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

Excess cardiovascular mortality might be specifically related to adrenal crisis.

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

• 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 sourceDisputed

  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.

  Experimental — accuracy not yet measured

Bilateral oophorectomy without estrogen replacement before the age of 45 increases cardiovascular mortality.

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

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

Studies have suggested that 10-18% of high-risk pituitary patients have unrecognized CH with low-normal fT4 levels.

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

• cites [77] Persani, 2000, Circulating thyrotropin bioactivity in sporadic central hypothyroidism, J Clin Endocrinol MetabNot matched

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

• cites [79] Jonklaas, 2014, Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement, Thyroid sourceCould 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)

  Experimental — accuracy not yet measured

Patients with primary hypothyroidism usually require high-normal or slightly elevated fT4 levels to normalize TSH levels.

“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.”

• cites [78] Alexopoulou, 2004, Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients, Eur J Endocrinol sourceCould 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)

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Stress doses of glucocorticoid replacement for intercurrent illnesses and minor stress are similar to those used in primary adrenal insufficiency.

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

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

A cortisol day curve has little value for routine clinical use.

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

• cites [108] Kahric-Janicic, 2007, Tandem mass spectrometry improves the accuracy of free thyroxine measurements during pregnancy, Thyroid sourceCould 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)

  Experimental — accuracy not yet measured
• cites [28] Bancos, 2015, Diagnosis and management of adrenal insufficiency, Lancet Diabetes Endocrinol sourceSupported

Clinicians are increasingly using newer liquid chromatography-mass spectrometric-based assays with suggested improved sensitivity and reduced interference, particularly for steroids such as estradiol and testosterone, and for thyroid and peptide hormones.

“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).”

• 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 sourceCould 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.

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• cites [105] Sikaris, 2005, Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [78] Alexopoulou, 2004, Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients, Eur J Endocrinol sourceCould 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.

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• cites [106] Rosner, 2013, Challenges to the measurement of estradiol: an Endocrine Society Position Statement, J Clin Endocrinol Metab sourcePartly supported

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

  Experimental — accuracy not yet measured

Cortisol secretion exhibits a distinct circadian rhythm: low at sleep onset, rising early morning, peaking just after waking, then falling during the day.

“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).”

• cites [28] Bancos, 2015, Diagnosis and management of adrenal insufficiency, Lancet Diabetes Endocrinol sourceSupported
• cites [107] Kane, 2007, Measurement of serum testosterone in women; what should we do?, Ann Clin Biochem sourceNot checked — no full text of the source

A high proportion of patients on conventional corticosteroid replacement therapy for adrenal insufficiency are overtreated or on inappropriate replacement regimens.

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

• cites [120] Stavreva, 2009, Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription, Nat Cell Biol sourcePartly 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)

  Experimental — accuracy not yet measured

Visceral adipose tissue mass is decreased by 9% in female patients receiving growth hormone replacement.

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

• cites [166] Clemmons, 2014, Growth hormone should be used only for approved indications, J Clin Endocrinol Metab sourceCould 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)

  Experimental — accuracy not yet measured

Treatment with estrogens until age 45 years or longer may reduce the risk of cardiovascular disease and mortality.

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

• cites [47] Løkkegaard, 2006, The association between early menopause and risk of ischaemic heart disease: influence of hormone therapy, Maturitas sourceNot checked — no full text of the source
• cites [49] Rocca, 2012, Premature menopause or early menopause and risk of ischemic stroke, Menopause sourcePartly 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)

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

  Experimental — accuracy not yet measured

Other pituitary hormone deficits and/or their treatment also affect bone mineral density and the risk of fracture in central hypogonadism.

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

• cites [131] Klose, 2013, Central hypothyroidism and its replacement have a significant influence on cardiovascular risk factors in adult hypopituitary patients, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [159] van der Klift, 2004, Risk factors for incident vertebral fractures in men and women: the Rotterdam Study, J Bone Miner Res sourceCould 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)

  Experimental — accuracy not yet measured
• cites [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 sourceNot checked — no full text of the source

The literature on primary ovarian failure supports the beneficial effects of estrogen on bone.

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

• cites [154] Cardozo, 2004, A systematic review of the effects of estrogens for symptoms suggestive of overactive bladder, Acta Obstet Gynecol Scand sourceNot checked — no full text of the source
• cites [157] Popat, 2009, Bone mineral density in estrogen-deficient young women, J Clin Endocrinol Metab sourceSupported
• cites [158] Lindsay, 1980, Prevention of spinal osteoporosis in oophorectomised women, Lancet sourceNot checked — no full text of the source

The need for immediate glucocorticoid replacement and fluid resuscitation is the same in central adrenal insufficiency as in primary adrenal insufficiency.

