Minipuberty in Daughters of Women with Hypothyroidism during Pregnancy.

Minipuberty is a term describing transient postnatal activation of the hypothalamic-pituitary-gonadal axis, likely playing an important role in the postnatal growth of female genital organs and breasts. Unlike infant boys, there are no data concerning the impact of gestational hypothyroidism on the course of minipuberty in infant girls. Therefore, the aim of the current study was to investigate the reproductive axis and genital organs in daughters of women with thyroid hypofunction during pregnancy. The study population included three matched groups of infant girls: offspring of women with thyroid hypofunction non-substituted or inadequately treated during gestation (group 1), descendants of women adequately substituted throughout pregnancy (group 2), and daughters of healthy women (group 3). Salivary concentrations of estradiol, progesterone, 17-hydroxyprogesterone, and androgens (testosterone, androstenedione, and dehydroepiandrosterone sulfate) and urine levels of gonadotropins were measured monthly from month 1 to month 6, once every two months between postnatal months 6 and 12, and once every three months between postnatal months 12 and 18. During each visit, we also determined ovarian volume, uterine length, and breast diameter. Concentrations of FSH, LH, and estradiol were lowest in group 1, and this group was also characterized by the shortest detection period for gonadotropins and estradiol. These differences were paralleled by differences in ovarian volume, uterine length, and breast diameter. There were no differences between groups 2 and 3 in levels of both hormones and in the size of the measured structures. The obtained results seem to indicate that non-substituted or inadequately substituted hypothyroidism during pregnancy may impair the course of minipuberty in the female offspring.

The Impact of Atorvastatin on Cardiometabolic Risk Factors in Sisters of Women with Polycystic Ovary Syndrome.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a frequent endocrinopathy in young women with significantly increased cardiometabolic risk. Siblings of women with this disorder are at increased risk of insulin resistance and androgen excess. The current study was aimed at investigating cardiometabolic effects of atorvastatin in sisters of women with PCOS. METHODS: This prospective observational study compared two age-, body mass index-, blood pressure-, and plasma lipid-matched groups of women with hypercholesterolemia: sisters of PCOS probands (group A) and unrelated control subjects (group B), receiving atorvastatin (40 mg daily). Plasma lipids, glucose homeostasis markers, concentrations of sex hormones, high-sensitivity C-reactive protein (hsCRP), homocysteine, fibrinogen and uric acid, and the urinary albumin-to-creatinine ratio (UACR) were measured before entering the study and 6 months later. RESULTS: Both groups differed in the degree of insulin resistance, testosterone, free androgen index (FAI), circulating levels of hsCRP and homocysteine, and UACR. There were no between-group differences in the impact of atorvastatin on plasma lipids. Despite reducing hsCRP and homocysteine in both groups of women, the effect on these biomarkers was stronger in group B than in group A. Only in group B, atorvastatin did reduce fibrinogen, uric acid, and UACR. Only in group A, atorvastatin did worsen insulin sensitivity and tended to reduce testosterone and FAI. The impact of atorvastatin on hsCRP, homocysteine, fibrinogen, uric acid, and UACR inversely correlated with testosterone and FAI. CONCLUSION: The obtained results suggest that sisters of women with PCOS may benefit to a lesser degree from atorvastatin treatment than other women.

Rosuvastatin Potentiates Gonadotropin-Lowering Effects of Metformin in Postmenopausal Women: A Pilot Study.

INTRODUCTION: Metformin reduces elevated levels of FSH and LH. In some studies, gonadotroph secretory function was inhibited by statins. The aim of the present study was to investigate whether statin therapy modulates the impact of metformin on hypothalamic-pituitary-gonadal axis activity in postmenopausal women. METHODS: The study population included 60 postmenopausal women with prediabetes, 40 of whom, because of high cardiovascular risk, received rosuvastatin (20-40 mg daily). One group of rosuvastatin-treated women (group A, n = 23) and all statin-naïve patients (group B, n = 20) were matched for age, glucose homeostasis markers, and gonadotropin levels. Over the entire study period (6 months), these women received metformin. The third group (group C) included 17 rosuvastatin-treated women refusing metformin treatment. We assessed baseline and follow-up plasma lipids, glucose homeostasis markers, and concentrations of FSH, LH, thyrotropin, prolactin, adrenocorticotropic hormone (ACTH), insulin-like growth factor-1, estradiol, progesterone, and anti-Müllerian hormone (in selected patients). RESULTS: Fifty-three women (18 in groups A and B and 17 in group C) completed the study. At study entry, rosuvastatin-treated and statin-naïve women differed in levels of total cholesterol, LDL-cholesterol, and ACTH. In statin-naïve women, metformin reduced FSH levels and tended to reduce LH levels. In rosuvastatin-treated women, metformin decreased FSH and LH levels, and both effects were stronger than in statin-naïve women. Although observed in both groups, the impact on glucose homeostasis markers was more pronounced in individuals not receiving statin therapy. Metformin treatment did not affect circulating levels of lipids, thyrotropin, prolactin, ACTH, insulin-like growth factor-1, estradiol, and anti-Müllerian hormone. In group C, plasma lipids, glucose homeostasis markers, and hormone levels remained at a similar level throughout the study period. CONCLUSION: The obtained results indicate that statin therapy may enhance gonadotropin-lowering effects of metformin.

