Remarks on the Hormonal Background of the Male Equivalent of Polycystic Ovary Syndrome.

The hypothesis that the most common female endocrine disease, the polycystic ovarian syndrome (PCOS), has a male equivalent, has recently become more widely accepted. The male form of PCOS is marked by alterations in the secretion of gonadotropins, increased insulin resistance, and changes of the levels of several steroid hormones, with clinical manifestations including premature androgenic alopecia (AGA). Because these symptoms are not always found in men with genetic predispositions, knowledge of the male equivalent of PCOS needs to be supplemented by measurements of adrenal 11-oxygenated C19 steroids, particularly 11-keto-, and 11ß-hydroxy-derivatives of testosterone and dihydrotestosterone, by focusing on the newly-realized role of skin as an endocrine organ, and by confirming any age-related factors in glucose metabolism disorders in such predisposed men.

Hypogonadismus obézních mužů.

Male hypogonadism associated with obesity by yet not fully understood mechanisms promote fat depositions and on contrary obesity induces decrease of androgen production. It is necessary to diagnose hypogonadism correctly and to treat it. The definition of hypogonadism is based on subnormal levels of circulating testosterone and on the occurrence of symptoms, which, however, are not much specific. As obesity decreases substantially the concentrations of sex hormone binding globulin SHBG it is recommended in these men to check not only the level of total testosterone but also the concentration of free testosterone or the value of the index of free androgens. Proven hypogonadism in obese men should be treated as well as by testosterone substitution as the body mass reduction. The most effective treatment in this respect is considered bariatric surgery.

Activation of Adrenal Steroidogenesis and an Improvement of Mood Balance in Postmenopausal Females after Spa Treatment Based on Physical Activity.

Spa treatment can effectively reestablish mood balance in patients with psychiatric disorders. In light of the adrenal gland's role as a crossroad of psychosomatic medicine, this study evaluated changes in 88 circulating steroids and their relationships with a consolidation of somatic, psychosomatic and psychiatric components from a modified N-5 neurotic questionnaire in 46 postmenopausal 50+ women with anxiety-depressive complaints. The patients underwent a standardized one-month intervention therapy with physical activity and an optimized daily regimen in a spa in the Czech Republic. All participants were on medication with selective serotonin reuptake inhibitors. An increase of adrenal steroidogenesis after intervention indicated a reinstatement of the hypothalamic-pituitary-adrenal axis. The increases of many of these steroids were likely beneficial to patients, including immunoprotective adrenal androgens and their metabolites, neuroactive steroids that stimulate mental activity but protect from excitotoxicity, steroids that suppress pain perception and fear, steroids that consolidate insulin secretion, and steroids that improve xenobiotic clearance. The positive associations between the initial values of neurotic symptoms and their declines after the intervention, as well as between initial adrenal activity and the decline of neurotic symptoms, indicate that neurotic impairment may be alleviated by such therapy provided that the initial adrenal activity is not seriously disrupted.

Non-hematogenic activity of erythropoietin.

The cytokine erythropoietin is the main hemopoietic factor synthesized mainly by the kidney. However, erythro-poietin and its receptors are expressed in several tissues and exert pleiotropic activities also in nonhemopoietic tissues. Erythropoietin has an antiapoptotic activity and plays a potential neuroprotective, nefroprotective and cardioprotective role against ischemia and other type of injury. Erythropoietin is also involved in angiogenesis, neurogenesis, and the immune response. It can prevent metabolic alterations, vascular and neuronal degeneration, and inflammatory cell activation. Erythropoietin reduces hyperglycaemia and retards proliferative retinopathy in diabetic patients. Consequently, erythropoietin may be of therapeutic value for a variety of disorders. This short review provides an insight into the nonhemopoietic role of erythropoietin and its mechanisms of action. For elimination of polycythaemia after erythropoietin administration analogues without haematopoietic activity were prepared and tested in animals and in some cases also evaluated in clinical trials.

