Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline

In the paper

“Excess cardiovascular mortality might be specifically related to AC (30).”

What the sources say

• Disputed

  The Discussion (pp. 8–9) says this cohort’s excess mortality was not accounted for by cardiovascular or cerebrovascular deaths; cardiovascular mortality did not significantly exceed that of the reference population. It instead identifies adrenal crisis as a contributor to deaths associated with infection, so the paper does not link an excess of cardiovascular deaths to adrenal crisis. (LLM, conf=0.87)

  Checked by a reasoning model — may be wrong.

  cites [30] Burman, 2013, Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality, J Clin Endocrinol Metab sourceExperimental — accuracy not yet measured

In the paper

“Accordingly, bilateral oophorectomy without estrogen replacement before the age of 45 increases cardiovascular mortality (51).”

What the sources say

• Supported

  The Results section reports increased cardiovascular mortality among women who underwent bilateral oophorectomy before age 45 and were not treated with estrogen through age 45 (HR 1.84 versus referent women). The paper presents this as an observed association. (LLM, conf=0.92)

  cites [51] Rivera, 2009, Increased cardiovascular mortality after early bilateral oophorectomy, Menopause source

In the paper

“Studies have suggested that 10-18% of high-risk pituitary patients have unrecognized CH with low-normal fT4 levels (77,79).”

What the sources say

• ?Not checked — no full text of the sourcecites [77] Persani, 2000, Circulating thyrotropin bioactivity in sporadic central hypothyroidism, J Clin Endocrinol Metab source
• ?Could not verify

  The available Discussion of the clinical literature passages address thyroid hormone replacement, not the prevalence of unrecognized central hypothyroidism in high-risk pituitary patients. Searches for central hypothyroidism, low-normal FT4, pituitary patients, and the 10–18% figure found no passage supporting the claim. Our copy is truncated, so a relevant later section may be missing. (LLM, conf=0.73)

  cites [79] Jonklaas, 2014, Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement, Thyroid sourceExperimental — accuracy not yet measured

In the paper

“Since patients with primary hypothyroidism usually require high-normal or slightly elevated fT4 levels to normalize TSH levels (78), low-normal fT4 levels in hypopituitary patients may suggest the presence of CH.”

What the sources say

• ?Could not verify

  The Discussion recommends upper-normal fT4 as a marker of adequate treatment in central hypothyroidism, not primary hypothyroidism. I searched for the claimed fT4 level needed to normalize TSH in primary hypothyroidism, but no passage in our copy states it. (LLM, conf=0.73)

  cites [78] Alexopoulou, 2004, Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients, Eur J Endocrinol sourceExperimental — accuracy not yet measured

In the paper

“Stress doses of GC replacement for intercurrent illnesses and minor stress are similar to those used in primary AI (72).”

What the sources say

• Supported

  The guideline’s Suggested Action table (page not provided) gives stress doses for febrile illness and minor-to-moderate surgical stress in primary adrenal insufficiency. Its sick-day rules also call for doubling the routine oral glucocorticoid dose during illness or before a small outpatient procedure. These passages support the cited primary-adrenal-insufficiency dosing used as the comparison. (LLM, conf=0.88)

  cites [72] Bornstein, 2016, Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab source

In the paper

“Researchers have used a cortisol day curve (108), but it has little value for routine clinical use (28).”

What the sources say

• ?Could not verify

  The Discussion addresses the clinical usefulness of free-thyroxine measurement by LC/MS/MS, not cortisol day curves. Searches for a cortisol day curve and its routine clinical utility found no passage addressing the claim in our copy. (LLM, conf=0.76)

  cites [108] Kahric-Janicic, 2007, Tandem mass spectrometry improves the accuracy of free thyroxine measurements during pregnancy, Thyroid sourceExperimental — accuracy not yet measured
• Supported

  The Chronic Replacement Therapy section (p. 12) explicitly says cortisol day curves are of limited value in routine monitoring. This supports the claim about routine clinical use. (LLM, conf=0.95)

  cites [28] Bancos, 2015, Diagnosis and management of adrenal insufficiency, Lancet Diabetes Endocrinol source

In the paper

“Clinicians are increasingly using newer liquid chromatography-mass spectrometric-based assays with suggested improved sensitivity and reduced interference.This is particularly true for steroids, namely E2, T (104,105), and thyroid and peptide hormones (78,106).”

What the sources say

• ?Could not verify

  Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.

  cites [104] De Bellis, 1999, A longitudinal study of vasopressin cell antibodies, posterior pituitary function, and magnetic resonance imaging evaluations in subclinical autoimmune central diabetes insipidus, J Clin Endocrinol Metab sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [105] Sikaris, 2005, Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays, J Clin Endocrinol Metab source
• ?Could not verify

  Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.

  cites [78] Alexopoulou, 2004, Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients, Eur J Endocrinol sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [106] Rosner, 2013, Challenges to the measurement of estradiol: an Endocrine Society Position Statement, J Clin Endocrinol Metab sourceExperimental — accuracy not yet measured

In the paper

“Cortisol secretion exhibits a distinct circadian rhythm; low at the time of sleep onset, rising early morning, peaking just after the time of waking, then falling during the day (28,107).”

What the sources say

• Supported

  The Diagnosis of Adrenal Insufficiency section (p. 8) describes cortisol rising in the early morning, peaking at 6–9 a.m., and falling to low levels in the evening and very low levels around midnight. This supports the claimed circadian pattern; the paper gives clock times rather than timing the peak and low point to waking and sleep onset. (LLM, conf=0.88)

  cites [28] Bancos, 2015, Diagnosis and management of adrenal insufficiency, Lancet Diabetes Endocrinol source
• ?Not checked — no full text of the sourcecites [107] Kane, 2007, Measurement of serum testosterone in women; what should we do?, Ann Clin Biochem source

In the paper

“A high proportion of patients on “conventional” corticosteroid replacement therapy for AI are over treated or on inappropriate replacement regimens (120).”

What the sources say

• Partly supported

  The Discussion says corticosteroid replacement regimens for patients with hypocortisolaemia lack effective ultradian rhythmicity, which supports a concern about how replacement is administered. It does not say that a high proportion of patients are overtreated or quantify how many receive inappropriate regimens. (LLM, conf=0.84)

  cites [120] Stavreva, 2009, Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription, Nat Cell Biol sourceExperimental — accuracy not yet measured

In the paper

“Visceral adipose tissue mass is decreased by 9% in female patients receiving GH replacement ( 166”

What the sources say

• ?Could not verify

  The paper’s concluding section says GH replacement can benefit patients with documented pituitary disease, and its References list studies of body composition. Neither the supplied passages nor searches for visceral adipose tissue and a 9% reduction report that result in female patients. (LLM, conf=0.76)

  cites [166] Clemmons, 2014, Growth hormone should be used only for approved indications, J Clin Endocrinol Metab sourceExperimental — accuracy not yet measured

In the paper

“Treatment with estrogens until age 45 years or longer may reduce the risk of cardiovascular disease and mortality (47,49,51).”

What the sources say

• ?Not checked — no full text of the sourcecites [47] Løkkegaard, 2006, The association between early menopause and risk of ischaemic heart disease: influence of hormone therapy, Maturitas source
• Partly supported

  The Results (Findings from individual studies; page unavailable) report that women who had bilateral oophorectomy before age 45 and received hormone therapy through age 45 did not have increased cardiovascular-disease risk, and suggest that premature estrogen deficiency may explain increased cardiovascular mortality. This supports a possible benefit, but the evidence concerns women with early bilateral oophorectomy and cardiovascular mortality—not a general reduction in mortality for everyone treated with estrogen until age 45 or longer. (LLM, conf=0.84)

  cites [49] Rocca, 2012, Premature menopause or early menopause and risk of ischemic stroke, Menopause sourceExperimental — accuracy not yet measured
• Partly supported

  The Conclusions state that estrogen treatment through age 45 or longer may reduce cardiovascular mortality among women who underwent early bilateral oophorectomy; the Results report no increased cardiovascular mortality in the treated group. The cited paper does not establish a reduction in cardiovascular disease incidence or mortality generally, as the citing sentence could imply. (LLM, conf=0.85)

  cites [51] Rivera, 2009, Increased cardiovascular mortality after early bilateral oophorectomy, Menopause sourceExperimental — accuracy not yet measured

In the paper

“Other pituitary hormone deficits and/or their treatment also affect BMD and the risk of fracture in central hypogonadism (131,159,160).”

