Obstructive Sleep Apnea Is Associated With Low Testosterone Levels in Severely Obese Men.

Background: Disrupted sleep affects cardio-metabolic and reproductive health. Obstructive sleep apnea syndrome represents a major complication of obesity and has been associated with gonadal axis activity changes and lower serum testosterone concentration in men. However, there is no consistent opinion on the effect of obstructive sleep apnea on testosterone levels in men. Objective: The aim of this study was to determine the influence of obstructive sleep apnea on total and free testosterone levels in severely obese men. Materials and methods: The study included 104 severely obese (Body Mass Index (BMI) ≥ 35 kg/m2) men, aged 20 to 60, who underwent anthropometric, blood pressure, fasting plasma glucose, lipid profile, and sex hormone measurements. All participants were subjected to polysomnography. According to apnea-hypopnea index (AHI) patients were divided into 3 groups: <15 (n = 20), 15 - 29.9 (n = 17) and ≥ 30 (n = 67). Results: There was a significant difference between AHI groups in age (29.1 ± 7.2, 43.2 ± 13.2, 45.2 ± 10.2 years; p < 0.001), BMI (42.8 ± 5.9, 43.2 ± 5.9, 47.1 ± 7.8 kg/m2; p = 0.023), the prevalence of metabolic syndrome (MetS) (55%, 82.4%, 83.6%, p = 0.017), continuous metabolic syndrome score (siMS) (4.01 ± 1.21, 3.42 ± 0.80, 3.94 ± 1.81, 4.20 ± 1.07; p = 0.038), total testosterone (TT) (16.6 ± 6.1, 15.2 ± 5.3, 11.3 ± 4.44 nmol/l; p < 0.001) and free testosterone (FT) levels (440.4 ± 160.8, 389.6 ± 162.5, 294.5 ± 107.0 pmol/l; p < 0.001). TT level was in a significant negative correlation with AHI, oxygen desaturation index (ODI), BMI, MetS and siMS. Also, FT was in a significant negative correlation with AHI, ODI, BMI, age, MetS and siMS. The multiple regression analysis revealed that both AHI and ODI were in significant correlation with TT and FT after adjustment for age, BMI, siMS score and MetS components. Conclusion: Obstructive sleep apnea is associated with low TT and FT levels in severely obese men.

Effects of continuous-combined oral drospirenone- estradiol on blood pressure, body weight & lipid profile in early menopausal women.

Background & objectives: Drospirenone (DRSP) is a progestin with antimineralocorticoid and anti-androgenic activity. When administered in combination with estradiol (E2), it relieves menopausal symptoms. The aim of this study was to evaluate the effects of DRSP/E2 on the reduction of cardiovascular risk factors in menopausal women with hypertension. Methods: A retrospective study was conducted at the Clinical Center of Serbia. The participants were 64 menopausal women [mean age=49.19±4.62 yr, mean body mass index (BMI)=25.08±2.94 kg/m2, mean amenorrhoeic period=2.48±2.46 yr]. The effects of DRSP 2 mg/E2 1 mg on 24 h blood pressure (BP) variability, heart rate (HR), anthropometric characteristics and hormone and lipid levels were evaluated in early menopausal women with previously untreated stage 1 hypertension. All analyses were carried out before and after six and 12 months of therapy. Results: DRSP/E2 significantly reduced daytime BP values during six and 12 months of therapy. The reductions in systolic and diastolic BPs ranged from about -4.50 to -8.50 and from -4.00 to -5.00 mmHg, respectively. There were no significant changes in nocturnal 24 h BPs. DRSP/E2 significantly reduced HR daytime and night-time during the follow up period. DRSP/E2 significantly lowered the BMI, concentrations of total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B, while high-density lipoprotein cholesterol and apolipoprotein concentration increased. Interpretation & conclusions: Continuous long-term therapy with DRSP 2 mg/E2 1 mg significantly lowered 24 h systolic and diastolic BPs and reduced the risk of cardiovascular disease in early menopausal women with stage 1 hypertension. Timely initiated menopausal hormone therapy can have beneficial effects on BP and can reduce the incidence of cardiovascular disease in menopausal women.

Foeniculum vulgare Miller, a New Chemotype from Montenegro.

