Biomedical subjects

Lynnette K Nieman

Publications and source records attributed to Lynnette K Nieman.

At least 37 records · Page 2Linked to original sources

PubMed2004

Glucocorticoid excess and hypertension.

Cushing's syndrome is a rare disorder characterized by chronic, excess glucocorticoid exposure. Hypertension is one of the most discriminating features of the disease, as it is present in 80% of patients. Patients with Cushing's syndrome have a mortality rate four times that of the general population, most likely secondary to an increased number of cardiovascular risk factors, including hypertension. In this article, we review several pathogenetic mechanisms of glucocorticoid-induced hypertension, including the role of sodium/water and mineralocorticoid excess, as well as involvement of the vasculature and kidney. Although treatment of hypertension with available antihypertensive medications is only moderately successful, after cure of Cushing's syndrome, approximately 30% of patients have persistent hypertension.

Cushing Syndrome↗

PubMed2004

Urine vascular endothelial growth factor-A is not a useful marker for endometriosis.

OBJECTIVE: To determine whether urine VEGF is elevated in women with endometriosis. DESIGN: Prospective observational study. SETTING: Tertiary care government and private hospitals. PATIENT(S): During laparoscopy for pelvic pain or infertility, urine was collected and possible endometriosis lesions were excised. Of 62 women, 40 had histology-proven endometriosis and 22 had no histological proof of the disease. INTERVENTION: None. MAIN OUTCOME MEASURE(S): Urine VEGF-A(121, 165) was measured and compared in women with and without biopsy-proven endometriosis. RESULT(S): Urine VEGF levels corrected for creatinine excretion were similar in women with (83.6 +/- 11.3 pg/mg Cr) and without (88.5 +/- 10.4 pg/mg Cr) endometriosis (P =.77). The frequency distribution of urine VEGF measurements for women with and without endometriosis was similar. No significant difference was noted in urine VEGF levels when comparing endometriosis stages or in those with endometriomas compared to controls. Urine VEGF did not vary significantly over the menstrual cycle or between groups by cycle phase. No cutoff point discriminated individuals with and without the condition. CONCLUSION(S): It is unlikely that urine VEGF-A(121, 165), as measured in this study, will be a useful non-invasive marker for endometriosis.

Adult↗

PubMed2004

CD10 immunohistochemical staining enhances the histological detection of endometriosis.

OBJECTIVE: To determine whether the use of CD10 immunohistochemistry in addition to hematoxylin and eosin (H&E) staining would increase the sensitivity of surgically suspected endometriosis lesions. DESIGN: Retrospective cohort study. SETTING: Tertiary care government research hospital. PATIENT(S): Thirty-one women with chronic pelvic pain. INTERVENTION(S): Immunohistochemical analysis for CD10 was performed on 108 possible endometriotic lesions and in the corresponding endometrial biopsy samples obtained during laparoscopy. When CD10 immunohistochemistry results were positive, the corresponding H&E section was reviewed to determine if the initial diagnosis should be revised. MAIN OUTCOME MEASURE(S): Histologic diagnosis of endometriosis by adjunctive use of CD10 immunohistochemistry in conjunction with H&E-stained specimens. RESULT(S): In endometrial stroma, CD10 was consistently present. Of the 70 specimens judged negative initially by H&E staining, CD10 staining led to the diagnosis of endometriosis in 11. The addition of CD10 immunohistochemistry detected more positive endometriosis lesions than H&E staining alone (45% vs. 35%). In three women with minimal endometriosis at surgery but initially negative histopathology, CD10 immunohistochemistry changed the histologic diagnosis to endometriosis. CONCLUSION(S): The adjunctive use of CD10 immunohistochemistry improves diagnostic sensitivity for endometriosis, especially for women with minimal disease.

Adult↗

PubMed2004

The role of [(18)F]fluorodeoxyglucose positron emission tomography and [(111)In]-diethylenetriaminepentaacetate-D-Phe-pentetreotide scintigraphy in the localization of ectopic adrenocorticotropin-secreting tumors causing Cushing's syndrome.