Cardiometabolic Risk Factors in Atorvastatin-Treated Women with Euthyroid Autoimmune Thyroiditis.

INTRODUCTION: Autoimmune thyroiditis seems to be associated with increased cardiometabolic risk. Statins, the mainstay of cardiovascular risk reduction and prevention, were found to reduce thyroid antibody titers. The aim of this study was to investigate plasma markers of cardiometabolic risk in statin-treated women with thyroid autoimmunity. METHODS: We compared two matched groups of euthyroid women with hypercholesterolemia receiving atorvastatin treatment: subjects with autoimmune (Hashimoto's) thyroiditis (group A, n = 29) and subjects without thyroid pathology (group B, n = 29). Plasma lipids, glucose homeostasis markers, as well as circulating levels of uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen, homocysteine, and 25-hydroxyvitamin D were measured before atorvastatin treatment and 6 months later. RESULTS: At entry, both groups differed in antibody titers, insulin sensitivity, and plasma levels of uric acid, hsCRP, fibrinogen, homocysteine, and 25-hydroxyvitamin D. Atorvastatin-induced reduction in hsCRP and homocysteine, but not in total cholesterol and LDL-cholesterol, was more pronounced in group B than in group A. Only in group B, the drug decreased uric acid and fibrinogen and increased 25-hydroxyvitamin D. In group A, atorvastatin reduced insulin responsiveness. CONCLUSION: The obtained results indicate that euthyroid women with Hashimoto's thyroiditis may benefit to a lesser degree from atorvastatin treatment than other populations of women with hypercholesterolemia.

Cabergoline-Induced Hypoprolactinemia May Attenuate Cardiometabolic Effects of Atorvastatin: A Pilot Study.

INTRODUCTION: Hypoprolactinemia, which is usually a consequence of treatment with inadequate high doses of dopaminergic agents, is a poorly understood clinical condition. The aim of the current study was to investigate whether the cardiometabolic effects of statin therapy differ between patients with low prolactin production and patients with normal levels of this hormone. METHODS: We studied two groups of cabergoline-treated premenopausal women with hypercholesterolemia matched for age, plasma lipids, cabergoline dose, and treatment duration: 11 women with hypoprolactinemia (group A) and 15 women with plasma levels of this hormone within the reference range (group B). The control group (C) included 25 dopaminergic-naïve normoprolactinemic women, matched for age and lipid levels. Plasma lipids, insulin sensitivity, and levels of uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen, homocysteine, and 25-hydroxyvitamin D were measured before and after 14-week treatment with atorvastatin (20 mg daily). RESULTS: Patients with hypoprolactinemia were more insulin-resistant, had lower values of total testosterone and free androgen index, and had higher levels of hsCRP and fibrinogen than individuals with normal prolactin levels. Although atorvastatin reduced total and LDL cholesterol and hsCRP in all study groups, this effect was stronger in groups B and C than in group A. Only in groups B and C, the drug decreased uric acid, fibrinogen, and homocysteine and increased 25-hydroxyvitamin D. In turn, only in group A, atorvastatin worsened insulin sensitivity and reduced free androgen index. CONCLUSION: Coexisting hypoprolactinemia may have an unfavorable impact on the pleiotropic effects of statins.

Gluten-free diet attenuates the impact of exogenous vitamin D on thyroid autoimmunity in young women with autoimmune thyroiditis: a pilot study.

