Milka Drezgic

Drospirenone in the treatment of severe premenstrual cerebral edema in a woman with antiphospholipid syndrome, lateral sinus thrombosis, situs inversus and epileptic seizures.

We report herein the case of 32-year-old woman with situs inversus, thrombophilia, antiphospholipid syndrome and severe premenstrual syndrome (PMS) with cerebral edema and epileptic seizures prior to menstruation. Seven days prior to regular menstruation she developed severe PMS, including headache, blurred vision, epileptic seizures, urinary incontinence, craving for food, depression and irritability. Papilledema was detected. Daily hormone analyses prior to and during menstruation confirmed an ovulatory cycle with extremely high progesterone, prolactin and insulin levels in the late luteal phase. From day 29 to day 31, progesterone and insulin decreased sharply and the estradiol/progesterone ratio changed, leading to epileptic seizures and the peak of her symptoms. Diuretic treatment was administered. All symptoms disappeared during the first few days of menstruation. A novel oral contraceptive, containing ethinyl estradiol and drospirenone, an antimineralocorticoid progestogen, was given during the next cycle and hormone analyses were repeated. All symptoms were reduced significantly and no cerebral edema and epileptic seizures occurred. This is the first report of a woman with severe PMS and cerebral edema being treated successfully with an oral contraceptive containing drospirenone.

Gonadotropin pulsatility in Cushing's syndrome compared with polycystic ovary syndrome

Many of the presenting features in women with Cushings syndrome (CS) are similar to those observed for patients with polycystic ovary syndrome (PCOS). The aim of this study was to compare gonadotropin pulsatility characteristics in CS and PCOS. We evaluated 32 females divided into three groups. The first group comprised 12 females with clinically and biochemically proven CS, subsequently confirmed by histology (seven with Cushings syndrome, five with adrenal adenoma). The second group comprised ten females with clinical, endocrine and ultrasonographic parameters for PCOS, while the third group comprised ten healthy females with regular menstrual cycles to serve as controls. Blood samples were taken at 15-min intervals for 6 h in the follicular phase, for determination of luteinizing hormone (LH) and follicle-stimulation hormone (FSH). Pulse analysis was carried out using the PulsDetekt program, and statistical analysis was done using the Kruskal–Wallis test. The following data, presented as median (minimum–maximum), were found for the three groups respectively. Number of LH pulses: 0 (0–5), 7 (3–8) and 3 (2–7); LH pulse amplitude: 2.29 (1.98–3.49), 2.27 (1.15–5.90) and 2.03 (1.02–4.46) mU/l; LH pulse mass: 17.81 (14.82–26.20), 29.85 (8.59–185.82) and 27.57 (7.63–66.69) mU/l × min. Number of FSH pulses: 3 (0–3), 2 (0–5) and 3 (1–5); FSH pulse amplitude: 1.62 (1.29–1.94), 1.49 (1.19–4.40) and 2.02 (1.37–2.52) mU/l; FSH pulse mass: 12.17 (9.64–41.69), 11.18 (8.92–33.02) and 15.16 (10.31–18.93) mU/l × min. Only the number of pulses was compared because other parameters of pulsatile secretion cannot be estimated when no pulses are detected. The difference in number of LH pulses between groups was statistically significant (p < 0.05); however, there was no difference in the number of detected FSH pulses between groups (p > 0.05). Attenuation of pulsatile LH secretion indicating gonadotropin deficiency in the majority of women with CS is mostly due to alterations in serum cortisol levels. Our data also suggest that different mechanisms alter LH pulsatile secretion in CS and PCOS.

Gaining weight and components of metabolic syndrome in the period of menopause

INTRODUCTION Menopause induces redistribution of fat mass and development of abdominal obesity, increasing risk for metabolic syndrome (MS) by 60%. Related cardiovascular diseases become a leading cause of morbidity and mortality in women after fifty years of age. OBJECTIVE The aim of this study was to investigate the influence of gaining weight on components of MS in the menopause. METHOD The study included 50 obese women, BMI=31.92 +/- 5.83 kg/m2, age 54.40 +/- 3.64, time since menopause 5.90 +/- 5.46 years, and 37 normal weight women, BMI = 23.50 +/- 2.13 kg/m2, age 53.92 +/- 3.95, time since menopause 5.96 +/- 4.92 years. Both groups were divided according to the presence of MS into two subgroups. Anthropometric characteristics and blood pressure were measured. Blood was taken at 8 am for the following: fasting glucose, triglycerides, cholesterol, HDL, LDL, apolipoprotein A (ApoA), apolipoprotein B (ApoB), lipoprotein(a) (Lp(a)), C-reactive protein (CRP), fibrinogen, FSH, LH, prolactin, oestrogen, progesterone, testosterone and sex hormone-binding globulin (SHBG). RESULTS 66% of obese women had MS compared with 22% normal weight women. Significant differences between groups were found for the following: weight, BMI, waist, hip circumference, waist/hip ratio, diastolic blood pressure, Lp(a), FSH, LH, prolactin (all p < 0.01) and fasting glucose (p < 0.05). Obese women with and without MS were significantly diverse for the following: waist/hip ratio, systolic blood pressure and fasting glucose (all p < 0.01); age, BMI, waist circumference, triglycerides, HDL, Lp(a) and SHBG (all p < 0.05). Normal weight women with and without MS had significantly different values of waist/hip ratio, systolic, diastolic blood pressure, triglycerides (all p < 0.01); HDL and testosterone (p < 0.05). Significant differences were found between obese and normal weight women with MS in anthropometric characteristics, ApoA, Lp(a), fibrinogen (all p < 0.01) and FSH (p < 0.05). CONCLUSION Abdominal obesity significantly increases incidence of MS as a cluster of cardiovascular risk factors in the menopause.