Conventional imaging modalities cannot localize the source of ACTH in 30-50% of patients with Cushing's syndrome (CS) caused by ectopic ACTH secretion (EAS). We prospectively evaluated whether [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) or [(111)In]-diethylenetriaminepentaacetate-D-Phe-pentetreotide (OCT) at higher than standard doses of radionuclide (18 mCi; H-OCT), can detect these tumors. Seventeen patients with presumed EAS based on inferior petrosal sinus sampling results underwent routine anatomical imaging studies [computed tomography (CT) and magnetic resonance imaging (MRI)] and OCT scintigraphy with 6 mCi (L-OCT). Research studies included FDG-PET in all patients and H-OCT if L-OCT was negative. ACTH-secreting tumors were localized in 13 patients and were occult in four. Nine of 17 CT, six of 16 MRI, six of 17 FDG-PET, eight of 17 L-OCT, and one of nine H-OCT studies were true positives. The sensitivity of CT and combined H- and L-OCT scintigraphy was higher (both 53%; 95% confidence interval, 29-76%) than that of MRI (37%; 95% confidence interval, 16-64%) or FDG-PET (35%; 95% confidence interval, 15-61%). FDG-PET did not detect tumors that were occult on CT/MRI. L-OCT was a useful complementary modality to CT and MRI. As H-OCT identified a tumor in one patient with otherwise negative imaging, it should be considered only when other imaging modalities fail to localize the ACTH-secreting tumor in patients with EAS.

ACTH Syndrome, Ectopic↗

PubMed2004

Jugular venous sampling: an alternative to petrosal sinus sampling for the diagnostic evaluation of adrenocorticotropic hormone-dependent Cushing's syndrome.

Bilateral sampling of the inferior petrosal sinuses (IPSS) to distinguish Cushing's disease from the ectopic ACTH syndrome is accurate but risky and technically difficult. Bilateral sampling of the internal jugular vein (JVS) is simpler and presumably safer. To compare jugular and petrosal sinus venous sampling for distinguishing Cushing's disease from ectopic ACTH syndrome, we studied 74 patients with surgically proven Cushing's disease, 11 with surgically confirmed, and three with occult ectopic ACTH secretion. Patients underwent JVS and IPSS with administration of CRH on separate days. Ratios of central-to-peripheral ACTH in venous samples were calculated. At 100% specificity, IPSS correctly identified 61 of 65 patients with Cushing's disease [sensitivity, 94%; confidence interval (CI), 84-98%]. When patients with abnormal venous drainage were excluded, sensitivity was 98% (CI, 90-100%). JVS had a sensitivity of 83% (CI, 71-91%) at 100% specificity. Receiver operated characteristics plot areas under the curve were similar (0.968 +/- 0.020 and 0.974 +/- 0.016, area under the curve +/- se, JVS vs. IPSS). Although petrosal sampling had better diagnostic accuracy, CIs overlapped (95% CI, 90-100% vs. 86% CI, 78-94%). Centers with limited sampling experience may choose to use the simpler JVS and refer patients for IPSS when the results are negative.

ACTH Syndrome, Ectopic↗

PubMed2003

The Keeper, a menstrual collection device, as a potential cause of endometriosis and adenomyosis.

Barrier contraceptive devices like the cervical cap and diaphragm and menstrual collecting devices may block menstrual flow, increase retrograde menstruation, and thus theoretically increase the likelihood of developing endometriosis or adenomyosis. We describe the case of a woman with a prior tubal ligation who after four years of regular use of the Keeper, a menstrual collecting device, developed endometriosis and adenomyosis.

Adult↗

PubMed2003

Ectopic luteinizing hormone secretion and anovulation.

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Adult↗

PubMed2003

Diagnostic accuracy of laparoscopy, magnetic resonance imaging, and histopathologic examination for the detection of endometriosis.