Exposure to bisphenols and parabens during pregnancy and relations to steroid changes.

BACKGROUND: The harmful effects of endocrine disrupting compounds (EDCs) on human health are generally well-known, and exposure during fetal development may have lasting effects. Fetal exposure to bisphenol A (BPA) has been recently relatively well-studied; however, less is known about alternatives such as bisphenol S (BPS), bisphenol F (BPF) and bisphenol AF (BPAF), which have started to appear in consumer products. Parabens are another widespread group of EDCs, with confirmed transplacental passage. The usage of many cosmetic, pharmaceutical and consumer products during the pregnancy that may contain parabens and bisphenols has led to the need for investigation. OBJECTIVES: To shed more light into the transplacental transport of BPA, its alternatives, and parabens, and to study their relation to fetal steroidogenesis. METHODS: BPA, BPS, BPF, BPAF, methylparaben, ethylparaben, propylparaben, butylparaben, benzylparaben and 15 steroids including estrogens, corticoids, androgens and immunomodulatory ones were determined in 27 maternal (37th week of pregnancy) and cord plasma samples using liquid chromatography - tandem mass spectrometry methods. RESULTS: In cord blood, significantly higher BPA levels (p=0.0455) were observed compared to maternal plasma. The results from multiple regression models showed that in cord blood, methylparaben (ß=-0.027, p=0.027), propylparaben (ß=-0.025, p=0.03) and the sum of all measured parabens (ß=-0.037, p=0.015) were inversely associated with testosterone levels. CONCLUSION: To the best of our knowledge, this is the first study reporting the simultaneous detection of BPA, alternative bisphenols, parabens and steroids in maternal and cord plasma. Our study confirmed the transplacental transport of BPA, with likely accumulation in the fetal compartment. The negative association of cord blood parabens and testosterone levels points to possible risks with respect to importance of testosterone for prenatal male development.

[Anabolic steroid induced hypogonadism in men: overview and case report]. / Muzský hypogonadizmus indukovaný steroidními anaboliky: prehled poznatku a kazuistika.

An important potential consequence of the anabolic steroid misuse is hypogonadotropic hypogonadism due to the inhibition of pituitary secretion of gonadotropins. By the symptoms as testicular atrophy, spermatogenic and fertility disturbances or dysfunction in sexual life, the anabolic steroids induced hypogonadism (ASIH) could be differentiated from organic hypogonadotropic hypogonadism only with difficulty unless the misuse is reported by the user. When diagnosed, the crucial step in the therapy is the stop of anabolic use. Convalescence lasts usually several months or even more than one year. First could be seen the retreat of testicular atrophy followed by the rearrangement of spermatogenesis. The users mainly well informed from internet use for amelioration of the symptoms injections of human choriogonadotropin (hCG), selective estrogen receptor modulators (SERM) or aromatase inhibitors.Key words: anabolic steroids - doping - hypogonadotropic hypogonadism - side effects.

The Response of C19 Δ5-steroids to ACTH Stimulation and Hypoglycemia in Insulin Tolerance Test for Adrenal Insufficiency.

Studies on the time course of ACTH- or insulin-induced hypoglycemia stimulating adrenal androgens are usually limited to dehydroepiandrosterone and/or its sulphate. Our data on dehydroepiandrosterone (DHEA) and its hydroxylated metabolites clearly show that measurements of DHEA and its sulphate (DHEAS) are valuable markers of the integrity of the HPA (hypothalamus-pituitary-adrenal) axis. Assessments of HPA function should rely on measurements of baseline and/or stimulated serum cortisol concentrations, and C19 Δ5-steroids may provide additional information. The art of stimulation of 7- and 16-hydroxylated metabolites of DHEA can help our understanding of the formation sequence of these compounds.

A Comparison of Salivary Steroid Levels during Diagnostic Tests for Adrenal Insufficiency.

