Quality of life after long-term biochemical control of acromegaly.

PURPOSE: To assess long-term quality of life (QoL) in patients with sustained biochemical control of acromegaly, comparing those receiving vs not receiving pharmacotherapy (primary analysis); to assess change in QoL over time (secondary analysis). METHODS: Cross-sectional study, with a secondary longitudinal component, of 58 patients with biochemically controlled acromegaly. All had participated in studies assessing QoL years previously, after having undergone surgery ± radiotherapy. One cohort received medical therapy [MED (n = 33)]; the other did not [NO-MED (n = 25)]. QoL was assessed by the 36-Item-Short-Form Health Survey (SF-36), Acromegaly Quality of Life Questionnaire (AcroQoL), Gastrointestinal Quality of Life Index (GIQLI), Symptom Questionnaire, and QoL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). RESULTS: Mean (± SD) duration of biochemical control was 15.0 ± 6.4 years for MED and 20.4 ± 8.2 years for NO-MED (p = 0.007). 58% of subjects scored < 25% of normal on ≥ 1 SF-36 domain and 32% scored < 25% of normal on ≥ 4 of 8 domains. Comparing MED vs NO-MED and controlling for duration of biochemical control, there were no significant differences in QoL by SF-36, AcroQOL, GIQLI, Symptom Questionnaire, or QoL-AGHDA. Growth hormone deficiency (GHD) but not radiotherapy predicted poorer QoL. In MED, QoL improved over time in three AcroQoL domains and two GIQLI domains. In NO-MED, QoL worsened in two SF-36 domains and two Symptom Questionnaire domains; QoL-AGHDA scores also worsened in subjects with GHD. CONCLUSION: A history of acromegaly and development of GHD, but not pharmacologic or radiotherapy, are detrimental to QoL, which remains poor over the long-term despite biochemical control.

Effects of growth hormone receptor antagonism and somatostatin analog administration on quality of life in acromegaly.

OBJECTIVE: Acromegaly is associated with impaired quality of life (QoL). We investigated the effects of biochemical control of acromegaly by growth hormone receptor antagonism vs somatostatin analog therapy on QoL. DESIGN: Cross-sectional. PATIENTS: 116 subjects: n = 55 receiving a somatostatin analog (SSA group); n = 29 receiving pegvisomant (PEG group); n = 32 active acromegaly on no medical therapy (ACTIVE group). MEASUREMENTS: Acromegaly QoL Questionnaire (AcroQoL), Rand 36-Item Short Form Survey (SF-36) and Gastrointestinal QoL Index (GIQLI); fasting glucose, insulin and IGF-1 levels (LC/MS, Quest Diagnostics). RESULTS: There were no group differences in mean age, BMI or sex [(whole cohort mean ± SD) age 52 ± 14 years, BMI 30 ± 6 kg/m2 , and male sex 38%]. Mean IGF-1 Z-scores were higher in ACTIVE (3.9 ± 1.0) vs SSA and PEG, which did not differ from one another (0.5 ± 0.7 and 0.5 ± 0.7, P < .0001 vs ACTIVE). Eighty-three per cent of PEG previously received somatostatin analogs, which had been discontinued due to lack of efficacy (52%) or side effects (41%). There were no differences in the four QoL primary end-points (AcroQoL Global Score, SF-36 Physical Component Summary Score, SF-36 Mental Health Summary Score and GIQLI Global Score) between SSA and PEG. Higher HbA1c, BMI and IGF-1 Z-scores were associated with poorer QoL in several domains. CONCLUSION: Our data support a comparable QoL in patients receiving pegvisomant vs somatostatin analogs, despite the fact that the vast majority receiving pegvisomant did not respond to or were not able to tolerate somatostatin analogs.

Injection testosterone and adverse cardiovascular events: A case-crossover analysis.

