Clinical features, presentation and hormonal parameters in patients with pubertal gynecomastia.

OBJECTIVE: Gynecomastia is benign enlargement of breast in male. It is postulated that its development is primarily due to a mismatch in ratio of oestrogen and androgen at breast tissue. The aim of this study was to highlight the clinical features, presentation and hormonal parameters at the time of consultation. METHODS: All adolescent patients who attended endocrinology department with the complaint of breast enlargement were taken into study. We analysed their thyroid function test, oestrogen, testosterone, prolactin, alpha-fetoprotein, follicle-stimulating hormone, luteinizing hormone, beta HCG (human chorionic gonadotropin) and liver function. Clinical features and anthropometry were recorded. RESULTS: Out of 50 patients enrolled, 34 (68%) had bilateral gynaecomastia while 16 patients (32%) had unilateral disease. Mastalgia was seen in 44 patients (88%). Psychological disturbance in the form of depression was seen in 60% of adolescent boys with gynecomastia. Tanner stage B had positive correlation with oestrogen to testosterone (E2/TTE) ratio (r = 0.47; P = 0.034). All other hormonal parameters were normal. CONCLUSION: Mastalgia was one of the presenting complaints in majority of patients and many had bilateral enlargement. Altered oestrogen to testosterone ratio is altered in majority of patients thus may be reason for pubertal gynecomastia.

Cushing disease with pregnancy.

Pregnancy occurs rarely in patients with Cushing syndrome (CS) due to hypercortisolism. So far, about 150 cases of CS in pregnancy have been reported in the literature. We describe a 22-year-old female who presented in pregnancy with clinical features of CS. She delivered at 34 weeks of gestation and baby had transient adrenal insufficiency in the neonatal period. Mother underwent transsphenoidal surgery 1 year postpartum and on follow up she is under remission. Neonatal hypoadrenalism should be anticipated in maternal CS.

Ectopic posterior pituitary and stalk abnormality predicts severity and coexisting hormone deficiencies in patients with congenital growth hormone deficiency.

Certain pituitary imaging abnormalities are a specific indicator of hypopituitarism. The objective of this study is to compare phenotypical features with radiological findings in patients with congenital growth hormone deficiency (GHD). Magnetic Resonance imaging (MRI) was performed in 103 patients [72 with Isolated GHD (IGHD) and 31 with Combined Pituitary Hormone Deficiency (CPHD)]. Images were assessed for the following abnormalities: (1) small/absent anterior pituitary, (2) thin or interrupted pituitary stalk (PSA), and (3) Ectopic posterior pituitary (EPP), and (4) others. Radiological findings were correlated with the clinical and biochemical parameters. MRI abnormalities were observed in 48.6% patients with IGHD, 93.5% with CPHD. Jaundice, hypoxia, hypoglycemia and breech deliveries were more common in EPP/PSA group. EPP/PSA was observed in 87.1% patients with severe GHD (peak GH < 3 µg/L) as compared to 12.9% with mild to moderate GHD (peak GH: 3-10 µg/L). Amongst CPHD, EPP/PSA was present in 80% of subjects with associated hypocortisolism ± hypothyroidism as compared to 18.2% of subjects with hypogonadism. Over a mean follow up period of 4.5 years, 5.4% of subjects with IGHD and abnormal MRI progressed to CPHD while none of those with normal MRI progressed. This study emphasizes a significant clinico-radiological correlation in Asian Indian GHD patients. MRI abnormalities in the hypothalamic pituitary area, especially EPP/PSA are more common in patients with CPHD and severe GHD. Among CPHD, EPP/PSA predicts association with hypothyroidism or hypocortisolism. IGHD with MRI abnormality may evolve into CPHD.

Phenotype and radiological correlation in patients with growth hormone deficiency.

