovery after surgically resecting ACTH-secreting tumors. (1|)

3.2 After curative surgery for Cushings disease, we recommend retesting thyroid and GH axes before starting replacement treatment. (1|)

3.3 We recommend reassessing all pituitary axes in patients with macroprolactinoma and central hypogonadism who have had successful dopamine agonist treatments. (1|)

3.4 We suggest low-dose GH replacement in patients with cured acromegaly and documented GHD in the absence of known contraindications. (2|)

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 68 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 710 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|)

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 2575 mg HC per 24 hours (usually for 12 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|)

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|)

3.20 We recommend that clinicians monitor fT4 or total T4 levels every 46 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|)

3.21 In pregnant women with pre-existing DI, we suggest continuing DDAVP during pregnancy and adjusting doses if required. (2|)

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|)

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|)

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|)

The Clinical Guidelines Subcommittee (CGS) of the Endocrine Society deemed hormonal replacement in hypopituitarism a priority area in need of practice guidelines and appointed a Task Force to formulate evidence-based recommendations. The Task Force followed the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation group, an international group with expertise in the development and implementation of evidence-based guidelines (1). A detailed description of the grading scheme has been published elsewhere (2). The Task Force used the best available research evidence to develop the recommendations. The Task Force also used consistent language and graphical descriptions of both the strength of a recommendation and the quality of evidence. In terms of the strength of the recommendation, strong recommendations use the phrase we recommend and the number 1, and weak recommendations use the phrase we suggest and the number 2. Cross-filled circles indicate the quality of the evidence, such that denotes very low quality evidence; , low quality; , moderate quality; and , high quality. The Task Force has confidence that persons who receive care according to the strong recommendations will derive, on average, more good than harm. Weak recommendations require more careful consideration of the persons circumstances, values, and preferences to determine the best course of action. Linked to each recommendation is a description of the evidence and the values that the Task Force considered in making the recommendation. In some instances there are remarks, a section in which the Task Force offers technical suggestions for testing conditions, dosing, and monitoring. These technical comments reflect the best available evidence applied to a typical person being treated. Often this evidence comes from the unsystematic observations of the Task Force and its values and preferences; therefore, one should consider these remarks as suggestions.

In this guideline, the Task Force made several statements to emphasize the importance of shared decision making, general preventive care measures, and basic principles of hormonal replacement in hypopituitarism. The Task Force labeled these as Ungraded Good Practice Statement. Direct evidence for these statements was either unavailable or not systematically appraised; therefore, the Task Force considers these statements out of the scope of this guideline. The intention of these statements is to draw attention to and remind providers of these principles; one should not consider these statements as graded recommendations (3).

The Endocrine Society maintains a rigorous conflict-of-interest review process for developing clinical practice guidelines. All Task Force members must declare any potential conflicts of interest by completing a conflict-of-interest form. The CGS reviews all conflicts of interest before the Societys Council approves the members to participate on the Task Force and periodically during the development of the guideline. All those participating in the guidelines development must also disclose any conflicts of interest in the matter under study, and a majority of these participants must be without any conflicts of interest. The CGS and the Task Force have reviewed all disclosures for this guideline and resolved or managed all identified conflicts of interest.

Conflicts of interest are defined as remuneration in any amount from commercial interest(s) in the form of grants; research support; consulting fees; salary; ownership interest (eg, stocks, stock options [excluding diversified mutual funds]); honoraria or other payments for participation in speakers bureaus, advisory boards, or boards of directors; or other financial benefits. Completed forms are available through the Endocrine Society office.

Funding for this guideline was derived solely from the Endocrine Society; the Task Force received no funding or remuneration from commercial or other entities.

The guideline Task Force commissioned two systematic reviews to assist with summarizing the evidence base for this guideline.

The first review addressed the question of whether adults with panhypopituitarism of any cause have increased all-cause mortality. The review identified 12 studies reporting on 26 017 patients. Studies were observational, with incomplete adjustment for confounders. Meta-analysis suggested increased mortality in patients with panhypopituitarism (RR, 1.55; 95% confidence interval [CI], 1.142.11). Factors associated with increased mortality were female gender, younger age at diagnosis, an underlying diagnosis of a craniopharyngioma or aggressive tumor, the presence of DI, and prior treatment with surgery or radiotherapy. The most common causes of death were malignancies, cardiovascular disease, and cerebrovascular disease.

The second review attempted to answer the question of whether GH replacement is associated with a risk of pituitary tumor recurrence, secondary malignancy, or stroke. The review included seven studies reporting on 22 654 patients. Meta-analysis did not show an association between GH replacement and pituitary tumor recurrence (RR, 0.87; 95% CI, 0.561.33) or the risk of secondary malignancies (RR, 1.24; 95% CI, 0.652.33). There were no data on the outcome of stroke.

Each review addressed a question of association and both demonstrated that the evidence (overall) warrants low certainty in the provided estimates.

Hypopituitarism results from complete or partial deficiency in pituitary hormones and includes AI, hypothyroidism, hypogonadism, GHD, and (more rarely) DI. Not all disorders that affect anterior pituitary function may cause DI, and DI can occur without anterior pituitary dysfunction. Hypopituitarism is the consequence of diseases that either reduce or destroy secretory function or interfere with the hypothalamic secretion of pituitary-releasing hormones.

The prevalence (probably underestimated) is approximately 45 cases per 100 000, with an incidence of about four cases per 100 000 per year (4). Considering evidence from the commissioned systematic review and other evidence extracted mostly from contemporary studies on the management of hypopituitarism due to heterogeneous etiologies, it seems that mortality associated with hypopituitarism is indeed high (510). Recently published evidence indicates that pituitary hormonal deficits managed with the currently used replacement protocols (including nonsupraphysiological doses of HC and appropriate thyroid and gonadal hormone replacement) might not adversely affect mortality (11).

Hypopituitary patients exhibit increased incapacitation and sick days, lower health status, and higher cost of care (12, 13). Those with GHD are less often working full time, more often on sick leave/disability, and often live alone or with parents (14). Despite receiving long-term GH replacement, the working capacity of hypopituitary patients remains lower than the general population (14).

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