What the sources say

• ?Not checked — no full text of the sourcecites [131] Klose, 2013, Central hypothyroidism and its replacement have a significant influence on cardiovascular risk factors in adult hypopituitary patients, J Clin Endocrinol Metab source
• ?Could not verify

  The Results (p. 1) link low BMD with incident vertebral fractures, and the Discussion (p. 6) discusses estrogen exposure and menopause. Neither addresses whether other pituitary hormone deficits or their treatment affect BMD or fracture risk in central hypogonadism; searches for pituitary deficits, central hypogonadism, and hormone replacement found no such passage. (LLM, conf=0.76)

  cites [159] van der Klift, 2004, Risk factors for incident vertebral fractures in men and women: the Rotterdam Study, J Bone Miner Res sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [160] Mo, 2015, Fracture risk in adult patients treated with growth hormone replacement therapy for growth hormone deficiency: a prospective observational cohort study, Lancet Diabetes Endocrinol source

In the paper

“Nonetheless, the literature on primary ovarian failure supports the beneficial effects of estrogen on bone.”

What the sources say

• ?Not checked — no full text of the sourcecites [154] Cardozo, 2004, A systematic review of the effects of estrogens for symptoms suggestive of overactive bladder, Acta Obstet Gynecol Scand source
• Supported

  The Discussion (page unavailable) reports that time without hormone replacement was significantly related to lower bone density in young women with primary ovarian insufficiency. The Modifiable risk factors section likewise identifies not taking hormone replacement as associated with low bone density. These findings support the broad claim that estrogen benefits bone, although the study was observational. (LLM, conf=0.91)

  cites [157] Popat, 2009, Bone mineral density in estrogen-deficient young women, J Clin Endocrinol Metab source
• ?Not checked — no full text of the sourcecites [158] Lindsay, 1980, Prevention of spinal osteoporosis in oophorectomised women, Lancet source

In the paper

“The need for immediate GC replacement and fluid resuscitation is the same in central AI as it is in primary AI (72).”

What the sources say

• Partly supported

  Section 4.0, “Management and prevention of adrenal crisis in patients with PAI,” recommends immediate hydrocortisone and fluid resuscitation for suspected adrenal crisis. The guideline distinguishes primary from secondary adrenal insufficiency in its General Introduction, but the retrieved passages do not say that the need for these treatments is the same in central adrenal insufficiency. (LLM, conf=0.87)

  cites [72] Bornstein, 2016, Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab sourceExperimental — accuracy not yet measured

In the paper

“The mean dose ratio of sublingual to intranasal DDAVP is 1:24 (181); we list dose comparisons in Table 6.”

What the sources say

• ?Could not verify

  The Introduction and Results discuss hyponatremia and mortality, not desmopressin dosing. Searches for the 1:24 sublingual-to-intranasal DDAVP ratio and for desmopressin dose conversion found no passage addressing the claim in our copy. (LLM, conf=0.78)

  cites [181] Corona, 2013, Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis, PLoS One sourceExperimental — accuracy not yet measured

In the paper

“However, recent evidence suggests that mild hyperthyroidism or hypothyroidism may increase overall and cardiovascular-specific mortality and morbidity (213)(214)(215)(216)(217)(218).”

What the sources say

• ?Not checked — no full text of the sourcecites [213] Agha, 2004, Conventional glucocorticoid replacement overtreats adult hypopituitary patients with partial ACTH deficiency, Clin Endocrinol (Oxf) source
• ?Not checked — no full text of the sourcecites [214] Peacey, 2012, Glucocorticoid replacement therapy and fibrinolysis in patients with hypopituitarism, Clin Endocrinol (Oxf) source
• Partly supported

  The introduction (p. 2) reports an association between subclinical hypothyroidism and coronary heart disease mortality and events, and the Results (p. 4) examine those outcomes. The paper does not establish the broader claim about mild hyperthyroidism or overall mortality; its reported outcomes here are coronary heart disease-specific. (LLM, conf=0.88)

  cites [215] Collet, 2014, Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis, J Clin Endocrinol Metab sourceExperimental — accuracy not yet measured

In the paper

“A morning cortisol measurement might be useful even after intraoperative administration of dexamethasone (237).”

What the sources say

• Partly supported

  The Discussion (page unavailable in our copy) describes morning serum cortisol as a first-line test for assessing postoperative adrenal function. It does not address whether the measurement remains useful after intraoperative dexamethasone; a search for dexamethasone found no passage supporting that condition. (LLM, conf=0.85)

  cites [237] Tohti, 2015, Is peri-operative steroid replacement therapy necessary for the pituitary adenomas treated with surgery? A systematic review and meta analysis, PLoS One sourceExperimental — accuracy not yet measured

In the paper

“Lower doses of HC might be needed in women with hypopituitarism (compared with primary AI) who are not treated with GC replacement (28,110,112,183,184).”

What the sources say

• Partly supported

  The Prognosis section (p. 21) reports that hypopituitary patients taking 20 mg or less of hydrocortisone had metabolic profiles similar to those with an intact HPA axis. It does not say that women with hypopituitarism need lower doses than patients with primary adrenal insufficiency, or address the stated condition of not receiving GC replacement. (LLM, conf=0.73)

  cites [28] Bancos, 2015, Diagnosis and management of adrenal insufficiency, Lancet Diabetes Endocrinol sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [110] Howlett, 1997, An assessment of optimal hydrocortisone replacement therapy, Clin Endocrinol (Oxf) source
• ?Not checked — no full text of the sourcecites [112] Grossman, 2010, Clinical Review#: the diagnosis and management of central hypoadrenalism, J Clin Endocrinol Metab source
• ?Not checked — no full text of the sourcecites [183] Oiso, 2013, Clinical review: treatment of neurohypophyseal diabetes insipidus, J Clin Endocrinol Metab source
• ?Not checked — no full text of the sourcecites [184] Janus, 2014, Adipsic diabetes insipidus in pediatric patients, Indian J Pediatr source

In the paper

“Treatment with estrogens through age 45 years or longer may reduce the risk of cardiovascular disease and mortality (47,49,51).”

What the sources say

• ?Not checked — no full text of the sourcecites [47] Løkkegaard, 2006, The association between early menopause and risk of ischaemic heart disease: influence of hormone therapy, Maturitas source
• Partly supported

  The Results (Findings from individual studies; page unavailable) report that women who underwent bilateral oophorectomy before age 45 and received hormone therapy through age 45 did not have an increased risk of cardiovascular disease, including stroke. The paper also suggests that premature estrogen deficiency may explain increased cardiovascular mortality. The claim omits that population restriction and does not specify cardiovascular mortality; the paper does not establish a reduction in mortality generally. (LLM, conf=0.83)

  cites [49] Rocca, 2012, Premature menopause or early menopause and risk of ischemic stroke, Menopause sourceExperimental — accuracy not yet measured
• Partly supported

  The Conclusions state that estrogen treatment through age 45 years or longer may reduce the risk of death involving cardiovascular disease in women who underwent early bilateral oophorectomy. The Results report no increased cardiovascular mortality among women treated through at least age 45. The paper does not establish a separate reduction in the incidence of cardiovascular disease or in mortality from all causes. (LLM, conf=0.82)

  cites [51] Rivera, 2009, Increased cardiovascular mortality after early bilateral oophorectomy, Menopause sourceExperimental — accuracy not yet measured

In the paper

“However, we cannot extrapolate these results to younger women with premature ovarian failure (219).”

What the sources say

• ?Could not verify

  The COMMENT section says the study’s findings on subclinical hyperthyroidism have limited generalizability to younger adults because few young men and premenopausal women were included. A search of our copy for the Women’s Health Initiative and premature ovarian failure found no passage addressing whether that initiative’s results can be extrapolated to younger women. (LLM, conf=0.78)

  cites [219] Collet, 2012, Subclinical hyperthyroidism and the risk of coronary heart disease and mortality, Arch Intern Med sourceExperimental — accuracy not yet measured

In the paper

“while lean body mass improves by up to 7% during the first year of GH replacement (167,168).”