OBJECTIVE: To confirm that MRI findings like hypoplastic anterior pituitary, thin or interrupted pituitary stalk, and ectopic posterior pituitary (EPP) in patients with growth hormone deficiency are a good indicator of the severity of hypopituitarism. METHODS: MR images were obtained for 44 patients (IGHD: CPHD; 30:14) and analyzed to define one or more of the following triad of abnormalities: small/absent anterior pituitary, thin or interrupted pituitary stalk, and EPP, as well as for any other associated anomalies. The findings were correlated with the clinical and biochemical presentation. RESULTS: Pituitary abnormalities were common in both groups (53% with IGHD, 79% with CPHD). Breech delivery, neonatal hypoglycemia, jaundice, micropenis, birth asphyxia occurred more commonly in CPHD compared to IGHD. In patients whose peak growth hormone (GH) level was less than 3 ng/ml (n: 37), 68% had the MR triad; while none of them with GH>3 ng/ml had pituitary abnormality on MRI. CONCLUSIONS: The presence of structural anomalies in the hypothalamic pituitary area in patients with GHD suggests severity of hypopituitarism and MRI of hypothalamic pituitary area may aid in diagnosis of patients with suspected GHD.

Cushing disease in children and adolescents: twenty years' experience in a tertiary care center in India.

OBJECTIVE: To analyze the clinical presentation, diagnostic evaluation, treatment modalities, and follow-up of pediatric patients with Cushing disease. METHODS: In this retrospective analysis, we reviewed records of children (younger than 20 years) with Cushing disease who had undergone transsphenoidal adenomectomy in a tertiary health care center in India during the period of 1988 to 2008. Endogenous hypercortisolism was identified by a serum cortisol value ≥1.8 µg/dL during a low-dose dexamethasone suppression test (LDDST) with or without elevated midnight serum cortisol (≥3.2 µg/dL). Corticotropin dependence was defined by a basal plasma corticotropin concentration ≥5 pg/mL. Patients with normal pituitary imaging underwent bilateral inferior petrosal sinus sampling (BIPSS). Those with persistent or recurrent disease after surgery were treated with second-line interventions on a case-by-case basis. RESULTS: Twenty-nine boys and 19 girls were included. Mean age was 14.85 (±2.5) years. Weight gain (98%), round facies (98%), and growth arrest (83%) were the most common manifestations. LDDST and midnight cortisol had 100% sensitivity for detecting endogenous hypercortisolism, while midnight corticotropin measurement had 100% sensitivity for defining corticotropin dependence. Magnetic resonance imaging and unstimulated BIPSS had 71% and 89% sensitivity, respectively, for diagnosing Cushing disease. Twenty-seven patients (56%) achieved remission after the first transsphenoidal operation with higher remission rates in those with microadenoma (75%). Basal serum cortisol <5 mg/dL on the fifth postoperative day predicted cure. Eight patients received postoperative radiotherapy, with 4 achieving remission. CONCLUSIONS: Clinical presentation and diagnostic yield with various tests were similar to those previously reported in the literature. Remission rates were poor after first transsphenoidal operation in patients with macroadenoma and outcome was dismal with a second transsphenoidal operation. Serum cortisol concentration <5 mg/dL on the fifth postoperative day predicted cure.

Clinical profile of insulinoma: analysis from a tertiary care referral center in India.

OBJECTIVE: To describe the clinical presentation, localization techniques, surgical procedures and outcome in patients with insulinoma. METHODS: Retrospective analysis of case records of patients diagnosed with insulinoma between January 1993 and June 2009 at a tertiary-care hospital was done. Seventeen patients underwent diagnostic 72-h fast. The sensitivity of computed tomography (CT) of pancreas was judged using intraoperative findings as the gold standard. RESULTS: Twenty-six patients (19 women) with mean age 42.2 years (median age 39.5 years) with biochemical/imaging evidence of insulinoma were included. All patients who underwent 72-h fast developed symptomatic hypoglycemia within 48 h. The sensitivity and positive predictive value (PPV) of CT of pancreas was 68.4% and 92.8%, respectively. Twenty patients underwent surgery, of whom four were operated on without preoperative localization. Four patients had recurrence of symptoms. Of the six patients who were not operated upon, the lesion was localized in four. CONCLUSION: This audit shows that all patients with insulinoma develop hypoglycemia within 48 h of fasting. CT of pancreas localizes the lesion in two thirds of cases and would be a useful initial investigation in patients with suspected insulinoma.

Bone age and factors affecting skeletal maturation at diagnosis of paediatric Cushing's disease.

