A Neutral Effect of Metformin Treatment on Macroprolactin Content in Women with Macroprolactinemia.

Background: Metformin decreases serum levels of monomeric prolactin. No previous study has investigated the effect of metformin on macroprolactin content in patients with macroprolactinemia. Methods: We studied three age-, sex- and weight-matched groups of patients: 15 women with monomeric prolactin, 12 women with macroprolactin, as well as 15 women with normal prolactin levels. Because of coexisting 2 diabetes or prediabetes all patients were treated with metformin (1.7-3 g daily). Plasma lipids, glucose homeostasis markers, as well as serum levels of prolactin and macroprolactin were assessed at baseline and after 4 months of metformin treatment. Results: As expected, metformin reduced plasma glucose and triglycerides, as well as improved insulin sensitivity in all treatment groups. Moreover, the drug reduced post-polyethylene glycol prolactin levels and tended to reduce pre-polyethylene glycol prolactin levels in women with monomeric prolactin but not in women with macroprolactinemia and women with normal prolactin levels. Conclusion: The obtained results indicate that metformin has a negligible effect on macroprolactin levels.

The Effect of Ezetimibe/Statin Combination and High-Dose Statin Therapy on Thyroid Autoimmunity in Women with Hashimoto's Thyroiditis and Cardiovascular Disease: A Pilot Study.

Background: Intensive statin therapy was found to reduce thyroid autoimmunity in women with Hashimoto's thyroiditis. No similar data are available for other hypolipidemic agents. Methods: The participants of the study were 16 women with Hashimoto's thyroiditis and coronary artery disease. On the basis of statin tolerance, they were divided into 2 groups. 8 patients who did not tolerate high-dose statin therapy were treated with a statin, the dose of which was reduced by half, together with ezetimibe. The remaining 8 patients tolerating the treatment continued high-dose statin therapy. Plasma lipids, serum levels of thyrotropin, free thyroxine and free triiodothyronine, as well as titers of thyroid peroxidase and thyroglobulin antibodies were measured at the beginning of the study and 6 months later. Results: Replacing high-dose statin therapy with ezetimibe/statin combination therapy increased serum titers of thyroid peroxidase as well as led to an insignificant increase in serum titers of thyroglobulin antibodies. At the end of the study, thyroid peroxidase and thyroglobulin antibody titers were higher in patients receiving the combination therapy than in those treated only with high-dose statin. Conclusions: Our study shows that high-dose statin therapy produces a stronger effect on thyroid autoimmunity than ezetimibe/statin combination therapy.

The Effect of Metformin on Hypothalamic-Pituitary-Thyroid Axis Activity in Women with Interferon-Induced Hypothyroidism: A Pilot Study.

BACKGROUND: One of the most frequent adverse effects of interferon-α therapy is thyroiditis. Metformin was found to improve insulin sensitivity in hepatitis C patients, as well as to reduce elevated thyrotropin levels in patients with hypothyroidism. The aim of this study was to investigate the effect of metformin on hypothalamic-pituitary-thyroid axis activity in patients with interferon-induced thyroiditis. METHODS: The study included 2 matched groups of women with type 2 diabetes and untreated subclinical hypothyroidism: patients with interferon-induced thyroiditis (n=8) and patients with Hashimoto's thyroiditis (n=12). Fasting plasma glucose, the homeostatic model assessment 1 of insulin resistance ratio (HOMA1-IR), glycated hemoglobin, the estimated glomerular filtration rate, as well as serum levels of thyrotropin, thyroid hormones, prolactin and insulin-like growth factor-1 (IGF-1) were assessed at baseline and after 4 months of metformin treatment. RESULTS: Apart from reducing plasma glucose, HOMA1-IR and glycated hemoglobin, metformin decreased serum levels of thyrotropin. Circulating levels of thyroid hormones, prolactin and IGF-1 remained at a similar level throughout the study. The effect of metformin on serum thyrotropin was stronger in patients with interferon-induced thyroiditis than in patients with Hashimoto's thyroiditis, as well as correlated with its impact on insulin sensitivity. CONCLUSIONS: Our results indicate that metformin may be an effective agent in patients with interferon-induced hypothyroidism.

The association between macroprolactin levels and vitamin D status in premenopausal women with macroprolactinemia: a pilot study.

BACKGROUND: Macroprolactinemia is a frequent cause of misdiagnosis and mismanagement of patients with elevated prolactin levels. Its pathogenesis and clinical significance are still controversial. METHODS: The aim of this study was to investigate the relationship between elevated macroprolactin content and vitamin D status. The study population included 20 premenopausal women with isolated macroprolactinemia, 10 of whom were later treated with vitamin D (2 000 IU daily). Serum prolactin, macroprolactin, 25-hydroxyvitamin D and PTH levels were assessed at baseline and after 4 months of treatment. RESULTS: Compared with the control age- and weight-women with normal prolactin levels (n=11), patients with macroprolactinemia were characterized by lower levels of 25-hydroxyvitamin D and slightly higher levels of PTH. Vitamin D administered to patients with macroprolactinemia increased 25-hydroxyvitamin, reduced total prolactin and macroprolactin, as well tended to reduce PTH. The effect of vitamin D on total prolactin and macroprolactin correlated with their baseline values and baseline 25-hydroxyvitamin D levels. CONCLUSIONS: The results of our study suggest the association between vitamin D status and elevated macroprolactin levels in premenopausal women.

