Impact of frailty on short-term outcomes in patients undergoing transsphenoidal pituitary surgery.

OBJECTIVE: Frailty, a state of decreased physiological reserve, has been shown to significantly impact outcomes of surgery. The authors sought to examine the impact of frailty on the short-term outcomes of patients undergoing transsphenoidal pituitary surgery. METHODS: Weighted data from the 2000-2014 National (Nationwide) Inpatient Sample were studied. Patients diagnosed with pituitary tumors or disorders who had undergone transsphenoidal pituitary surgery were identified. Frailty was determined using the Johns Hopkins Adjusted Clinical Groups (ACG) frailty-defining diagnoses indicator. Standard descriptive techniques and matched propensity score analyses were used to explore the odds ratios of postoperative complications, discharge dispositions, and costs. RESULTS: A total of 115,317 cases were included in the analysis. Frailty was present in 1.48% of cases. The mean age of frail versus non-frail patients was 57.14 ± 16.96 years (mean ± standard deviation) versus 51.91 ± 15.88 years, respectively (p < 0.001). A greater proportion of frail compared to non-frail patients had an age ≥ 65 years (37.08% vs 24.08%, respectively, p < 0.001). Frail patients were more likely to be black or Hispanic (p < 0.001), possess Medicare or Medicaid insurance (p < 0.001), belong to lower-median-income groups (p < 0.001), and have greater comorbidity (p < 0.001). Results of propensity score-matched multivariate analysis revealed that frail patients were more likely to develop fluid and electrolyte disorders (OR 1.61, 95% CI 1.07-2.43, p = 0.02), intracranial vascular complications (OR 2.73, 95% CI 1.01-7.49, p = 0.04), mental status changes (OR 3.60, 95% CI 1.65-7.82, p < 0.001), and medical complications including pulmonary insufficiency (OR 2.01, 95% CI 1.13-4.05, p = 0.02) and acute kidney failure (OR 4.70, 95% CI 1.88-11.74, p = 0.01). The mortality rate was higher among frail patients (1.46% vs 0.37%, p < 0.001). Frail patients also demonstrated a greater likelihood for nonroutine discharges (p < 0.001), higher mean total charges ($109,614.33 [95% CI $92,756.09-$126,472.50] vs $56,370.35 [95% CI $55,595.72-$57,144.98], p < 0.001), and longer hospitalizations (9.27 days [95% CI 7.79-10.75] vs 4.46 days [95% CI 4.39-4.53], p < 0.001). CONCLUSIONS: Frailty in patients undergoing transsphenoidal pituitary surgery is associated with worse postoperative outcomes and higher costs, indicating that state's potential role in routine preoperative risk stratification.

Consensus-driven in-hospital cortisol assessment after ACTH-secreting pituitary adenoma resection.

PURPOSE: Remission from Cushing disease (CD) after pituitary adenoma resection may be predicted by a postoperative reduction in serum cortisol level. A 2008 consensus statement recommends assessing morning cortisol levels during the first postoperative week, and replacing glucocorticoid (GC) if cortisol nadir of < 2 or < 5 µg/dL is achieved. We sought to evaluate adherence to consensus recommendations following adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma resection at our tertiary medical center, and assess time to cortisol nadir to better define the window for assessment and intervention. METHODS: We retrospectively analyzed data extracted from in-hospital electronic medical records for CD surgeries between January 1991 and September 2015. We compared cortisol levels and collection times, ACTH measurement, and postoperative and discharge GC treatment before and after consensus statement publication in July 2008. RESULTS: 107 surgeries were performed in 92 patients with CD. After 2008, more surgeries had at least one cortisol value assessed (67.9% before vs. 91.3% after, p = 0.033), with median initial cortisol measurement at 14 h post-surgery. However, ACTH measurement remained unchanged (42.9% vs. 43.5%; p > 0.99). Cortisol collection during GC treatment tended to increase (32.7% vs. 57.1%; p = 0.068). Of surgeries performed without prior GC treatment, 31.7 and 55.0% had a cortisol nadir of < 2 and < 5 µg/dL, respectively, within 72 h postoperative. CONCLUSIONS: Our physicians were more diligent in measuring in-hospital postoperative cortisol levels consistent with 2008 consensus recommendations. Better management of cortisol measurements and their timing is an opportunity for improvement.