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

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

  Experimental — accuracy not yet measured

The mean dose ratio of sublingual to intranasal desmopressin is 1:24.

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

• cites [181] Corona, 2013, Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis, PLoS One sourceCould 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)

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Recent evidence suggests that mild hyperthyroidism or hypothyroidism may increase overall and cardiovascular-specific mortality and morbidity.

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

• cites [213] Agha, 2004, Conventional glucocorticoid replacement overtreats adult hypopituitary patients with partial ACTH deficiency, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [214] Peacey, 2012, Glucocorticoid replacement therapy and fibrinolysis in patients with hypopituitarism, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• 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 sourcePartly 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)

  Experimental — accuracy not yet measured

A morning cortisol measurement might be useful even after intraoperative administration of dexamethasone.

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

• 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 sourcePartly 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)

  Experimental — accuracy not yet measured

Lower doses of HC might be needed in women with hypopituitarism (compared with primary AI) who are not treated with GC replacement.

“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).”

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

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

Treatment with estrogens through age 45 years or longer may reduce the risk of cardiovascular disease and mortality.

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

• cites [47] Løkkegaard, 2006, The association between early menopause and risk of ischaemic heart disease: influence of hormone therapy, Maturitas sourceNot checked — no full text of the source
• cites [49] Rocca, 2012, Premature menopause or early menopause and risk of ischemic stroke, Menopause sourcePartly 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)

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

  Experimental — accuracy not yet measured

We cannot extrapolate the results of the Women's Health Initiative to younger women with premature ovarian failure.

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

• cites [219] Collet, 2012, Subclinical hyperthyroidism and the risk of coronary heart disease and mortality, Arch Intern Med sourceCould 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)

  Experimental — accuracy not yet measured

Lean body mass improves by up to 7% during the first year of GH replacement.

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

• cites [167] Melmed, 2013, Idiopathic adult growth hormone deficiency, J Clin Endocrinol Metab sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [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 MetabNot matched

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

Combined estrogen and progesterone may decrease lamotrigine levels.

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

• cites [276] Werk, 1964, Effect of diphenylhydantoin on cortisol metabolism in man, J Clin Invest sourceCould 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)

  Experimental — accuracy not yet measured

More than 50% of patients eventually require hormonal replacement after pituitary apoplexy.

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

• cites [257] Källén, 1995, Diabetes insipidus and use of desmopressin (Minirin) during pregnancy, Eur J Endocrinol sourceNot checked — no full text of the source
• cites [258] Vila, 2015, Pregnancy outcomes in women with growth hormone deficiency, Fertil Steril sourceCould 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)

  Experimental — accuracy not yet measured
• cites [261] Veldhuis, 1980, Endocrine function after spontaneous infarction of the human pituitary: report, review, and reappraisal, Endocr Rev sourceNot checked — no full text of the source

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

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

• cites [268] Verrees, 2004, Pituitary tumor apoplexy: characteristics, treatment, and outcomes, Neurosurg Focus sourceCould 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)

  Experimental — accuracy not yet measured

Administering dopamine agonists to patients with macroprolactinoma leads to normoprolactinemia in 68% (range 40-100%).

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

• 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) sourceCould 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)

  Experimental — accuracy not yet measured

Very few studies have assessed the impact of glucocorticoid dose optimization on markers of bone formation and resorption.

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

• cites [120] Stavreva, 2009, Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription, Nat Cell Biol sourceCould 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)

  Experimental — accuracy not yet measured

Administering dopamine agonists to patients with macroprolactinoma leads to tumor shrinkage in 62% (range 20-100%).

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

• 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) sourceCould 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)

  Experimental — accuracy not yet measured

Rates of pituitary axes recovery or new onset hypopituitarism after transsphenoidal surgery vary significantly between studies.

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

• cites [115] Johannsson, 2014, Improving outcomes in patients with adrenal insufficiency: a review of current and future treatments, Curr Med Res Opin sourceNot checked — no full text of the source
• cites [233] Miller, 2010, Growth hormone deficiency after treatment of acromegaly: a randomized, placebo-controlled study of growth hormone replacement, J Clin Endocrinol Metab sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [234] Giavoli, 2012, GH replacement improves quality of life and metabolic parameters in cured acromegalic patients with growth hormone deficiency, J Clin Endocrinol Metab sourceNot checked — no full text of the source

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

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

The most common causes of death in panhypopituitarism were malignancies, cardiovascular disease, and cerebrovascular disease.

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

There were no data on the outcome of stroke in the review of GH replacement and risk of pituitary tumor recurrence, secondary malignancy, or stroke.

