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Ectopic corticotropin-releasing hormone produced by a transfected cell line chronically activates the pituitary-adrenal axis in transkaryotic rats.

Hypothalamic CRH is the primary positive regulatory factor of the pituitary-adrenal axis. The purpose of our study was to analyze the chronic effects of CRH on the production and secretion of POMC peptides from both the anterior lobe (AL) and neurointermediate lobe (NIL) of the pituitary by mimicking the syndrome of ectopic CRH secretion from neuroendocrine tumors. We first generated stably transfected W2 medullary thyroid carcinoma cell lines with a rat CRH expression vector under the transcriptional control of a cytomegalovirus gene promoter. These cell lines constitutively expressed the foreign gene, accurately processed the encoded prepro-CRH, and secreted biologically active CRH with an estimated potency equivalent to that of synthetic CRH-(1-41)NH2. The cell line designated W2CRH-7 was implanted sc in the syngeneic rat strain WAG/Rij and produced tumors that abundantly secreted CRH into the peripheral circulation. Four weeks postimplantation, W2CRH-7, but not wild-type W2, cells caused significant increases in the AL content of beta-endorphin-like immunoreactivity comparable to that caused by adrenalectomy (ADX). Plasma ACTH and serum beta-endorphin-like immunoreactivity were increased to a greater extent by ADX than by W2CRH-7 cell implantation. The NIL of both male and female rats showed either no change or a tendency to decreased beta-endorphin concentrations with no change in the acetylation or carboxy-shortening profiles judged by cation exchange chromatography in response to the ectopic CRH treatment. Rats of both sexes maintained a profound activation of the pituitary adrenal axis up to 16 weeks postimplantation, with normalized adrenal gland weights 5 times that of controls. The chronic secretion of CRH by W2CRH-7 cells resulted in a complete cessation of body growth in all rats up to the maximum time tested of 16 weeks. The lack of growth was partly ameliorated by concomitant ADX, suggesting an important role for adrenal glucocorticoids in these effects. We conclude that 1) the transplantable W2CRH-7 cell line provides a highly effective and reproducible means of sustained CRH treatment that mimics the syndrome of ectopic CRH expression by neuroendocrine tumors; 2) AL corticotrophs respond to chronic CRH by a sustained production and secretion of POMC peptides, leading to a marked adrenal cortical hyperplasia, with no evidence of biologically significant desensitization; 3) chronic CRH tends to decrease the NIL content of beta-endorphin,with remarkably little effect on posttranslational processing; and 4) the syndrome of chronic ectopic CRH in WAG/Rij rats includes a cessation of body growth at least partly due to products of the adrenal glands.

Adrenalectomy↗

Ectopic adrenocorticotropin syndrome caused by lung cancer that responded to corticotropin-releasing hormone.

ACTH responses to corticotropin-releasing hormone (CRH) were studied in three patients with the ectopic ACTH syndrome caused by lung cancer. Plasma ACTH responded to synthetic CRH in two of three patients. Tumor tissues obtained from these two patients contained CRH and ACTH. In one patient, tumor ACTH secretion was stimulated by CRH in vitro. Tumor CRH was immunologically, chromatographically, and biologically similar to hypothalamic CRH. In addition, multiple forms of immunoreactive beta-endorphin were present in plasma and the tumor extracts. From these results, we conclude that some patients with the ectopic ACTH syndrome have tumors that produce both ACTH and CRH and that CRH can stimulate ACTH secretion by such tumors. Other patients with the ectopic ACTH syndrome do not have ACTH responses to CRH. Therefore, procedures other than CRH testing are needed to differentiate patients with Cushing's syndrome due to ectopic ACTH/CRH production from those with Cushing's disease, since the latter also usually have ACTH responses to CRH.

ACTH Syndrome, Ectopic↗

11 beta-Hydroxysteroid dehydrogenase activity in Cushing's syndrome: explaining the mineralocorticoid excess state of the ectopic adrenocorticotropin syndrome.