Although both exogenous vitamin D and a gluten-free diet were found to reduce thyroid antibody titers, no study investigated interactions between gluten intake and vitamin D status in patients with autoimmune thyroid disorders. The aim of the present study was to assess whether the gluten-free diet determines the effect of vitamin D treatment on thyroid autoimmunity and thyroid function in young women with autoimmune (Hashimoto's) thyroiditis. The study compared two groups of euthyroid premenopausal women with this disorder, matched for thyroid antibody titers: 31 women with non-celiac gluten sensitivity complying for at least 12 months with the gluten-free diet and 31 unaffected sisters of women with non-celiac gluten sensitivity remaining without any dietary intervention. Plasma titers of thyroid peroxidase and thyroglobulin antibodies, as well as plasma concentrations of thyrotropin, free thyroid hormones, prolactin, 25-hydroxyvitamin D and high-sensitive C-reactive protein were measured at entry and after a six-month follow-up. Moreover, at both time points, the structure parameters of thyroid homeostasis were assessed. Although exogenous vitamin D decreased titers of thyroid peroxidase and thyroglobulin antibodies and increased 25-hydroxyvitamin D levels in each treatment group, this effect was less pronounced in patients on the gluten-free diet than in patients not following any dietary recommendations. Only in the latter group of patients, vitamin D increased SPINA-GT. Treatment-induced changes in thyroid peroxidase and thyroglobulin antibodies correlated with the impact of treatment on 25-hydroxyvitamin D levels. The obtained results suggest that gluten-free diet may impair beneficial effects of exogenous vitamin D in individuals with Hashimoto's thyroiditis.

Rosuvastatin potentiates the thyrotropin-lowering effect of metformin in men with non-autoimmune subclinical hypothyroidism and prediabetes.

WHAT IS KNOWN AND OBJECTIVE: Metformin treatment decreases thyrotropin levels in individuals with hypothyroidism and this effect seems to be mediated by the 5'-adenosine monophosphate-activated protein kinase pathway in the pituitary. The activity of this pathway is also stimulated by statins. The current study was aimed at investigating whether the impact of metformin on hypothalamic-pituitary-thyroid axis activity is affected by statin use. METHODS: The study included three matched groups of men with non-autoimmune hypothyroidism and prediabetes: patients treated for at least 6 months with high-intensity rosuvastatin therapy (20-40 mg daily) [groups A (n = 24) and C (n = 19)] and men not receiving statin therapy [group B (n = 24)]. Over the entire study period (6 months), groups A and B received metformin (2.55-3 g daily). Moreover, groups A and C continued rosuvastatin therapy. The lipid profile, glucose homeostasis markers, and plasma concentrations of thyrotropin, total and free thyroid hormones, prolactin, FSH, LH, ACTH and insulin-like growth factor-1 were determined at baseline and 6 months later. RESULTS AND DISCUSSION: Fifty-nine patients completed the study. There were differences between groups A and C and group B in baseline values of total cholesterol, LDL-cholesterol, gonadotropins and ACTH. Although observed in both groups of metformin-treated patients, the effect on thyrotropin levels was more pronounced in group A than in group B. The impact on fasting glucose and insulin sensitivity was stronger in group B than group A. In turn, only in group A metformin tended to reduce gonadotropin levels. There were no differences between follow-up and baseline values of lipids, total and free thyroid hormones, prolactin, ACTH and insulin-like growth factor-1 in both these groups. In group C, all assessed variables remained at a similar level. WHAT IS NEW AND CONCLUSION: The results of the current study suggest that rosuvastatin potentiates the inhibitory effect of metformin on thyrotrope secretory function.

The impact of vitamin D on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity in myo-inositol-treated and myo-inositol-naïve women with autoimmune thyroiditis: A pilot study.

WHAT IS KNOWN AND OBJECTIVE: Vitamin D and myo-inositol reduce thyroid antibody titers in subjects with autoimmune thyroiditis. No previous study has investigated interactions between these agents. The aim of the current study was to determine whether the impact of exogenous vitamin D on thyroid autoimmunity and thyroid function in women with Hashimoto's thyroiditis depends on myo-inositol supplementation. METHODS: The study population consisted of three thyroid antibody- and insulin sensitivity-matched groups of women with autoimmune thyroiditis and high-normal or slightly elevated TSH levels. Forty-one women (21 in group A and 20 in group C) had been treated for at least 6 months with myo-inositol (group A), while 21 women (group B) had not received myo-inositol preparations. Over the entire study period (6 months), groups A and C continued treatment with myo-inositol (2 g daily), while groups A and B received exogenous vitamin D (4000 IU daily). Plasma titers of thyroid peroxidase and thyroglobulin antibodies, as well as plasma concentrations of glucose, insulin, TSH, free thyroid hormones, prolactin, and 25-hydroxyvitamin D (25-OH-D) were assessed at entry and 6 months later. Moreover, baseline and follow-up values of the structure parameters of thyroid homeostasis were calculated RESULTS AND DISCUSSION: In groups A and B, vitamin D improved insulin sensitivity and increased 25-OH-D levels. Although follow-up antibody titers in both these groups were lower than baseline ones, the impact of vitamin D on thyroid peroxidase and thyroglobulin antibodies was stronger in group A than in group B. Only in group A, vitamin D decreased TSH levels and increased SPINA-GT. There were no differences between baseline and follow-up free values of glucose, thyroid hormones, prolactin, Jostel's index, and SPINA-GD. The impact of vitamin D treatment on antibody titers correlated with treatment-induced changes in 25-OH-D levels and the degree of improvement in insulin sensitivity. In group C, glucose homeostasis markers, antibody titers and hormone levels remained at a similar level throughout the study period. WHAT IS NEW AND CONCLUSION: The obtained results suggest that the impact of vitamin D on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity in subjects with autoimmune thyroiditis is more pronounced if they receive myo-inositol.