Lower airway disease and pituitary surgery: Is there an association with postoperative cerebrospinal fluid leak?

OBJECTIVES/HYPOTHESIS: To explore the relationship between lower airway disease and postoperative cerebrospinal fluid (CSF) rhinorrhea among patients undergoing pituitary surgery STUDY DESIGN: Retrospective review. METHODS: A retrospective review of the Healthcare Cost and Utilization Project's 2013 National Inpatient Sample was conducted to characterize the hospital stay and surgical outcomes of patients undergoing pituitary surgery. Patients with lower airway disease (including chronic obstructive pulmonary disease and asthma) were compared to a disease-free population identifying demographics and complications over-represented in the lower airway group. RESULTS: The majority of hypophysectomies (92.1%) were performed via a transsphenoidal approach. Among transsphenoidal patients, individuals with asthma (92.8% of the lower airway disease cohort) harbored a greater postoperative CSF leak rate (4.7% vs. 2.7%, P = .022), and were more likely to develop postoperative diabetes insipidus (6.2% vs. 4.1%, P = .024) and neurological complications (13.0% vs. 9.6%, P = .010) when compared to a lower airway disease-free cohort. Patients with CSF rhinorrhea had longer lengths of stay (7.8 days vs. 4.5 days, P < .001) and higher discharge costs ($148,309 vs. $76,246, P < .001). A binary logistic regression model identified having asthma (P = .042), being female (P = .011), and having gastroesophageal reflux disease (P = .006) as independent predictors of postoperative CSF rhinorrhea. CONCLUSIONS: Several patient comorbidities including asthma are associated with a greater risk of postoperative CSF rhinorrhea. Perioperative lower airway assessment and disease control may potentially decrease one's risk of this complication, although further inquiry is urgently needed to identify optimal preventive strategies. LEVEL OF EVIDENCE: 2c. Laryngoscope, 127:1543-1550, 2017.

Assessment of the outcomes of the treatment of Cushing's disease in the hospitals of Castilla-La Mancha.

OBJECTIVE: Treatment of Cushing's disease poses interesting dilemmas in clinical practice. The aim of our study was to analyze the outcomes of the different treatments, the control and recurrence rates, and the complications derived from them. MATERIAL AND METHODS: Data were collected from the clinical records of 22 patients over 18 years of age (86.4% women). They had been diagnosed with Cushing's disease between 2000 and 2012, and were monitored at Complejo Hospitalario Universitario-Albacete, Hospital Virgen de la Salud-Toledo Hospital General Universitario de Ciudad Real, Hospital Virgen de la Luz-Cuenca, Hospital Nuestra Señora del Prado-Talavera de la Reina, and Complejo Hospitalario la Mancha Centro-Alcázar de San Juan. RESULTS: Surgery was the treatment of choice in all patients. Biochemical cure was achieved in 72.2% of patients. Nine patients developed in the early postoperative period diabetes insipidus, which became in 2 patients only. Surprisingly, 3 patients with normal postoperative neurohypophyseal function later developed permanent diabetes insipidus. New hormone deficiencies occurred in 7 patients. Seventeen patients received ketoconazole before surgery (5 of them after surgery also), and 70% of them achieved normal urinary free cortisol levels. Three patients also received radiotherapy, and all of them were cured after a median follow-up of 85.5 months; they developed no tumors or other complications. CONCLUSIONS: Our study reports the outcomes of management of Cushing's disease in non-reference centers for this disease, possibly giving a realistic picture of standard clinical practice for the condition in Spain.

Current trends in surgical approach and outcomes following pituitary tumor resection.