A characteristic feature of the ectopic ACTH syndrome is a state of mineralocorticoid excess, although the etiology remains obscure. Some forms of endocrine hypertension, such as licorice ingestion, have been explained by cortisol acting as a mineralocorticoid in the setting of inhibition or deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). This enzyme is responsible for the conversion of cortisol (F) to hormonally inactive cortisone, and its activity in vivo can be inferred from the ratio of the urinary excretion of tetrahydrocortisol (THF) and its isomer (5 alpha THF) to tetrahydrocortisone. Twenty-two patients with Cushing's syndrome (11 pituitary dependent, 9 ectopic, and 2 adrenal adenomas) and 13 controls were studied. Compared to controls. Cushing's patients had a significant increase (P < 0.001) in the excretion of all principal metabolites of F, secondary to a 5- to 6-fold increase in the cortisol secretion rate [median, 34.0 (range, 13.3-327) mg/day in Cushing's vs. 6.1 (range, 2.5-10.3) mg/day in controls]. The THF plus 5 alpha THF/tetrahydrocortisone ratio was significantly increased in Cushing's syndrome regardless of etiology [mean, 1.81 (range, 1.09-9.99) in Cushing's vs. 0.81 (range, 0.51-1.47) in controls; P < 0.001), indicative of defective 11 beta HSD activity. Furthermore, compared to patients with pituitary-dependent Cushing's, this ratio was significantly higher in patients with the ectopic ACTH syndrome (4.12 vs. 1.49; P < 0.01) and was inversely correlated with serum potassium levels (r = -0.57; P = 0.01; n = 22). One explanation for the mineralocorticoid excess state of the ectopic ACTH syndrome appears to be that cortisol gains inappropriate access to the mineralocorticoid receptor through failure of its normal metabolism by 11 beta HSD. The reason for the defective 11 beta HSD activity is unclear, but it may be secondary to substrate saturation, inhibition by other adrenal steroids, or product inhibition.

11-beta-Hydroxysteroid Dehydrogenases↗

Nonsurgical management of ectopic teeth.

Four cases have been presented involving malpositioned premolars and molars that were brought into the arch. From the cases presented, it appears that aggressive surgical intervention to redirect ectopic premolars creates significant secondary problems. Interference with the bone surrounding the ectopic tooth may compromise the adjacent teeth and bone level. Pressure against the root of the impacted tooth may cause resorption. If the buccal or labial plate is removed, orthodontic movement will be impeded. Specific biochemical changes in bone are induced by the application of orthodontic forces. In these cases, creating space with coiled spring appliances resulted in remarkable reorientation and proper eruption of ectopic, impacted teeth. When surgical intervention is required in cases involving ectopic teeth, close collaboration between orthodontist and oral and maxillofacial surgeon is imperative to achieve successful results without negative sequelae.

Bicuspid↗

Role of adrenalectomy in ectopic ACTH syndrome.

Evaluation of adrenalectomy in patients diagnosed with ectopic ACTH syndrome was studied. Twenty-three clinical cases diagnosed with ectopic ACTH syndrome were analyzed at Chinese Academy of Medical Sciences and Peking Union Medical College Hospital (PUMCH). Cases consisted of 14 males and 9 females, with mean age of 38 years. All 23 cases had positive clinical, biochemical and radiology evidence for diagnosis of Cushing's syndrome. Sixteen of the 23 cases were treated with total adrenalectomy and the remaining 7 were treated without surgical intervention. Sixteen cases, having no identifiable source of ectopic hormone production, experienced resolution of presenting signs and symptoms after undergoing bilateral or unilateral total adrenalectomy; 1-year survival was 67%, 2-year survival 41% and 5-year survival 15%. In patients treated conservatively without surgical intervention, 1-year survival was 0%. In patients with no identifiable source of ectopic hormone production, bilateral adrenalectomy followed by hormone replacement treatment is effective.

ACTH Syndrome, Ectopic↗

Suppression of concentration of endometrial prostaglandin in early intra-uterine and ectopic pregnancy in women.