Previous studies relating to prolonged and fractionated distillation procedures highlighted essential oils' (EOs) chemical composition to be significantly dependent on the extraction duration and harvesting time. As a continuation, a hydrodistillation procedure was applied to ripe fruit material of fennel, Foeniculum vulgare Miller (Apiaceae), collected from three localities in Montenegro (Podgorica, Niksic, and Kotor) to furnish a total of 12 EOs. Liquid and vapor phases of the samples were analyzed by Gas Chromatography/Mass Spectrometry and Headspace-Gas Chromatography/Mass Spectrometry techniques, and 18 compounds have been identified. Although both quantitative and qualitative differences between the samples were notable, the phenylpropanoids anethole (ANE) and estragole and the monoterpenoids α-terpineol (TER) and fenchone (FEN) could be singled out as the most abundant constituents. The EOs from Podgorica belong to the most common ANE-rich chemotype, while the predominance of the monoterpenoid fraction is characteristic of the samples from Niksic and Kotor. The latter is particularly rich in TER (up to 56.5%), with significant amounts of FEN and ANE. This chemical profile could represent a new chemotype of fennel EO. Vapor phases contained mainly monoterpenoids, with increased amounts of FEN and TER, while the number of phenylpropanoids was significantly decreased.

Approach to the Patient with Subclinical Cushing's Syndrome.

A growing number of patients with adrenal incidentalomas and subclinical Cushing's syndrome (SCS) led to an increasing number of different guidelines, and diagnostic and treatment recommendations. Excess cortisol secretion in patients with SCS is associated with several comorbidities, such as hypertension, dyslipidemia, type 2 diabetes mellitus, and obesity, which in the long-term increase mortality of these patients. Subtle cortisol secretion affects bone health, quality of life and causes depression, but due to the unapparent clinical features, patients with SCS are often at risk between over and under treatment. This narrative review aimed to summarize the latest recommendations on the approach to the patient with subclinical Cushing's syndrome.

Menopausal hyperinsulinism and hypertension - new approach.

Aim: to test effects of estradiol (E2) 1 mg and drospirenone (DRSP) 2 mg in treatment of normal weight menopausal women with typical menopausal symptoms, hyperinsulinism, and grade I hypertension.Material and methods: The participants were 133 menopausal women, mean age 51.82 ± 3.25 years, body mass index (BMI) 24.9 ± 2.6 kg/m2, waist/hip 0.80 ± 0.05, amenorrhoeic period 2.12 ± 2.10 years. All patients were treated with E2 1 mg and DRSP 2 mg during 12 months period. Blood samples were taken at 8 am before and during 12 months of therapy for: glycemia, lipids, hormonal analysis, follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, testosterone (T), prolactin (PRL), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG). Oral glucose tolerance test (OGTT) was performed with 75 g glucose in order to assess insulin secretion. All had grade I hypertension 24 h blood pressure monitoring was performed before and after 12 months of therapy.Results: E2/DRSP significantly decreased total cholesterol, low-density lipoprotein (LDL), apolipoprotein B (ApoB), and increased high-density lipoprotein cholesterol (HDL) and apolipoprotein A (ApoA). Insulin area under the curve (AUC) significantly decreased (6586.1 ± 4194.2 vs. 5315.3 ± 2895.0, p < .05) and homeostatic model assessment (HOMA) (3.53 ± 2.18 vs. 3.0 ± 1.8, p < .05). FSH, LH decreased, E2 increased significantly. Of 24 h day blood pressure decreased significantly.Conclusions: E2/DRSP represents suitable therapy for hyperinsulinemic, grade I hypertensive menopausal women with typical symptoms and normal weight.

Laboratory scale UV-visible degradation of acetamiprid in aqueous marketed mixtures - Structural elucidation of photoproducts and toxicological consequences.