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

Lower doses of hydrocortisone seem to correlate with improved quality of life, health status, and mood.

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

• cites [121] Mager, 2003, Integrated QSPR–pharmacodynamic model of genomic effects of several corticosteroids, J Pharm Sci sourceNot checked — no full text of the source
• cites [27] Bleicken, 2010, Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients, Am J Med Sci sourceNot checked — no full text of the source
• cites [122] Peacey, 1997, Glucocorticoid replacement therapy: are patients over treated and does it matter?, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

Three-times-daily intake of hydrocortisone was not superior to two-times-daily intake.

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

• cites [121] Mager, 2003, Integrated QSPR–pharmacodynamic model of genomic effects of several corticosteroids, J Pharm Sci sourceNot checked — no full text of the source

In a cross-sectional study, hydrocortisone doses above 30 mg/day were associated with adverse health status by validated self-assessment questionnaires.

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

• cites [27] Bleicken, 2010, Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients, Am J Med Sci sourceNot checked — no full text of the source

Men with non-replaced hypogonadism due to non-functioning pituitary adenomas scored significantly worse in parameters of health-related quality-of-life questionnaires compared to those with an intact gonadotroph axis or on hormone replacement.

“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).”

• cites [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) sourceNot checked — no full text of the source

Nonrandomized and observational studies report improved fatigue, weight or BMI, waist circumference, and cholesterol levels correlating with higher levothyroxine doses and free thyroxine levels.

“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).”

• cites (75,77,(127)(128)(129)Not matched

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

One cross-sectional study of central hypothyroidism patients reported that mean levothyroxine doses of 1.9 mcg/kg led to free thyroxine levels in the upper half of the normal range.

“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).”

• cites [130] Filipsson Nyström, 2012, The metabolic consequences of thyroxine replacement in adult hypopituitary patients, Pituitary sourceNot checked — no full text of the source

Central hypothyroidism patients receiving glucocorticoid therapy do not appear to require levothyroxine dose adjustments.

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

• cites [77] Persani, 2000, Circulating thyrotropin bioactivity in sporadic central hypothyroidism, J Clin Endocrinol MetabNot matched

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

Estrogen therapy increased mean levothyroxine dose requirements in patients with central hypothyroidism from 1.3 to 1.8 mcg/kg/day.

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

• cites [77] Persani, 2000, Circulating thyrotropin bioactivity in sporadic central hypothyroidism, J Clin Endocrinol MetabNot matched

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

Some studies also report increased free triiodothyronine levels with no significant effects on TSH levels.

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

• cites [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 sourceNot checked — no full text of the source
• cites [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 sourceNot checked — no full text of the source
• cites [192] Qureshi, 2007, The influence of the route of oestrogen administration on serum levels of cortisol-binding globulin and total cortisol, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

In patients with growth hormone deficiency, 36-47% of euthyroid patients and 16-18% of treated central hypothyroidism patients developed low free thyroxine levels within 3-6 months of starting growth hormone therapy.

“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).”

• cites [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 sourceNot checked — no full text of the source
• cites [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) sourceNot checked — no full text of the source

The risk of fracture correlated with untreated growth hormone deficiency, urinary cortisol values, and cortisone doses.

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

• cites [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 sourceNot checked — no full text of the source

The safety profile for growth hormone treatment using appropriate replacement doses appears favorable in long-term surveillance studies.

“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).”

• cites [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 sourceNot checked — no full text of the source

In hypopituitary men randomized to three commonly used hydrocortisone dose regimens, low-dose hydrocortisone 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.

“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)”

• cites [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 sourceNot checked — no full text of the source

One study showed that women on oral estrogen might require a growth hormone replacement dose up to 50% higher compared with women or men who are not on estrogen.

“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).”

• cites [199] Gibney, 2005, Comparison of the metabolic effects of raloxifene and oral estrogen in postmenopausal and growth hormone-deficient women, J Clin Endocrinol Metab sourceNot checked — no full text of the source

About one quarter of diabetes insipidus patients with an intact thirst mechanism who are treated with desmopressin have mild hyponatremia caused by the inability to reverse the antidiuretic effect of the drug when fluid intake exceeds requirements.

“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).”

• cites [176] Götherström, 2007, Ten-year GH replacement increases bone mineral density in hypopituitary patients with adult onset GH deficiency, Eur J Endocrinol sourceNot checked — no full text of the source

Most patients at increased risk of developing central hypothyroidism while receiving growth hormone and who had previously undergone surgery and/or radiation therapy for pituitary tumors had lower basal thyroxine levels and were more likely to have other multiple hormone deficiencies.