OBJECTIVES/HYPOTHESIS: The goals of pituitary tumor resection include normalizing endocrine function, relieving mass effect, and minimizing risk of recurrence. This study investigated current trends in costs and complications for transfrontal and transsphenoidal pituitary surgery. STUDY DESIGN: Retrospective review of the 2008-2011 Nationwide Inpatient Sample for patients undergoing pituitary lesion resection. METHODS: Demographics and outcomes were compared between transfrontal and transsphenoidal surgical approaches using χ(2) tests. Multivariate analysis was performed to investigate outcomes while controlling for confounders. RESULTS: There were 8,543 admissions for resection of pituitary lesions that met our inclusion criteria. Most (>90%) were treated transsphenoidally. The transfrontal approach was most frequent in the young (<35 years) and in the South. Rates of mortality and complications were higher in patients undergoing transfrontal surgery. Multivariate analysis found transsphenoidal resection was associated with a reduction in hospital costs and length of stay by over 50%; low-volume hospitals had increased cost and length of stay. There was an increased rate of transfrontal approaches at low-volume centers. CONCLUSIONS: Multiple factors influence outcomes of pituitary tumor resection. Transsphenoidal pituitary surgery is associated with a shorter length of stay, lower cost, and lower complication rates when compared to transfrontal surgery. Case specifics, including tumor location and size, influence approach and lead to a selection bias that cannot be controlled for in the present study. The prevalence of transfrontal resections at low-volume centers may indicate an area of further investigation. Additionally, when controlling for surgical approach, low-volume centers were found to adversely affect economic outcomes and also warrants investigation. LEVEL OF EVIDENCE: 2c.

Cost-effectiveness of the endoscopic versus microscopic approach for pituitary adenoma resection.

OBJECTIVES/HYPOTHESIS: To evaluate the cost-effectiveness of an endoscopic versus microscopic approach to pituitary adenoma resection. STUDY DESIGN: Markov decision tree economic evaluation. METHODS: An economic evaluation using a Markov decision tree model was performed. The economic perspective was that of the healthcare third-party payer. Effectiveness and probability data were obtained from a single meta-analysis of 38 studies. Costs were obtained from the Healthcare Cost and Utilization Project database and wholesale pharmaceutical pricing. Multiple sensitivity analyses were performed including a probabilistic sensitivity analysis. Comparative treatment groups were: 1) endoscopic approach and 2) microscopic approach to pituitary adenoma resection. The primary outcome was cost per quality-adjusted life year (QALY). The time horizon was 25 years, and costs were discounted at a rate of 3.5%. RESULTS: The endoscopic approach cost a total of $17,244.63 and produced a total of 24.30 QALYs. The microscopic approach cost a total of $23,756.60 and produced a total of 24.20 QALYs. In the reference case, the endoscopic approach was a dominant intervention (both less costly and more effective); therefore, an incremental cost-effectiveness ratio was not calculated. The sensitivity analysis demonstrated 79% certainty that the endoscopic approach is the cost-effective decision, at a willingness to pay threshold of $50,000 per QALY. CONCLUSIONS: This economic evaluation suggests that the endoscopic approach is the more cost-effective intervention compared to the microscopic approach for patients requiring a pituitary adenoma resection.

Selective use of the insulin tolerance test to diagnose hypopituitarism.

The insulin tolerance test is considered the gold standard for assessing the hypothalamic-pituitary-adrenal and growth hormone (GH) axes, but its use varies considerably among different endocrine units. We recommend using the insulin tolerance test to assess the hypothalamic-pituitary-adrenal axis within 3 months of pituitary surgery, where adrenocorticotropic hormone 1-24 testing is equivocal, and to assess for GH deficiency where the patient is being considered for GH replacement therapy. We also discuss safety issues, how to ensure adequate hypoglycaemia and possible alternative tests, such as the overnight metyrapone test and glucagon test.

[Epidemiology of acromegaly in Spain]. / Epidemiología de la acromegalia en España.

