Association of serum testosterone levels and testicular volume in adult patients.

A retrospective observational study was undertaken to gain new insight into the relationship between total testicular volume and levels of serum testosterone, luteinising hormone, follicle-stimulating hormone, prolactin and clinical variables. A total of 312 men with sexual dysfunction or infertility were divided into groups A and B (156 each) on the basis of basal plasma testosterone ≤5 nmol/L of ≥12 nmol/L respectively. Group A was subclassified in A1 (primary hypogonadism) and A2 (secondary hypogonadism). There were significant differences in total testicular volume between group A (15.33 ± 11.94 ml) and group B (36.74 ± 6.9; p < .001) and also between subgroup A1 (11.07 ± 8.49 ml) and subgroup A2 (23.62 ± 13.04 ml; p < .001). Only 13.5% of patients in group B had a total testicular volume <30 ml. Differences in all studied parameters were found between group A and group B. There were no variations when comparing age, body mass index and testosterone in groups A1 and A2 . The use of total testicular volume and body mass index together for predicting testosterone levels yields a sensitivity and specificity of 85.3% and 86.5% respectively. Logistic regression analysis, univariate and multivariate models, using the measurement of total testicular volume resulted in a high capacity to predict testosterone levels.

Metabolic syndrome in Mediterranean women with polycystic ovary syndrome: when and how to predict its onset.

Polycystic ovary syndrome (PCOS) is associated with the metabolic syndrome (MetS). The metabolic disorders are not universal and may vary with race, age and phenotype. Our purpose was to determine the clinical and biochemical characteristics of Mediterranean PCOS women with MetS, compare them with non-MetS PCOS patients, and assess the ability of clinical data and biochemical tests to predict these abnormalities within our population. A total of 218 subjects, 196 PCOS women and 22 controls, undergo a physical examination and laboratory evaluation for a diagnosis of MetS. MetS was categorized according to NCEP ATP III guidelines. PCOS patients were analyzed separately and compared in three subgroups: three or more MetS criteria, two criteria, one or no criteria. The overall prevalence of MetS was 21.4%. Women with MetS had higher glucose (G) levels than PCOS women with two criteria (5.7 ± 1.5 vs 5 ± 0.4, p < 0.05). Both groups were comparable for all the other parameters. Waist circumference (WC), body mass index (BMI), systolic (SBP) and diastolic blood pressure (DBP), bioavailable testosterone (uT), triglycerides (TG) and insulin (I) levels were significantly higher and sex hormone-binding globulin (SHBG) levels, high-density lipoprotein (HDL), HOMA and QUICKI indexes significantly lower in both groups, MetS and patients with two criteria, compared with women with one or no criteria and the control group. WC, HDL and TG were the best predictors of PCOS patients at risk for MetS. In conclusion, we recommend considering PCOS patients with two criteria of MetS as having the same risk as patients with the full syndrome. Waist circumference with HDL and triglycerides is an efficient combined test to identify PCOS women at risk for metabolic and cardiovascular diseases.

Long-lasting subclinical Addison's disease.

OBJECTIVE: To report a patient with autoimmune adrenal disease and increased ACTH with longstanding hyperpigmentation as an isolated symptom. METHODS: A 49-year-old woman requested a diagnostic work-up for hyperpigmentation initiated 9 years before, associated with increased ACTH. She was receiving replacement therapy for autoimmune hypothyroidism. Basal and dynamic tests of glucocorticoid axis, basal investigation of mineralocorticoid axis and measurement of organ specific autoantibodies were performed. RESULTS: Plasma ACTH (143 pmol/l; normal <13.2 pmol/l) and antibodies against 21-hydroxylase (115 UI/ml; normal <1) were remarkably high, thyroid peroxidase and parietal cell antibodies were positive at low titer and all additional tests were normal. CONCLUSION: Autoimmune adrenal disease can have a very long preclinical period even with high concomitant ACTH and specific antibody titers.

Influence of exogenous insulin on C-peptide levels in subjects with type 2 diabetes.