Acetamiprid is a neonicotinoid pesticide, which is extensively used on agricultural crops, but has a high toxic effect on beneficial insects and the human body. It is exposed to sunlight irradiation on crops but also in surface waters where it is found at a high level due to its resistance to common water treatments. The aim of the present work was to study the UV-visible photodegradation of acetamiprid, alone and in two marketed mixtures (Polysect Ultra SL® and Roseclear Ultra®). Ten photoproducts were characterized using LC-HR-MS/MS analysis. Photodegradation pathways were proposed based on the chemical structures of photoproducts and kinetic measurements; a matrix effect has been evidenced for commercial mixtures. Most photoproducts exhibit potential developmental toxicity twice higher than that of the parent compound. Regarding potential mutagenicity, all photoproducts are less toxic than acetamiprid. Estimated oral rat LD50 values show that the potential toxicities of photoproducts are similar or lower than that of acetamiprid. In vitro tests on Vibrio fischeri bacteria showed that the ecotoxicities of marketed mixtures are significantly higher than that of acetamiprid in aqueous solution; they slightly increase after UV-light exposure.

Premature ovarian insufficiency - novel hormonal approaches in optimizing fertility.

Premature ovarian insufficiency (POI) is a delicate medical problem in young women. This condition is not unchangeable and permanent but is associated with intermittent and unpredictable ovarian activity, resulting in low conception rate. Over the period of 8 years, the evaluation of secondary amenorrhea was conducted in 90 patients below the age of 40 who wished to restore fertility. Having confirmed the diagnosis and investigated the etiology of POI, hormone replacement therapy was applied (sequential administration of estradiol and norethisterone acetate) in the first 30 patients (group A). Estrogen-progestogen therapy with daily supplementation of 25 mg of micronized oral dehydroepiandrosterone (DHEA) was conducted in 44 patients (group B), whereas a combined regime (estrogen-progestogen therapy, DHEA supplementation in daily dose of 25 mg, and melatonin supplementation in daily dose of 3 mg) was conducted in 16 patients (group C). In the course of our study, 16 pregnancies were realized (18% of all cases: 17% in group A; 18% in group B; 19% in group C) 6 to 20 months after the initiation of hormone therapy, and there have been 13 completed term pregnancies so far with normal fetal growth and development. We concluded that estrogen-progestogen therapy combined with DHEA and melatonin could optimize fertility and lead to successful pregnancy in POI patients.

Gender Dysphoria: Bioethical Aspects of Medical Treatment.

Gender affirmation surgery remains one of the greatest challenges in transgender medicine. In recent years, there have been continuous discussions on bioethical aspects in the treatment of persons with gender dysphoria. Gender reassignment is a difficult process, including not only hormonal treatment with possible surgery but also social discrimination and stigma. There is a great variety between countries in specified tasks involved in gender reassignment, and a complex combination of medical treatment and legal paperwork is required in most cases. The most frequent bioethical questions in transgender medicine pertain to the optimal treatment of adolescents, sterilization as a requirement for legal recognition, role of fertility and parenthood, and regret after gender reassignment. We review the recent literature with respect to any new information on bioethical aspects related to medical treatment of people with gender dysphoria.

Endometrium receptivity in premature ovarian insufficiency - how to improve fertility rate and predict diseases?

More empathized approach is required and is obligatory to women with premature ovarian insufficiency (POI) interested for pregnancy. In order to improve fertility rate in POI patients our suggestions would be: (1) To decrease FSH value to 10-15 IU/L by increasing estrogen. Oocyte donation can be suggested after a minimum of six month interval from FSH between 10-15 IU/L and when no dominant follicles are found. (2) To perform oral glucose tolerance test (OGTT). Insulin sensitizing agents has to be included, when indicated, 3-6 month before pregnancy. (3) TSH has to be 1-2.5 mM/L during 3-6 months before pregnancy. (4) Tests for thrombophyllia (Leiden V, FII, MTHFR, PAI) have to be obligatory. They are less expensive than those repeated in vitro fertilizations. Therapy has to be included according to the indications. (5) In order to regulate disturbed immune response in POI patients with endometriosis oral contraceptive therapy is needed for atleast six months prior to the pregnancy. (5) Encourage the patients and advice them about healthy life style and eating habits. (6) Add other drugs, when they are indicated. Complex interplay between endocrine, immunological, haematological, and psychological factors are very often underdetected in POI patients. It is very important to find out the real time for oocyte donation after correcting all the disturbances, improving endometrium receptivity and reaching women's acceptable psychological status. Untreated disturbances induce cardiovascular diseases, diabetes mellitus, thyroid diseases, coagulopathioes etc.