Epidemiology of acromegaly in Spain does not differ from that reported in other published series. Prevalence rate is approximately 60 cases per million, peak incidence occurs in middle age, more women are affected (61%), and there is a substantial delay between occurrence of the first symptoms and diagnosis. Studies REA (Spanish Acromegaly Registry) and OASIS analyzed the epidemiology, clinical characteristics, and management of the disease in Spain. Surgery, performed in more than 80% of patients, has been (and continues to be) the main treatment for the past four decades. In the past decade, however, more patients have received somatostatin analogs (SSAs) as first-line treatment. Use of radiation therapy has significantly decreased in recent decades. Somatostatin analogs (SSAs) are the most commonly used drugs, administered to 85% of patients; however, only 12%-15% continue on drug treatment alone. The surgical remission rate was 38.4% in the last decade, with a significant improvement over decades. Preoperative treatment with SSAs has no influence on surgical cure rates. Second-line therapies used after surgical failure in the past decade included SSAs in 49% of patients, repeat surgery in 27%, radiotherapy in 11%, pegvisomant in 15%, and dopamine agonists in 5%. Mean cost of acromegaly treatment was 9.668€ (data estimated in 2009 and adjusted in 2010), of which 71% was due to the cost of SSAs. Patients treated with pegvisomant have a more aggressive form of the disease and higher comorbidity rates.

Treatment-related morbidity and the management of pediatric craniopharyngioma: a systematic review.

OBJECT: Craniopharyngiomas are benign tumors but their close anatomical relationship with critical neurological, endocrine, and vascular structures makes gross-total resection (GTR) with minimal morbidity difficult to achieve. Currently, there is controversy regarding the extent, timing, and modality of treatment for pediatric craniopharyngioma. METHODS: The authors performed a systematic review of the published literature on pediatric craniopharyngioma to determine patterns of clinical practice and the reported outcomes of standard treatment strategies. This yielded 109 studies, which contained data describing extent of resection for a total of 531 patients. Differences in outcome were examined based upon extent of resection and choice of radiation treatment. RESULTS: Gross-total resection was associated with increased rates of new endocrine dysfunction (OR 5.4, p < 0.001), panhypopituitarism (OR 7.8, p = 0.006), and new neurological deficits (OR 9.9, p = 0.03) compared with biopsy procedures. Subtotal resection (STR) was not associated with an increased rate of new neurological deficits. Gross-total was associated with increased rates of diabetes insipidus (OR 7.7, p = 0.05) compared with the combination of STR and radiotherapy (RT). The addition of RT to STR was associated with increased rates of panhypopituitarism (OR 9.9, p = 0.01) but otherwise similar rates of morbidities. CONCLUSIONS: Although subject to the limitations of a literature review, this report suggests that GTR is associated with increased rates of endocrinopathies compared with STR + RT, and this should be considered when planning goals of surgery.

Variations in referral patterns for hypophysectomies among pediatric patients with sellar and parasellar tumors.

PURPOSE: It has been shown that patients admitted to high-volume hospitals for resection of sellar and parasellar lesions experience reduced mortality and morbidity. It remains unknown what preoperative factors influence admission to high-volume centers. We report a nationwide analysis of patients <18 years of age undergoing neurosurgical intervention for these lesions. METHODS: A retrospective analysis of the Nationwide Inpatient Sample was performed with additional factors from the Area Resource File. International Classification of Diseases, 9th Revision diagnosis/procedural codes were used to identify patients undergoing resection of tumors from the pituitary gland or related structures. Patients >or=18 years old were excluded. Covariates included age, gender, race, and insurance status. Multivariate analysis was performed using multiple logistic regression models. A p value <0.05 was considered statistically significant. RESULTS: In total, 1,063 patients were identified. Most (69.8%) were seen at low-volume centers. Mean (median) patient age was 13.7 (15) years. The majority of patients were female (54.8%), white (61.9%), and insured (90.3%). Hispanics were 44% less likely (odds ratio (OR) 0.56, 95% confidence interval (CI) 0.34-0.92, p < 0.05) to be seen at high-volume centers than their Caucasian counterparts. Each increase in 2-year patient age category was associated with greater access to high-volume centers (OR 1.12, 95% CI 1.03-1.23, p < 0.05), relative to 0-2 years old. Female gender, insurance status, county poverty, neurosurgeon density, and calendar year were not significantly associated with admission to high-volume centers. CONCLUSIONS: Age and racial disparities play a significant role in access neurosurgical care, affecting admission of pediatric patients to high-volume neurosurgical centers across the USA.

[Cost-effectiveness analysis of two therapeutic methods for prolactinoma].