What the sources say

• Partly supported

  The passage on GH replacement (labeled Abstract in our copy; page unavailable) says that treatment enhances lean body mass in adults meeting the diagnostic criteria for GH deficiency, and Table 3 lists an increase in lean mass. Neither passage gives a 7% increase or specifies that it occurs during the first year. (LLM, conf=0.88)

  cites [167] Melmed, 2013, Idiopathic adult growth hormone deficiency, J Clin Endocrinol Metab sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [168] Johannsson, 1996, The individual responsiveness to growth hormone (GH) treatment in GH-deficient adults is dependent on the level of GH-binding protein, body mass index, age, and gender, J Clin Endocrinol Metab source

In the paper

“Combined estrogen and progesterone may decrease lamotrigine levels (276), and endogenous and exogenous sex steroids may affect seizure activity and epilepsy in women ( 277).”

What the sources say

• ?Could not verify

  The Results and Discussion examine how diphenylhydantoin affects cortisol metabolism, not how combined estrogen and progesterone affect lamotrigine levels. Searches for lamotrigine and for combined sex-hormone effects found no passage addressing the attributed claim; the indexed passages provide no page number. (LLM, conf=0.78)

  cites [276] Werk, 1964, Effect of diphenylhydantoin on cortisol metabolism in man, J Clin Invest sourceExperimental — accuracy not yet measured

In the paper

“More than 50% of patients eventually require hormonal replacement (257,258,261).”

What the sources say

• ?Not checked — no full text of the sourcecites [257] Källén, 1995, Diabetes insipidus and use of desmopressin (Minirin) during pregnancy, Eur J Endocrinol source
• ?Could not verify

  The Background Characteristics and Discussion describe hormone deficiencies and replacement in pregnant patients with growth hormone deficiency, not in patients after pituitary apoplexy. Searches for pituitary apoplexy and long-term hormone replacement found no passage reporting that more than 50% of apoplexy patients eventually require replacement. (LLM, conf=0.76)

  cites [258] Vila, 2015, Pregnancy outcomes in women with growth hormone deficiency, Fertil Steril sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [261] Veldhuis, 1980, Endocrine function after spontaneous infarction of the human pituitary: report, review, and reappraisal, Endocr Rev source

In the paper

“The addition of carbamazepine, oxcarbazepine, lamotrigine, perapanel, or felbamate to DDAVP therapy can cause hyponatremia by increasing DDAVP renal responsiveness (268).”

What the sources say

• ?Could not verify

  The discussion of diabetes insipidus in the section labelled Abstract concerns pituitary apoplexy and antidiuretic-hormone transport, not DDAVP drug interactions; no page number is provided in our copy. Searches for the named antiseizure drugs, desmopressin, hyponatremia, and increased renal responsiveness found no passage addressing the claim. (LLM, conf=0.76)

  cites [268] Verrees, 2004, Pituitary tumor apoplexy: characteristics, treatment, and outcomes, Neurosurg Focus sourceExperimental — accuracy not yet measured

In the paper

“Administering dopamine agonists to patients with macroprolactinoma leads to normoprolactinemia in 68% (range 40-100%) and tumor shrinkage in 62% (range 20-100%) (224).”

What the sources say

• ?Could not verify

  The Patients and methods section says that most prolactin-secreting microadenomas were treated with dopamine agonists, but it reports no normoprolactinemia rate for macroprolactinomas. Searches for the 68% figure and for dopamine-agonist outcomes found no supporting passage in our copy; the cited paper studied microadenomas. (LLM, conf=0.78)

  cites [224] Mathioudakis, 2012, ACTH-secreting pituitary microadenomas are associated with a higher prevalence of central hypothyroidism compared to other microadenoma types, Clin Endocrinol (Oxf) sourceExperimental — accuracy not yet measured

In the paper

“Very few studies have assessed the impact of GC dose optimization on markers of bone formation and resorption (120).”

What the sources say

• ?Could not verify

  The Discussion addresses glucocorticoid treatment timing and its possible side effects, but not how many studies have assessed dose optimization. Searches for bone formation, bone resorption, and dose optimization found no passage about bone-turnover markers in our copy. (LLM, conf=0.76)

  cites [120] Stavreva, 2009, Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription, Nat Cell Biol sourceExperimental — accuracy not yet measured

In the paper

“Administering dopamine agonists to patients with macroprolactinoma leads to normoprolactinemia in 68% (range 40-100%) and tumor shrinkage in 62% (range 20-100%) (224).”

What the sources say

• ?Could not verify

  The Patients and methods section says most patients with prolactin-secreting microadenomas received dopamine agonists, but it does not report tumor shrinkage. Searches for macroprolactinoma outcomes and the 62% shrinkage figure found no supporting passage in our copy; no page numbers were available. (LLM, conf=0.74)

  cites [224] Mathioudakis, 2012, ACTH-secreting pituitary microadenomas are associated with a higher prevalence of central hypothyroidism compared to other microadenoma types, Clin Endocrinol (Oxf) sourceExperimental — accuracy not yet measured

In the paper

“Rates of pituitary axes recovery or new onset hypopituitarism after transsphenoidal surgery vary significantly between studies (115,233,234).”

What the sources say

• ?Not checked — no full text of the sourcecites [115] Johannsson, 2014, Improving outcomes in patients with adrenal insufficiency: a review of current and future treatments, Curr Med Res Opin source
• Partly supported

  The Discussion (page unavailable) reports that 55% of patients treated for acromegaly with surgery alone developed severe growth hormone deficiency, supporting the possibility of a new pituitary deficiency after surgery. It does not address recovery of pituitary axes or show that rates vary significantly between transsphenoidal-surgery studies. (LLM, conf=0.82)

  cites [233] Miller, 2010, Growth hormone deficiency after treatment of acromegaly: a randomized, placebo-controlled study of growth hormone replacement, J Clin Endocrinol Metab sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [234] Giavoli, 2012, GH replacement improves quality of life and metabolic parameters in cured acromegalic patients with growth hormone deficiency, J Clin Endocrinol Metab source

In the paper

“Meta-analysis suggested increased mortality in patients with panhypopituitarism (RR 1.55; 95% CI, 1.14-2.11).”

In the paper

“The most common causes of death were malignancies, cardiovascular disease, and cerebrovascular disease.”

In the paper

“There were no data on the outcome of stroke.”

In the paper

“However, a lower doses of HC seems to correlate with improved QOL, health status, and mood.”

What the sources say

• ?Not checked — no full text of the sourcecites [121] Mager, 2003, Integrated QSPR–pharmacodynamic model of genomic effects of several corticosteroids, J Pharm Sci source
• ?Not checked — no full text of the sourcecites [27] Bleicken, 2010, Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients, Am J Med Sci source
• ?Not checked — no full text of the sourcecites [122] Peacey, 1997, Glucocorticoid replacement therapy: are patients over treated and does it matter?, Clin Endocrinol (Oxf) source

In the paper

“Three-times-daily intake of HC was not superior to 2-times-daily intake.”

What the sources say

• ?Not checked — no full text of the sourcecites [121] Mager, 2003, Integrated QSPR–pharmacodynamic model of genomic effects of several corticosteroids, J Pharm Sci source

In the paper

“In a cross-sectional study (27), HC doses above 30 mg/day were associated with adverse health status by validated self-assessment questionnaires.”

What the sources say

• ?Not checked — no full text of the sourcecites [27] Bleicken, 2010, Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients, Am J Med Sci source

In the paper

“Men with non-replaced hypogonadism due to non-functioning pituitary adenomas scored significantly worse in parameters of health-related QOL questionnaires compared to those with an intact gonadotroph axis or on hormone replacement (37).”

What the sources say

• ?Not checked — no full text of the sourcecites [37] Capatina, 2013, Current treatment protocols can offer a normal or near-normal quality of life in the majority of patients with non-functioning pituitary adenomas, Clin Endocrinol (Oxf) source

In the paper

“Nonrandomized and observational studies also report similar findings, with improved fatigue, weight or BMI, waist circumference, and cholesterol levels correlating with higher L-T4 doses and fT4 levels (75,77,(127)(128)(129).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites (75,77,(127)(128)(129)

In the paper

“One cross-sectional study of CH patients reported that mean L-T4 doses of 1.9 mcg/kg led to fT4 levels in the upper half of the normal range (130).”