Differences in levothyroxine action on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity between metformin- and myo-inositol-treated women with autoimmune subclinical hypothyroidism.

WHAT IS KNOWN AND OBJECTIVE: Insulin resistance impairs the impact of levothyroxine on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity. Both metformin and myo-inositol were found to improve insulin sensitivity and to reduce thyrotropin levels in individuals with hypothyroidism. The aim of the present study was to compare the effect of levothyroxine on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity between women receiving metformin and myo-inositol. METHODS: The study included two groups of women with autoimmune hypothyroidism, treated for at least 6 months with either metformin (group A; n = 25) or myo-inositol (group B; n = 25). Both groups were matched for age, insulin sensitivity, hormone levels and antibody titers. For the following 6 months, all women received levothyroxine. Plasma levels of glucose, insulin, thyrotropin, free thyroid hormones, prolactin, 25-hydroxyvitamin D and high-sensitivity C-reactive protein (hsCRP), as well as titers of thyroid peroxidase and thyroglobulin antibodies were assessed at the beginning and at the end of the study. RESULTS AND DISCUSSION: At baseline there were not differences between the study groups. Although levothyroxine reduced thyrotropin levels, increased free thyroid hormone levels and decreased antibody titers in both study groups, these effects were more pronounced in group A than group B. Only in group A, levothyroxine increased 25-hydroxyvitamin D, decreased hsCRP and improved insulin sensitivity. The impact of levothyroxine on thyrotropin and free thyroid hormones correlated with treatment-induced changes in insulin sensitivity, antibody titers, 25-hydroxyvitamin D and hsCRP. WHAT IS NEW AND CONCLUSION: The present study suggests that the impact of levothyroxine on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity is stronger in women receiving metformin than in women treated with myo-inositol.

Myo-Inositol Enhances the Inhibitory Effect of Metformin on Gonadotropin Levels in Postmenopausal Women.

OBJECTIVES: Metformin decreased circulating levels of anterior pituitary hormones and its effect on thyrotropin concentration was found to be stronger in individuals receiving myo-inositol. Phospholipids containing inositols are precursors of second messengers of several hormones, including gonadotropins and insulin. The aim of the current study was to investigate whether the concomitant use of myo-inositol changes the effect of metformin on gonadotropin levels. DESIGN: A prospective observational study. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: This study, conducted at a university-affiliated medical center, included two groups of postmenopausal women with prediabetes, matched for age, FSH and LH levels, and insulin sensitivity: women taking myo-inositol preparations for at least 6 months (group A, n = 23) and women not receiving inositol preparations (group B, n = 23). All participants were treated with metformin (850 mg twice daily) for the following 6 months. At the beginning and at the end of the study, we assessed plasma glucose, insulin, FSH, LH, thyrotropin, prolactin, adrenocorticotropic hormone, insulin-like growth factor-1, estradiol, and glycated hemoglobin. RESULTS: The impact of metformin on glucose levels, the homeostatic model assessment 1 of insulin resistance ratio, and glycated hemoglobin was more pronounced in group A than in group B. Metformin administered with myo-inositol reduced both FSH and LH. No significant changes in gonadotropin levels were observed in women receiving only metformin. The impact on FSH and LH levels correlated with their baseline concentrations and with the degree of improvement in insulin sensitivity. Levels of the remaining hormones did not change throughout the study. LIMITATIONS: The most important limitation of the study is a relatively small number of participants. Moreover, the study protocol does not allow to conclude whether similar effects are observed in premenopausal women. CONCLUSIONS: Myo-inositol may enhance the inhibitory effect of metformin on gonadotropin production in postmenopausal women.

The impact of metformin on hypothalamic-pituitary-thyroid axis activity in postmenopausal women with untreated non-autoimmune subclinical hypothyroidism.