Ultraviolet-visible phototransformation of dehydroacetic acid - Structural characterization of photoproducts and global ecotoxicity.

RATIONALE: The present work is devoted to the structural elucidation of by-products issued from the direct ultraviolet-visible (UV-vis) irradiation of dehydroacetic acid (DHA) in solution and in cosmetic emulsion. METHODS: Analyses were carried out using gas chromatography coupled with ion trap mass spectrometry and by high-performance liquid chromatography coupled with ultrahigh-resolution Fourier transform ion cyclotron resonance mass spectrometry (LC/UHRMS). The potential toxicities of by-products were estimated by in silico calculations based on a QSAR (Quantitative Structure-Activity Relationship) approach and by in vitro bioassays conducted on Vibrio fischeri bacteria. RESULTS: Three photoproducts were detected by LC/MS while one photoproduct was detected by GC/MS. The first photoproduct (PP1) corresponds to an isomer of DHA while two isomeric compounds correspond to dimeric structures. The oral rat LD50 of PP1 was evaluated to be 4.5 times lower than that of the parent molecule which classes it in the category 'moderately toxic' on the Hodge and Sterne toxicity classification. In vitro assays on Vibrio fischeri bacteria showed that the global ecotoxicity of the DHA solution increases with irradiation time. CONCLUSIONS: With the exception of one photoproduct, the structures proposed for the photoproducts on the basis of mass spectral interpretation have not been reported in previous studies. All photoproducts, with the exception of dimers, were detected after irradiation in the cosmetic emulsion. This result shows that personal care products containing DHA must be protected from direct sunlight to prevent photodegradation.

Luteinizing hormone and insulin resistance in menopausal patients with adrenal incidentalomas: The cause-effect relationship?

OBJECTIVE: A high prevalence of insulin resistance (IR) has proven to manifest in patients with adrenal incidentalomas (AI). It has been demonstrated that an increase in IR is related to the size of tumourous masses; additionally, luteinizing hormone (LH)-dependent adrenal pathologies are well documented in patients with LH-responsive adrenal tumours occurring under conditions of physiologically elevated LH. We hypothesized that an association between LH and insulin might play a role in adrenal tumourigenesis and steroidogenesis. DESIGN: The aim of our study was to investigate the association between LH and IR; adrenal tumour size (ATS) and IR; LH and cortisol after the 1 mg overnight dexamethasone test (1 mg DST); and ATS and 1 mg DST cortisol in AI patients. This was a case-control study conducted in the Clinic for Endocrinology, Diabetes and Metabolic Diseases in Belgrade, Serbia. The total study group consisted of 105 menopausal women: 75 AI patients [27 with nonfunctional AI (NAI) and 48 with (possible) autonomous cortisol secretion ((P)ACS)] and 30 age-, BMI-, LH- and menopause duration-matched healthy control (HC) women. To estimate IR, we used homeostasis model assessment (HOMA-IR). RESULTS: Luteinizing hormone and ATS are in a significant positive correlation with HOMA-IR and 1 mg DST cortisol in menopausal patients with AI and (P)ACS. CONCLUSIONS: Our data point to a possible cause-effect relationship between LH and insulin in patients with AI and (P)ACS adding to the body of evidence of their involvement in adrenal tumourigenesis and steroidogenesis.

THE ROLE OF E2/P RATIO IN THE ETIOLOGY OF FIBROCYSTIC BREAST DISEASE, MASTALGIA AND MASTODYNIA.

- The aim of the study was to assess the role of the estradiol and progesterone relationship during the late luteal phase and the occurrence of fibrocystic breast disease (FBD). The concentration of estradiol/progesterone was measured in the group of women with FBD as study group (n=50) and control group of women without FBD (n=40). All women had regular ovulation cycles. Blood samples for estradiol (E2), progesterone (P) and prolactin determination were obtained in the morning at 8 am on days 21 and 24 of menstrual cycle. Significant mastalgia and mastodynia history in women with FBD was obtained with yes or no questionnaire. FBD diagnosis was confirmed with ultrasound (size and number of simple cysts). In the control group, a reduced E2/P ratio was noticed from day 21 to day 24 of the cycle (from 14.8±11.5 pg/mL to 9.1±6.1 pg/mL; p<0.05), which was not recorded in the group of women with FBD (study group). Even the slightest disturbance of the E2/P ratio may contribute to the occurrence of FBD with clinical manifestations of mastalgia and mastodynia.