OBJECTIVE: To evaluate the therapeutic responses to transsphenoidal surgery and medical therapy in terms of normalization of prolactin (PRL), mortality, morbidity and the cost-effectiveness of PRL normalization in order to establish an individualized therapeutic protocol for the patients with prolactinoma. METHODS: A retrospective study was undertaken of a consecutive series of patients with prolactinoma who were followed for at least 1 year after transsphenoidal surgery or medical treatment. The clinical characteristics and the long-term outcomes (normalization of PRL, morbidity or mortality) were assessed. Utilizing the principle of medical economics and data from the two types of treatment, we worked out a Markov chain and calculated the lowest cost of two kinds of therapeutic protocols. RESULTS: (1) The success rate of normalizing serum PRL through surgical treatment in microadenoma was 85% (22/26), and that of medical treatment was 95% (19/20). There was no statistical difference between the two therapies (P > 0.05). The success rate of normalizing serum PRL through surgical treatment in macroadenoma was 45% (19/42), and that of medical treatment was 5/5. There was a statistical difference between the two therapies (P < 0.05). (2) According to the Markov model, it would cost a microprolactinoma patient 25,129.25 yuan to normalize serum PRL by surgical treatment. This is comparable to the cost of medical treatment which would be 24,943.99 yuan. Whereas for a macroprolactinoma patient surgery would cost 35,208.20 yuan and medical treatment would cost 25,344.38 yuan. CONCLUSIONS: Medical therapy is superior to surgical treatment in regard to complication rate and cost-effectiveness for macro- and extra big prolactinomas. Transsphenoidal surgery remains an option for patients with microadenomas. Markov model is an effective way to predict the treatment cost for patients with hyperprolactinoma at different ages and with different causes.

Pre-operative assessment of patients undergoing endoscopic, transnasal, transsphenoidal pituitary surgery.

OBJECTIVE: To demonstrate the importance of pre-operative ear, nose and throat assessment in patients undergoing endoscopic, transsphenoidal surgery for pituitary tumours. CASE REPORTS: Literature pertaining to the pre-operative otorhinolaryngological assessment and management of patients undergoing endoscopic anterior skull base surgery is sparse. We describe two cases from our series of 59 patients undergoing endoscopic pituitary surgery. The first case involved a young male patient with a large pituitary macroadenoma. His main complaint was visual impairment. He had no previous history of sinonasal pathology and did not complain of any nasal symptoms during the pre-operative neurosurgical assessment. At the time of surgery, a purulent nasal discharge was seen emanating from both middle meati. Surgery was abandoned due to the risk of post-operative meningitis, and postponed until the patient's chronic rhinosinusitis was optimally managed. The second patient was a 47-year-old woman with a large pituitary macroadenoma, who presented to the neurosurgical department with a main complaint of diplopia. She too gave no history of previous nasal problems, and she underwent uneventful surgery using the endoscopic, transnasal approach. Two weeks after surgery, she presented to the emergency unit with severe epistaxis. A previous diagnosis of hereditary haemorrhagic telangiectasia was discovered, and further surgical and medical intervention was required before the epistaxis was finally controlled. CONCLUSIONS: Pre-operative otorhinolaryngological assessment is essential prior to endoscopic pituitary or anterior skull base surgery. A thorough otorhinolaryngological history will determine whether any co-morbid diseases exist which could affect the surgical field. Nasal anatomy can be assessed via nasal endoscopy and sinusitis excluded. Computed tomography imaging is a valuable aid to decisions regarding additional procedures needed to optimise access to the pituitary fossa.

Recombinant rat and mouse growth hormones: risk assessment of carcinogenic potential in 2-year bioassays in rats and mice.