Metformin was found to reduce elevated thyrotropin levels in subjects with hypothyroidism. The impact on thyrotropin levels was stronger in women receiving oral contraceptive pills than in women not using any contraception. The aim of the present study was to determine whether physiological levels of oestradiol determine the effect of metformin on hypothalamic-pituitary-thyroid axis activity. The study population included 40 postmenopausal women with prediabetes and untreated non-autoimmune subclinical hypothyroidism, using (group A; n = 18) or not using (group B; n = 22) oestradiol replacement therapy. Over the entire study periods, all subjects were treated with metformin (2.55-3.00 g daily). Plasma levels of glucose, lipids, insulin, thyrotropin, free thyroxine, free triiodothyronine, prolactin, gonadotropins and oestradiol were measured, while the structure parameters of thyroid homeostasis and the degree of insulin sensitivity were calculated at the beginning of the study and 6 months later. At entry, both groups differed in gonadotropin and oestrogen levels. Despite improving insulin sensitivity, thyrotropin levels and Jostel's thyrotropin index in both study groups, these effects were stronger in group A than group B. Only in group A, metformin increased SPINA-GT, while only in group B the drug decreased FSH levels. Levels of the other variables remained at a similar level throughout the study. The effect of treatment on thyrotropin levels correlated with its baseline values, as well as with the improvement of insulin sensitivity. The results obtained suggest that the impact of metformin on hypothalamic-pituitary-thyroid axis activity depends on the oestrogen status of patients.

The impact of vitamin D status on cardiometabolic effects of fenofibrate in women with atherogenic dyslipidemia.

Vitamin D deficiency is a risk factor for cardiometabolic disease. The aim of this study was to determine the role of vitamin D status in the impact of fenofibrate on plasma levels of cardiometabolic risk factors. The study population (n = 61) consisted of three matched groups of women with atherogenic dyslipidaemia: vitamin D-naïve women with vitamin D insufficiency (group A), women receiving vitamin D preparations because of vitamin D deficiency (group B), as well as vitamin D-naïve women with normal vitamin D status (group C), who were treated with micronized fenofibrate (200 mg daily). Glucose homeostasis markers, plasma lipids, as well as plasma levels of 25-hydroxyvitamin D, uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen and homocysteine were determined at the beginning of the study and 6 months later. At entry, group A was characterized by lower levels of 25-hydroxyvitamin D, reduced insulin sensitivity and higher concentrations of uric acid, hsCRP, fibrinogen and homocysteine. Apart from a weaker effect on HDL-cholesterol and triglycerides in group A, there were no differences between the treatment arms in the effect of fenofibrate on plasma lipids. However, only in groups B and C the drug improved insulin sensitivity and reduced circulating levels of uric acid and hsCRP, as well as increased levels of 25-hydroxyvitamin D and these effects correlated with the degree of improvement in insulin sensitivity. Treatment-induced increase in homocysteine was observed only in group A. The results of the study indicate that cardiometabolic effects of fibrates may depend on the vitamin D status of patients.

The impact of metformin on prolactin levels in postmenopausal women.

WHAT IS KNOWN AND OBJECTIVE: Metformin-induced reduction in prolactin levels is more pronounced in users of hormonal contraception than in non-users. The current study was aimed at investigating whether physiological concentrations of estradiol determine the impact of metformin on lactotrope secretory function. METHODS: We studied two matched groups of postmenopausal women with elevated prolactin levels. Twenty-three women were on hormone replacement therapy (group 1), while the remaining ones (group 2, n = 23) did not use sex hormones. Because of coexistent prediabetes, all individuals received metformin (2.55-3 g daily) for the following six months. Circulating levels of total prolactin, monomeric prolactin, thyrotropin, gonadotropins, free thyroid hormones and estradiol were determined at the beginning and at the end of the study. RESULTS AND DISCUSSION: Compared with group 1, group 2 was characterized by higher gonadotropin levels and lower estrogen levels. Although metformin reduced monomeric prolactin levels in both study groups, this effect was more pronounced in group 1 than in group 2. Only in group 1, metformin decreased total prolactin levels, while only in group 2 the drug reduced FSH levels. Metformin treatment did not affect circulating levels of the remaining hormones. The impact of metformin on total and monomeric prolactin levels correlated with baseline prolactin levels and with the degree of improvement in insulin sensitivity. WHAT IS NEW AND CONCLUSION: The obtained results indicate that the impact of metformin on lactotrope secretory function is partially determined by the estrogen status of patients.

Vitamin D status determines the impact of metformin on circulating prolactin levels in premenopausal women.