Numerous diagnostic tests are used to evaluate the hypothalamic-pituitary-adrenal axis (HPA axis). The gold standard is still considered the insulin tolerance test (ITT), but this test has many limitations. Current guidelines therefore recommend the Synacthen test first when an HPA axis insufficiency is suspected. However, the dose of Synacthen that is diagnostically most accurate and sensitive is still a matter of debate. We investigated 15 healthy men with mean/median age 27.4/26 (SD±4.8) years, and mean/median BMI (body mass index) 25.38/24.82 (SD±3.2) kg/m2. All subjects underwent 4 dynamic tests of the HPA axis, specifically 1 µg, 10 µg, and 250 µg Synacthen (ACTH) tests and an ITT. Salivary cortisol, cortisone, pregnenolone, and DHEA (dehydroepiandrosterone) were analysed using liquid chromatography-tandem mass spectrometry. During the ITT maximum salivary cortisol levels over 12.5 nmol/l were found at 60 minutes. Maximum cortisol levels in all of the Synacthen tests were higher than this; however, demonstrating that sufficient stimulation of the adrenal glands was achieved. Cortisone reacted similarly as cortisol, i.e. we did not find any change in the ratio of cortisol to cortisone. Pregnenolone and DHEA were higher during the ITT, and their peaks preceded the cortisol peak. There was no increase of pregnenolone or DHEA in any of the Synacthen tests. We demonstrate that the 10 µg Synacthen dose is sufficient stimulus for testing the HPA axis and is also a safe and cost-effective alternative. This dose also largely eliminates both false negative and false positive results.

[Testosterone and mortality]. / Testosteron a mortalita.

Subnormal levels of testosterone are frequently found in men of higher age category. Hypogonadal men have lower life expectancy than men with full androgenization and cardiovascular disease, obesity or diabetes is often associated with hypotestosteronemia. Low testosterone level is risk factor for these diseases. However, until now it is not clear whether testosterone deficiency is a cause or consequence of atherosclerosis or metabolic syndrome. A handful of symptoms and metabolic risk markers in hypogonadal men can be ameliorated by testosterone supplementation. Testosterone treatment increased sexual activity and well-being and had a moderate benefit with respect to depressive symptoms but no significant benefit to vitality. Testosterone has a beneficial effect on cardiovascular risk factors, but there is not clear whether it reduces mortality.Key words: civilization diseases - late onset hypogonadism - morbidity - mortality - testosterone - testosterone supplementation.

Fetal complications due to intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder of pregnancy. Diagnosis is based on the clinical picture, particularly the presence of pruritus with a deterioration of liver function tests, and typically elevated serum levels of total bile acids. ICP manifests in the second half of pregnancy, predominantly during the third trimester. Symptoms of the disease resolve spontaneously after delivery. Etiology is still not fully understood. Genetic defects in specific transport proteins, elevated levels of sex hormones, and various environmental factors are thought to play a role in the development of this disorder. Although practically benign for the pregnant woman, ICP represents a serious threat to the fetus. It increases the risk of preterm delivery, meconium excretion into the amniotic fluid, respiratory distress syndrome, and sudden intrauterine fetal death. Identifying fetuses at risk of ICP complications remains challenging. The ideal obstetrical management of ICP needs to be definitively determined. The aim of this review is to summarize the current knowledge on fetal complications of ICP and describe management options for their prevention.

The comparison of selected cerebrospinal fluid and serum cytokine levels in patients with multiple sclerosis and normal pressure hydrocephalus.

