Serum estradiol after single dose hCG administration correlates with Leydig cell reserve in hypogonadal men: reassessment of the hCG stimulation test.

The hCG stimulation test with assessment of serum testosterone (T) is used for evaluation of testicular function. This retrospective study was undertaken to estimate the diagnostic value of stimulated estradiol (E2) levels in the assessment of Leydig cell function. Serum T and E2 before and after repeated daily hCG injections in 23 adult men with clinically suspected or established primary hypogonadism were studied. After hCG administration serum T increased gradually with peak levels after 72 hours (delta84%, p=0.003). In contrast, serum E2 concentrations reached their maximal levels 24 hours after the first injection (delta168%, p=0.001). Serum T and E2 responses were more attenuated in men with LH > or =17 IU/L as compared to men with lower LH levels. Peak E2 levels after 24 hours correlated significantly with peak T levels after 3 days. We conclude that the increase in serum E2 levels 24 hours after a single hCG injection is an useful additional measure of Leydig cell function. Assessment of E2 increments would render the test procedure more practical, less time-consuming and more cost-effective than assessing peak T levels after 72 hours.

Restoration of euthyroidism accelerates bone turnover in patients with subclinical hypothyroidism: a randomized controlled trial.

This study evaluated the effect of physiological l-thyroxine (L-T4) treatment on bone metabolism in patients with subclinical hypothyroidism. Sixty-six women with subclinical hypothyroidism (TSH 11.7 +/- 0.8 mIU/l) were randomly assigned to receive L-T4 or placebo for 48 weeks. Sixty-one of 66 patients completed the study. Individual L-T4 replacement (mean dosage 85.5 +/- 4.3 microg/day) was performed targeting euthyroid thyroid-stimulating hormone (TSH) levels. The primary outcome measure was 24- and 48-week change in markers of bone formation (total and bone alkaline phosphatase [ALP, bone ALP], osteocalcin [OC]) and resorption (pyridinoline [PYD] and deoxypyridinoline [DPD], C-terminal cross-linking telopeptide type I [CTX]). Secondary outcomes were 48-week changes in bone mineral density (BMD) of the lumbar spine and hip, measured by dual-energy X-ray absorptiometry. Compared with placebo, l-thyroxine ( n=31) resulted in significant activation of bone turnover. Overall, a significant treatment effect was observed for DPD (between-group difference 16.0%; 95%CI, 10.9 to 21.1), CTX (29.9%; 95%CI, 23.3 to 36.5), and bone ALP (13.2%; 95%CI, 6.6 to 19.7) after 24 weeks. At the end of the study, lumbar BMD in the both treatment groups differed by 1.3% (95%CI, -2.9 to 0.5) with lower levels in l-thyroxine treated women. Significant difference in BMD between groups was also observed at the trochanter. We conclude that physiological l-thyroxine treatment accelerates bone turnover reflecting early activation of bone remodeling units in the initial replacement of subclinical hypothyroidism. The observed bone loss could be interpreted as an adaptive mechanism on decreased bone turnover in preexistent hypothyroidism, and not as l-thyroxine-induced clinically important bone loss. However, long-term studies are needed to confirm this assumption.

Prolactin dysregulation in women with subclinical hypothyroidism: effect of levothyroxine replacement therapy.

This study investigated the effect of levothyroxine treatment on serum prolactin (PRL) levels in women with subclinical hypothyroidism. Sixty-six women (mean age, 58.5 +/- 1.3 years) with confirmed subclinical hypothyroidism (mean thyrotropin [TSH], 11.7 +/- 0.8 mIU/L) were randomly assigned to receive levothyroxine or placebo for 48 weeks. Based on blinded TSH monitoring, physiologic levothyroxine replacement (85.5 +/- 4.3 microg/d; TSH, 3.1 +/- 0.3 mIU/L) was ascertained throughout the study. PRL levels were measured before and after administration of thyrotropin-releasing hormone (TRH) at baseline, after 24 and 48 weeks. Sixty-three of the 66 women completed the study. At baseline, basal PRL levels were elevated in 19% of the patients. None of the patients reported menstrual disturbances, infertility, or galactorrhea. In the levothyroxine group (n = 31) basal and peak PRL levels were significantly reduced after 24 and 48 weeks (p = 0.03 and p = 0.001). Mean changes in PRL levels differed significantly between the two treatment groups after 24 weeks (p = 0.03 and p = 0.01). The treatment effect was more pronounced in patients with PRL and TSH levels above the median at baseline (i.e., PRL > 16 ng/mL; TSH > 11 mIU/L). Based on this double-blinded, placebo-controlled study we demonstrate that in subclinical hypothyroidism PRL regulation is altered with elevated basal and stimulated PRL levels, and that physiologic levothyroxine treatment restores PRL concentrations.

Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and a double-blind, placebo-controlled trial.

Hypothyroidism is associated with premature atherosclerosis and cardiovascular disease. Recently, total homocysteine (tHcy) and C-reactive protein (CRP) emerged as additional cardiovascular risk factors. We first investigated CRP and tHcy in different severities of primary hypothyroidism and in a second study we evaluated the effect of L-thyroxine treatment in patients with subclinical hypothyroidism (SCH) in a double-blind, placebo-controlled trial. One hundred and twenty-four hypothyroid patients (63 with subclinical, 61 with overt hypothyroidism, OH) and 40 euthyroid controls were evaluated. CRP was measured using a latex-based high sensitivity immunoassay; tHcy was determined by a fluorescence polarization immunoassay. tHcy values were significantly elevated in OH (P=0.01). In SCH tHcy levels were not augmented as compared to controls. CRP values were significantly increased in OH (P=0.016) and SCH (P=0.022) as compared to controls. In a univariate analysis tHcy correlated significantly with fT4, vitamin B12, folic acid and creatinine levels. In multiple regression analysis only fT4 (beta=0.33) had a significant effect on tHcy. CRP did not correlate with thyroid hormones. In SCH, L-T4 replacement had no significant effect on either tHcy or CRP levels. This is the first paper to show that CRP values increase with progressive thyroid failure and may count as an additional risk factor for the development of coronary heart disease in hypothyroid patients. In contrast to overt disease, only CRP, but not tHcy values, are affected in SCH, yet without significant improvement after L-thyroxine therapy.