WHAT IS KNOWN AND OBJECTIVE: Metformin was found to normalize secretory function of overactive pituitary cells. Its effect on circulating thyrotropin levels was more pronounced in women receiving exogenous vitamin D. The aim of the current study was to investigate whether vitamin D status determines the impact of metformin on prolactin levels in premenopausal women with hyperprolactinaemia. METHODS: The study population consisted of three groups of women with prediabetes and elevated prolactin levels: vitamin D-naïve women with vitamin D insufficiency (group 1; n = 19), women receiving vitamin D preparations because of vitamin D deficiency (group 2 n = 20), as well as vitamin D-naïve women with normal vitamin D status (group 3 n = 23). All participants were then treated with metformin (2.55-3 g daily). Circulating levels of glucose, insulin, prolactin, thyrotropin, free thyroid hormones, gonadotropins, estradiol, calcium and 25-hydroxyvitamin were determined at baseline and six months later. RESULTS AND DISCUSSION: At baseline, prolactin levels were higher in group 1 than in the remaining groups of patients. Although metformin decreased glucose levels and improved insulin sensitivity in all treatment groups, this effect was more pronounced in groups 2 and 3. Only in subjects with 25-hydroxyvitamin D levels within the reference range, metformin reduced prolactin levels. The impact on prolactin levels correlated with 25-hydroxyvitamin D levels and with the improvement in insulin sensitivity. The drug produced a neutral effect on circulating levels of thyrotropin, free thyroid hormones, gonadotropins, estradiol, calcium and 25-hydroxyvitamin D. WHAT IS NEW AND THE CONCLUSION: The results of the current study suggest that the impact of metformin on secretory function of overactive lactotropes depends on the vitamin D status of patients.

Hypothalamic-pituitary-gonadal axis and sexual functioning in metformin-treated men after discontinuation of testosterone replacement therapy: A pilot study.

WHAT IS KNOWN AND OBJECTIVE: Metformin was found to reduce elevated gonadotropin levels. The aim of the present study was to determine whether metformin modulates the impact of discontinuation of testosterone therapy on hypothalamic-pituitary-gonadal axis activity and sexual function in men with low testosterone levels. METHODS: The study included 28 men with late-onset hypogonadism (defined according to the criteria of the European Male Aging Study group) receiving testosterone undecanoate (120 mg in three equal doses), 12 of whom had been treated with oral metformin (1.7-3 g daily). Both testosterone and metformin had been administered for at least six months before enrolment. In all patients, testosterone replacement required to be discontinued. The control group included 16 testosterone- and metformin-treated men with late-onset hypogonadism who during the entire study period continued their treatment. Glucose homeostasis markers, as well as plasma levels of insulin, gonadotropins, testosterone, calculated bioavailable testosterone, dehydroepiandrosterone-sulphate, oestradiol, thyrotropin, free thyroxine, prolactin, insulin-growth factor-1 and cortisol were measured at the beginning of the study and four months later. Moreover, at the beginning and the end of the study, all enrolled patients completed a questionnaire assessing their sexual functioning (IIEF-15). RESULTS AND DISCUSSION: Discontinuation of testosterone therapy resulted in a decrease in total testosterone and bioavailable testosterone (by 42% and 45% in metformin-treated patients, and by 52% and 54% in metformin-naïve patients), as well as impaired all aspects of male sexual function. Changes in bioavailable testosterone, as well as in erectile function, orgasmic function and sexual desire were less pronounced if subjects received metformin. Only in metformin-naïve men, follow-up FSH and LH levels were higher than at baseline (by 75% and 62%). Moreover, discontinuation of testosterone therapy in metformin-naïve men increased glycated haemoglobin, as well as worsened insulin sensitivity. There were no differences between baseline and follow-up levels of the remaining hormones. In metformin-naïve subjects, the increase in gonadotropin levels correlated with the changes in testosterone levels and insulin sensitivity. No effect on glucose homeostasis markers, hormone levels and sexual functioning was observed in the control group. WHAT IS NEW AND CONCLUSION: The obtained results suggest that metformin treatment mitigates the unfavourable effect of discontinuation of testosterone treatment on hypothalamic-pituitary-testicular axis activity and sexual function in men with late-onset hypogonadism.

Sexual function and depressive symptoms in young women with hypoprolactinaemia.