The effect of metformin on the hypothalamic-pituitary-thyroid axis in patients with type 2 diabetes and subclinical hyperthyroidism.

In hypothyroid patients, metformin was found to reduce serum levels of TSH. No previous study investigated metformin action on hypothalamic-pituitary-thyroid axis in patients with hyperthyroidism. The aim of our study was to assess the effect of metformin treatment on thyroid function tests in patients with untreated subclinical hyperthyroidism. We studied 15 patients with low but detectable TSH levels (0.1-0.4 mIU/L) (group 1), 12 patients with suppressed TSH levels (less than 0.1 mIU/L) (group 2) and 15 euthyroid patients with a history of hyperthyroidism, who because of coexisting 2 diabetes were treated with metformin (2.55-3 g daily). Glucose homeostasis markers, as well as serum levels of TSH and total and free thyroxine and triiodothyronine levels were assessed at baseline and after 3 and 6 months of therapy. As expected, metformin reduced plasma glucose, insulin resistance and glycated hemoglobin. However, with the exception of an insignificant decrease in TSH levels after 3-month therapy in group 2, metformin therapy did not affect thyroid function tests. Our results indicate that metformin has a negligible effect on hypothalamic-pituitary-thyroid axis activity in type 2 diabetic patients with subclinical hyperthyroidism.

The effects of 1 month antihypertensive treatment with perindopril, bisoprolol or both on the ex vivo ability of monocytes to secrete inflammatory cytokines.

INTRODUCTION: Monocytes are key elements in pathogenesis of atherosclerosis and inflammation. The data regarding associations between antihypertensive treatment and monocytes' function are still lacking. The aim of this study was to evaluate the influence of antihypertensive drugs (bisoprolol, perindopril or both) in patients suffering from mild to moderate hypertension. PATIENTS AND METHODS: The study population consisted of 67 patients divided into 3 groups (2 consisted of patients with Grade I essential hypertension and one consisted of patients with Grade II essential hypertension). At baseline and 1 month after treatment we performed 24-h ambulatory noninvasive blood pressure monitoring and measured IL-1beta, IL-6, IL-10, MCP-1 and TNF-alpha in a medium derived from LPS-stimulated monocytes' culture. RESULTS: Both monotherapies with bisoprolol or perindopril were equally effective in lowering blood pressure (reduction in mean 24-h systolic blood pressure 12.07 vs. 15.91 mmHg, p = 0.678). Antihypertensive treatment led to significant decrease in IL-1b, IL-6, MCP-1 and TNF-alpha concentration and significant rise in IL-10 level compared to the baseline levels and the decrease was associated with reduction in blood pressure. CONCLUSIONS: Bisoprolol and perindopril effectively reduced elevated blood pressure. As a result, an alteration in cytokine net was observed at the end of the study. These results support the concept of possible anti-inflammatory effects of antihypertensive drugs (e.g., perindopril and bisoprolol).

Biologically active analogues of arginine vasopressin containing conformationally restricted dipeptide fragments.

In this study we described the synthesis and pharmacological properties of five new analogues of arginine vasopressin (AVP). Four of these analogues contained ethylene-bridged dipeptide Phe-Phe in positions 2 and 3; one had two N-Me-Phe residues. All new peptides were tested for vasopressor and antidiuretic activities. We also estimated the uterotonic activities of these compounds in vitro. Three analogues were highly potent V1-antagonists. One of them, namely [Cpa1,(Phe-Phe)2,3,Val4]AVP, which seemed to not interact with either V2 and oxytocic receptors, was outstandingly selective. It is interesting that the high antipressor potency of our second peptide, [(N-Me-Phe)2,3]AVP, was achieved without modification of position 1. Our results open new possibilities for the design of very potent and selective V1-antagonists of AVP.

Influence of L-naphthylalanine in position 3 of AVP and its analogues on their pharmacological properties.

We describe the synthesis and pharmacological properties of two series of analogues: one which consists of three peptides having L-1-naphthylalanine in position 3 and the second composed of analogues substituted in position 3 with L-2-naphthylalanine. All peptides were tested in bioassays for pressor and antidiuretic activities. We also checked the uterotonic activity in vitro. We observed that the activity of counterparts in both series is, in two cases, strikingly different. One of the new analogues, [(L-2-Nal)3,(D-Arg)8]VP is among the most potent antagonists of the vasopressor response to AVP. Moreover, it is the first potent V1 antagonist devoid of antiuterotonic activity. This analogue was designed without modification of position 1, which was previously thought to be essential for substantial pressor antagonism. Two other peptides, [Mpa1;(L-2-Nal)3;(D-Arg)8]VP and [Mpa1,(L-1-Nal)3,D-Arg)8]VP, are highly potent V2 agonists. The second analogue is highly selective. With the exception of [(L-2-Nal)3]AVP, which showed weak antioxytocic activity, (L-Nal)3 modification resulted in the almost complete removal of interaction of our analogues with oxytocic receptors in vitro. Our results suggest that position 3 in AVP and its analogues is important not only for binding and recognition as previously though, but also for pressor, antidiuretic and uterotonic activities. We also assume that the hindering effect caused by bulky naphthyl moiety has a significant impact on the bioactive conformations of molecules which contain Nal residue, and can thus influence their interaction with V1, V2 and oxytocic receptors.