OBJECTIVE: To evaluate the utility of fat-suppressed magnetic resonance imaging (MRI) in the diagnosis of endometriosis. DESIGN: A prospective clinical trial. SETTING: A government research hospital. PATIENT(S): Forty-eight women with pelvic pain. INTERVENTION(S): Magnetic resonance imaging followed by surgical excision and pathologic diagnosis of endometriosis. MAIN OUTCOME MEASURE(S): Presence and extent of endometriosis suggested by preoperative MRIs compared with surgical inspection and biopsy. RESULT(S): A preoperative MRI in 46 women detected fewer endometriosis lesions than histopathology or laparoscopy (78 vs. 101 vs. 150). Few MRI lesions correlated with those identified by laparoscopy (50 of 150) or pathology (38 of 101). Of 42 women with surgically diagnosed endometriosis, 28 had at least one corresponding abnormality on MRI, 5 had abnormalities that didn't correlate with surgical findings, and 9 had normal MRIs. The sensitivity of MRI in detecting biopsy-proven endometriosis for any woman was 69% (25 of 36), and the specificity was 75%. CONCLUSION(S): Although MRI identifies fewer areas of endometriosis than seen at surgery, it suggested endometriosis in 75% of those with at least mild disease. Only 67% of lesions identified at surgery contained histologic evidence of endometriosis.

Adult↗

PubMed2003

Strategy for elucidating differentially expressed genes in leiomyomata identified by microarray technology.

OBJECTIVE: cDNA microarray technology identifies genes that are differentially expressed between tissues. Our previous study identified several genes that might contribute to the fibroid phenotype. We therefore sought to confirm genes involved in three distinct signal transduction pathways. DESIGN: Evaluation of differential mRNA and protein expression of Dlk, Frizzled-2, and CD-24 in fibroids compared with adjacent myometrium. University hospital. PATIENT(S): Five women undergoing medically indicated hysterectomy for symptomatic fibroids. INTERVENTION(S): Microarray analysis of up to 33000 genes, reverse transcriptase-polymerase chain reaction (RT-PCR), real-time RT-PCR, Western blot, and immunohistochemistry. MAIN OUTCOME MEASURE(S): Expression of mRNA transcripts and protein in fibroid compared with myometrium.A more extensive microarray confirmed differential expression of Frizzled-2 and CD-24 but did not confirm Dlk overexpression. RT-PCR and real-time PCR demonstrated equivalent Dlk mRNA expression between fibroid and myometrium (ratio, 1.02), a slight Frizzled-2 overexpression (ratio, 2.09), and robust CD-24 overexpression in fibroids (ratio, 12.35). Western blot and immunohistochemistry confirmed Frizzled-2 overexpression, but did not confirm Dlk overexpression. CONCLUSION(S): Microarray technology is the first phase of tissue evaluation, but changes in gene expression must be confirmed. Confirmed genes can then be used to generate hypotheses testing their involvement in fibroid development.

Antigens, CD↗

PubMed2003

Development of the selective progesterone receptor modulator CDB-2914 for clinical indications.

CDB-2914 (17 alpha-acetoxy-11 beta-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione) is a 19-norprogesterone derivative that acts as an antagonist in progesterone-responsive tissues. It binds to progesterone receptors A and B with high affinity. After oral dosing in humans, CDB-2914 serum levels peak at 60-90 min. CDB-2914 binds to serum proteins and is cleared slowly. Doses of 1, 10 and 50 mg exhibit proportional increases in peak serum levels, but serum levels from higher doses, 100 and 200 mg, are not dose-dependent, suggesting saturation of carrier sites. The biological effects of CDB-2914 vary according to time of the menstrual cycle that the drug is given. In the mid-follicular phase, CDB-2914 (50 mg) inhibits follicular development and delays ovulation and menses. At 100 mg, in some cases the original follicle ceases development and a new follicle is recruited. Endometrial maturation is delayed at all doses tested (10, 50, 100 mg). Given at mid-luteal phase, there was a dose-dependent effect on menses, with higher doses (100-200 mg) resulting in earlier menses. On average, CDB-2914 tends to lengthen the menstrual cycle by approximately 1-2 days although the amount of delay varies with timing in the menstrual cycle and dose.