“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.”

• cites [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 sourceNot checked — no full text of the source
• cites [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) sourceNot checked — no full text of the source

In a cross-sectional study of male hypopituitary patients receiving median daily doses of hydrocortisone 30 mg and cortisone 35 mg, 60% of patients had vertebral fractures.

“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.”

• cites [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 sourceNot checked — no full text of the source

Alexopoulou et al. reported that only men with central hypothyroidism required increased levothyroxine doses after starting growth hormone therapy (1.8 vs. 1.6 mcg/kg/day).

“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).”

• cites [77] Persani, 2000, Circulating thyrotropin bioactivity in sporadic central hypothyroidism, J Clin Endocrinol MetabNot matched

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

Patients with growth hormone deficiency in the setting of hypopituitarism demonstrate an increased cortisol/cortisone metabolite ratio.

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

• cites [185] Stewart, 2001, Growth hormone, insulin-like growth factor-I and the cortisol-cortisone shuttle, Horm Res sourceNot checked — no full text of the source
• cites [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) sourceNot checked — no full text of the source

Growth hormone administration does not appear to increase the rate of pituitary adenoma recurrence (RR 0.887, 95% CI, 0.56-1.33).

“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]).”

• cites [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) sourceNot checked — no full text of the source
• cites (Jasim, S; A systematic review and meta-analysis, JCEM [In Press])Not matched

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

There is no apparent dose-dependent difference in integrated cortisol daily curves between patients on half-dose or no HC replacement.

“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.”

• cites [211] Danilowicz, 2008, Correction of cortisol overreplacement ameliorates morbidities in patients with hypopituitarism: a pilot study, Pituitary sourceNot checked — no full text of the source

There is no consensus on whether surgical treatment improves pituitary function in pituitary apoplexy.

“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).”

There are no prospective studies on the relationship between GH use before and during pregnancy and pregnancy outcomes.

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

• cites [255] Durr, 1996, Diagnosis and management of diabetes insipidus during pregnancy, Endocr Pract sourceNot checked — no full text of the source

Some analytes, such as E2, T, GH, fT4, and to a lower extent gonadotropins, had large inter-assay variability.

“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).”

• cites [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 MedNot checked — no full text of the source

Peripheral indices of thyroid hormone action lack sufficient sensitivity and specificity for diagnosing or monitoring CH.

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

• cites (33,(80)(81)(82)Not matched

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

In contrast to primary hypothyroidism, TSH and fT4 levels do not correlate in CH.

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

• cites [33] Persani, 2012, Clinical review: central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges, J Clin Endocrinol Metab sourceNot checked — no full text of the source

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

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

Delaying treatment of AI can result in adrenal crisis and death.

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

• cites (16,(28)(29)(30)Not matched

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

Early menopause is associated with increased risk of cardiovascular and cerebrovascular disease.

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

• cites (47)(48)(49)(50)Not matched

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

Untreated congenital GHD does not lead to shortened life expectancy.

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

• cites [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 sourceNot checked — no full text of the source

Mortality associated with hypopituitarism is indeed high.

“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).”

• cites (5)(6)(7)(8)(9)(10)Not matched

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

Cortisol levels <18.1 mcg/dl (500 nmol/l) post-stimulation are indicative of AI.

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

• cites (Table 3)Not matched

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

Clinicians can assess central AI using insulin tolerance and low-dose and standard-dose ACTH stimulation tests.

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

• cites (Table 3)Not matched

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

Untreated gonadotropin deficiency is an independent factor affecting mortality (HR 1.86 [99% CI 1.15-2.45]).

“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).”

• cites [9] Tomlinson, 2001, Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group, Lancet sourceNot checked — no full text of the source

The finding of a random low normal ACTH level may not be helpful in diagnosing central AI.

“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).”

• cites [73] Cooper, 2005, Diagnosis and treatment of ACTH deficiency, Rev Endocr Metab Disord sourceNot checked — no full text of the source

Peak cortisol levels <18.1 mcg/dl (500 nmol/l) at 30 or 60 minutes indicate AI.

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

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]) in patients with gonadotropin deficiency.

“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).”

• cites [9] Tomlinson, 2001, Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group, Lancet sourceNot checked — no full text of the source

Oral estrogen can increase corticosteroid-binding globulin (CBG) and thereby total serum cortisol levels.

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

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.

“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.”

Many cases of hypopituitarism are associated with hyperprolactinemia that occurs due to stalk interruption and the absence of dopamine inhibition.

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

• cites [63] Tritos, 2015, Hyperprolactinemia, JAMA sourceNot checked — no full text of the source

Pituitary hormonal deficits managed with currently used replacement protocols (including non-supraphysiological doses of HC and appropriate thyroid and gonadal hormone replacement) might not adversely affect mortality.