OBJECTIVES: Cytokine production and immune activation are associated with various pathological conditions including neurodegenerative disorders. One of them is multiple sclerosis (MS), known autoimmune disease. Inflammatory changes were also reported in normal pressure hydrocephalus (NPH), neurodegenerative disorder, which pathophysiology remains still unclear. The aim of this research was to compare the group of MS subjects with NPH patients and controls and to evaluate the potential inflammatory substance of NPH in comparison with autoimmune inflamed MS. METHODS: The levels of IL-1ß, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, INF-γ, sCD40L and TNF-α were measured in cerebrospinal fluid (CSF) and plasma in subjects with MS (n=15), NPH (n=18) and controls (n=11) by multiplex assay. RESULTS: The increased levels of IL-1ß, IL-6, IL-10, IL-21 and TNF-α in cerebrospinal fluid of NPH subjects in comparison with MS patients and controls were found. Regarding the MS patients, we have confirmed increased IL-33 levels in cerebrospinal fluid and periphery as well as the increase of IL-1ß and IL-10 in cerebrospinal fluid and IL-4 and sCD40L in plasma. CONCLUSION: The enlarged brain ventricles in NPH may repress and activate brain structures to the production of IL-1ß, IL-6, IL-10, IL-21 and TNF-α, reflecting the inflammatory basis in NPH affected brain. The elevation of the above mentioned cytokines in MS was confirmed.

Daily profiles of dehydroepiandrosterone and its hydroxylated metabolites with respect to food intake.

Eight women of reproductive age with normal body mass index were given 5 standardised meals, and their hormonal milieu was determined during the course of the day. Plasma from 12 withdrawals was analysed for dehydroepiandrosterone and its 7- and 16-hydroxylated metabolites. Overall, there was a maximum in the levels of steroid hormones in the morning, followed by decreases throughout the day. There was also an additional significant decrease found for dehydroepiandrosterone and its 7α-hydroxyderivative in association with the consumption of main meals, but not for the 7ß-isomer or 16α-hydroxyderivative.

How Does Energy Intake Influence the Levels of Certain Steroids?

The influence of steroid hormones on food intake is well described. However, there are only a few studies on the effect of food intake on steroid levels. The study involved eight non-smoker women (average age 29.48±2.99 years; average BMI 21.3±1.3 kg/m2); they did not use any kind of medication affecting steroidogenesis. We analysed the influence of four various stimuli on the levels of steroid hormones and melatonin. During their follicular phase of menstrual cycle, each woman had an oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGTT), a standard breakfast and psyllium (a non-caloric fibre). Cortisol declined during each test, which is a physiological decline in the morning hours. In all tests (except of the application of the non-caloric fibre, psyllium), however, this decline was modified. After the standard breakfast there was an increase in cortisol at 40th minute. The OGTT and IVGTT tests led to a plateau in cortisol levels. Testosterone levels and those of other steroid hormones showed no relationships to tested stimulations. Oral and intravenous glucose have influenced physiological decline of melatonin levels. During the IVGTT test, melatonin levels started to increase at 20th minute, reaching a maximum at 40th minute. The OGTT test led to a delayed increase in melatonin levels, compared to IVGTT. Despite the fact that we performed the tests in the morning hours, when steroid hormone levels physiologically start to change due to their diurnal rhythm, we still found that food intake influences some of the hormone levels.

Changes in the Concentrations of Corticoid Metabolites--The Effect of Stress, Diet and Analytical Method.

A precisely measured corticoid level is important for decision-making in daily clinical practice. These levels can be influenced in the pre-analytical phase, when the effect of stress, timing, and diet can be important. The aim of this study was to elucidate optimal conditions for blood sampling as well as the choice of analytical methods, which they will be used in measuring of corticoids. By studying ten women, we focused on the influences of the stress of cannulation and a large lunchtime meal on cortisol, cortisone, aldosterone and corticosterone levels. We further compared results of cortisol measurements from RIA and LC-MS/MS. Stress from cannulation caused increase of cortisol, cortisone and corticosterone already, when the cannula was being inserted. This indicates that this increase is stimulated by fear of the blood withdrawing rather, than just by the needle insertion itself. The effect of stress on corticosterone disappeared after an hour, while effect on other corticoids was still apparent. Concerning the lunchtime meal, we found an increase in all measured corticoids between 11 and 12 o'clock. After the food, there were marked decreases in cortisone and aldosterone, while declining levels of cortisol and corticosterone had rather plateaus. We compared cortisol in 90 plasma samples measured by a commercial RIA kit and the LC-MS/MS method. Results from both methods showed a strong correlation (r=0.85). When measuring corticoid metabolites, the chosen analytical method, eliminating stress factors, and precisely timed blood sampling considering the daily rhythm and food intake are critical.