UV-vis degradation of α-tocopherol in a model system and in a cosmetic emulsion-Structural elucidation of photoproducts and toxicological consequences.

The UV-vis photodegradation of α-tocopherol was investigated in a model system and in a cosmetic emulsion. Both gas chromatography coupled with tandem mass spectrometry (GC-MS/MS) and high performance liquid chromatography coupled with ultrahigh resolution Fourier transform ion cyclotron resonance mass spectrometry (LC-UHR-MS) were used for photoproducts structural identification. Nine photoproduct families were detected and identified based on their mass spectra and additional experiments with α-tocopherol-d9; phototransformation mechanisms were postulated to rationalize their formation under irradiation. In silico QSAR (Quantitative Structure Activity Relationship) toxicity predictions were conducted with the Toxicity Estimation Software Tool (T.E.S.T.). Low oral rat LD50 values of 466.78mgkg-1 and 467.9mgkg-1 were predicted for some photoproducts, indicating a potential toxicity more than 10 times greater that of α-tocopherol (5742.54mgkg-1). In vitro assays on Vibrio fischeri bacteria showed that the global ecotoxicity of the α-tocopherol solution significantly increases with irradiation time. One identified product should contribute to this ecotoxicity enhancement since in silico estimations for D. magna provide a LC50 value 4 times lower than that of the parent molecule.

Influence of obesity and hormone disturbances on sexuality of women in the menopause.

OBJECTIVE: To assess influence of obesity and hormone disturbances on sexuality in the menopause. METHODS: The study included 73 menopausal women, who were divided into groups according to body mass index (BMI) ≥ 26.7 kg/m2. Anthropometric characteristics and blood pressure were measured. Blood was taken at 08:00 for hormones. All the participants filled in McCoy Female Sexual Questionnaire for the assessment of sexual life. STATISTICS: Student's t-test, correlation, analysis of variance (ANOVA). RESULTS: Follicle-stimulating hormone (FSH), luteinizing hormone (LH) and sex hormone-binding globulin (SHBG) were very significantly lower in obese compared to controls. E2 and systolic blood pressure were very significantly, while diastolic blood pressure significantly higher in obese compared to controls. Obese women had significantly decreased frequency of pain during sexual intercourse (3.48 ± 2.64 vs. 4.09 ± 2.81). Influence of age on frequency of sexual intercourse was very significant. Significant influence in interaction between BMI and age on frequency of sexual fantasies as well as significant influence of BMI on satisfaction with partner as lover is also found. CONCLUSION: Obesity has influence on different aspects of sexuality in the postmenopausal women. Our results suggest the need of awareness toward obesity and its impact on sexuality in the menopause.

Photodegradation of fluorene in aqueous solution: Identification and biological activity testing of degradation products.

Degradation of fluorene under UV-vis irradiation in water was investigated and structural elucidation of the main photoproducts was achieved using gas chromatography coupled with mass spectrometry. Twenty-six photoproducts were structurally identified, mainly on the basis of electron ionization mass spectra interpretation. The main generated transformation products are hydroxy derivatives. Some secondary photoproducts including fluorenone, hydroxy fluorenone, 2-biphenyl carboxylic acid, biphenylene, methanol fluorene congeners and hydroxy fluorene dimers were also observed. A photodegradation pathway was suggested on the basis of the chemical structures of photoproducts. Fluorene as well as its main photoproducts for which chemical standards were commercially available were tested for their ability to elicit cytotoxic, estrogenic and dioxin-like activity by using in vitro cell-based bioassays. None of the tested compounds was cytotoxic at concentrations up to 100 µM. However, 2-hydroxyfluorene and 3-hydroxyfluorene exerted significant estrogenic and dioxin-like activity on a concentration range of 3-30 µM, while fluorene and 9-hydroxyfluorene were weakly or not active, respectively, in our assays. This supports the view that photodegradation processes can generate by-products of higher toxicological concern than the parent compound and strengthens the need to further identify transformation products in the aquatic environment.