CONTEXT: Exogenous testosterone administration may affect blood clotting, polycythaemia, and may increase atherosclerosis, though any association with cardiovascular events is unclear. While the literature is inconclusive, some studies have suggested testosterone use may increase short-term risk of cardiovascular events and stroke, and injection testosterone may convey higher risks than other dosage forms. OBJECTIVE: We sought to evaluate the short-term cardiovascular risk of receiving injection testosterone. DESIGN: We conducted a case-crossover analysis comparing injection testosterone exposure in the 7 days prior to an outcome event to referent windows in the past to estimate the acute association of cardiovascular outcomes with the receipt of testosterone injections. PATIENTS: We identified adult male testosterone users hospitalized with myocardial infarction (MI), stroke or a composite of MI, stroke or unstable angina in US commercial claims (2000-2013) or Medicare (2007-2010) databases. MEASUREMENTS: We identified testosterone use for the patients from pharmacy dispensing claims or in-office procedure codes in the insurance billing data. RESULTS: We identified 2898 commercially insured men with events and recent testosterone use, and 339 from Medicare. Injected testosterone was associated with an increased risk of adverse events (composite outcome of myocardial infarction, stroke or unstable angina) in the immediate postinjection period for the older, Medicare population only: commercial insurance, odds ratios (OR) = 0.98 (95% confidence intervals [CI]: 0.86-1.12); Medicare, OR = 1.45 (1.07, 1.98). This association was either greatly attenuated or not present when evaluating receipt of any testosterone dosage forms (injection, gel, patch, implant): commercial insurance, OR = 1.01 (0.92, 1.11); Medicare, OR = 1.26 (95% CI: 0.98-1.63). CONCLUSIONS: Testosterone injections were uniquely associated with short-term risk of acute cardio- and cerebrovascular events in older adult men following injection receipt.

Comparative Safety of Testosterone Dosage Forms.

IMPORTANCE: Increases in testosterone use and mixed reports of adverse events have raised concerns about the cardiovascular safety of testosterone. Testosterone is available in several delivery mechanisms with varying pharmacokinetics; injections cause spikes in testosterone levels, and transdermal patches and gels cause more subtle but sustained increases. The comparative cardiovascular safety of gels, injections, and patches has not been studied. OBJECTIVE: To determine the comparative cardiovascular safety of testosterone injections, patches, and gels. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted using administrative claims from a commercially insured (January 1, 2000, to December 31, 2012) and Medicare (January 1, 2007, to December 31, 2010) population in the United States and general practitioner records from the United Kingdom (January 1, 2000, to June 30, 2012). Participants included men (aged ≥18 years) who initiated use of testosterone patches, gels, or injections following 180 days with no testosterone use. Our analysis was conducted from December 11, 2013, to November 12, 2014. EXPOSURES: New initiation of a testosterone dosage form, with use monitored for up to 1 year. MAIN OUTCOMES AND MEASURES: Inpatient or outpatient medical records, diagnoses, or claims for cardiovascular and cerebrovascular events including myocardial infarction (MI), unstable angina, stroke, and composite acute event (MI, unstable angina, or stroke); venous thromboembolism (VTE); mortality; and all-cause hospitalization. RESULTS: We identified 544,115 testosterone initiators between the 3 data sets: 37.4% injection, 6.9% patch, and 55.8% gel. The majority of men in the Medicare cohort were injection initiators (51.2%), most in the US commercially insured population were gel initiators (56.5%), and the UK database included equal proportions of injections and gel users (approximately 41%). With analysis conducted using hazard ratios and 95% CIs, compared with men using gels, injection initiators had higher hazards of cardiovascular events (ie, MI, unstable angina, and stroke) (1.26; 1.18-1.35), hospitalization (1.16; 1.13-1.19), and death (1.34; 1.15-1.56) but not VTE (0.92; 0.76-1.11). Compared with gels, patches did not confer increased hazards of cardiovascular events (1.10; 0.94-1.29), hospitalization (1.04; 1.00-1.08), death (1.02; 0.77-1.33), or VTE (1.08; 0.79-1.47). CONCLUSIONS AND RELEVANCE: Testosterone injections were associated with a greater risk of cardiovascular events, hospitalizations, and deaths compared with gels. Patches and gels had similar risk profiles. However, this study did not assess whether patients met criteria for use of testosterone and did not assess the safety of testosterone among users compared with nonusers of the drug.

Metachronous Bilateral Testicular Leydig-Like Tumors Leading to the Diagnosis of Congenital Adrenal Hyperplasia (Adrenogenital Syndrome).