“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).”

• cites [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 sourceNot checked — no full text of the source

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

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

• cites [14] Holmer, 2013, Psychosocial health and levels of employment in 851 hypopituitary Swedish patients on long-term GH therapy, Psychoneuroendocrinology sourceNot checked — no full text of the source

Low-normal fT4 levels in hypopituitary patients may suggest the presence of CH.

“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.”

Mild ACTH deficiency may manifest as clinically important AI with stress.

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

• cites [31] Wass, 2012, How to avoid precipitating an acute adrenal crisis, BMJ sourceNot checked — no full text of the source

Modified-release hydrocortisone 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.

“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.”

• cites [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 sourceNot checked — no full text of the source
• cites [124] Ragnarsson, 2014, The relationship between glucocorticoid replacement and quality of life in 2737 hypopituitary patients, Eur J Endocrinol sourceNot checked — no full text of the source
• cites [125] Johannsson, 2009, Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study, Eur J Endocrinol sourceNot checked — no full text of the source

Few studies have compared different replacement regimens for central adrenal insufficiency.

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

GnRH testing provides no extra diagnostic information over baseline gonadotropin values measured by currently available ultrasensitive assays.

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

• cites [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 sourceNot checked — no full text of the source

Age-adjusted IGF-1 values measured in an accredited laboratory provide valuable information of net GH bioactivity.

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

Despite intact mineralocorticoid function, patients with secondary adrenal insufficiency have a similar, if not higher, risk of adrenal crisis.

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

• cites (19,(29)(30)(31)110,112)Not matched

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

In most cases of isolated diabetes insipidus, MRI imaging of the sellar area shows a progressive loss of the posterior pituitary bright spot.

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

• cites [102] Silveira, 2013, Approach to the patient with hypogonadotropic hypogonadism, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Many young adults previously requiring GH therapy for short stature during childhood (isolated GHD with normal pituitary imaging) prove to be GH-sufficient on subsequent retesting.

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

The level of serum testosterone below which symptoms of hypogonadism occur has not been clearly established.

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

About 20% of adults with GHD may have normal IGF-1 levels, particularly males.

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

• cites [85] Molitch, 2011, Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Most GH reserve tests are associated with high false positive rates.

“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.”

Multiple factors, including nutritional and hormonal status, exercise, body weight, and age, may influence pituitary GH secretion.

“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).”

• cites [85] Molitch, 2011, Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [86] Biller, 2002, Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency, J Clin Endocrinol Metab sourceNot checked — no full text of the source

The physiological rise in cortisol early in the morning is not well mimicked by modified-release hydrocortisone.

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

• cites [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 sourceNot checked — no full text of the source
• cites [124] Ragnarsson, 2014, The relationship between glucocorticoid replacement and quality of life in 2737 hypopituitary patients, Eur J Endocrinol sourceNot checked — no full text of the source
• cites [125] Johannsson, 2009, Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study, Eur J Endocrinol sourceNot checked — no full text of the source

Hormone replacement therapy invariably causes a reduction in circulating FSH and LH levels.

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

• cites [101] Drincic, 2003, Men with acquired hypogonadotropic hypogonadism treated with testosterone may be fertile, Pituitary sourceNot checked — no full text of the source

The diagnosis of central hypogonadism in females requires exclusion of other conditions causing impaired ovulation and menstrual irregularities, including hyperprolactinaemia, hyperandrogenism, and thyroid dysfunction.

“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).”

• cites [40] Karavitaki, 2010, Disorders of the anterior pituitary gland sourceNot checked — no full text of the source

Total, free, and bioavailable testosterone levels demonstrate a circadian rhythm with maximum serum values between 5:30 and 8 a.m. and trough levels approximately 12 hours later.

“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).”

• cites (87)(88)(89)Not matched

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

One study reported cases of males with acquired hypogonadotropic hypogonadism remaining fertile after testosterone treatment.

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

• cites [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 sourceNot checked — no full text of the source

Data on the impact of testosterone replacement on fracture risk are not currently available.

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

Studies have not validated following free triiodothyronine levels or peripheral indicators of thyroid function during levothyroxine therapy.

“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).”

• cites [33] Persani, 2012, Clinical review: central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [77] Persani, 2000, Circulating thyrotropin bioactivity in sporadic central hypothyroidism, J Clin Endocrinol MetabNot matched

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

The standard therapy for central hypothyroidism is levothyroxine at approximately 1.6 mcg/kg/day.