Paediatric Cushing's disease (CD) is usually associated with growth retardation, but there are only few published data on skeletal maturation at diagnosis. We analysed factors contributing to skeletal maturation and final height in Asian Indian patients with paediatric CD. We conducted retrospective analysis of 48 patients (29 males; 19 females) with mean age: 14.84 years at diagnosis (range 9-19 years). A single observer using the Greulich Pyle method determined the bone age (BA) of each child. BA delay, i.e. the difference between chronological age (CA) and BA, was compared with clinical and biochemical variables. BA delay was present in 35/48 (73%) patients (mean delay 1.6 years, range 0.5-5 years) and correlated negatively with height SDS (r = -0.594, P < 0.001) and positively with CA at diagnosis (r = 0.247, P < 0.05). There was no correlation with duration of symptoms before diagnosis, basal cortisol, midnight cortisol, ACTH or percentage suppression of low dose dexamethasone suppression cortisol (LDDST). We could not demonstrate any relationship between the duration of history before diagnosis and height SDS at final height. Mean final height SDS in patients was -1.84. We found that most children with CD had delayed BA and correlated significantly with CA and height SDS at diagnosis. Early diagnosis may reduce delay in skeletal maturation and thus contribute to optimal catch-up growth.

Efficacy of cabergoline in uncured (persistent or recurrent) Cushing disease after pituitary surgical treatment with or without radiotherapy.

OBJECTIVE: To evaluate the efficacy of cabergoline therapy in patients with Cushing disease who remained uncured (had persistent or recurrent disease) after a pituitary surgical procedure with or without radiotherapy. METHODS: We undertook a prospective, open-label, single-arm study, with short-term (5 months) and longterm (1 year) evaluations. In 20 patients with uncured Cushing disease, treatment was initiated with cabergoline at a dosage of 1 mg/wk, with a monthly increment of 1 mg, until midnight serum cortisol (MNSC) or low-dose dexamethasone suppression serum cortisol (LDSC) (or both) normalized or a maximal dosage of 5 mg/wk was reached. RESULTS: Overall, 5 of 18 patients (28%) responded in terms of LDSC or MNSC (or both) at a mean dosage of 3.6 mg/wk (range, 2 to 5). When the response was defined with use of either LDSC or MNSC level as an isolated criterion, it was achieved in 4 of 16 patients (25%) and 3 of 18 patients (17%), respectively. Four patients were treated for 1 year, and the response was persistent in 2 and 3 patients on the basis of MNSC and LDSC levels, respectively. Lower baseline serum cortisol (basal, MNSC, and LDSC) values were predictive of a therapeutic response. CONCLUSION: Cabergoline was an effective therapy in 28%, 25%, and 17% of patients with uncured Cushing disease in terms of LDSC or MNSC (or both), LDSC alone, and MNSC alone, respectively. Further studies are needed to address the persistence of the drug response and the effects on the dynamics of the hypothalamic-pituitary-adrenal axis.

Radiotherapy in paediatric Cushing's disease: efficacy and long term follow up of pituitary function.

Pituitary radiotherapy (RT) is an effective second-line treatment for paediatric Cushing's disease (CD). We report long-term efficacy and anterior pituitary function in a cohort of paediatric CD patients treated with RT. Between 1988 and 2008, from our cohort of 48 paediatric CD patients, eight paediatric CD patients (5 males and 3 females) underwent second-line pituitary RT (45 Gy in 25 fractions), following unsuccessful transsphenoidal surgery. Out of eight whose long term follow up is available, four patients were cured by RT. Minimum follow up of 2 years is available for all patients. Four patients achieved cure after RT. Two patients were not cured even after follow up of 60 and 132 months, respectively. Out of four uncured patients, two of them had suppressible low dose dexamethasone cortisol with altered circadian rhythm suggesting possibility of response in near future with follow up of just 26 months. Five patients were hypogonadal and one patient was hypothyroid. All patients were below their target height at the time of last follow up. None of the patients had posterior pituitary dysfunction. This series of patients illustrates the efficacy and long-term follow up of pituitary function in children with CD treated with RT. This study also emphasizes the need of growth hormone statues assessment and timely intervention.

Prepubertal gynecomastia a rare complication of growth hormone therapy.

We report a case of prepubertal gynecomastia diagnosed during growth hormone (GH) treatment. In our patient gynecomastia appeared 6 months after GH was started. This condition appears to be self-limited and benign. In our patient gynaecomastia resolved on its own.

Treatment of hypogonadism with testosterone in patients with type 2 diabetes mellitus.