A 33-year-old male with a history of left testis Leydig cell tumor (LCT), 3-month status after left radical orchiectomy, presented with a rapidly enlarging (0.6 cm to 3.7 cm) right testicular mass. He underwent a right radical orchiectomy, sections interpreted as showing a similar Leydig cell-like oncocytic proliferation, with a differential diagnosis including metachronous bilateral LCT and metachronous bilateral testicular tumors associated with congenital adrenal hyperplasia (a.k.a. "testicular adrenal rest tumors" (TARTs) and "testicular tumors of the adrenogenital syndrome" (TTAGS)). Additional workup demonstrated a markedly elevated serum adrenocorticotropic hormone (ACTH) and elevated adrenal precursor steroid levels. He was diagnosed with congenital adrenal hyperplasia, 3ß-hydroxysteroid dehydrogenase deficiency (3BHSD) type, and started on treatment. Metachronous bilateral testicular masses in adults should prompt consideration of adult presentation of CAH. Since all untreated CAH patients are expected to have elevated serum ACTH, formal exclusion of CAH prior to surgical resection of a testicular Leydig-like proliferation could be accomplished by screening for elevated serum ACTH.

Evidence that GnRH decreases with gonadal steroid feedback but increases with age in postmenopausal women.

UNLABELLED: Studies of the effects of gonadal steroid negative feedback and age on the hypothalamic-pituitary axis in postmenopausal women (PMW) have identified significant but inconsistent changes in gonadotropin dynamics. In the current study, we investigated the effect of gonadal steroid replacement and age on overall GnRH secretion estimated by using submaximal GnRH receptor blockade. Twenty-four healthy PMW, 45-55 yr (n = 13) and 70-80 yr (n = 11), were studied. Subjects were studied at baseline (BL) on no hormone replacement therapy, after 1 month of transdermal estrogen (50 microg/d; E) and again after a further month of E and 7 d of transvaginal progesterone (100 mg bid; E + P). At each admission, blood was sampled every 30 min for 4 (BL and E) or 8 h (E + P) before and 10 h after sc administration of a submaximal dose (5 microg/kg) of the NAL-GLU GnRH antagonist ([Ac-D2Nal(1), D4ClPhe(2), DPal(3), Arg(5), DGlu(AA)(6), DAla(10)] GnRH). Percent inhibition of LH was calculated by expressing the difference between the nadir following GnRH antagonist administration and the preantagonist baseline as a percent of the baseline. Physiologic E and P levels were achieved with the appropriate hormone replacement regimens. Mean LH levels decreased from baseline with E alone and decreased further with E + P (81.4 +/- 6.6, 68.2 +/- 8.1 and 48.0 +/- 4.3 IU/liter, respectively; P < 0.005). Percent inhibition of LH following submaximal GnRH receptor blockade decreased with age (57.6 +/- 1.8% in young PMW vs. 51.4 +/-2.2% in old PMW; P < 0.05) implying an increase in GnRH secretion with age. There was an increase in percent inhibition of LH in response to submaximal GnRH receptor blockade with E and a further increase with E + P (54.8 +/-1.5%, 58.8 +/- 1.9% and 69.9 +/- 2.8%, respectively; P < 0.05), indicating a progressive decrease in endogenous GnRH secretion with gonadal steroid feedback. Mean LH and FSH levels were lower at baseline in old compared with young PMW. However, the effect of gonadal steroid feedback on endogenous GnRH secretion was similar in young and old PMW. IN CONCLUSION: 1) The overall quantity of GnRH secretion increases with age as demonstrated by the progressive decrease in LH inhibition following submaximal GnRH antagonist administration with increasing age; 2) E negative feedback is associated with a decrease in GnRH secretion (as indicated by an increased percent inhibition of LH following submaximal GnRH receptor blockade); 3) E2 and P are associated with a further decease in overall amount of GnRH secreted; and 4) Age does not dampen the inhibition of hypothalamic GnRH secretion by E and P in PMW.

Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011.