OBJECTIVE: Dopamine agonist treatment may result in hypersexuality in men. The aim of this study was to investigate for the first time female sexual functioning and depressive symptoms in women with very low prolactin levels. DESIGN: A prospective case-control study. PATIENTS AND MEASUREMENTS: The study population consisted of three age-matched groups of young women with normal, regular menstrual cycles: 15 subjects with cabergoline-induced hypoprolactinaemia (group A), 25 cabergoline-treated individuals with prolactin levels within the reference range (group B) and 30 dopamine agonist-naïve women with normoprolactinemia. Because of low prolactin levels, the dose of cabergoline in group A (but not in group B) was then reduced. Apart from measuring serum levels of prolactin, testosterone, sex hormone-binding globulin, dehydroepiandrosterone sulphate, estradiol and gonadotropins, at the beginning of the study and 6 months later, all included women filled in questionnaires evaluating female sexual function (FSFI) and depressive symptoms (BDI-II). RESULTS: At the beginning of the study, there were no differences between groups B and C in the mean total FSFI score, all domain scores and in the BDI-II score. In group A, the total FSFI score and domain scores for desire and arousal were lower, while the BDI-II score was higher than in the remaining study groups. Compared with groups of B and C, women with cabergoline-induced hypoprolactinaemia were also characterized by lower total testosterone levels and lower values of the free androgen index. Cabergoline dose reduction normalized the FSFI score, desire, arousal, the BDI-II score, as well as normalized prolactin, total testosterone and the free androgen index. CONCLUSIONS: The obtained results suggest that dopamine agonist-induced hypoprolactinaemia impairs sexual functioning and well-being in young women, as well as that these disturbances are secondary to low prolactin levels, not to specific properties of cabergoline.

Macroprolactinaemia modulates cardiometabolic effects of fenofibrate in men with atherogenic dyslipidaemia: A pilot study.

WHAT IS KNOWN AND OBJECTIVE: Cardiometabolic effects of hypolipidaemic agents depend on plasma levels of monomeric prolactin. Although macroprolactinaemia seems to be associated with increased cardiometabolic risk, no previous study has investigated whether macroprolactinaemia modulates pleiotropic effects of hypolipidaemic agents. METHODS: The study population included two age-, weight-, blood pressure- and lipid-matched groups of men: 12 men with elevated levels of big-big prolactin and 16 men with prolactin levels within the reference range. Because of atherogenic dyslipidaemia, all subjects were treated for 6 months with fenofibrate (200 mg daily). Glucose homeostasis markers and plasma lipids, as well as plasma levels of uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen, homocysteine and 25-hydroxyvitamin D, were determined in patients at the beginning and at the end of the study. RESULTS AND DISCUSSION: Men with elevated levels of big-big prolactin were characterized by higher levels of hsCRP and fibrinogen and lower levels of 25-hydroxyvitamin D as well as decreased insulin sensitivity than subjects with prolactin levels within the reference range. In men without macroprolactinaemia, fenofibrate decreased circulating levels of total and LDL cholesterol, triglycerides, uric acid, hsCRP and fibrinogen, and increased concentrations of HDL cholesterol, homocysteine and 25-hydroxyvitamin D, as well as improved insulin sensitivity. In subjects with macroprolactinaemia, fenofibrate action was limited to the changes in HDL cholesterol, triglycerides, hsCRP and homocysteine. With the exception of homocysteine, cardiometabolic effects of fenofibrate were stronger in subjects without than in subjects with elevated levels of big-big prolactin. WHAT IS NEW AND CONCLUSION: The results of the study indicate that macroprolactinaemia exerts a negative impact on cardiometabolic effects of fenofibrate.

The effect of spironolactone on thyroid autoimmunity in euthyroid men with Hashimoto's thyroiditis.

WHAT IS KNOWN AND OBJECTIVE: Hashimoto's thyroiditis, also referred to as autoimmune thyroiditis, is characterized by sexual dimorphism, suggesting an important role of sex hormones in its development. No interventional study has investigated whether drugs exerting antiandrogen properties affect thyroid antibody titres and thyroid function tests in subjects with autoimmune thyroiditis. METHODS: This study included 35 levothyroxine-naïve men with euthyroid Hashimoto's thyroiditis. At the physician's discretion, 18 men were then treated with spironolactone (50-200 mg daily), while the remaining patients (n = 17) received other diuretics. Serum levels of thyrotropin, free thyroid hormones, testosterone and 25-hydroxyvitamin D, as well as titres of thyroid peroxidase and thyroglobulin, were measured at the beginning of the study and 6 months later. Based on hormone levels, constant structure parameters of thyroid homeostasis were calculated. RESULTS AND DISCUSSION: At baseline, there was no difference between the treatment arms in terms of thyroid antibody titres, hormone levels and the calculated parameters of thyroid homeostasis. Thirty-two patients completed the study. Spironolactone increased thyroid antibody titres, decreased testosterone and 25-hydroxyvitamin D levels and reduced SPINA-GT. The drug produced a neutral effect on serum levels of thyrotropin, free thyroid hormones, Jostel's thyrotropin index and SPINA-GD. The effect of spironolactone on antibody titres correlated with treatment-induced changes in SPINA-GT, testosterone and 25-hydroxyvitamin D. No significant changes in antibody titres, hormone levels and the calculated parameters of thyroid homeostasis were observed in spironolactone-naïve men. WHAT IS NEW AND CONCLUSION: The obtained results indicate that spironolactone may exert an unfavourable effect on progression of autoimmune thyroiditis in men.