OBJECTIVE: To investigate the effect of testosterone treatment on insulin resistance, glycemic control, and dyslipidemia in Asian Indian men with type 2 diabetes mellitus (T2DM) and hypogonadism. METHODS: We conducted a double-blind, placebo-controlled, crossover study in 22 men, 25 to 50 years old, with T2DM and hypogonadism. Patients were treated with intramuscularly administered testosterone (200 mg every 15 days) or placebo for 3 months in random order, followed by a washout period of 1 month before the alternative treatment phase. The primary outcomes were changes in fasting insulin sensitivity (as measured by homeostasis model assessment [HOMA] in those patients not receiving insulin), fasting blood glucose, and hemoglobin A1c. The secondary outcomes were changes in fasting lipids, blood pressure, body mass index, waist circumference, waist-to-hip ratio, and androgen deficiency symptoms. Statistical analysis was performed on the delta values, with the treatment effect of placebo compared with the effect of testosterone. RESULTS: Treatment with testosterone did not significantly influence insulin resistance measured by the HOMA index (mean treatment effect, 1.67 +/- 4.29; confidence interval, -6.91 to 10.25; P>.05). Mean change in hemoglobin A1c (%) (-1.75 +/- 5.35; -12.46 to 8.95) and fasting blood glucose (mg/dL) (20.20 +/- 67.87; -115.54 to 155.94) also did not reach statistical significance. Testosterone treatment did not affect fasting lipids, blood pressure, and anthropometric determinations significantly. CONCLUSION: In this study, testosterone treatment showed a neutral effect on insulin resistance and glycemic control and failed to improve dyslipidemia, control blood pressure, or reduce visceral fat significantly in Asian Indian men with T2DM and hypogonadism.

Primary hyperparathyroidism in children and adolescents.

OBJECTIVE: Primary hyperparathyroidism (PHPT) in children and adolescents is a rare condition. Awareness should improve in order to lower threshold for screening and allow intervention before serious and permanent sequelac occur. METHODS: A retrospective analysis of 15 children and adolescents with PHPT (age <20 yr) seen in our clinic between 1993 and 2006. RESULTS: Mean age of patients was 17.73 yr (Range - 13-20, Male-3: Female-12). Average duration of symptoms was 18.87 (range: 0-48) mo. Clinical features at presentation included bone pain (86.67%), proximal myopathy (46.67%), bony deformities (53.33%), fractures (60%), palpable osteitis fibrosa cystica (33.3%), renal calculi (40%), palpable neck swelling (13.3%) and acute pancreatitis (6.67%). None had positive family history or features suggestive of multiple endocrine neoplasia (MEN). After biochemical confirmation, tumor was localised in all prior to surgery. Histopathology confirmed adenoma in all cases. Post-operative hungry bone syndrome occurred in 33.3%. CONCLUSION: PHPT is more common in females. Presentation of the disease is similar to their adult counterparts except for more severe bone disease and less severe renal disease. MEN and familial non-MEN PHPT do not constitute a major cause of pediatric PHPT as against to worldwide data. The incidence of hyperplasia as a cause of PHPT is rare in our pediatric population.

A rare case of central precocious puberty due to hypothalamic hamartoma diagnosed in utero.

OBJECTIVE: To report a rare case of central precocious puberty attributable to hypothalamic hamartoma that was diagnosed in utero. METHODS: We present the clinical, laboratory, and imaging data pertaining to our case and discuss the diagnostic features and recommended treatment of central precocious puberty in patients with hypothalamic hamartoma. RESULTS: A 3-month-old male child had had excessively rapid growth velocity and weight gain since birth. On investigation, the patient was diagnosed as having hypothalamic hamartoma with central precocious puberty. On inquiry, his mother described a history of prenatal ultrasonography and fetal magnetic resonance imaging suggesting the presence of a cystic lesion in his brain at 9 months of gestation. Because of continued rapid growth and acceleration of puberty during a 4-month observation period, we decided to treat the patient with leuprolide acetate. The patient responded well to treatment, with stabilization of growth. CONCLUSION: To the best of our knowledge, this patient is the youngest in the medical literature diagnosed to have central precocious puberty and also to receive treatment with leuprolide acetate.

Giant prolactinoma and effectiveness of medical management.