AIM: The aim of this study was to determine whether the influence of insulin therapy on fasting and stimulated C-peptide levels in type 2 diabetic subjects is due to plasma glucose reduction or a direct effect of exogenous insulin. METHODS: Plasma glucose and serum C-peptide levels were determined before and after IV injection of 1mg glucagon on three separate days in 21 type 2 diabetic subjects. Day 1: without pharmacological treatment and fasting plasma glucose > 11.1 mmol/L; day 2: fasting plasma glucose 4.4-7.8 mmol/L, 1h after withdrawing intravenous regular insulin infusion; day 3: fasting plasma glucose 4.4-7.8 mmol/L with bed-time NPH insulin. RESULTS: Fasting and glucagon stimulated C-peptide levels were higher on day 1 than days 2 and 3. Fasting, but not stimulated C-peptide levels, were lower on day 3 than day 2. These differences were not appeared when the percentage of C-peptide increment or the C-peptide/glucose ratio were compared in the three days. CONCLUSIONS: Blood glucose reduction instead of exogenous insulin is responsible for the C-peptide decrease during insulin therapy in type 2 diabetic subjects.

A novel germline mutation in exon 5 of the multiple endocrine neoplasia type 1 gene.

The autosomal dominant multiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by neoplasia of parathyroids, anterior pituitary, and gastrointestinal and pancreatic neuroendocrine tissues. Recently the gene responsible for the MEN1 syndrome has been identified on chromosome region 11q13. Most of the described mutations are nucleotide substitutions and small deletions affecting exons 2 and 3, causing protein truncation. Only one mutation in exon 5 has been found, and this corresponds to a MEN1 sporadic case. Small insertions are also rare. We studied a MENI family composed of five members, two of whom were clinically affected. We found a new germline 1 basepair insertional mutation affecting the exon 5 of the MEN1 gene in the two members affected in this MEN1 family.

Postpartum thyroiditis in women with hypothyroidism antedating pregnancy?

In women with hypothyroidism, levothyroxine (LT) requirements after delivery are assumed to return to prepregnancy values. The occasional observation of discordances prompted this study. Forty-one women (31 receiving LT replacement therapy and 10 receiving suppressive therapy for thyroid carcinoma) were followed during the first year after delivery. A control group of 31 nonpregnant women with hypothyroidism (n = 21) or thyroid carcinoma (n = 10) were also followed during a similar period. Twenty-three patients of 41 (56.1%) had discordant requirements at follow-up after delivery vs. 3 of 31 in the control group (9.7%; P < 0.001). The patterns of discordance in the postdelivery group were hyperthyroidism in 12, increase in LT dose in 5, hyper- and hypothyroidism in 5, and recurrence of Graves' disease in 1 women. Those in the control group were increase in LT dose, hyperthyroidism, and hypo- and hyperthyroidism. The rate of patients with discordant prepregnancy-postpartum LT doses was higher in the noncarcinoma subgroup (67.7% vs. 20.0%; P < 0.01), whereas in the control group, both subgroups displayed a similar rate of discordance (9.5% vs. 10%; P = NS). In conclusion, this study documents that women with hypothyroidism antedating pregnancy display changes in LT requirements in the first year after delivery that suggest postpartum thyroiditis.

Emerging cardiovascular risk factors in subclinical hypothyroidism: lack of change after restoration of euthyroidism.

Subclinical hypothyroidism (SH) is a frequent condition that may be associated with increased cardiovascular risk. There is current interest in determining the effect, if any, of substitutive therapy with l-thyroxine (L-T4) on cardiovascular risk factors in SH and, particularly, on those associated with emerging cardiovacular risk, such as apolipoprotein (apo) B, lipoprotein (Lp) (a), total homocysteine (t-Hcy), and C-reactive protein (CRP). Thus, the aim of this study was to assess the impact of euthyroidism restoration on these emerging risk factors in SH. Forty-two patients diagnosed with SH were consecutively recruited before treatment. These patients were treated with L-T4 for 3 to 6 months with the dose necessary to restore euthyroidism. Lp(a), fasting and postmethionine (n = 28) t-Hcy, and CRP did not change with substitutive therapy, regardless of the respective baseline values, and the decrease in apo B paralleled that of low-density lipoprotein (LDL) cholesterol. Similarly, no treatment effect was observed on homocysteine or CRP in patients with thyrotropin-stimulating hormone (TSH) >10 mIU/L. Monitoring of emerging risk factors did not offer additional arguments for treating patients with SH and, thus, is not justified in their clinical management.