What the sources say

• ?Not checked — no full text of the sourcecites [130] Filipsson Nyström, 2012, The metabolic consequences of thyroxine replacement in adult hypopituitary patients, Pituitary source

In the paper

“CH patients receiving GC therapy do not appear to require L-T4 dose adjustments (77).”

What the sources say

• ?Not checked — no full text of the sourcecites [77] Persani, 2000, Circulating thyrotropin bioactivity in sporadic central hypothyroidism, J Clin Endocrinol Metab source

In the paper

“Estrogen therapy increased mean L-T4 dose requirements in patients with CH from 1.3 to 1.8 mcg/kg/day (77).”

What the sources say

• ?Not checked — no full text of the sourcecites [77] Persani, 2000, Circulating thyrotropin bioactivity in sporadic central hypothyroidism, J Clin Endocrinol Metab source

In the paper

“Some studies also report increased fT3 levels with no significant effects on TSH levels.”

What the sources say

• ?Not checked — no full text of the sourcecites [81] Slawik, 2007, Thyroid hormone replacement for central hypothyroidism: a randomized controlled trial comparing two doses of thyroxine (T4) with a combination of T4 and triiodothyronine, J Clin Endocrinol Metab source
• ?Not checked — no full text of the sourcecites [191] Shifren, 2007, A randomized, open-label, crossover study comparing the effects of oral versus transdermal estrogen therapy on serum androgens, thyroid hormones, and adrenal hormones in naturally menopausal women, Menopause source
• ?Not checked — no full text of the sourcecites [192] Qureshi, 2007, The influence of the route of oestrogen administration on serum levels of cortisol-binding globulin and total cortisol, Clin Endocrinol (Oxf) source

In the paper

“In patients with GHD, 36-47% of euthyroid patients and 16-18% of treated CH patients developed low fT4 levels within 3-6 month of starting GH therapy (191,193).”

What the sources say

• ?Not checked — no full text of the sourcecites [191] Shifren, 2007, A randomized, open-label, crossover study comparing the effects of oral versus transdermal estrogen therapy on serum androgens, thyroid hormones, and adrenal hormones in naturally menopausal women, Menopause source
• ?Not checked — no full text of the sourcecites [193] Jørgensen, 1994, Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triiodothyronine in a dose-dependent manner and suppresses circadian thyrotrophin levels: studies in GH-deficient adults, Clin Endocrinol (Oxf) source

In the paper

“The risk of fracture correlated with untreated GHD, urinary cortisol values, and cortisone doses.”

What the sources say

• ?Not checked — no full text of the sourcecites [160] Mo, 2015, Fracture risk in adult patients treated with growth hormone replacement therapy for growth hormone deficiency: a prospective observational cohort study, Lancet Diabetes Endocrinol source

In the paper

“Although the development of new cancers and new-onset diabetes are of concern, the safety profile for GH treatment (using appropriate replacement doses) appears favorable in long-term surveillance studies (174).”

What the sources say

• ?Not checked — no full text of the sourcecites [174] Sesmilo, 2000, Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial, Ann Intern Med source

In the paper

“Another small open crossover study in hypopituitary men randomized to three commonly used HC dose regimens reported that low-dose HC replacement (10 mg a.m. and 5 mg p.m.) was associated with increased bone formation and positive bone remodeling balance and with probable long-term beneficial effects on bone health.( 203)”

What the sources say

• ?Not checked — no full text of the sourcecites [203] Ragnar Agnarsson, 2014, The impact of glucocorticoid replacement on bone mineral density in patients with hypopituitarism before and after 2 years of growth hormone replacement therapy, J Clin Endocrinol Metab source

In the paper

“One study showed that women on oral estrogen might require a GH replacement dose up to 50% higher compared with women or men who are not on estrogen (199).”

What the sources say

• ?Not checked — no full text of the sourcecites [199] Gibney, 2005, Comparison of the metabolic effects of raloxifene and oral estrogen in postmenopausal and growth hormone-deficient women, J Clin Endocrinol Metab source

In the paper

“About one quarter of DI patients with an intact thirst mechanism who are treated with DDAVP have mild hyponatremia caused by the inability to reverse the antidiuretic effect of the drug when fluid intake exceeds requirements (176).”

What the sources say

• ?Not checked — no full text of the sourcecites [176] Götherström, 2007, Ten-year GH replacement increases bone mineral density in hypopituitary patients with adult onset GH deficiency, Eur J Endocrinol source

In the paper

“Most patients, who were at increased risk of developing CH while receiving GH and who had previously undergone surgery and/or radiation therapy for pituitary tumors, had lower basal T4 levels and were more likely to have other multiple hormone deficiencies.”

What the sources say

• ?Not checked — no full text of the sourcecites [191] Shifren, 2007, A randomized, open-label, crossover study comparing the effects of oral versus transdermal estrogen therapy on serum androgens, thyroid hormones, and adrenal hormones in naturally menopausal women, Menopause source
• ?Not checked — no full text of the sourcecites [193] Jørgensen, 1994, Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triiodothyronine in a dose-dependent manner and suppresses circadian thyrotrophin levels: studies in GH-deficient adults, Clin Endocrinol (Oxf) source

In the paper

“In a cross-sectional study (160) of male hypopituitary patients receiving a median daily doses of HC 30 mg and cortisone 35 mg, 60% of patients had vertebral fractures.”

What the sources say

• ?Not checked — no full text of the sourcecites [160] Mo, 2015, Fracture risk in adult patients treated with growth hormone replacement therapy for growth hormone deficiency: a prospective observational cohort study, Lancet Diabetes Endocrinol source

In the paper

“Alexopoulou et al. reported that only men with CH required increased L-T4 doses after starting GH therapy (1.8 vs. 1.6 mcg/kg/day) (77).”

What the sources say

• ?Not checked — no full text of the sourcecites [77] Persani, 2000, Circulating thyrotropin bioactivity in sporadic central hypothyroidism, J Clin Endocrinol Metab source

In the paper

“Patients with GHD in the setting of hypopituitarism demonstrate an increased cortisol/cortisone metabolite ratio (185,186).”

What the sources say

• ?Not checked — no full text of the sourcecites [185] Stewart, 2001, Growth hormone, insulin-like growth factor-I and the cortisol-cortisone shuttle, Horm Res source
• ?Not checked — no full text of the sourcecites [186] Gelding, 1998, The effect of growth hormone replacement therapy on cortisol-cortisone interconversion in hypopituitary adults: evidence for growth hormone modulation of extrarenal 11 β-hydroxysteroid dehydrogenase activity, Clin Endocrinol (Oxf) source

In the paper

“GH administration does not appear to increase the rate of pituitary adenoma recurrence (RR 0.887, 95% CI, 0.56-1.33)(175)(Jasim, S; A systematic review and meta-analysis, JCEM [In Press]).”

What the sources say

• ?Not checked — no full text of the sourcecites [175] Drake, 2001, The influence of gender on the short and long-term effects of growth hormone replacement on bone metabolism and bone mineral density in hypopituitary adults: a 5-year study, Clin Endocrinol (Oxf) source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites (Jasim, S; A systematic review and meta-analysis, JCEM [In Press])

In the paper

“There is no apparent dosedependent difference in integrated cortisol daily curves between patients on half-dose or no HC replacement (211), suggesting that current conventional full GC replacement doses might over-treat patients with partial ACTH deficiency.”

What the sources say

• ?Not checked — no full text of the sourcecites [211] Danilowicz, 2008, Correction of cortisol overreplacement ameliorates morbidities in patients with hypopituitarism: a pilot study, Pituitary source

In the paper

“There is no consensus on whether surgical treatment improves pituitary function, but one study reported an increased incidence of hormonal deficiencies with conservative management (266).”

In the paper

“GH use before and during pregnancy was not related to pregnancy outcomes; however, there are no prospective studies on this (255).”