Genetic Etiology of Primary Premature Ovarian Insufficiency

Primary premature ovarian insufficiency (PPOI) is characterized by hypergonadotropic amenorrhea and hypoestrogenism in women under 40 years of age. PPOI incidence is 1:10,000 in women aged 18-25, 1:1000 in women aged 25-30 and 1:100 in women aged 35-40. In 10%-28% of cases, PPOI causes primary and in 4%-18% secondary amenorrhea. The process is a consequence of accelerated oocyte atresia, diminished number of germinated cells, and central nervous system aging. Specific genes are responsible for the control of oocyte number undergoing the ovulation process and the time to cessation of the reproductive function. A positive family history of PPOI is found in 15% of women with PPOI, indicating the existing genetic etiology. Primary POI comprises genetic aberrations linked to chromosome X (monosomy, trisomy, translocation, deletion) or to autosomal chromosome. Secondary POI implies surgical removal of ovaries, chemotherapy and radiotherapy, and infections. Diagnostic criteria include follicle stimulating hormone level >40 IU/L and estradiol level <50 pmol/L.

Matrix metalloproteinase-9 index as a possible parameter for predicting acute coronary syndrome in diabetics.

BACKGROUND/AIM: Matrix metalloproteinase-9 (MMP-9) index is the ratio of active MMP-9 and total MMP-9 levels. It reflects the importance of MMP-9 in acute coronary syndrome (ACS). METHODS: The study included 3 groups of patients (n = 87): the group 1 - non-diabetic subjects without ACS (control); the group 2 - diabetic patients with ACS [subgroups with unstable angina pectoris (UAP), myocardial infarction (MI) or reinfarction]; and the group 3 non-diabetics patients with ACS. Total and active MMP-9 were measured and used to create MIP-9 index. RESULTS: MMP-9 index, as a marker showed good sensitivity and specificity, of ACS in diabetics, with a cut-off value over 58.2. MMP-9 was higher in the study groups than in the control one. MMP-9 correlated with ACS occurrence and type of cardiovascular event. A statistically significant difference was found among the groups according to active MMP-9 (p < 0.001). The same was found with active MMP-9 between the control and the group with MI (p < 0.001). The control was highly statistically significantly different from the group of patients with UAP (p < 0.01). Statically significant differences in MMP-9 index was found between the control and the diabetics with ACS (P < 0.001). Statistically significant difference of MMP-9 index was also found in the controls compared to the value in non-diabetic patients with ACS (p < 0.01). CONCLUSION: MMP-9 index may be a possible marker of atheromatous plaque rupture in diabetics.

Acquired Hypertrichosis Lanuginosa: Typical Presentation and Unusual Association.

Paraneoplastic syndrome might be the first clinical manifestation of malignancy. We present a menopausal female with the acquired hypertrichosis lanuginosa (AHL) as an initial clinical presentation of rectal adenocarcinoma, unusually associated with paraneoplastic cerebellar degeneration (PCD) and disseminated intravascular coagulation (DIC).

[Complete androgen insensitivity syndrome].

SUMMARY INTRODUCTION: Androgen insensitivity syndrome (AIS) belongs to disorders of sex development, resulting from complete or partial resistance to the biological actions of androgens in persons who are genetically males (XY) with normally developed testes and age-appropriate for males of serum testosterone concentration. CASE OUTLINE: A 21-year-old female patient was admitted at our Clinic further evaluation and treatment of testicular feminization syndrome, which was diagnosed at the age of 16 years.The patient had never menstruated. On physical examination, her external genitalia and breast development appeared as completely normal feminine structures but pubic and axillary hair was absent. Cytogenetic analysis showed a 46 XY karyotype. The values of sex hormones were as in adult males. The multi-sliced computed tomography (MSCT) showed structures on both sides of the pelvic region, suggestive of testes. Bilateral orchiectomy was performed. Hormone replacement therapy was prescribed after gonadectomy. Vaginal dilatation was advised to avoid dyspareunia. CONCLUSION: The diagnosis of complete androgen insensitivity is based on clinical findigs, hormonal analysis karyotype, visualization methods and genetic analysis. Bilateral gonadectomy is generally recommended in early adulthood to avoid the risk of testicular malignancy. Vaginal length may be short requiring dilatation in an effort to avoid dyspareunia. Vaginal surgery is rarely indicated for the creation of a functional vagina.