Effects of a cyproterone-containing oral contraceptive on hormonal levels in polycystic ovarian disease.

The management of polycystic ovarian disease in women not desiring pregnancy is controversial. To avoid the progressive androgenic effects on peripheral target organs, some advocate the use of oral contraceptives. This study reports the effects of a preparation with 50 micrograms ethinyl estradiol and 2 mg cyproterone acetate on gonadotropins, prolactin, testosterone, sex hormone binding globulin (SHBG), androstenedione, and calculated free testosterone index before and after six months of treatment. Gonadotropins, testosterone, and androstenedione levels decreased, prolactin did not change, and sex hormone binding globulin increased as the result of the treatment. This led to a net decrease in the calculated free testosterone.

Molecular pathology of multiple endocrine neoplasia type I: two novel germline mutations and updated classification of mutations affecting MEN1 gene.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined development of tumors in several endocrine glands and other tissues. The MEN1 gene was recently identified and isolated by positional cloning. This gene was screened in two unrelated MEN1 Spanish kindreds (with four affected members and seven asymptomatic members) using single-strand conformation polymorphism, DNA sequencing, and restriction enzyme analysis. Two novel germline mutations were identified: a missense in exon 2 (H139R) and a splice-site in intron 9 (1461-2A>C). These findings allowed us to identify the MEN1 carriers among the seven asymptomatic members analyzed. An updated review of the mutations and polymorphisms found in the analysis of the MEN1 gene is provided. The report of all germline mutations causing MEN1 and easy access to this updated information are both of special diagnostic interest, because this greatly facilitates the task of attributing the disorder to a specific mutation found in a given MEN1 family. This is especially helpful in the critical differentiation of missense mutations from nonsynonymous polymorphisms that fit the pattern of segregation of the disease, but do not cause it.

Effect of cholecystokinin-A receptor blockade on postprandial insulinaemia and gastric emptying in humans.

Our aim was determine the relationship between cholecystokinin (CCK)-A receptor blockade, glucose levels, insulin secretion and gastric emptying in humans, and to assess the effect of CCK-A blockade on pancreatic polypeptide secretion. After a 12-h fast, six healthy volunteers were given [99mTc]iminodiacetic acid monosodium salt (IDA) intravenously (5 mCi). One hour later they were offered a 577 kcal liquid meal containing [99mTc]diethylenetriaminepentaacetic acid (DTPA) (2 mCi) and glucose (105 g). Scintigraphic gastric and gallbladder activity, and plasma glucose, insulin and pancreatic polypeptide responses were monitored. In a second experiment, a continuous intravenous infusion of loxiglumide (7.5 mg kg h(-1)) was started 60 min before and continued until 120 min after test meal ingestion to block the CCK-A receptors. Gallbladder emptying was blocked by loxiglumide. Loxiglumide accelerated gastric emptying, increased insulin secretion without alteration of glucose profiles, and abolished all phases of the postprandial pancreatic polypeptide response. Blockade of peripheral CCK-A receptors accelerates gastric emptying of liquids with an increase in postprandial insulin levels. The lack of changes in glycaemia suggests that alternative homeostatic mechanisms also control postprandial glucose levels. Inhibition of pancreatic polypeptide release may reflect an independent effect of loxiglumide on vagal control involved in pancreatic polypeptide release.

Growth hormone response to growth hormone-releasing hormone stimulation in oligozoospermic patients.