Contraceptive Agents↗

PubMed2003

Management of surgically hypogonadal patients unable to take sex hormone replacement therapy.

Lifestyle changes in diet, exercise and the environment may help to prevent or ameliorate hot flashes and low bone density in men and women after surgical castration. Conventional medications, including megestrol acetate, SSRIs or clonidine, may improve hot flashes but may have limiting side effects. Some complementary and alternative approaches, including black cohosh, vitamin E, and soy products, work as well as placebo to decrease hot flashes and may be helpful, because they have low toxicity. Acupuncture and neurontin are promising but must be studied further. With regards to the prevention of osteoporosis and fractures in men and women, bisphosphonates are the most potent of the currently available agents; calcitonin is less effective. PTH has a large beneficial effect but is not yet available and is less well studied. In women, continued sexual intercourse and use of vaginal lubricants and moisturizers help to minimize symptoms of vaginal atrophy but do not ameliorate urinary symptoms. Low dose local estrogen treatment is a promising approach for the latter complaints.

Contraindications↗

PubMed2003

Luteal phase dose-response relationships of the antiprogestin CDB-2914 in normally cycling women.

BACKGROUND: Progesterone receptor modulators have potential therapeutic use in progesterone-dependent conditions such as endometriosis, fibroids and induction of labour. The synthetic steroid CDB-2914 binds to the progesterone and glucocorticoid receptors. In animals it has antiprogestational activity at doses 50-fold less than those required for antiglucocorticoid effects. METHODS AND RESULTS: We evaluated the biological activity, blood levels and safety of CDB-2914 at escalating single doses, in 36 normally cycling women at mid-luteal phase. CDB-2914 at doses of 1-100 mg did not change luteal phase length, but after 200 mg, all women had early endometrial bleeding. Four women with early menses had concurrent functional luteolysis (one at 10, 50, 100 and 200 mg). There were no biochemical or clinical signs of toxicity, and no effect on urinary cortisol or circulating thyroxine, prolactin, adrenocorticotrophic hormone or renin levels. Higher serum equivalents of CDB-2914 were observed by radioimmunoassay than by high performance liquid chromatography detection, indicating a considerable contribution of metabolites. CONCLUSIONS: Mid-luteal administration of CDB-2914 antagonizes progesterone action on the endometrium, in a dose-dependent fashion, without apparent antiglucocorticoid effects. Further study of CDB-2914 is needed to determine its clinical role.

Adult↗

PubMed2003

Spoiled gradient recalled acquisition in the steady state technique is superior to conventional postcontrast spin echo technique for magnetic resonance imaging detection of adrenocorticotropin-secreting pituitary tumors.

Recent studies show that the standard T1-weighted spin echo (SE) technique for magnetic resonance imaging (MRI) fails to identify 40% of corticotrope adenomas. We hypothesized that the superior soft tissue contrast and thinner sections obtained with spoiled gradient recalled acquisition in the steady state (SPGR) would improve tumor detection. We compared the performance of SE and SPGR MRI in 50 patients (age, 7-67 yr) with surgically confirmed corticotrope adenoma. Coronal SE and SPGR MR images were obtained before and after administration of gadolinium contrast, using a 1.5 T scanner. SE scans were obtained over 5.1 min (12-cm field of view; interleaved sections, 3 mm). SPGR scans were obtained over 3.45 min (12- or 18-cm field of view, contiguous 1- or 2-mm slices). The MRI interpretations of two radiologists were compared with findings at surgical resection. Compared with SE for detection of tumor, SPGR had superior sensitivity (80%; confidence interval, 68-91; vs. 49%; confidence interval, 34-63%), but a higher false positive rate (2% vs. 4%). We recommend the addition of SPGR to SE sequences using pituitary-specific technical parameters to improve the MRI detection of ACTH-secreting pituitary tumors.

Adenoma↗

PubMed2002

Location, color, size, depth, and volume may predict endometriosis in lesions resected at surgery.