OBJECTIVE: To review our experience with long-term cabergoline and bromocriptine therapy in the treatment of giant prolactinomas. METHODS: Patients with giant prolactinomas diagnosed and treated at our center in Mumbai, India, between January 2005 and January 2009 were included. Diagnostic criteria for giant prolactinoma included tumor diameter greater than 40 mm, serum prolactin concentration higher than 1000 ng/mL, and invasive tumor growth pattern with mass effects. Cabergoline was started at a dosage of 0.5 mg weekly and progressively increased as necessary up to 3.5 mg weekly. Patients were followed up with hormone measurements, sellar magnetic resonance imaging, and vision examinations. RESULTS: The study group included 10 patients (5 male and 5 female), aged 17 to 50 years (mean, 36.1 years), treated for giant prolactinoma. In 8 patients, cabergoline was first-line therapy. Two patients had previously been prescribed bromocriptine, and this regimen was maintained. Mean serum prolactin concentration before treatment was 10,789 +/- 14,278 ng/mL (range, 1256-43,163 ng/mL; reference range, 5-17 ng/mL). Following treatment, levels normalized in 7 patients within 2 to 18 months (mean, 8.8 months) and decreased in 1 patient to a level 3 to 4 times that of normal. Tumor diameter, which measured from 4 to 7 cm at diagnosis, showed a mean maximal decrease of 49.28 +/- 18.27%; response was first noted about 6 months after treatment was begun. Seven patients had visual field defects at diagnosis; vision returned to normal in 3 and improved in 4. Testosterone levels, initially low in all male patients, normalized in 3. CONCLUSION: Cabergoline should be first-line therapy for aggressive prolactinomas, even in those patients who present with visual field defects.

Clinical profile of adrenoleukodysrophy.

X-linked Adrenoleukodystrophy (ALD) is the most common of the peroxisomal disorder and is associated with functional defect of the very long chain fatty acid (VLCFA) oxidation leading to the accumulation of VLCFA in the white matter and adrenal cortex. Retrospective evaluation of medical records of ALD patients were carried out. In all the 5 patients the duration of the symptoms varied from 1-7 years. Most of them presented with Addisonian crisis (4/5) and hyperpigmentation (5/5), white half of them (3/5) had neurological symptoms. All patients had biochemical evidence of the adrenal insufficiency. All siblings of patients should be screened for the possibility of ALD with VLCFA.

Clinical profile of ectopic thyroid in Asian Indians: a single-center experience.

OBJECTIVE: To assess clinical characteristics of patients with ectopic thyroid seen at a single tertiary care center in India. METHODS: In this case series, we retrospectively reviewed the data of patients who presented with ectopic thyroid between January 1995 and March 2008. Clinical presentation, nuclear imaging findings, endocrine profile, and clinical management were analyzed. RESULTS: Records of 22 female patients and 14 male patients were reviewed. Ectopic thyroid was more common in female patients. Mean age of presentation was 14.3 years (median, 14 years; range, 5 months to 40 years). Seventeen patients (47%) presented with lingual thyroid, detected incidentally or because of dysphagia and bleeding while eating, and 19 patients (53%) had sublingual thyroid, which mainly presented as an anterior neck swelling. Thirty patients (83%) had hypothyroidism (overt or subclinical). In 29 patients (81%), ectopic thyroid either in the neck or in the lingual area was the only functional thyroid tissue. Thirty-one patients (86%) were treated medically, and surgery was performed in only 5 patients (14%) who had either recurrent bleeding or dysphagia. CONCLUSIONS: Ectopic thyroid should be considered during the evaluation of a midline neck mass or hypothyroidism. Careful clinical examination, thyroid function tests, and radionuclide imaging help establish the diagnosis and localize ectopic thyroid. Appropriate treatment should be decided on an individual basis.

Utility of single luteinizing hormone determination 3 h after depot leuprolide in monitoring therapy of gonadotropin-dependent precocious puberty.