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

• cites [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) sourceNot checked — no full text of the source

It is not clear whether the timing of blood sampling in relation to levothyroxine dose ingestion affects decisions regarding levothyroxine dose adjustment in central hypothyroidism.

“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.”

Research has not consistently reported cardiovascular risk profile improvement with growth hormone replacement.

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

• cites [171] Götherström, 2009, Ten years of growth hormone (GH) replacement normalizes muscle strength in GH-deficient adults, J Clin Endocrinol Metab sourceNot checked — no full text of the source

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

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

Many features of hypopituitarism, such as visceral obesity, insulin resistance, osteoporosis, and increased vascular mortality, are reminiscent of Cushing's syndrome.

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

• cites [183] Oiso, 2013, Clinical review: treatment of neurohypophyseal diabetes insipidus, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [184] Janus, 2014, Adipsic diabetes insipidus in pediatric patients, Indian J Pediatr sourceNot checked — no full text of the source

Glucocorticoid deficiency induces impaired free renal water clearance, resulting in the masking of polyuria in diabetes insipidus.

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

• cites [200] Mah, 2005, Estrogen replacement in women of fertile years with hypopituitarism, J Clin Endocrinol Metab sourceNot checked — no full text of the source

The greatest risk of increased overall and cardiovascular mortality in patients with ACTH deficiency receiving higher GC replacement doses is in those receiving daily HC doses higher or equal to 30 mg.

“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).”

• cites [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 sourceNot checked — no full text of the source

The increased levothyroxine dose requirement with increased serum estrogen is due to estrogen-dependent liver production of thyroid-binding globulin.

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

• cites [196] Losa, 2008, Long-term effects of growth hormone replacement therapy on thyroid function in adults with growth hormone deficiency, Thyroid sourceNot checked — no full text of the source

Data suggest that adrenal insufficiency should be conclusively excluded prior to initiating levothyroxine therapy for central hypothyroidism.

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

• cites [33] Persani, 2012, Clinical review: central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Physiologic and pharmacologic doses of glucocorticoids suppress TSH levels.

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

• cites [188] Mazziotti, 2013, Glucocorticoids and the regulation of growth hormone secretion, Nat Rev Endocrinol sourceNot checked — no full text of the source

Increased serum estrogen levels, whether endogenous (pregnancy) or exogenous (estrogen replacement therapy, oral contraceptives), result in increased levothyroxine dose requirements in patients with primary hypothyroidism.

“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).”

• cites [196] Losa, 2008, Long-term effects of growth hormone replacement therapy on thyroid function in adults with growth hormone deficiency, Thyroid sourceNot checked — no full text of the source

In patients with altered thirst mechanism, there is high risk of both hypernatremia and hyponatremia, as patients cannot adjust fluid intake according to thirst.

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

• cites [176] Götherström, 2007, Ten-year GH replacement increases bone mineral density in hypopituitary patients with adult onset GH deficiency, Eur J Endocrinol sourceNot checked — no full text of the source

Higher GC replacement doses in patients with ACTH deficiency are associated with increased overall and cardiovascular mortality.

“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).”

• cites [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 sourceNot checked — no full text of the source

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

“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.”

• cites [220] Rhee, 2013, Subclinical hypothyroidism and survival: the effects of heart failure and race, J Clin Endocrinol Metab sourceNot checked — no full text of the source

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

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

• cites [240] Jia, Utility of a glucocorticoid sparing strategy in the management of patients following transsphenoidal surgery [published online April 28, 2016], Endocr Pract sourceNot checked — no full text of the source

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

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

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.

“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).”

• cites [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 sourceNot checked — no full text of the source

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.

“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).”

• cites [209] Filipsson, 2006, The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients, J Clin Endocrinol Metab sourceNot checked — no full text of the source

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

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

• cites [247] Raff, 1990, Cortisol inhibition of vasopressin and ACTH responses to arterial hypotension in conscious dogs, Am J Physiol sourceNot checked — no full text of the source
• cites [248] Baylis, 1990, Glucocorticoids and control of glomerular filtration rate, Semin NephrolNot checked — no full text of the source

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

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

• cites [235] Greenman, 1995, Relative sparing of anterior pituitary function in patients with growth hormone-secreting macroadenomas: comparison with nonfunctioning macroadenomas, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Current conventional full GC replacement doses might over-treat patients with partial ACTH deficiency.

“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.”

• cites [211] Danilowicz, 2008, Correction of cortisol overreplacement ameliorates morbidities in patients with hypopituitarism: a pilot study, Pituitary sourceNot checked — no full text of the source

A postoperative morning cortisol level higher than 15 mcg/dL may mitigate the requirement for postoperative GC treatment.