What the sources say

• ?Not checked — no full text of the sourcecites [255] Durr, 1996, Diagnosis and management of diabetes insipidus during pregnancy, Endocr Pract source

In the paper

“However, some analytes, such as E2, T, GH, fT4, and to a lower extent gonadotropins, had large inter-assay variability; therefore, clinicians should consider differences among assays and use the same assay for serial and longitudinal measurements (Appendix A) (103).”

What the sources say

• ?Not checked — no full text of the sourcecites [103] Ushiroyama, 2004, Adequate reduction degree of pituitary gonadotropin levels in the clinical management of short-term hormone replacement therapy of women with menopausal symptoms, J Med

In the paper

“Peripheral indices of thyroid hormone action lack sufficient sensitivity and specificity for diagnosing or monitoring (33,(80)(81)(82).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites (33,(80)(81)(82)

In the paper

“In contrast to primary hypothyroidism, TSH and fT4 levels do not correlate (33).”

What the sources say

• ?Not checked — no full text of the sourcecites [33] Persani, 2012, Clinical review: central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges, J Clin Endocrinol Metab source

In the paper

“In several instances where data were lacking on the central deficiency state, we extrapolated it from studies on primary gland failure.”

In the paper

“as delaying treatment can result in AC and death.(16,(28)(29)(30).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites (16,(28)(29)(30)

In the paper

“Early menopause is associated with increased risk of cardiovascular and cerebrovascular disease (47)(48)(49)(50).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites (47)(48)(49)(50)

In the paper

“Untreated congenital GHD does not lead to shortened life expectancy (61).”

What the sources say

• ?Not checked — no full text of the sourcecites [61] Aguiar-Oliveira, 2010, Longevity in untreated congenital growth hormone deficiency due to a homozygous mutation in the GHRH receptor gene, J Clin Endocrinol Metab source

In the paper

“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 (5)(6)(7)(8)(9)(10).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites (5)(6)(7)(8)(9)(10)

In the paper

“Although assays have evolved, cortisol levels <18.1 mcg/dl (500 nmol/l) post-stimulation are indicative of AI (Table 3).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites (Table 3)

In the paper

“Clinicians can assess central AI using insulin tolerance and low-dose and standard-dose ACTH stimulation tests (Table 3).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites (Table 3)

In the paper

“Untreated gonadotropin deficiency is an independent factor affecting mortality (HR 1.86 [99% CI 1.15-2.45]),and sex steroid replacement has been associated with a significantly reduced standard mortality ratio (SMR) ( 1.42 [99% CI 0.97-2.07] vs. 2.97 [99% CI 2.13-4.13])(men and women were not considered separately) (9).”

What the sources say

• ?Not checked — no full text of the sourcecites [9] Tomlinson, 2001, Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group, Lancet source

In the paper

“While high ACTH values are diagnostic of primary AI, the finding of a random low normal ACTH level may not be helpful in diagnosing central AI (73).”

What the sources say

• ?Not checked — no full text of the sourcecites [73] Cooper, 2005, Diagnosis and treatment of ACTH deficiency, Rev Endocr Metab Disord source

In the paper

“Peak cortisol levels <18.1 mcg/dl (500 nmol/l) at 30 or 60 minutes indicate AI. (2|⊕⊕OO)”

In the paper

“Untreated gonadotropin deficiency is an independent factor affecting mortality (HR 1.86 [99% CI 1.15-2.45]),and sex steroid replacement has been associated with a significantly reduced standard mortality ratio (SMR) ( 1.42 [99% CI 0.97-2.07] vs. 2.97 [99% CI 2.13-4.13])(men and women were not considered separately) (9).”

What the sources say

• ?Not checked — no full text of the sourcecites [9] Tomlinson, 2001, Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group, Lancet source

In the paper

“Clinicians should also consider the duration of GC treatment and the influence of oral estrogen on total serum cortisol levels, which can increase CBG.”

In the paper

“The combination of a low fT4 and a non-markedly-elevated TSH in patients with known pituitary disease is diagnostic of CH, unless a patient is severely ill and could have nonthyroidal illness-induced changes in thyroid hormone levels.”

In the paper

“However, many cases of hypopituitarism are associated with hyperprolactinemia that occurs due to stalk interruption (63) and the absence of dopamine inhibition.”

What the sources say

• ?Not checked — no full text of the sourcecites [63] Tritos, 2015, Hyperprolactinemia, JAMA source

In the paper

“Recently published evidence indicates that pituitary hormonal deficits managed with the currently used replacement protocols (including non-supraphysiological doses of HC and appropriate thyroid and gonadal hormone replacement) might not adversely affect mortality (11).”

What the sources say

• ?Not checked — no full text of the sourcecites [11] Ntali, 2016, Mortality in patients with non-functioning pituitary adenoma is increased: systematic analysis of 546 cases with long follow-up, Eur J Endocrinol source

In the paper

“Despite receiving long-term GH replacement, the working capacity of hypopituitary patients remains lower than the general population (14).”

What the sources say

• ?Not checked — no full text of the sourcecites [14] Holmer, 2013, Psychosocial health and levels of employment in 851 hypopituitary Swedish patients on long-term GH therapy, Psychoneuroendocrinology source

In the paper

“Since patients with primary hypothyroidism usually require high-normal or slightly elevated fT4 levels to normalize TSH levels (78), low-normal fT4 levels in hypopituitary patients may suggest the presence of CH.”

In the paper

“Mild ACTH deficiency may manifest as clinically important AI with stress (31).”

What the sources say

• ?Not checked — no full text of the sourcecites [31] Wass, 2012, How to avoid precipitating an acute adrenal crisis, BMJ source

In the paper

“Modified release HC is commercially approved in Europe as a once-a-day tablet with combined immediate and extended release characteristics capable of achieving a more physiological plasma cortisol profile.”

What the sources say

• ?Not checked — no full text of the sourcecites [123] Benson, 2012, Effects of standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, crossover study in patients with secondary adrenal insufficiency, Eur J Endocrinol source
• ?Not checked — no full text of the sourcecites [124] Ragnarsson, 2014, The relationship between glucocorticoid replacement and quality of life in 2737 hypopituitary patients, Eur J Endocrinol source
• ?Not checked — no full text of the sourcecites [125] Johannsson, 2009, Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study, Eur J Endocrinol source

In the paper

“Few studies have compared different replacements regimens for central AI.”

In the paper

“The value of GnRH testing provides no extra diagnostic information over that derived from baseline gonadotropin values measured by currently available ultrasensitive assays (100).”

What the sources say

• ?Not checked — no full text of the sourcecites [100] Dunn, 1981, Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma, J Clin Endocrinol Metab source

In the paper

“Age-adjusted values measured in an accredited laboratory provide valuable information of net GH bioactivity.”

In the paper

“Despite intact mineralocorticoid function, patients with secondary AI have a similar (if not higher) risk of AC (19,(29)(30)(31)110,112).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites (19,(29)(30)(31)110,112)

In the paper

“However, in most cases of isolated DI, MRI imaging of the sellar area shows a progressive loss of the posterior pituitary bright spot (102).”

What the sources say

• ?Not checked — no full text of the sourcecites [102] Silveira, 2013, Approach to the patient with hypogonadotropic hypogonadism, J Clin Endocrinol Metab source

In the paper

“Many of these patients prove to be GH-sufficient on subsequent retesting.”

In the paper

“The level of serum T below which symptoms of hypogonadism occur has not been clearly established.”

In the paper

“Nevertheless, about 20% of adults with GHD may have normal IGF-1 levels, particularly males (85).”

What the sources say

• ?Not checked — no full text of the sourcecites [85] Molitch, 2011, Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab source

In the paper

“As most GH reserve tests are associated with high false positive rates, patients should have a rigorous biochemical evaluation only when there is a high probability for GHD.”

In the paper

“While interpreting GH values, one should also consider multiple factors, including nutritional and hormonal status, exercise, body weight, and age, all of which may influence pituitary GH secretion (85,86).”

What the sources say

• ?Not checked — no full text of the sourcecites [85] Molitch, 2011, Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab source
• ?Not checked — no full text of the sourcecites [86] Biller, 2002, Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency, J Clin Endocrinol Metab source

In the paper

“However, the physiological rise in cortisol early morning is not well mimicked (123-125).”