Effect of restoration of euthyroidism on peripheral blood cells and erythropoietin in women with subclinical hypothyroidism.

BACKGROUND: In overt hypothyroidism (OH) anemia is common, while less frequently basophilia has been described. In subclinical hypothyroidism (SCH), however, data on the distribution of peripheral blood cells are lacking. Therefore, we evaluated the effects of L-T4 replacement therapy on peripheral blood elements in female patients with SCH before and after restoration of euthyroidism in a randomized, double-blind and placebo-controlled study. PATIENTS AND METHODS: Sixty-six women with SCH (TSH 12.9 +/- 8.2 mU/L) were randomly assigned to receive L-thyroxine or placebo for 48 weeks. 63 of the 66 women completed the study. Peripheral blood cells were measured at baseline and 48 weeks after L-thyroxine or placebo treatment, respectively. RESULTS: The percentage of lymphocytes decreased (p<0.05), whereas percent of monocytes (p<0.05) and eosinophiles (p<0.05) increased significantly upon restoration of euthyroidism after 48 weeks. Hemoglobin and hematocrit remained unchanged throughout the study period. However, erythropoietin levels increased significantly (p<0.01) during L-T4 treatment. In the placebo group all parameters remained unchanged throughout the study. CONCLUSIONS: Overall, we observed subtle alterations of the leuco-lympho-monocytic distribution of the peripheral blood cells upon restoration of euthyroidism in patients with SCH. Hemoglobin and Hematocrit remained unchanged; however, the increasing level of erythropoietin during L-T4 treatment suggests an already stimulated, yet compensated erythropoietic system in mild thyroid failure.

Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies.

Subclinical hypothyroidism is a frequent syndrome affecting about 10 million people in the United States. The management of such patients is open to debate. In a long-term prospective study we analyzed the spontaneous course and the value of predictive factors in the development of overt thyroid failure. We studied 82 female patients with subclinical hypothyroidism prospectively over a mean observation period of 9.2 yr. TSH, thyroid hormones, thyroid reserve after TRH administration, thyroid antibodies, and clinical parameters were assessed at yearly intervals. The cumulative incidence of overt hypothyroidism was calculated using life-table analysis and Kaplan-Meier curves. According to the initial serum TSH concentrations (TSH, 4-6/>6-12/>12 mU/liter), Kaplan-Meier estimates of the incidence of overt hypothyroidism were 0%, 42.8%, and 76.9%, respectively, after 10 yr (P < 0.0001). When only patients with TSH levels greater than 6 mU/liter were analyzed, the cumulative incidence was 55.3%. The incidence of overt hypothyroidism increased in patients with impaired thyroid reserve (52.6% vs. 38.1%; P = 0.05) and positive microsomal antibodies (58.5% vs. 23.2%; P = 0.03). This prospective long-term study demonstrates that only a part of the cohort of patients with subclinical hypothyroidism develops overt hypothyroidism over time and that a major group remains in the subclinical state after 10 yr. The measurement of TSH, microsomal (thyroperoxidase) antibodies, and thyroid reserve allows initial risk stratification for the development of overt thyroid failure (risk ratio ranging from 1.0-15.6). Our study helps to recognize the spontaneous course of subclinical hypothyroidism and in the identification of patients most likely to progress to overt hypothyroidism.

Laparoscopic adrenalectomy: the new standard?

PRINCIPLES: Since 1994 we have been removing most non-malignant classified pathologies of the adrenal gland laparoscopically. Does this minimal invasive procedure involve advantages over the conventional approach? METHODS: Retrospective analysis of 22 all-consecutive laparoscopic adrenalectomies in 21 patients (10 women, 11 men, age 26-70 years, mean 43 years, 11 right, 9 left, one bilateral in MEN IIa syndrome). These procedures were performed between 1994 and 2001 transperitoneally in the lateral decubitus position, recently by use of the Ultracision device and once with a handport. These results are compared with 20 consecutive open transperitoneal unilateral adrenalectomies with similar pathologies (13 women, 7 men, age 28-77 years, median 51.5 years, 8 right, 12 left) carried out between 1988 and 1993. RESULTS: The mean operating times were 150 and 115 minutes with the laparoscopic and the open procedure respectively (p <0.011). On the other hand, mean hospital stay (6 versus 15 days, p <0.00001), intraoperative blood loss (200 versus 300 ml, p <0.04) and postoperative need for analgesics were significantly shorter or lower. Two out of the first five laparoscopic operations had to be converted into open adrenalectomy due to intraabdominal adhesions and a diaphragmatic injury with pneumothorax. In both groups three complications occurred (14% and 15%). CONCLUSION: Laparoscopic adrenalectomy is a safe, effective and useful procedure involving a shorter hospital stay, lower intraoperative blood loss and a lower postoperative analgesics requirement compared with the open approach. The laparoscopic approach is the procedure of choice for all benign adrenal pathologies.