Recombinant rat growth hormone (rrGH) and recombinant mouse growth hormone (rmGH) were developed to evaluate the potential carcinogenicity of each biologically active growth hormone (GH) as assessed in the respective species. Biological activities of rrGH and rmGH were demonstrated by showing an increase in body weight gain and serum levels of insulin-like growth factor-1 (IGF-1) in hypophysectomized rats receiving daily sc injections for 6 days. With the exception of pharmacologically mediated weight gain, rrGH and rmGH had no adverse effects in 5-week oral toxicity studies and no production of anti-recombinant GH antibodies. The high doses selected for the carcinogenicity studies provided systemic exposures of GH up to approximately 10-fold over basal levels. In the 105-week mouse carcinogenicity study, daily sc injections of rmGH at 0.1, 0.2, or 0.5 mg/kg/day were well tolerated and had no effects on survival or incidence of tumors. In the 106-week rat carcinogenicity study, daily sc injections of rrGH at 0.2, 0.4, or 0.8 mg/kg/day had a favorable effect on longevity in female rats administered 0.4 or 0.8 mg/kg/day, an increased weight gain in females and males, and no increase in the incidence of tumors. The absence of carcinogenic effects of recombinant GH administered daily for 2 years to rodents was consistent with publications of clinical experience, indicating a lack of convincing evidence for an increased risk of cancer in children receiving human recombinant GH replacement therapy.

The long-term predictive accuracy of the short synacthen (corticotropin) stimulation test for assessment of the hypothalamic-pituitary-adrenal axis.

CONTEXT: The high-dose short Synacthen (corticotropin) test (SST) is widely used to investigate suspected secondary adrenal insufficiency, but concern remains about falsely reassuring results. OBJECTIVE: Our objective was to evaluate the long-term safety of the SST. METHOD: We retrospectively evaluated the clinical outcome in 178 patients who achieved 30-min cortisol values in the lowest 15th percentile of normal healthy responses. Thirty patients were later excluded because of missing case notes (20 patients) or unsubstantiated pituitary pathology (10 patients). The remaining 148 patients were divided into two groups: group 1, patients with cortisol response between the 5th and 15th percentiles of normal response (551-635 nmol/liter, 98 patients); and group 2, patients with borderline response between the 2.5th and 5th percentiles (510-550 nmol/liter, 50 patients). Patients did not receive routine glucocorticoid therapy, but those in group 2 were advised to take hydrocortisone in case of intercurrent illness. RESULTS: The median follow-up period from the initial SST was 4.2 yr (range, 4 months to 7 yr). A total of 137 patients showed no clinical or biochemical evidence of adrenal insufficiency during follow-up. Of the remaining 11 patients, seven became hypoadrenal after subsequent pituitary surgery or radiotherapy, one patient in group 1 developed adrenal insufficiency at 2 yr, and one patient in group 2 developed adrenal insufficiency at 6 months. The other two patients who were in group 2 had clinical diagnostic uncertainty. CONCLUSION: The high-dose SST is safe for the purpose of excluding clinically significant secondary adrenal insufficiency and is indicated as the first line of investigation for this purpose.

Assessment of the postoperative discomfort of intra-auricularly hypophysectomized rats.

Rats subjected to hypophysectomy make up one of the largest groups of experimental animals in Europe, since there is a legal demand for batch testing of industrially produced growth hormones. To describe the clinical performance of rats having undergone hypophysectomy, animals were examined postoperatively by monitoring behaviour, body temperature and food intake. Behavioural changes were observed in rats that had only been anaesthetized, as well as in sham-operated rats, while no behavioural deviations could be shown in hypophysectomized rats. On the first day after surgery all rats had declining body temperature and food intake; and this change was not reversed by treatment with carprofen, buprenorphine or oxytetracycline. The mortality rate in rats treated with buprenorphine was increased, as was the mortality rate in rats hypophysectomized when weighing more than 100 g. As there seemed to be no differences whether methohexital or a combination of fentanyl, fluanison and midazolam was used, the latter anaesthesia is recommended due to its analgesic potential. For post-surgical analgesic treatment, carprofen is recommended rather than buprenorphine. At best, the use of hypophysectomized rats should be replaced in industrial batch testing by an existing in vitro method.

Assessment of the in vitro and in vivo biological activities of the human follicle-stimulating isohormones.