OBJECTIVE: To evaluate the GH response to growth hormone-releasing hormone (GH-RH) stimulation in oligozoospermic men. SETTING: Outpatient Clinic of Andrology at the Fundación Puigvert and the Department of Clinical Chemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. PATIENTS: Fifteen oligozoospermic patients and 15 normozoospermic fertile men matched for age and body mass index. INTERVENTION: Endocrine status was determined by assay of basal levels of gonadotropins (FSH, LH), T, E2, inhibin, and insulin-like growth factor I (IGF-I). Serum GH levels were measured before and after GH-RH administration. RESULTS: GH response to GH-RH was significantly greater in patients than in controls. There was a positive correlation between the GH response and IGF-I levels in oligozoospermic patients only. Regression analysis showed a significant negative association of GH peak with inhibin after controlling for IGF-I in oligozoospermic patients. CONCLUSION: The results indicate that there is an altered responsiveness of pituitary to GH-RH administration in oligozoospermic patients; this did not appear to be due to the influence of gonadal steroid levels but rather to inhibin or some related peptide.

Long-acting repeatable bromocriptine in the treatment of patients with microprolactinoma intolerant or resistant to oral dopaminergics.

OBJECTIVE: To study the efficacy of long-acting repeatable bromocriptine in suppressing abnormal PRL secretion in microprolactinoma patients. To assess the incidence and nature of side effects induced by the product. DESIGN: Longitudinal, open label, noncontrolled. SETTING: Human hyperprolactinemic volunteers in an academic clinical research environment. PATIENTS: Ten patients with radiologically proven microademonas resistant or intolerant to oral bromocriptine were included. INTERVENTIONS: The patients were treated with 50 to 150 mg of long-acting bromocriptine monthly during 6 months. MAIN OUTCOME MEASURE: The serum PRL concentrations and the side-effects were assessed before and after each new injection. RESULTS: Serum PRL levels decreased during the first cycle to normal values in four patients. At the end of the study the PRL levels were normalized in five cases and were only slightly increased in three. One patient was resistant to the treatment. Two among four infertile women became pregnant. In nine patients the accompanying symptoms disappeared after the 2nd month. Adverse events were mild or moderate and circumscribed to the 1st month of treatment. CONCLUSION: The long-acting bromocriptine is both effective and well tolerated and is a good alternative to the oral approach in the management of microprolactinoma patients.

Circulant anti-triiodothyronine antibodies in a patient with Graves' disease: effects on measurement of T3 with different RIA procedures.

High levels of triiodothyronine have been found in a patient with Graves' disease caused by circulating antibodies able to bind specifically with serum triiodothyronine. High values found were due to the interference of the endogenous antibody with the conventional techniques of radioimmunoassay used for the evaluation of the hormone. An analytical pattern to identify these antitriiodothyronine antibodies is described.

Thyroglobulin autoantibody levels below the cut-off for positivity can interfere with thyroglobulin measurement.

Antithyroglobulin antibodies can interfere with the measurement of thyroglobulin yielding spuriously high or low levels depending on the method used. Interference is unrelated to the antibody concentration and can occur at very low concentrations. We report a patient in whom antithyroglobulin antibodies below the cut-off for positivity nearly led to an incorrect diagnosis of thyrotoxicosis factitia.

Transient pituitary hypothyroidism in a patient with ectopic adrenocorticotrophic hormone secretion.

We report the case of a 55-year-old woman who presented with hypercortisolism secondary to ectopic adrenocorticotrophic hormone secretion and severe non-thyroidal illness syndrome (NTIS) due to metastatic small cell lung carcinoma associated with severe infections. The patient initially showed hormonal profiles of pituitary hypothyroidism and gonadal hypofunction. After decrease in cortisol production following treatment with chemotherapy and metyrapone, serum thyroid hormones and thyroid-stimulating hormone (TSH) concentrations normalized. Study of the relative contributions of cortisol and pro-inflammatory cytokines (interleukin-6 and tumour necrosis factor alpha) to the overall variability in thyroid function tests disclosed a significant and independent effect of serum cortisol on serum TSH concentrations; the variability in free thyroid hormone concentration was explained only by changes in TSH concentration. These observations indicate that cortisol could be the major determinant of changes in serum TSH concentrations in clinical conditions accompanied by hypercortisolism, as occurs in NTIS.