What the sources say

• ?Not checked — no full text of the sourcecites [123] Benson, 2012, Effects of standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, crossover study in patients with secondary adrenal insufficiency, Eur J Endocrinol source
• ?Not checked — no full text of the sourcecites [124] Ragnarsson, 2014, The relationship between glucocorticoid replacement and quality of life in 2737 hypopituitary patients, Eur J Endocrinol source
• ?Not checked — no full text of the sourcecites [125] Johannsson, 2009, Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study, Eur J Endocrinol source

In the paper

“HRT invariably causes a reduction in circulating FSH and LH levels (101).”

What the sources say

• ?Not checked — no full text of the sourcecites [101] Drincic, 2003, Men with acquired hypogonadotropic hypogonadism treated with testosterone may be fertile, Pituitary source

In the paper

“The diagnosis of central hypogonadism is females requires the exclusion of other conditions causing impaired ovulation and menstrual irregularities, including hyperprolactinaemia, hyperandrogenism, and thyroid dysfunction (40).”

What the sources say

• ?Not checked — no full text of the sourcecites [40] Karavitaki, 2010, Disorders of the anterior pituitary gland source

In the paper

“T levels (total, free, and bioavailable) demonstrate a circadian rhythm with maximum serum values between 5:30 and 8 a.m. and trough levels approximately 12 hours later (87)(88)(89).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites (87)(88)(89)

In the paper

“Notably, one study reported cases of males with acquired hypogonadotropic hypogonadism remaining fertile after T treatment (99).”

What the sources say

• ?Not checked — no full text of the sourcecites [99] Wu, 2008, Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study, J Clin Endocrinol Metab source

In the paper

“Nevertheless, data on the impact on fracture risk are not currently available.”

In the paper

“Some investigators recommend following fT3 levels or peripheral indicators of thyroid function during L-T4 therapy, since elevated fT3 levels can indicate overtreatment, although studies have not validated this (33,77).”

What the sources say

• ?Not checked — no full text of the sourcecites [33] Persani, 2012, Clinical review: central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges, J Clin Endocrinol Metab source
• ?Not checked — no full text of the sourcecites [77] Persani, 2000, Circulating thyrotropin bioactivity in sporadic central hypothyroidism, J Clin Endocrinol Metab source

In the paper

“The standard therapy for CH is L-T4 (~1.6 mcg/kg/day).”

What the sources say

• ?Not checked — no full text of the sourcecites [80] Koulouri, 2011, Diagnosis and treatment of hypothyroidism in TSH deficiency compared to primary thyroid disease: pituitary patients are at risk of under-replacement with levothyroxine, Clin Endocrinol (Oxf) source

In the paper

“It is not clear whether the timing of blood sampling in relation to L-T4 dose ingestion affects decisions regarding L-T4 dose adjustment in CH.”

In the paper

“However, research has not consistently reported cardiovascular risk profile improvement (171).”

What the sources say

• ?Not checked — no full text of the sourcecites [171] Götherström, 2009, Ten years of growth hormone (GH) replacement normalizes muscle strength in GH-deficient adults, J Clin Endocrinol Metab source

In the paper

“Studies assessing the clear impact of estrogen treatment on fracture risk are not available.”

In the paper

“Many features of hypopituitarism, such as visceral obesity, insulin resistance, osteoporosis, and increased vascular mortality are reminiscent of Cushing's syndrome (183,184).”

What the sources say

• ?Not checked — no full text of the sourcecites [183] Oiso, 2013, Clinical review: treatment of neurohypophyseal diabetes insipidus, J Clin Endocrinol Metab source
• ?Not checked — no full text of the sourcecites [184] Janus, 2014, Adipsic diabetes insipidus in pediatric patients, Indian J Pediatr source

In the paper

“GC deficiency induces impaired free renal water clearance, resulting in the masking of polyuria in DI (200).”

What the sources say

• ?Not checked — no full text of the sourcecites [200] Mah, 2005, Estrogen replacement in women of fertile years with hypopituitarism, J Clin Endocrinol Metab source

In the paper

“Higher GC replacement doses in patients with ACTH deficiency are associated with increased overall and cardiovascular mortality; the greatest risk is in patients receiving daily HC doses higher or equal to 30 mg (8).”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Sherlock, 2009, ACTH deficiency, higher doses of hydrocortisone replacement, and radiotherapy are independent predictors of mortality in patients with acromegaly, J Clin Endocrinol Metab source

In the paper

“This is due to the estrogen-dependent liver production of thyroid-binding globulin (TBG).”

What the sources say

• ?Not checked — no full text of the sourcecites [196] Losa, 2008, Long-term effects of growth hormone replacement therapy on thyroid function in adults with growth hormone deficiency, Thyroid source

In the paper

“Data suggest that AI should be conclusively excluded prior to initiating L-T4 therapy for CH.”

What the sources say

• ?Not checked — no full text of the sourcecites [33] Persani, 2012, Clinical review: central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges, J Clin Endocrinol Metab source

In the paper

“Physiologic and pharmacologic doses of GC suppress TSH levels (188).”

What the sources say

• ?Not checked — no full text of the sourcecites [188] Mazziotti, 2013, Glucocorticoids and the regulation of growth hormone secretion, Nat Rev Endocrinol source

In the paper

“Increased serum estrogen levels, whether endogenous (pregnancy), or exogenous (estrogen replacement therapy, oral contraceptives), result in increased L-T4 dose requirements in patients with primary hypothyroidism (196).”

What the sources say

• ?Not checked — no full text of the sourcecites [196] Losa, 2008, Long-term effects of growth hormone replacement therapy on thyroid function in adults with growth hormone deficiency, Thyroid source

In the paper

“In these cases there is high risk of both hypernatremia and hyponatremia, as patients cannot adjust fluid intake according to thirst (176).”

What the sources say

• ?Not checked — no full text of the sourcecites [176] Götherström, 2007, Ten-year GH replacement increases bone mineral density in hypopituitary patients with adult onset GH deficiency, Eur J Endocrinol source

In the paper

“Higher GC replacement doses in patients with ACTH deficiency are associated with increased overall and cardiovascular mortality; the greatest risk is in patients receiving daily HC doses higher or equal to 30 mg (8).”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Sherlock, 2009, ACTH deficiency, higher doses of hydrocortisone replacement, and radiotherapy are independent predictors of mortality in patients with acromegaly, J Clin Endocrinol Metab source

In the paper

“An analysis of 19 studies on the effects of administering T esters intramuscularly (220) reported a small, dosage-dependent decrease in HDL cholesterol and a concomitant reduction in total and LDL cholesterol.”

What the sources say

• ?Not checked — no full text of the sourcecites [220] Rhee, 2013, Subclinical hypothyroidism and survival: the effects of heart failure and race, J Clin Endocrinol Metab source

In the paper

“DI occurs commonly in the immediate period (day 1-2) after pituitary or hypothalamic surgery (240).”

What the sources say

• ?Not checked — no full text of the sourcecites [240] Jia, Utility of a glucocorticoid sparing strategy in the management of patients following transsphenoidal surgery [published online April 28, 2016], Endocr Pract source

In the paper

“Patients with partial central AI might be more likely to be over-treated.”

In the paper

“Whereas, a small prospective study of patients with hypopituitarism taking 30 mg HC did not report improvements in weight, 24-hour urine-free cortisol, glucose, or HbA1C (210).”

What the sources say

• ?Not checked — no full text of the sourcecites [210] Behan, 2016, Low-dose hydrocortisone replacement is associated with improved arterial stiffness index and blood pressure dynamics in severely adrenocorticotrophin-deficient hypopituitary male patients, Eur J Endocrinol source

In the paper

“When patients cut their GC dose in half (from 20-30 mg to 10-15 mg HC daily), mean body weight decreased by 7.1 kg after 6-12 months (209).”

What the sources say

• ?Not checked — no full text of the sourcecites [209] Filipsson, 2006, The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients, J Clin Endocrinol Metab source

In the paper

“Studies have suggested lower doses of HC (25-75 mg/24 hour) for surgical stress in secondary AI (247,248).”