[Functional hypothalamic amenorrhea]. / Funkcní hypotalamická amenorea.

Functional hypothalamic amenorrhea (FHA) besides pregnancy and syndrome of polycystic ovary is one of the most common causes of secondary amenorrhea. FHA results from the aberrations in pulsatile gonadotropin-releasing hormone (GnRH) secretion, which in turn causes impairment of the gonadotropins (follicle-stimulating hormone and luteinizing hormone). FHA is a form of the defence of organism in situations where life functions are more important than reproductive function. FHA is reversible; it can be normalized after ceasing the stress situation. There are three types of FHA: weight loss related, stress-related, and exercise-related amenorrhea. The final consequences are complex hormonal changes manifested by profound hypoestrogenism. Additionally, these patients present mild hypercortisolemia, low serum insulin levels, low insulin-like growth factor 1 (IGF-1) and low total triiodothyronine. Women health in this disorder is disturbed in several aspects including the skeletal system, cardiovascular system, and mental problems. Patients manifest a decrease in bone mass density, which is related to an increase in fracture risk. Therefore, osteopenia and osteoporosis are the main long-term complications of FHA. Cardiovascular complications include endothelial dysfunction and abnormal changes in the lipid profile. FHA patients present significantly higher depression and anxiety and also sexual problems compared to healthy subjects.

How smoking cessation influence hormonal levels in postmenopausal women?

Smoking represents the most widespread substance dependence in the world. Nicotine alters women hormonal homeostasis. Women smokers have higher testosterone and lower estradiol levels throughout life compared to nonsmokers. We monitored the effect of smoking discontinuation on steroid spectrum with 25 postmenopausal women smokers. They had been examined before discontinuation of smoking and after 6, 12, 24 and 48 weeks of abstinence. Blood was collected to determine steroid spectrum (measured by GC-MS), luteinizing hormone, follicle stimulating hormone and sex hormone binding globulin (measured by IRMA). Repeated measures ANOVA model was used for evaluation of the data. In postmenopausal women, an increase in testosterone, dihydrotestosterone, dehydroepiandrosterone and other androgens occurred. Neither nicotine replacement therapy nor weight changes nor age play a role in androgen level increase. The higher androgens levels correlated with failure in smoking cessation. Women smokers have higher androgen levels, which might play a role in smoking dependence development. Women successful in smoking cessation, compared to the non-successful ones, have lower androgen levels initially and also after smoking discontinuation.

Reduced urine pregnenolone concentration after clinical response in patients with depression: An open-label short-term prospective study.

BACKGROUND: Identifying biological alterations in patients with depression, particularly those that differ between responders and non-responders, is of interest to clinical practice. Biomarker candidates involve neuroactive steroids, including pregnenolone (PREG) and allopregnanolone (ALLO). However, alterations in PREG and ALLO associated with treatment response are understudied. This study's main aim was to evaluate the effects of antidepressant treatment, clinical response, and treatment duration on PREG and ALLO in depression. MATERIALS AND METHODS: In a 4-week, open-label trial, participants were allocated randomly to the venlafaxine (n = 27) or mirtazapine (n = 30) group. Urine concentrations of PREG and ALLO were assessed through gas chromatography-mass spectrometry. Participants collected night urine between 10:30 p.m. and 8:00 a.m. Two primary outcomes were analyzed. Firstly, the effect of treatment (mirtazapine or venlafaxine), clinical response (operationalized through the Hamilton Depression Rating Scale), and time (baseline compared to 28 days) on the urine concentrations of PREG or ALLO in depression. Finally, the effect of clinical response and time on the urine concentration of PREG or ALLO, independently of the antidepressant given (mirtazapine or venlafaxine). Linear mixed models were carried out. RESULTS: There was no significant difference in PREG and ALLO concentrations between baseline and 28 days in responders and non-responders when investigating the venlafaxine or the mirtazapine group. However, we found a significant reduction of urine PREG concentration after 28 days of treatment in responders who received either venlafaxine or mirtazapine (estimate = -0.56; p = 0.016; 95CI [-1.003; -0.115]; Cohen's d = -0.61). CONCLUSIONS: Our main results indicate that responders in depression show reduced urinary PREG concentrations after 4-weeks of therapy, independently of the antidepressant used. More studies are needed to confirm these findings.