Concentrations of prostaglandin F2 alpha (PGF2 alpha) and prostaglandin E (PGE) were measured in endometrium from 18 women with ectopic pregnancies. In the nine pregnancies not associated with vaginal bleeding or an intra-uterine contraceptive device (IUCD; intact ectopics), concentrations of PGF2 alpha (12.8 +/- 7.4 (S.E.M.) ng/g) and PGE (4.7 +/- 3.0 ng/g) were similar to those in decidua from nine intra-uterine pregnancies of comparable gestational age (14.4 +/- 4.4 and 8.2 +/- 2.2 ng/g respectively). In both ectopic and intra-uterine pregnancies concentrations of prostaglandins were significantly lower than those found in endometrium throughout the normal menstrual cycle (P < 0.01). In nine ectopic pregnancies with associated vaginal bleeding and/or an IUCD, concentrations of PGF2 alpha and PGE were significantly higher than in the intact group (P < 0.05), although the concentration of PGF2 alpha remained significantly lower than levels in normal secretory endometrium (P < 0.05). These results suggested that suppression of endometrial synsthesis of prostaglandin during early pregnancy may be mediated systemically rather than through a local action of the conceptus.

Chorionic Gonadotropin↗

Hypomethylation in the promoter region of POMC gene correlates with ectopic overexpression in thymic carcinoids.

The ectopic ACTH syndrome is caused by abnormal expression of the POMC gene product arising from non-pituitary tumors in response to the ectopic activation of the pituitary-specific promoter of this gene. It has been proved that methylation of the CpG island in the promoter region is associated with silencing of some genes. Using bisulphite sequencing, we identified hypermethylation in the 5' promoter region of the POMC gene in three normal thymuses and one large cell lung cancer, and hypomethylation in five thymic carcinoid tumors resected from patients with ectopic ACTH syndrome. The region undergoing hypermethylation was narrowed to coordinates -417 to -260 of the POMC promoter. Furthermore, we observed that the levels of POMC expression correlated with the methylation density at -417 to -260 bp across the E2 transcription factor binding region of the POMC promoter. It is concluded that hypomethylation of the POMC promoter in thymic carcinoids correlates with POMC overexpression and the ectopic ACTH syndrome.

ACTH Syndrome, Ectopic↗

Ectopic pregnancy and prior induced abortion.

We compared the prior pregnancy histories of 85 multigravid women with an ectopic pregnancy and 498 multigravid delivery comparison subjects. We found a relationship between the number of prior induced abortions and the risk of ectopic pregnancy: the crude relative risk of ectopic pregnancy was 1.6 for women with one prior induced abortion and 4.0 for women with two or more prior induced abortions; however, use of multivariate techniques to control confounding factors reduced the relative risks to 1.3 (95 per cent confidence interval, 0.6-2.7) and 2.6 (95 per cent confidence interval, 0.9-7.4), respectively. The analysis suggests that induced abortion may be one of several risk factors for ectopic pregnancy, particularly for women who have had abortions plus pelvic inflammatory disease or multiple abortions.

Abortion, Induced↗

The relationship of smoking and ectopic pregnancy.

A case-control study, using data abstracted between 1983 and 1987 from a large perinatal registry, was conducted to explore the relationship between smoking and ectopic pregnancy. Women with ectopic pregnancy (n = 634) seen at University of Illinois Perinatal Network Hospitals were compared to women who were delivered of a single live-born infant (n = 4287). Adjusted for age and race, women who reported smoking during pregnancy had a greater than twofold risk of ectopic pregnancy (Odds Ratio = 2.5, 95% confidence interval = 1.9, 3.2) compared to women who never smoked. The estimated relative risk rose from 1.4 (95% CI = 0.8, 2.5) for a woman smoking fewer than 10 cigarettes a day to 5.0 (95% CI = 2.9, 8.7) at one and a half or more packs of cigarettes per day (p-value for trend less than 0.001). Although further basic and epidemiologic research is necessary, the observed dose-response relation strengthens the argument that smoking may be a causal factor in the development of ectopic pregnancy.

Abortion, Spontaneous↗

Increased risk of ectopic pregnancy with maternal cigarette smoking.

As part of a case-control study of ectopic pregnancy, we evaluated the potential etiologic role of cigarette smoking. Maternal cigarette smoking at the time of conception was associated with an increased risk of ectopic pregnancy with a dose-response relationship (adjusted odds ratios: 1.30 to 2.49). On the other hand, partner's smoking was not associated with ectopic pregnancy. The study provides a supplementary argument towards a causal effect of smoking in the development of ectopic pregnancy.