What the sources say

• ?Not checked — no full text of the sourcecites [247] Raff, 1990, Cortisol inhibition of vasopressin and ACTH responses to arterial hypotension in conscious dogs, Am J Physiol source
• ?Not checked — no full text of the sourcecites [248] Baylis, 1990, Glucocorticoids and control of glomerular filtration rate, Semin Nephrol

In the paper

“A meta-analysis showed that morbidity of early postoperative AI ranged from 0.96-12.90%,with an overall morbidity of 5.55% (235).”

What the sources say

• ?Not checked — no full text of the sourcecites [235] Greenman, 1995, Relative sparing of anterior pituitary function in patients with growth hormone-secreting macroadenomas: comparison with nonfunctioning macroadenomas, J Clin Endocrinol Metab source

In the paper

“There is no apparent dosedependent difference in integrated cortisol daily curves between patients on half-dose or no HC replacement (211), suggesting that current conventional full GC replacement doses might over-treat patients with partial ACTH deficiency.”

What the sources say

• ?Not checked — no full text of the sourcecites [211] Danilowicz, 2008, Correction of cortisol overreplacement ameliorates morbidities in patients with hypopituitarism: a pilot study, Pituitary source

In the paper

“However, a postoperative morning cortisol level higher than 15 mcg/dL may mitigate the requirement for postoperative GC treatment (236).”

What the sources say

• ?Not checked — no full text of the sourcecites [236] Berg, 2010, Recovery of pituitary function in the late-postoperative phase after pituitary surgery: results of dynamic testing in patients with pituitary disease by insulin tolerance test 3 and 12 months after surgery, Eur J Endocrinol source

In the paper

“In a large retrospective analysis, overall mortality was similar; however, cardiovascular mortality was higher in GHD associated with treated acromegaly versus GHD associated with non-functioning pituitary adenomas (SMR 3.03, p < 0.02) (230).”

What the sources say

• ?Not checked — no full text of the sourcecites [230] Mazziotti, 2015, Growth hormone deficiency in treated acromegaly, Trends Endocrinol Metab source

In the paper

“Acromegaly patients, after rigorous GH dynamic testing and documentation of GHD, may benefit from low-dose GH replacement (228).”

What the sources say

• ?Not checked — no full text of the sourcecites [228] Karavitaki, 2013, Does hypopituitarism recover when macroprolactinomas are treated with cabergoline?, Clin Endocrinol (Oxf) source

In the paper

“Given the lack of long-term randomized placebo controlled trials in males with central hypogonadism, the overall impact of T replacement on cardiovascular disease or mortality is unclear.”

In the paper

“However, when comparing low-dose versus high GC regimens (17.5 mg HC vs. 30 mg daily) for 2 weeks, fibrinolyticcoagulation parameters did not change (212).”

What the sources say

• ?Not checked — no full text of the sourcecites [212] Dunne, 1995, Cardiovascular function and glucocorticoid replacement in patients with hypopituitarism, Clin Endocrinol (Oxf) source

In the paper

“In a randomized crossover study (205), peripheral and hepatic insulin resistance did not differ between patients treated with HC twice daily (15 mg with breakfast, 5 mg with evening meal) versus those receiving physiological HC infusions.”

What the sources say

• ?Not checked — no full text of the sourcecites [205] Behan, 2014, Low-dose hydrocortisone replacement therapy is associated with improved bone remodelling balance in hypopituitary male patients, Eur J Endocrinol source

In the paper

“In a large retrospective analysis, overall mortality was similar; however, cardiovascular mortality was higher in GHD associated with treated acromegaly versus GHD associated with non-functioning pituitary adenomas (SMR 3.03, p < 0.02) (230).”

What the sources say

• ?Not checked — no full text of the sourcecites [230] Mazziotti, 2015, Growth hormone deficiency in treated acromegaly, Trends Endocrinol Metab source

In the paper

“The risk of developing new-onset, postoperative pituitary failure depends on tumor size, surgical expertise, and the extent of surgery (246).”

What the sources say

• ?Not checked — no full text of the sourcecites [246] Raff, 1987, Glucocorticoid inhibition of neurohypophysial vasopressin secretion, Am J Physiol source

In the paper

“Endothelial dysfunction, likely a direct effect of higher GC doses, may contribute to excess cardiovascular mortality in treated ACTH-deficient patients (207).”

What the sources say

• ?Not checked — no full text of the sourcecites [207] McConnell, 2002, Effects of low-dose oral hydrocortisone replacement versus short-term reproduction of physiological serum cortisol concentrations on insulin action in adult-onset hypopituitarism, Clin Endocrinol (Oxf) source

In the paper

“Plasma cortisol can be falsely “normal” because of increased CBG in the second and third trimesters (250).”

What the sources say

• ?Not checked — no full text of the sourcecites [250] Salem, 1994, Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem, Ann Surg source

In the paper

“If surgery is not urgent, it may be optimal to wait until CH is adequately treated to optimize surgical outcomes, however perioperative complications seem to be minor (238,239).”

What the sources say

• ?Not checked — no full text of the sourcecites [238] Marko, 2009, Use of morning serum cortisol level after transsphenoidal resection of pituitary adenoma to predict the need for long-term glucocorticoid supplementation, J Neurosurg source
• ?Not checked — no full text of the sourcecites [239] Manuylova, 2015, Morning serum cortisol level after transsphenoidal surgery for pituitary adenoma predicts hypothalamic-pituitary-adrenal function despite intraoperative dexamethasone use, Endocr Pract source

In the paper

“These benefits appear to occur without incurring the risk of glucose intolerance.”

In the paper

“A low morning cortisol <3 ug/dL in the presence of typical clinical presentation is diagnostic of AI (249).”

What the sources say

• ?Not checked — no full text of the sourcecites [249] Ahmed, 1999, Outcome of transphenoidal surgery for acromegaly and its relationship to surgical experience, Clin Endocrinol (Oxf) source

In the paper

“In contrast to primary hypothyroidism, serum TSH levels in CH are not useful for monitoring L-T4 doses in pregnancy.”

In the paper

“Combined estrogen and progesterone may decrease lamotrigine levels (276), and endogenous and exogenous sex steroids may affect seizure activity and epilepsy in women ( 277).”

What the sources say

• ?Not checked — no full text of the sourcecites [277] Carl, 2008, Effect of antiepileptic drugs on oral contraceptives, Am Fam Physician

In the paper

“However, women with CH may not require the same degree of L-T4 dose escalation due to human chorionic gonadotropin stimulation of an intact thyroid gland (at least during the first trimester).”

In the paper

“An observational study on 201 pregnancies in hypopituitary patients reported that >50% of patients continued GH replacement during pregnancy.”

What the sources say

• ?Not checked — no full text of the sourcecites [255] Durr, 1996, Diagnosis and management of diabetes insipidus during pregnancy, Endocr Pract source

In the paper

“AEDs only modestly decrease the concentrations of prednisone and prednisolone (270).”

What the sources say

• ?Not checked — no full text of the sourcecites [270] Sibal, 2004, Pituitary apoplexy: a review of clinical presentation, management and outcome in 45 cases, Pituitary source

In the paper

“Exposure to DDAVP during pregnancy is safe (254), and DDAVP is generally considered safe for the newborn in lactating mothers (252).”

What the sources say

• ?Not checked — no full text of the sourcecites [254] Suri, 2006, Assessment of adrenal reserve in pregnancy: defining the normal response to the adrenocorticotropin stimulation test, J Clin Endocrinol Metab source

In the paper

“Dexamethasone is metabolized primarily by hepatic CYP3A4 (269), and patients may need to increase dexamethasone doses (268).”

What the sources say

• ?Not checked — no full text of the sourcecites [269] Maccagnan, 1995, Conservative management of pituitary apoplexy: a prospective study, J Clin Endocrinol Metab source

In the paper

“Some AEDs also displace thyroid hormones from their binding protein, resulting in observed normal or even decreased free hormone levels (275).”

What the sources say

• ?Not checked — no full text of the sourcecites [275] Högler, 2010, Oxcarbazepine accelerates cortisol elimination via cytochrome P450 3A4 induction, Arch Dis Child source

In the paper

“CYP3A4mediated 6βhydroxylation may not contribute significantly to the breakdown of cortisol; therefore, AEDs are less likely to be clinically significant in patients treated with HC (271-273).”