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

• cites [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 sourceNot checked — no full text of the source

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

“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).”

• cites [230] Mazziotti, 2015, Growth hormone deficiency in treated acromegaly, Trends Endocrinol Metab sourceNot checked — no full text of the source

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

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

• cites [228] Karavitaki, 2013, Does hypopituitarism recover when macroprolactinomas are treated with cabergoline?, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

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.

“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.”

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

“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).”

• cites [212] Dunne, 1995, Cardiovascular function and glucocorticoid replacement in patients with hypopituitarism, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

In a randomized crossover study, 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.

“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.”

• cites [205] Behan, 2014, Low-dose hydrocortisone replacement therapy is associated with improved bone remodelling balance in hypopituitary male patients, Eur J Endocrinol sourceNot checked — no full text of the source

In a large retrospective analysis, overall mortality was similar between GHD associated with treated acromegaly and GHD associated with non-functioning pituitary adenomas.

“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).”

• cites [230] Mazziotti, 2015, Growth hormone deficiency in treated acromegaly, Trends Endocrinol Metab sourceNot checked — no full text of the source

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

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

• cites [246] Raff, 1987, Glucocorticoid inhibition of neurohypophysial vasopressin secretion, Am J Physiol sourceNot checked — no full text of the source

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

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

• cites [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) sourceNot checked — no full text of the source

Plasma cortisol can be falsely 'normal' because of increased CBG in the second and third trimesters.

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

• cites [250] Salem, 1994, Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem, Ann Surg sourceNot checked — no full text of the source

Perioperative complications seem to be minor in patients with preoperative CH when surgery is not urgent.

“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).”

• cites [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 sourceNot checked — no full text of the source
• cites [239] Manuylova, 2015, Morning serum cortisol level after transsphenoidal surgery for pituitary adenoma predicts hypothalamic-pituitary-adrenal function despite intraoperative dexamethasone use, Endocr Pract sourceNot checked — no full text of the source

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

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

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

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

• cites [249] Ahmed, 1999, Outcome of transphenoidal surgery for acromegaly and its relationship to surgical experience, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

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

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

Endogenous and exogenous sex steroids may affect seizure activity and epilepsy in women.

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

• cites [277] Carl, 2008, Effect of antiepileptic drugs on oral contraceptives, Am Fam PhysicianNot checked — no full text of the source

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

“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).”

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

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

• cites [255] Durr, 1996, Diagnosis and management of diabetes insipidus during pregnancy, Endocr Pract sourceNot checked — no full text of the source

AEDs only modestly decrease the concentrations of prednisone and prednisolone.

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

• cites [270] Sibal, 2004, Pituitary apoplexy: a review of clinical presentation, management and outcome in 45 cases, Pituitary sourceNot checked — no full text of the source

Exposure to DDAVP during pregnancy is safe.

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

• cites [254] Suri, 2006, Assessment of adrenal reserve in pregnancy: defining the normal response to the adrenocorticotropin stimulation test, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Dexamethasone is metabolized primarily by hepatic CYP3A4.

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

• cites [269] Maccagnan, 1995, Conservative management of pituitary apoplexy: a prospective study, J Clin Endocrinol Metab sourceNot checked — no full text of the source

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

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

• cites [275] Högler, 2010, Oxcarbazepine accelerates cortisol elimination via cytochrome P450 3A4 induction, Arch Dis Child sourceNot checked — no full text of the source

CYP3A4-mediated 6β-hydroxylation may not contribute significantly to the breakdown of cortisol.

“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).”

• cites [271] Paragliola, 2015, Treatment of hypopituitarism in patients receiving antiepileptic drugs, Lancet Diabetes Endocrinol sourceNot checked — no full text of the source
• cites [272] Gentile, 1996, Dexamethasone metabolism by human liver in vitro. Metabolite identification and inhibition of 6-hydroxylation, J Pharmacol Exp Ther sourceNot checked — no full text of the source
• cites [273] Bartoszek, 1987, Prednisolone and methylprednisolone kinetics in children receiving anticonvulsant therapy, Clin Pharmacol Ther sourceNot checked — no full text of the source

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

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

• cites [252] Lindsay, 2005, The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment, Endocr Rev sourceNot checked — no full text of the source

DDAVP is generally considered safe for the newborn in lactating mothers.

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

• cites [252] Lindsay, 2005, The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment, Endocr Rev sourceNot checked — no full text of the source

In one study of eight patients, transsphenoidal surgery achieved a return of normal pituitary function in most patients in the immediate postoperative period.

“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).”