Hyperprolactinaemia attenuates the inhibitory effect of vitamin D/selenomethionine combination therapy on thyroid autoimmunity in euthyroid women with Hashimoto's thyroiditis: A pilot study.

WHAT IS KNOWN AND OBJECTIVE: Vitamin D administered together with selenomethionine has been reported to markedly reduce thyroid antibody titres in patients with autoimmune thyroiditis. Hyperprolactinaemia exerts a complex pro-inflammatory effect. This study was aimed at investigating whether prolactin excess determines the effect of vitamin D/selenomethionine combination therapy on thyroid autoimmunity. METHODS: The study included two age-, body mass index-, hormone- and thyroid antibody-matched groups of young euthyroid women with Hashimoto's thyroiditis: 19 women with mild-to-moderate hyperprolactinaemia and 19 individuals with prolactin levels within the reference range. All participants were then treated with vitamin D (4000 IU daily) and selenomethionine (200 µg daily). Serum titres of thyroid peroxidase and thyroglobulin (TgAb) antibodies, serum levels of thyrotropin, free thyroxine, free triiodothyronine, prolactin and 25-hydroxyvitamin D, as well as the calculated parameters of thyroid homeostasis, were determined at baseline and 6 months later. RESULTS AND DISCUSSION: All women completed the study. With the exception of prolactin and 25-hydroxyvitamin D levels, there were no differences between the study groups in the investigated parameters. In both study groups, vitamin D/selenomethionine combination therapy reduced thyroid peroxidase and TgAb antibody titres, decreased the free thyroxine:free triiodothyronine ratio and increased 25-hydroxyvitamin D levels and SPINA-GD. The decrease in antibody titres, as well as the improvement in vitamin D status, was more pronounced in subjects with prolactin levels within the reference range than in subjects with hyperprolactinaemia and was inversely correlated with prolactin levels. Moreover, only in normoprolactinaemic women, the treatment reduced thyrotropin levels and increased SPINA-GT. WHAT IS NEW AND CONCLUSION: The obtained results suggest that hyperprolactinaemia attenuates the impact of vitamin D/selenomethionine combination on thyroid autoimmunity.

Different effects of metformin on hypothalamic-pituitary-thyroid axis activity in levothyroxine-treated and levothyroxine-naïve women with non-autoimmune hypothyroidism.

WHAT IS KNOWN AND OBJECTIVE: Metformin was found to reduce thyrotrophin levels in subjects with hypothyroidism. This case-control study was aimed at comparing metformin action on hypothalamic-pituitary-thyroid axis activity between levothyroxine-treated and levothyroxine-naïve women with non-autoimmune thyroid hypofunction. METHODS: The study included two groups of thyroid antibody-negative women with thyrotrophin levels in the range between 4.5 and 10 mIU/L and untreated prediabetes, matched for age, body mass index, thyrotrophin levels and glucose homeostasis markers. The first group had been treated for at least 6 months with levothyroxine, whereas the second group had not received thyroid hormones. All these women were then managed with metformin (3 g daily). Circulating levels of glucose, insulin, glycated haemoglobin, thyrotrophin, total and free thyroid hormones and prolactin were assessed at baseline and 6 months later. RESULTS AND DISCUSSION: Thirty-two women (16 in each treatment arm) completed the study. At baseline, both groups differed only in free and total thyroxine levels. Metformin reduced glucose levels and glycated haemoglobin, improved insulin sensitivity and decreased thyrotrophin levels. The impact on insulin sensitivity and thyrotrophin was stronger in women simultaneously treated with levothyroxine than in women not receiving this hormone. In levothyroxine-treated patients, metformin slightly reduced prolactin levels. In both study groups, metformin treatment exerted a neutral effect on free and total thyroxine and triiodothyronine. The thyrotrophin-lowering effect of metformin correlated with the improvement in insulin sensitivity and in levothyroxine-treated women with the changes in prolactin levels. WHAT IS NEW AND CONCLUSION: The obtained results suggest that metformin/levothyroxine combination therapy may be an interesting treatment option in women with non-autoimmune hypothyroidism poorly tolerating high-dose levothyroxine treatment.