What the sources say

• ?Not checked — no full text of the sourcecites [271] Paragliola, 2015, Treatment of hypopituitarism in patients receiving antiepileptic drugs, Lancet Diabetes Endocrinol source
• ?Not checked — no full text of the sourcecites [272] Gentile, 1996, Dexamethasone metabolism by human liver in vitro. Metabolite identification and inhibition of 6-hydroxylation, J Pharmacol Exp Ther source
• ?Not checked — no full text of the sourcecites [273] Bartoszek, 1987, Prednisolone and methylprednisolone kinetics in children receiving anticonvulsant therapy, Clin Pharmacol Ther source

In the paper

“During pregnancy, serum sodium and osmolarity are reduced due to a decreased threshold for ADH release and thirst mechanism (252).”

What the sources say

• ?Not checked — no full text of the sourcecites [252] Lindsay, 2005, The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment, Endocr Rev source

In the paper

“Exposure to DDAVP during pregnancy is safe (254), and DDAVP is generally considered safe for the newborn in lactating mothers (252).”

What the sources say

• ?Not checked — no full text of the sourcecites [252] Lindsay, 2005, The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment, Endocr Rev source

In the paper

“In one study of eight patients, transsphenoidal surgery achieved a return of normal pituitary function in most patients in the immediate postoperative period (257), although larger studies have not replicated these findings (263).”

What the sources say

• ?Not checked — no full text of the sourcecites [257] Källén, 1995, Diabetes insipidus and use of desmopressin (Minirin) during pregnancy, Eur J Endocrinol source

In the paper

“CYP3A4mediated 6βhydroxylation may not contribute significantly to the breakdown of cortisol; therefore, AEDs are less likely to be clinically significant in patients treated with HC (271-273).”

What the sources say

• ?Not checked — no full text of the sourcecites [271] Paragliola, 2015, Treatment of hypopituitarism in patients receiving antiepileptic drugs, Lancet Diabetes Endocrinol source
• ?Not checked — no full text of the sourcecites [272] Gentile, 1996, Dexamethasone metabolism by human liver in vitro. Metabolite identification and inhibition of 6-hydroxylation, J Pharmacol Exp Ther source
• ?Not checked — no full text of the sourcecites [273] Bartoszek, 1987, Prednisolone and methylprednisolone kinetics in children receiving anticonvulsant therapy, Clin Pharmacol Ther source

In the paper

“However, a recent report found that oxcarbazepine increases cortisol elimination in normal MAY 4, 2016 subjects (272), suggesting that attention should also be paid to symptoms of underdosing in patients on HC.”

What the sources say

• ?Not checked — no full text of the sourcecites [272] Gentile, 1996, Dexamethasone metabolism by human liver in vitro. Metabolite identification and inhibition of 6-hydroxylation, J Pharmacol Exp Ther source

In the paper

“GH use before and during pregnancy was not related to pregnancy outcomes; however, there are no prospective studies on this (255).”

What the sources say

• ?Not checked — no full text of the sourcecites [255] Durr, 1996, Diagnosis and management of diabetes insipidus during pregnancy, Endocr Pract source

In the paper

“Many women with primary hypothyroidism require significant (20-50%) increases in L-T4 doses early in pregnancy to maintain normal thyroid hormone levels (196) due to increased TBG levels secondary to high serum E2 levels.”

What the sources say

• ?Not checked — no full text of the sourcecites [196] Losa, 2008, Long-term effects of growth hormone replacement therapy on thyroid function in adults with growth hormone deficiency, Thyroid source

In the paper

“High-dose GC may also improve visual outcomes (260).”

What the sources say

• ?Not checked — no full text of the sourcecites [260] Arafah, 1990, Improvement of pituitary function after surgical decompression for pituitary tumor apoplexy, J Clin Endocrinol Metab source

In the paper

“In one study of eight patients, transsphenoidal surgery achieved a return of normal pituitary function in most patients in the immediate postoperative period (257), although larger studies have not replicated these findings (263).”

What the sources say

• ?Not checked — no full text of the sourcecites [263] Cardoso, 1984, Pituitary apoplexy: a review, Neurosurgery source

In the paper

“There is no consensus on whether surgical treatment improves pituitary function, but one study reported an increased incidence of hormonal deficiencies with conservative management (266).”

What the sources say

• ?Not checked — no full text of the sourcecites [266] Ayuk, 2004, Acute management of pituitary apoplexy–surgery or conservative management?, Clin Endocrinol (Oxf) source

In the paper

“Further research has reported the recovery of other hormonal axes following adenoma shrinkage (227)”

What the sources say

• ?Not checked — no full text of the sourcecites [227] Colao, 2004, Outcome of cabergoline treatment in men with prolactinoma: effects of a 24-month treatment on prolactin levels, tumor mass, recovery of pituitary function, and semen analysis, J Clin Endocrinol Metab source

In the paper

“AI can persist for years after surgical tumor resection.”

What the sources say

• ?Not checked — no full text of the sourcecites [112] Grossman, 2010, Clinical Review#: the diagnosis and management of central hypoadrenalism, J Clin Endocrinol Metab source

In the paper

“this was consistent with the direct or indirect suppression of bone remodeling and suppression of PTH levels (202).”

What the sources say

• ?Not checked — no full text of the sourcecites [202] Linas, 1980, Role of vasopressin in the impaired water excretion of glucocorticoid deficiency, Kidney Int source

In the paper

“A post-hoc analysis (201) from a prospective single-center study on 175 adult patients with hypopituitarism (including GHD) showed that patients with AI receiving near physiological doses of HC did not exhibit a greater therapeutic response to GH than their counterparts not on GC replacement.”

What the sources say

• ?Not checked — no full text of the sourcecites [201] Cook, 2004, Growth hormone and estrogen: a clinician’s approach, J Pediatr Endocrinol Metab

In the paper

“In the context of multiple pituitary deficiencies associated with Cushing's disease (222,223)”

What the sources say

• ?Not checked — no full text of the sourcecites [222] Whitsel, 2001, Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis, Am J Med source
• ?Not checked — no full text of the sourcecites [223] Nieman, 2015, Treatment of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab source

In the paper

“Muscle strength improvement is sustained for at least 10 years (168).”

What the sources say

• ?Not checked — no full text of the sourcecites [168] Johannsson, 1996, The individual responsiveness to growth hormone (GH) treatment in GH-deficient adults is dependent on the level of GH-binding protein, body mass index, age, and gender, J Clin Endocrinol Metab source

In the paper

“Serum lipoprotein profiles improve with reduced total and LDL cholesterol and increased high-density lipoprotein (HDL) cholesterol, triglycerides, and ApoB 100 levels (170).”

What the sources say

• ?Not checked — no full text of the sourcecites [170] Hoffman, 2004, Growth hormone (GH) replacement therapy in adult-onset gh deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial, J Clin Endocrinol Metab source

In the paper

“In patients with AI on three different replacement regimens (for at least 4 weeks), replacement was MAY 4, 2016 associated with low serum ionized calcium levels without any evidence of compensatory increased parathyroid hormone (PTH) levels”

What the sources say

• ?Not checked — no full text of the sourcecites [202] Linas, 1980, Role of vasopressin in the impaired water excretion of glucocorticoid deficiency, Kidney Int source

In the paper

“A meta-analyses of 11 randomized trials reported that adult GH replacement resulted in significantly enhanced maximum oxygen uptake and muscle power (169).”

What the sources say

• ?Not checked — no full text of the sourcecites [169] Beauregard, 2008, Growth hormone decreases visceral fat and improves cardiovascular risk markers in women with hypopituitarism: a randomized, placebo-controlled study, J Clin Endocrinol Metab source

In the paper

“In 16 studies assessing the recovery of adrenal function after successful treatment for Cushing's disease (112), most MAY 4, 2016 patients recovered HPA axis by 2 years.”

What the sources say

• ?Not checked — no full text of the sourcecites [112] Grossman, 2010, Clinical Review#: the diagnosis and management of central hypoadrenalism, J Clin Endocrinol Metab source