[The prevalence of metabolic syndrome in women with polycystic ovary syndrome]. / Výskyt metabolického syndromu u zen se syndromem polycystických ovarií.

BACKGROUND: Polycystic ovary syndrome (PCOS) affects between 4-10% women of fertile age and is often connected with insulin resistance. We aimed to ascertain the prevalence of metabolic syndrome in Czech women with PCOS and to describe relations of different features of metabolic syndrome with insulin sensitivity. METHODS AND RESULTS: 179 women with PCOS. Clinical examination was done and blood lipid spectrum was measured. Euglycaemic hyperinsulinaemic clamp was done in 114 subjects. Metabolic syndrome (according to ATP III criteria) was detected in 28.7% women. The most frequent features were an increased waist circumference, decreased concentration of HDL - cholesterol (both in 96%), and increased blood pressure (88%). Increased triglycerides (49%) and impaired fasting blood glucose or diabetes mellitus type 2 (37.3%) were less common. The average insulin sensitivity described as corrected glucose disposal (Mk) was 34.9 +/- 12.70 micromol/kg/min. The most tight correlations was that of Mk and waist circumference (r = -0.896), weight (r = -0.875) and BMI (r = -0.844). CONCLUSION: The increased risk of metabolic syndrome and the decreased insulin sensitivity in polycystic ovary syndrome is tightly connected with obesity, especially with its abdominal type.

7-Hydroxylated derivatives of dehydroepiandrosterone in the human ventricular cerebrospinal fluid.

OBJECTIVE: Dehydroepiandrosterone is a long established neuroactive steroid. Some authors documented that 7-oxygenated derivatives of this steroid may be responsive at least by part for its physiological activity. METHODS: In the ventricular cerebrospinal fluid obtained from 15 patients with hydrocephalus (8 postmenopausal women and 7 men) potentially neuroactive steroid 7-oxygenated derivatives of dehydroepiandrosterone were quantified using gas chromatography/mass spectrometry. RESULTS: Besides free dehydroepiandrosterone 7-oxygenated steroids such as 7alpha- and 7beta-hydroxy-dehydroepiandrosterone, 5-androstene-3beta,7alpha,17beta-triol and 5-androstene-3beta,7beta,17beta-triol in picomolar concentration in serum and cerebrospinal fluid were found. CONCLUSION: Dehydroepiandrosterone and its 7-oxygenated derivatives are present in ventricular cerebrospinal fluid in concentration 2 -100 times lower than in serum.

Dihydrotestosterone and testosterone throughout the life span of Czech men.

OBJECTIVE: The dihydrotestosterone:testosterone ratio seems to be an important factor in the expression of androgenic activity, especially in the prostate and pilosebaceous unit. Whereas the decline of testosterone (T) in aging men is well known, controversial data can be found in literature concerning the age dependence of dihydrotestosterone (DHT) levels. Data from the database of the Institute of Endocrinology served as the basis for the definition of the life span curve for the ratio dihydrotestosterone : testosterone. METHODS: The results of testosterone and dihydrotestosterone obtained immunoassays from 10 251 male patients were used in the construction of the curve. RESULTS: The data show that after a peak of DHT:T in infancy and a subsequent decrease in puberty, the ratio of both androgens remains practically without change from approx. 20 years of age till old age. CONCLUSION: High DHT:T ratio in infancy decreases at puberty and throughout the entire reproductive period of life this ration remains practically constant.