Gonadotropins are synthesized and released in different molecular forms. In this article, we present evidence that the glycosylation variants of human pituitary FSH exhibit differential and divergent effects at the target cell level and that less sialylated, short-lived variants may exert significant effects in in vivo conditions. Less acidic/sialylated glycoforms (elution pH value 6.60-4.60 as disclosed by high resolution chromatofocusing of anterior glycoprotein extracts), induced higher cAMP release, estrogen production and tissue-type plasminogen activator (tPA) enzyme activity as well as cytochrome P450 aromatase and tPA mRNA expression in cultured rat granulosa cells than the more acidic analogs (pH<4.76). By contrast, the more acidic/sialylated glycoforms induced higher alpha-inhibin subunit mRNA expression than their less acidic counterparts. In cumulus enclosed oocytes isolated from mice ovaries, addition of less acidic isoforms induced resumption of meiosis more efficiently than the more acidic analogs. Interestingly, the least acidic isoform (pH>7.10) behave as a strong antagonist of several FSH-mediated effects. Assessment of the in vivo effects of the isoforms on granulosa cell proliferation in follicles from immature rats, revealed that short-lived isoforms were equally or even more efficient than their more acidic counterparts in maintaining granulosa cell proliferation when administered immediately after hypophysectomy. These results show that the naturally occurring human FSH isoforms may exhibit differential or even unique effects at the target cell level and that factors other than the metabolic clearance rate of the molecule (including receptor-binding affinity and capability of the ligand to activate its receptor and trigger intracellular signaling) also play an important role in determining the net in vivo effects of a particular FSH variant.

The insulin hypoglycaemia and overnight metyrapone tests in the assessment of the hypothalamic-pituitary-adrenal axis following pituitary surgery.

OBJECTIVE: To compare the insulin hypoglycaemia test with the short overnight metyrapone test in the assessment of the hypothalamic-pituitary-adrenal (HPA) axis posthypophysectomy. DESIGN: Prospective comparative study of the insulin hypoglycaemia test and the overnight metyrapone test in 32 patients 4-6 weeks after pituitary surgery. SUBJECTS: Thirty-two patients with known pituitary disease. None with present or previous Cushing's syndrome. OUTCOME MEASUREMENTS: Maximum serum cortisol achieved during insulin induced hypoglycaemia compared with 0900 hours serum 11-deoxycortisol level following a weight related oral dose of metyrapone at 0000 h. RESULTS: One of the 32 patients required further surgery and was studied twice after each operation. Thirty-three results are therefore compared. Twenty-six of these had a normal cortisol response of 550 nmol/l or above leading to the cessation of replacement hydrocortisone. Six of these 26 patients however, failed the metyrapone test (11-deoxycortisol level less than 200 nmol/l). After 3-40 months (median 20 months) of follow-up off steroid therapy, no patient to date has displayed any clinical evidence of steroid deficiency. Of the seven patients who failed the insulin hypoglycaemia test, six also failed the metyrapone test. CONCLUSIONS: The overnight metyrapone test identified more patients with possible ACTH deficiency than the insulin hypoglycaemia test. Further follow-up of these patients is required before a final judgement can be made as to whether more subtle but clinically relevant ACTH deficiency can be detected by the metyrapone test. Our clinical follow-up to date would not support this.

Assessment of estrogenicity by using the delayed implanting rat model and examples.

Endocrine disrupting chemicals have recently drawn increased interest. The delayed implanting rat model is a method that can identify and quantify the estrogenic activity of a chemical. In rats hypophysectomized after breeding, the administration of progesterone delays embryo implantation, and exposure to one dose of an estrogenic substance initiates implantation. Although methoxychlor was ineffective at dosages below 400 mg/kg when given by injection, the administration of the chemical by gavage resulted in an increase in the percent of fertilized rats exhibiting implantation sites. These results were statistically significant at dosages of 50, 100, 200, and 300 mg methoxychlor/kg. When bisphenol A was administered, by subcutaneous injection, dosages of 50, 100, and 200 mg/kg induced implantation. Only the 400 mg/kg dose of 4-tert-octylphenol was effective. Doses of beta-sitosterol up to 30 mg/kg failed to initiate implantation. These data confirm previous evidence of the availability of this model for evaluating estrogenic activity and provide estimates of the estrogenic potencies of several environmentally important chemicals.