OBJECTIVE: To correlate the diagnosis of endometriosis in lesions excised at laparoscopy with pathologic diagnosis. DESIGN: Prospective study. SETTING: U.S. government research hospital. PATIENT(S): Women with chronic pelvic pain thought to be due to endometriosis. INTERVENTION(S): Excision of lesions suspicious for endometriosis. MAIN OUTCOME MEASURE(S): Histologic examination of lesions for color, width, depth, and location of endometriosis. Lesion colors were grouped as black, red, white, mixed color, or endometriomas. RESULT(S): Sixty-five women with a surgical diagnosis of endometriosis had minimal (n = 22), mild (n = 25), moderate (n = 9), or severe disease (n = 9) according to the revised American Fertility Society classification. Endometriosis was confirmed in all but seven patients with minimal and one with severe disease. Twelve other patients did not have endometriosis. Of 314 lesions excised, 189 (61%) were endometriotic. Black or red lesions were less often histologically confirmed to be endometriosis than were white lesions, mixed-color lesions or endometriomas. Lesions > 5 mm wide or deep were more likely to be endometriosis than were narrower or shallower implants. Endometriomas deeper than 1 cm were histologically confirmed to be endometriosis, and 50% of peritoneal windows contained endometriosis. CONCLUSION(S): White lesions, mixed-color lesions, endometriomas, and larger lesions by depth or width were more likely to be histologically confirmed endometriosis than were smaller, black, or red lesions.

Adult↗

PubMed2002

Medical therapy of Cushing's disease.

Surgical excision of an ACTH-producing pituitary tumor is the optimal therapy for Cushing's disease. However, medical therapy may have either a primary or adjunctive role if the patient cannot safely undergo surgery, if surgery fails, or if the tumor recurs. When medication is the only therapy, a major disadvantage is the need for lifelong therapy; in general, recurrence follows discontinuation of treatment. These compounds work through three broad mechanisms of action. "Neuromodulatory" compounds modulate corticotropin (ACTH) release from a pituitary tumor, steroidogenesis inhibitors reduce cortisol levels by adrenolytic activity and/or direct enzymatic inhibition and glucocorticoid antagonists block cortisol action at its receptor. In general, neuromodulatory compounds (bromocriptine, cyproheptidine, somatostatin and valproic acid) are not very effective agents for Cushing's disease. Treatment with a glucocorticoid antagonist and radiation therapy has been reported on a single patient only. Steroidogenesis inhibitors, including mitotane, metyrapone, ketoconazole, and aminoglutethimide, are the agents of choice for medical therapy of Cushing's disease. In general, ketoconazole is the best tolerated of these agents and is effective as monotherapy in about 70% of patients. Mitotane and metyrapone may be effective as single agents, while aminoglutethimide generally must be given in combination. The intravenously-administered etomidate may used when patients cannot take medications by mouth.

Adrenocorticotropic Hormone↗

PubMed2002

Diagnostic tests for Cushing's syndrome.

The diagnosis of Cushing's syndrome rests on the demonstration of clinical features and biochemical abnormalities that reflect hypercortisolism. If a patient presents with typical clinical features such as weight gain with truncal obesity and supraclavicular fat deposition, wide purple striae, and proximal muscle weakness, the diagnosis is clear-cut and is nearly always substantiated by a 24-hour urine free cortisol excretion value more than four times the normal level. However, many patients present with signs and symptoms that are common in the general population, such as hypertension, generalized weight gain, reproductive abnormalities, and depression. Many of these patients have normal cortisol excretion and do not have Cushing's syndrome. Others have mild hypercortisolism caused by psychiatric disorders, obligate exercise, morbid obesity, sleep apnea, or uncontrolled diabetes mellitus. These patients may be confused with those with the true Cushing's syndrome, and thus are considered to have a "pseudo-Cushing" state. Additional observation over time, and testing with midnight cortisol measurements, the 2-day-2-mg dexamethasone suppression test, or the dexamethasone suppression-CRH stimulation test may be useful to identify true Cushing's syndrome in these patients.