Adolescent↗

Combined use of serum HCG and sonography in the diagnosis of ectopic pregnancy.

During an 18 month period, 320 patients were referred with clinical suspicion of an ectopic pregnancy. This study is based on 19 patients with ectopic pregnancy who had both a sonographic examination of the pelvis and determination of serum beta human chorionic gonadotropin (HCG) before surgery. Emphasis is focused on the spectrum of sonographic appearances that may occur in ectopic gestation. These are illustrated, and the sonographic criteria that have been used both for a positive diagnosis and for the exclusion of ectopic pregnancy in the past are analyzed. It is suggested that the accuracy of sonography can be increased by determining the serum HCG level on the day of the scan and by interpreting the findings with reference to the discriminatory HCG zone.

Adult↗

The significance of human chorionic gonadotropin in blood serum for the early diagnosis of ectopic pregnancy.

Determination of human chorionic gonadotropin (HCG) values in the serum by the radioimmunoassay technique, was performed in 23 women with suspected ectopic pregnancies. In 16 cases the values of HCG were high and the diagnosis of ectopic pregnancy was verified by laparoscopy and laparotomy. In 7 cases low HCG values were found and ectopic pregnancy was excluded. The detection of HCG in the serum was found to be an excellent tool for the early diagnosis of ectopic pregnancy, thus helping to prevent the dangerous sequelae which follow the late diagnosis of this condition.

Chorionic Gonadotropin↗

The diagnostic value of ultrasonography in 342 suspected cases of ectopic pregnancy.

The value of ultrasonography as a diagnostic or screening tool is studied in 342 cases of potential ectopic pregnancy. Ultrasonography was used as a diagnostic technique when the echopattern was clear enough to pose a diagnosis of ectopic or non-ectopic pregnancy, including intra-uterine pregnancy, abortion or other pelvic abnormalities. Diagnosis was possible in 77 per cent of the examined patients, with 95 per cent correct diagnosis, 2 per cent false positives and 3 per cent false negatives. For ultrasonography simply as a screening technique whatever the echopattern might be, i.e. in all cases, 78 per cent were selected correctly, with 20 per cent false positives and 2 per cent false negatives. The high quality of the ultrasonic data, combined with the relative absence of the disadvantages of roentgen-rays and invasive techniques, makes ultrasonography the first examination of choice in cases of clinical suspicion of ectopic pregnancy.

False Negative Reactions↗

Clinical value of pregnancy-specific beta 1-glycoprotein (SP1) and beta-hCG determination in serum in suspected ectopic pregnancy.

We compared the clinical value of pregnancy-specific beta 1-glycoprotein (SP1) determination in serum by means of a highly sensitive enzyme-linked immunosorbent assay (ELISA) versus that of beta human chorionic gonadotropin (beta-hCG) determination in suspected ectopic pregnancy. The study comprised 58 women admitted consecutively with suspected ectopic pregnancy but without signs warranting immediate surgical intervention. Both SP1 and beta-hCG were found in 11 patients with ectopic pregnancy and in 8 patients with early intra-uterine pregnancy, whereas beta-hCG was detected in 4 and SP1 in 7 of 8 women with a recent abortion. Of 31 women presenting a non-pregnant condition, 2 were positive for both SP1 and beta-hCG. The measurement of SP1 in serum thus appears to be an alternative to beta-hCG measurement when ectopic pregnancy is suspected.

Adult↗

Doubling time and hCG score for the early diagnosis of ectopic pregnancy in asymptomatic women.

In a group of 20 asymptomatic women at increased risk for ectopic pregnancy, serum analyses were conducted prospectively early in pregnancy (amenorrhea less than or equal to 45 days) at 2-4-day intervals, to examine the rate of increase in hCG values. The initial serum hCG level, which was determined at the time of the first transvaginal ultrasound examination, was below the discriminatory zone of 1000 IU/l (2nd International Standard). In 8 out of the 9 women who were ultimately diagnosed as having an ectopic pregnancy, the increase in hCG progressed only slowly, with a doubling time exceeding 2.2 days. This slow hCG increase occurred in 2 out of the 11 women who were ultimately diagnosed as having an intra-uterine pregnancy; both women subsequently had an early spontaneous abortion. When Lindblom's hCG score was applied retrospectively to distinguish between intra-uterine and ectopic pregnancies, the hCG increase in all the ectopic pregnancies was below 190 IU/l per day and in 10 of the 11 women with an intra-uterine pregnancy above 190 IU/l per day. A slower rate of increase was observed in only one woman with an intra-uterine pregnancy; she had a spontaneous abortion. The doubling time of hCG and the hCG score are useful diagnostic aids in cases where transvaginal ultrasound has not (yet) given a definite answer regarding the presence of an intra-uterine pregnancy.