The role of matching menstrual data with hormonal measurements in evaluating effectiveness of postcoital contraception.

The effectiveness of postcoital contraception can only be estimated. The most commonly used method of calculation compares the expected pregnancy rate in the exposed population to the resultant pregnancies after treatment. Estimation of the fertile period and the day of ovulation are critical to calculate the expected pregnancies. The aim of this study was to improve the accuracy of calculations by evaluating the hormonal status on the day of contraceptive treatment. A total of 483 consecutive women requesting postcoital contraception was included in a prospective observational trial. A blood sample was obtained at the moment of consultation to measure serum luteinizing hormone, estradiol, and progesterone concentrations. An ethinylestradiol-levonorgestrel combination (100 micrograms/500 mg for two doses, 12 h apart) was then prescribed. The fertile period was estimated according to previous hormonal studies in the normal cycling population. Of 483 women, 64 (13.25%) women were excluded because they presented irregular menstrual cycles and 37 (7.6%) women were lost to follow-up. Two pregnancies occurred in the remaining 382 women. Following Wilcox's and Trussell's methods, 21.1 and 17.75 pregnancies should be expected, yielding an overall treatment effectiveness of 90.52% (95% confidence interval [CI] 62.58%-97.6%) and 88.73% (95% CI 55.93%-97.12%), respectively. Hormonal data were available in 356 women; 303 of whom presented with regular cycles. Hormonal information in this group restricted the number of exposed cases to 88 women. Of the women included in Trussell's method of analysis, only 51 (51.5%; p < 0.05) were at risk using hormonal data. Fifty-six percent (95% CI 34.9%-75.6%) of women with luteinizing hormone levels > 20 IU/L were not between days-1 and +1 of the cycle. Hormonal studies suggest that methods based on pregnancy risk calculated by cycle day do not faithfully reflect the real exposure.

Genetic, clinical, and biochemical analysis of unrelated Spanish families with multiple endocrine neoplasia type I.

OBJECTIVE: (1) To study seven unrelated Spanish families with multiple endocrine neoplasia type I (MEN I), describing clinical features and investigating the presence of germline mutations in the MEN1 gene, and (2) to establish reference values for pancreatic polypeptide and gastrin after a standardized test meal in a healthy control group, analyzing the usefulness of this test for detecting neuroendocrine gastroenteropancreatic tumors in subjects with MEN I. METHODS: Two or three generations of 7 kindreds with MEN I, consisting of a total of 39 individual family members, were investigated. Three of the families were subjected only to genetic analysis, and the other four families were also assessed clinically. A group of 23 healthy control subjects were also studied. RESULTS: Mutations in the MEN1 gene were found in six of the seven families studied. Of the 4 families studied clinically, 12 family members were genetically affected. In these study subjects, hyperparathyroidism, adrenal adenomas, neuroendocrine gastroenteropancreatic tumors, and pituitary adenomas developed in 100%, 50%, 16%, and 12%, respectively. All demonstrated pancreatic tumors were associated with abnormal results after a test meal, but 75% of them also showed high basal hormonal measurements. CONCLUSION: Analysis of the MEN1 gene decreases the total number of subjects who need to undergo repeated clinical and biochemical studies, but genetic mutations are not detected in all families with MEN I. Hyperparathyroidism is the most common manifestation of the syndrome, but the presence of adrenal adenomas has probably been underestimated. Ingestion of a standardized test meal for stimulation of gastrin and pancreatic polypeptide could be a complementary procedure for diagnosing gastroenteropancreatic tumors in selected patients with MEN I in whom basal gastrin and pancreatic polypeptide levels are normal.

Effects of long-term amiodarone treatment on thyroid function.