CONTEXT: New formulations, increased marketing, and wider recognition of declining testosterone levels in older age may have contributed to wider testosterone testing and supplementation in many countries. OBJECTIVE: Our objective was to describe testosterone testing and testosterone treatment in men in the United Kingdom and United States. DESIGN: This was a retrospective incident user cohort. SETTING: We evaluated commercial and Medicare insurance claims from the United States and general practitioner healthcare records from the United Kingdom for the years 2000 through 2011. PARTICIPANTS: We identified 410,019 US men and 6858 UK men who initiated a testosterone formulation as well as 1,114,329 US men and 66,140 UK men with a new testosterone laboratory measurement. MAIN OUTCOME MEASURES: Outcome measures included initiation of any injected testosterone, implanted testosterone pellets, or prescribed transdermal or oral testosterone formulation. RESULTS: Testosterone testing and supplementation have increased pronouncedly in the United States. Increased testing in the United Kingdom has identified more men with low levels, yet US testing has increased among men with normal levels. Men in the United States tend to initiate at normal levels more often than in the United Kingdom, and many men initiate testosterone without recent testing. Gels have become the most common initial treatment in both countries. CONCLUSIONS: Testosterone testing and use has increased over the past decade, particularly in the United States, with dramatic shifts from injections to gels. Substantial use is seen in men without recent testing and in US men with normal levels. Given widening use despite safety and efficacy questions, prescribers must consider the medical necessity of testosterone before initiation.

Comparison of multiple methods for identification of hyperprolactinemia in the presence of macroprolactin.

BACKGROUND: Macroprolactin is a large, heterogeneous form of prolactin with limited bioavailability. Detection of macroprolactin by different immunoassays varies widely. The objectives of this study were to determine the immunoreactivity of macroprolactin by the Ortho Clinical Diagnostics Vitros((R)) ECi prolactin immunoassay, establish the most effective method for interpreting the prolactin concentration after PEG-precipitation, and correlate the clinical features of hyperprolactinemia with the presence of macroprolactin. METHODS: PEG-precipitation was performed on 120 hyperprolactinemic specimens. Of these, 31 specimens with a recovery<80% were fractionated by GFC. Four different approaches for identifying true hyperprolactinemia were investigated. Clinical symptoms of hyperprolactinemia were determined by chart review. RESULTS: Macroprolactin was detected by the Vitros ECi prolactin immunoassay. Use of a PEG modified prolactin reference interval was effective for identifying hyperprolactinemia in the presence of macroprolactin. There was no difference in the prevalence of abnormal menses, galactorrhea, or abnormal MRI between those with and without macroprolactin (p>0.05). Accounting for macroprolactin in patients with hyperprolactinemia reduced the number of idiopathic cases. CONCLUSIONS: The Vitros ECi prolactin immunoassay detects macroprolactin. PEG-precipitation is an acceptable surrogate to detect hyperprolactinemia in the presence of macroprolactin when using a prolactin reference interval derived from PEG precipitated reference sera. Although testing for macroprolactin should not substitute for standard evaluation of hyperprolactinemia, identification of macroprolactin may clarify a diagnosis and direct appropriate therapy.

Predictors and incidence of central diabetes insipidus after endoscopic pituitary surgery.

OBJECTIVE: With the advent of minimally invasive endoscopic pituitary surgery, there has been concern that the technique may be associated with higher rates of complications such as diabetes insipidus (DI) than traditional approaches, particularly early in a center's experience. We report the incidence and predictors of diabetes insipidus in patients after endoscopic transnasal resection (minimally invasive pituitary surgery) of pituitary lesions. METHODS: Data were collected from hospital and clinic records on the first 119 consecutive patients undergoing endoscopic pituitary surgery at our center. RESULTS: The rate of postoperative diabetes insipidus is low in patients undergoing minimally invasive pituitary surgery (permanent, 2.7%; transient, 13.6%). Factors associated with development of DI after minimally invasive pituitary surgery include Rathke's cleft cyst histology, intraoperative cerebrospinal fluid leak, and previous nonendoscopic lesion resection. Elevated serum sodium (>145 mmol/L) within the first 5 days postoperatively has a high sensitivity (87.5%), specificity (83.5%), and negative predictive value (99.5%) for permanent postoperative DI development. CONCLUSION: Transitioning from microscopic to endoscopic pituitary surgery can be achieved with a low incidence of DI. An elevated serum sodium level in the first 5 postoperative days using standard monitoring can predict the chance of developing permanent DI. Patients having no elevated serum sodium measurements, defined as >145 mmol/L, in the first 5 days postoperatively will rarely, if ever, develop permanent DI, thereby validating short postoperative inpatient stays with minimal risk of readmission for DI management. Those with a single serum sodium measurement greater than 145 mmol/L have a 15% risk of developing permanent DI.