• cites [257] Källén, 1995, Diabetes insipidus and use of desmopressin (Minirin) during pregnancy, Eur J Endocrinol sourceNot checked — no full text of the source

AEDs are less likely to be clinically significant in patients treated with HC.

“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).”

• cites [271] Paragliola, 2015, Treatment of hypopituitarism in patients receiving antiepileptic drugs, Lancet Diabetes Endocrinol sourceNot checked — no full text of the source
• cites [272] Gentile, 1996, Dexamethasone metabolism by human liver in vitro. Metabolite identification and inhibition of 6-hydroxylation, J Pharmacol Exp Ther sourceNot checked — no full text of the source
• cites [273] Bartoszek, 1987, Prednisolone and methylprednisolone kinetics in children receiving anticonvulsant therapy, Clin Pharmacol Ther sourceNot checked — no full text of the source

Oxcarbazepine increases cortisol elimination in normal subjects.

“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.”

• cites [272] Gentile, 1996, Dexamethasone metabolism by human liver in vitro. Metabolite identification and inhibition of 6-hydroxylation, J Pharmacol Exp Ther sourceNot checked — no full text of the source

GH use before and during pregnancy was not related to pregnancy outcomes.

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

• cites [255] Durr, 1996, Diagnosis and management of diabetes insipidus during pregnancy, Endocr Pract sourceNot checked — no full text of the source

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

“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.”

• cites [196] Losa, 2008, Long-term effects of growth hormone replacement therapy on thyroid function in adults with growth hormone deficiency, Thyroid sourceNot checked — no full text of the source

High-dose GC may also improve visual outcomes in pituitary apoplexy.

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

• cites [260] Arafah, 1990, Improvement of pituitary function after surgical decompression for pituitary tumor apoplexy, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Larger studies have not replicated the finding that transsphenoidal surgery achieves return of normal pituitary function in most patients in the immediate postoperative period.

“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).”

• cites [263] Cardoso, 1984, Pituitary apoplexy: a review, Neurosurgery sourceNot checked — no full text of the source

One study reported an increased incidence of hormonal deficiencies with conservative management of pituitary apoplexy.

“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).”

• cites [266] Ayuk, 2004, Acute management of pituitary apoplexy–surgery or conservative management?, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

Recovery of other hormonal axes following adenoma shrinkage has been reported.

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

• cites [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 sourceNot checked — no full text of the source

Adrenal insufficiency can persist for years after surgical tumor resection.

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

• cites [112] Grossman, 2010, Clinical Review#: the diagnosis and management of central hypoadrenalism, J Clin Endocrinol Metab sourceNot checked — no full text of the source

The association of replacement with low serum ionized calcium without compensatory increased parathyroid hormone in adrenal insufficiency patients on three replacement regimens is consistent with direct or indirect suppression of bone remodeling and suppression of parathyroid hormone levels.

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

• cites [202] Linas, 1980, Role of vasopressin in the impaired water excretion of glucocorticoid deficiency, Kidney Int sourceNot checked — no full text of the source

In a post-hoc analysis of a prospective single-center study of 175 adult patients with hypopituitarism (including GHD), patients with adrenal insufficiency receiving near physiological doses of hydrocortisone did not exhibit a greater therapeutic response to growth hormone than counterparts not on glucocorticoid replacement.

“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.”

• cites [201] Cook, 2004, Growth hormone and estrogen: a clinician’s approach, J Pediatr Endocrinol MetabNot checked — no full text of the source

Multiple pituitary deficiencies are associated with Cushing's disease.

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

• cites [222] Whitsel, 2001, Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis, Am J Med sourceNot checked — no full text of the source
• cites [223] Nieman, 2015, Treatment of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Muscle strength improvement is sustained for at least 10 years.

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

• cites [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 MetabNot matched

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

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

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

• cites [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 sourceNot checked — no full text of the source

In patients with adrenal insufficiency on three different replacement regimens for at least 4 weeks, replacement was associated with low serum ionized calcium levels without evidence of compensatory increased parathyroid hormone levels.

“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”

• cites [202] Linas, 1980, Role of vasopressin in the impaired water excretion of glucocorticoid deficiency, Kidney Int sourceNot checked — no full text of the source

A meta-analysis of 11 randomized trials reported that adult GH replacement resulted in significantly enhanced maximum oxygen uptake and muscle power.

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

• cites [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 sourceNot checked — no full text of the source

In 16 studies assessing recovery of adrenal function after successful treatment for Cushing's disease, most patients recovered hypothalamic-pituitary-adrenal axis by 2 years.

“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.”

• cites [112] Grossman, 2010, Clinical Review#: the diagnosis and management of central hypoadrenalism, J Clin Endocrinol Metab sourceNot checked — no full text of the source