Chorionic Gonadotropin↗

Beta-HCG concentration in peritoneal fluid and serum in ectopic and intrauterine pregnancy.

OBJECTIVE: To evaluate the significance of beta-HCG levels in peritoneal fluid and serum in the diagnosis of ectopic pregnancy. STUDY DESIGN SETTING: Obstetrics and Gynecology department of a regional general hospital. SUBJECTS: Sixty-two women who presented with a differential diagnosis of ectopic pregnancy vs. nonviable intrauterine pregnancy. INTERVENTIONS: All patients underwent D & C and culdocentesis. beta-HCG was measured in simultaneously obtained peritoneal fluid (PF) and serum (S), and the PF/S ratio calculated. RESULTS: Twenty-three patients had an ectopic pregnancy (Group I). All 23 had higher beta-HCG concentrations in the PF than in the serum, with a mean PF/S ratio of 19.1 +/- 16.9. Twenty-four patients had an intrauterine pregnancy (Group II). The beta-HCG levels in the PF and serum were similar (mean PF/S 1.1 +/- 0.2). The difference in PF/S ratio between groups I and II was statistically significant (p < 0.001). CONCLUSION: The measurement of beta-HCG in peritoneal fluid and serum is a useful diagnostic tool in differentiating ectopic from intrauterine pregnancy.

Ascitic Fluid↗

How effectively do copper intrauterine devices prevent ectopic pregnancy?

OBJECTIVE: To assess the risk of ectopic pregnancy when using copper intrauterine devices relative to non-use of contraception and female sterilization. DESIGN: Case-control study. MATERIAL AND METHODS: All cases diagnosed with a histologically verified extrauterine pregnancy and who became spontaneously pregnant in one Norwegian county from January 1, 1987 through to December 31, 1990 were eligible. Non-pregnant control women were chosen at random from the Norwegian Population Registry. Eligible for study were sexually active women, from 20 to 39 years of age, and who defined themselves as fecund. Included in the final analyses were 168 cases and 1,169 controls, who had all been previously pregnant. STATISTICAL METHODS: Chi square test and unconditional logistic regression. RESULTS: Compared with non-users of contraception, the adjusted odds ratio (aOR) among current users of copper intrauterine devices was 0.09 (95%, confidence intervals (CI); 0.06-0.13). Compared with women who were sterilized, the aOR of having an ectopic pregnancy among current copper IUD users was 1.6 (95% CI; 0.7-3.5). CONCLUSION: Relative to non-users of contraception, current copper IUD users had a 91% (95% CI; 87-94%) protection against ectopic pregnancy, while compared with women who had had a tubal sterilization, current copper IUD users had a 60% non-significant increased risk of ectopic pregnancy.

Adult↗

Ectopic pregnancy. Diagnosis by sonography correlated with quantitative HCG levels.

Pelvic sonograms were correlated with simultaneous human chorionic gonadotropin (HCG) determinations in 150 women with early intrauterine pregnancy (N = 76) and ectopic pregnancy (N = 74). Of the 76 patients with intrauterine pregnancy (IUP), 55 had HCG levels exceeding 1,800 mIU/ml (Second International Standard), and in each case a gestational sac was identified. In comparison, 35 of 74 (47%) patients with ectopic pregnancy had HCG levels of 1,800 mIU/ml or more, and no case demonstrated a gestational sac. Although six patients (8%) with ectopic pregnancy demonstrated a "pseudogestational sac," no case was confused with a true gestational sac. We conclude that, when the HCG level exceeds 1,800 mIU/ml, an intrauterine gestational sac is normally detected and its absence is evidence for an ectopic pregnancy.

Chorionic Gonadotropin↗