Algorithms↗

PubMed2002

Association of hypertension and hypokalemia with Cushing's syndrome caused by ectopic ACTH secretion: a series of 58 cases.

Cushing's syndrome is associated with hypertension in approximately 80% of cases. Hypertension contributes to the marked increased mortality risk of past or current Cushing's syndrome, largely because of increased cardiovascular risk. Observation of the pathophysiological effect of chronically elevated ACTH and cortisol values in patients with ectopic ACTH secretion complements the available data from acute studies of the effects of ACTH and glucocorticoid infusions in normal volunteers. In a retrospective case review, we identified 58 patients with Cushing's syndrome caused by ectopic ACTH secretion, who were treated at the National Institutes of Health between 1983-1997. The diagnosis of an ectopic ACTH cause was confirmed by inferior petrosal sinus sampling and/or pathologic examination of tumor. The commonest causes were bronchial carcinoid (40%) and thymic carcinoid (10%), but 18 of 58 (31%) patients had an unknown source of ectopic ACTH. Hypertension (systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg in adults) was noted in 45 of 58 (78%) ectopic Cushing's patients, a prevalence similar to that noted in other endogenous Cushing's syndrome etiologies. Hypertension was severe, deemed to require 3 or more drugs by the treating physicians, in 26 of 58 (45%) patients. Hypokalemia was much more prevalent than in patients with other causes of Cushing's syndrome, affecting 33 of 58 (57%) patients. The range of plasma ACTH (17-1557 pg/mL, normal <60) and 24-hour urine cortisol (UC) excretion (192-1600 mcg/24 hr, normal <90) allowed analysis of the influence of these hormones on blood pressure and plasma potassium. There was a significant relationship between 24-hour UC excretion and the presence of hypokalemia (P = 0.003). Eight of nine patients with a UC >6000 mcg/24 hr had hypokalemia. There was no relation between ACTH level and hypokalemia. In addition, we did not find blood pressure severity to be related to UC excretion or ACTH levels. Urine and plasma cortisol and cortisol metabolite measurements suggest that cortisol may act as a mineralocorticoid when in excess, perhaps by saturating the 11beta-hydroxysteroid-dehydrogenase (11beta-HSD2 enzyme) that inactivates cortisol at the renal tubule. The current data suggest that high cortisol levels may be the principal cause of hypokalemic alkalosis in Cushing's syndrome, rather than inhibition of the 11betaHSD2 enzyme by ACTH or the effects of adrenal steroid biosynthetic intermediaries with mineralococorticoid activity.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗

PubMed2002

Nighttime salivary cortisol: a useful test for the diagnosis of Cushing's syndrome.

Clinical features such as weight gain, depression, hypertension, and menstrual irregularities, although common in the general population, may raise the possibility of Cushing's syndrome. Up to 30% of urine cortisol and dexamethasone suppression screening tests may return an incorrect result, suggesting that better tests are needed. This study evaluated the utility of nighttime salivary cortisol measurement as a screening test for Cushing's syndrome. We evaluated 139 inpatients and 4 outpatients with possible Cushing's syndrome, 16 inpatients and 7 outpatients with other nonadrenal disorders, and 34 healthy outpatients. Using cut points that excluded all subjects without Cushing's syndrome, we compared the sensitivity for the detection of Cushing's syndrome of nighttime salivary cortisol levels (2330 and 2400 h for inpatients and bedtime for outpatients), simultaneous inpatient serum cortisol levels, and urine glucocorticoid excretion. An assay- specific inpatient 2400-h salivary cortisol or an outpatient bedtime salivary cortisol greater than 550 ng/dl (15.2 nmol/liter) identified 93% of patients with Cushing's syndrome (confidence interval, 89-98%) and excluded all individuals without the disorder. Salivary cortisol measurements worked as well as plasma measurements and better than urine glucocorticoid excretion. We concluded that bedtime salivary cortisol measurement is a practical and accurate screening test for the diagnosis of Cushing's syndrome.

Adolescent↗