To determine utility of luteinizing hormone (LH) estimation, post intramuscular (IM) depot leuprolide in comparison with subcutaneous leuprolide stimulation test. Test for monitoring therapy in patients with gonadotropin dependent precocious puberty (GDPP). In seven patients of GDPP, who were treated with 11.25 mg depot leuprolide, the LH peak after subcutaneous (sc) test was compared with LH at hourly interval for 4 h after IM depot leuprolide for 13 tests and 3rd hour value for next ten tests. These two values were compared both before and after therapy. Before therapy, the mean +/- SD LH peak after subcutaneous leuprolide stimulation test was 20.6 +/- 7.85 IU/l (range 9.64-30.4 IU/l), and it was 27.3 +/- 12.21 IU/l 3 h after the first depot leuprolide injection (range 10.5-45.4 IU/l). During therapy, the mean +/- SD of LH peak after sc stimulation test was 1.96 +/- 0.75 IU/l (range 1.1-3.1 IU/l), and it was 2.58 +/- 0.54 IU/l (range 1.4-3.4 IU/l) 3 h after depot leuprolide injection. Three-hour LH value following IM depot leuprolide injection (11.25 mg) can be used for monitoring therapy in patients with GDPP because of its convenience and cost effectiveness.

Precocious puberty due to rathke cleft cyst in a child.

OBJECTIVE: To report a case of a child with precocious puberty attributable to Rathke cleft cyst (RCC). METHODS: The clinical features, laboratory results, and findings on ultrasonography of the pelvis and magnetic resonance imaging of the pituitary gland are presented. RESULTS: A 16-month-old child had breast enlargement, height increase, and an increase in growth velocity. On examination, she was found to have Tanner stage 3 breast development, and her vaginal mucosa was estrogenized. Her height was above the 97th percentile. Biochemically, she was diagnosed as having central precocious puberty, and magnetic resonance imaging of her pituitary gland disclosed RCC. Treatment with leuprolide resulted in normalization of her growth rate and regression of the breast development; the vaginal mucosa also became unestrogenized. CONCLUSION: Although RCC is a relatively common finding, it is a rare cause of precocious puberty. Magnetic resonance imaging of the pituitary gland should be performed in all children younger than 6 years of age who have precocious puberty, in an effort to detect any organic lesions.

Clinical profile and long term follow up of children and adolescents with prolactinomas.

We report clinical presentation, response to medical treatment, and long-term follow-up of 39 children and adolescents with prolactinoma (F:M; 30:9) (30 macro and 9 microadenoma) diagnosed at the age of 9-20 years. Mean duration of follow up was 56 months. All patients were treated with bromocriptine (BC) at doses ranging from 2.5 to 20 mg/day or by cabergoline at doses ranging from 0.5 to 2 mg/week orally. Two patients received external conventional radiotherapy after surgery. In patients with macroprolactinoma (F:M; 21:9), headache and/or visual defects were the first symptoms. All females had primary or secondary amenorrhea. Growth arrest was not observed in any patient and pubertal development was appropriate for their age. Spontaneous or provocative galactorrhea was observed in 23 patients (all females) and none of male patient had gynecomastia. Mean serum prolactin (PRL) concentration at the time of diagnosis was 322.50 ng/ml in patients with microadenoma, 522.38 ng/ml in patients with macroadenoma and 2,294.86 ng/ml in patients with macroadenoma with suprasellar extension. In 25 patients, BC normalized PRL levels and caused variable, but significant, tumor shrinkage. Cabergoline normalized PRL concentrations in 14 patients. Pregnancy occurred in 6 patients while on treatment. Pregnancies were uncomplicated, and the patients delivered normal newborns at term. Impairment of other pituitary hormone secretion was documented at the time of diagnosis in only one patient. Postoperatively six patients had other pituitary hormone deficiencies. In conclusion, the medical treatment with dopaminergic compounds is effective and safe in patients with prolactinoma with onset in childhood, allowing preservation of the anterior pituitary function.

Pheochromocytoma in children and adolescents.

Eleven subjects aged <20 yr with histologically proven pheochromocytoma between 1987 and 2006 were analyzed. Family history was present in 18%. In 2 patients, pheochromocytoma was part of VHL and in one it was associated with MEN 2. Twenty four hour urine VMA level was elevated in 100% and metanephrine level in 73%. CT/ MRI were showing the tumor in all. Prazosin extended release tablets (maximum 30 mg/day) were used in 73% and doxazosin (maximum 12 mg/ day) in 27%. Intraoperative BP fluctuations were seen in 27%. All were biochemically cured after surgery. Preoperative á blockade with extended release prazosin and doxazosin were effective in controlling perioperative BP fluctuations. Hence these drugs can be used in children and adolescents without fear of postoperative hypotension.