Serum determinations of total T4, total T3, reverse T3, free T3 index, free T4, free T4 index, TBG, T4/TBG ratio, TSH and cholesterol were carried out on 18 euthyroid patients with coronary heart disease. Serum samples were obtained before treatment and after 15 days, 2, 4, 6, 8, 10, 12, 14 and 16 months of treatment with amiodarone (400 mg/day). Patients were divided into two groups, according to patterns of TSH response to thyrotrophin-releasing hormone (TRH): (I) patients with normal responses (n = 12), and (II) patients with subnormal responses (n = 6). Patients of group I showed total T4, free T4 and reverse T3 increments and total T3 and free T3 index decreases, whereas patients of group II were distinguished by the absence of T3 decreases and a rise in free T4 levels that showed a significant correlation with a drop in serum cholesterol (r = -0.767; p. less than 0.001). No patient of either group showed clinical signs of thyroid dysfunction. These results show that the appearance of hormonal patterns of hyperthyroidism is unpredictable and very frequent in patients with no previous thyroid abnormalities undergoing long-term treatment with the drug.

[Strategies in screening of nonclassical forms of congenital adrenal hyperplasia caused by P450c21 deficiency in hyperandrogenic women]. / Estrategias para el escrutinio de formas no clásicas de hiperplasia suprarrenal congénita por deficiencia de P450c21 en mujeres hiperandrogénicas.

BACKGROUND: The value of the measurement of the serum level of 17-hydroxyprogresterone (170HP) and the stimulation test with adrenocorticotropin (ACTH) with and without previous slowing with dexamethasone was determined to detect congenital adrenal hyperplasia (CSH) due to a deficiency of P450c21 in hyperandrogenic women. METHODS: Three hundred seventy women consecutively attended for hyperandrogenism were studied. Stimulation tests of 170HP were performed with 250 micrograms i.v. of synthetic ACTH with previous administration of 1 mg of dexamethasone in 191 of the patients. The test was performed without previous dexamethasone in the remaining 179 patients. RESULTS: Nineteen patients with unclassical forms of CSH by deficiency of P450c21 were detected. Another 19 were considered as probable heterozygotes. The basal levels of 170HP with and without previous dexamethasone showed negative predictive value of nearly 100%, indicating the validity of their use in selecting patients for the stimulation test. No significant differences were seen in the increases of post ACTH 170HP observed between the tests carried out with and without dexamethasone. CONCLUSIONS: The frequency of congenital adrenal hyperplasia by deficiency of P450c21 in the hyperandrogenic women studied was found to be 5.1%. The low frequency together with the predictive value of the basal concentrations of 170HP indicate that the systematic routine use of the ACTH test as a means of scrutiny of CSH in hyperandrogenic women is unjustified.

[Inadequate TSH secretion. Clinical features, diagnostic criteria, and therapeutic possibilities]. / Secreción inadecuada de TSH. Rasgos clínicos, criterios diagnósticos y posibilidades terapéuticas.

Inadequate secretion of TSH (IST) is a disorder which is diagnosed more frequently and earlier after the introduction of new immunoassay techniques which can distinguish between normal and suppressed TSH levels. For diagnosis high or unsuppressed TSH in required in the presence of elevated levels of the thyroid hormones. Its etiology may be tumor (TSH secreting pituitary adenoma) or non tumoral due to pituitary or generalized resistance to the thyroid hormones. Differential diagnosis between both etiologies is not easy, and several tests have been proposed but are not always discriminatory. Five cases of IST are presented in whom the diagnostic, clinical and therapeutic criteria have been analyzed. The cases of neoplastic IST (patients n.o 3, 4, and 5) showed a loss in circadian rhythm of TSH and absence of suppression with triiodothyronine (T3), 3,5-diiodo 4-(3'-iodine 4'-hydroxyphenoxi) phenylacetic acid (TRIAC) and with bromocriptine. The circadian rhythm of TSH was maintained in the non neoplastic IST (patients n.o 1 and 2) as was suppressed with T3, TRIAC and bromocriptine. The subunit-alpha/TSH quotient and TSH response to TRH were variable with no stimulation being observed with metoclopramide in any case. Upon the demonstration of unsuppressed circulating TSH in the presence of biochemical hyperthyroidism, IST should be suspected to avoid erroneous diagnosis and treatments. Differentiation between neoplastic and non neoplastic origin may be difficult since the biochemical and neuropharmacologic parameters are not always discriminatory.