Temporal coupling of luteinizing hormone and follicle stimulating hormone secretion in polycystic ovary syndrome

The aim of this study was to assess the luteinizing hormone (LH) and follicle stimulating hormone (FSH) pulsatile secretion and their temporal relation (concordance) in subjects with polycystic ovary syndrome (PCOS). Fifteen subjects were included in the study (age 17–30 years ,body mass index (BMI) 19.38–33.46 kg/m2). For the LH and FSH determinations ,blood sampling started at 23.00 and lasted for 6 h with an intersample interval of 10 min. Pulse analysis was carried out using the PulsDetekt program. LH/FSH pulse concordance was calculated using the specific concordance index. Gonadotropin co-pulsatility was found in six subjects who were significantly younger than the others (median 18.5 vs. 22.5 years ,p = 0.036). BMI ,hirsutism grade ,insulin sensitivity ,estradiol ,progesterone, testosterone ,prolactin ,cortisol and results obtained from the pulsatility analysis did not significantly differ between the groups. A serum cortisol concentration was correlated with the increased LH/FSH lag time (ρ = 0.851 ,p = 0.036) all subjects were included. In conclusion ,two distinct LH/FSH secretory patterns were found in PCOS patients ,manifested by the presence or absence of the concordance of gonadotropin secretion. In the group where LH/FSH co-pulsatility was present ,correlation was found between the serum cortisol and the LH/FSH lag. We also confirmed the finding of previous studies that LH and FSH secretion are regulated by two different mechanisms.

Adrenal cortex function impairment in chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is defined as constellation of the prolonged fatigue and several somatic symptoms, in the absence of organic or severe psychiatric disease. However, this is an operational definition and conclusive biomedical explanation remains elusive. Similarities between the signs and symptoms of CFS and adrenal insufficiency prompted the research of the hypothalamo-pituitary-adrenal axis (HPA) derangement in the pathogenesis of the CFS. Early studies showed mild glucocorticoid deficiency, probably of central origin that was compensated by enhanced adrenal sensitivity to ACTH. Further studies showed reduced ACTH response to vasopressin infusion. The response to CRH was either blunted or unchanged. Cortisol response to insulin induced hypoglycaemia was same as in the control subjects while ACTH response was reported to be same or enhanced. However, results of direct stimulation of the adrenal cortex using ACTH were conflicting. Cortisol and DHEA responses were found to be the same or reduced compared to control subjects. Scott et all found that maximal cortisol increment from baseline is significantly lower in CFS subjects. The same group also found small adrenal glands in some CFS subjects. These varied and inconsistent results could be explained by the heterogeneous study population due to multifactorial causes of the disease and by methodological differences. The aim of our study was to assess cortisol response to low dose (1 µg) ACTH using previously validated methodology. We compared cortisol response in the CFS subjects with the response in control and in subjects with suppressed HPA axis due to prolonged corticosteroid use. Cortisol responses were analyzed in three subject groups: control (C) secondary adrenal insufficiency (AI), and in CFS. The C group consisted of 39 subjects, AI group of 22, and CFS group of nine subjects. Subject data are presented in table 1. Low dose ACTH test was started at 0800 h with the iv injection of 1 µg ACTH (Galenika, Belgrade, Serbia). Blood samples for cortisol determination were taken from the iv cannula at 0,15, 30, and 60 min. Data are presented as mean standard error (SE). Statistical analysis was done using ANOVA with the Games-Howell post-hoc test to determine group differences. ACTH dose per kg or per square meter of body surface was not different between the groups. Baseline cortisol was not different between the groups. However, cortisol concentrations after 15 and 30 minutes were significantly higher in the C group than in the AI group. Cortisol concentration in the CFS group was not significantly different from any other group (Graph 1). Cortisol increment at 15 and 30 minutes from basal value was significantly higher in C group than in other two groups. However there was no significant difference in cortisol increment between the AI and CFS groups at any time of the test. On the contrary, maximal cortisol increment was not different between CFS and other two groups, although it was significantly higher in C group than in the AI group. Maximal cortisol response to the ACTH stimulation and area under the cortisol response curve was significantly larger in C group compared to AI group, but there was no difference between CFS and other two groups. Several previous studies assessed cortisol response to ACTH stimulation. Hudson and Cleare analysed cortisol response to 1 µg ACTH in CFS and control subjects.They compared maximum cortisol attained during the test, maximum cortisol increment, and area under the cortisol response curve.There was no difference between the groups in any of the analysed parameters. However, authors commented that responses were generally low. On the contrary Scott et all found that cortisol increment at 30 min is significantly lower in the CFS than in the control group. Taking into account our data it seems that the differences found in previous studies papers are caused by the methodological differences. We have shown that cortisol increment at 15 and 30 min is significantly lower in CFS group than in C group. Nevertheless, maximum cortisol attained during the test, maximum cortisol increment, and area under the cortisol response curve were not different between the C and CFS groups. This is in agreement with our previous findings that cortisol increment at 15 minutes has the best diagnostic value of all parameters obtained during of low dose ACTH test. However, there was no difference between CFS and AI group in any of the parameters, although AI group had significantly lower cortisol concentrations at 15 and 30 minutes, maximal cortisol response, area under the cortisol curve, maximal cortisol increment, and maximal cortisol change velocity than C group. Consequently reduced adrenal responsiveness to ACTH exists in CFS. In conclusion, we find that regarding the adrenal response to ACTH stimulation CFS subjects present heterogeneous group. In some subjects cortisol response is preserved, while in the others it is similar to one found in secondary adrenal insufficiency.

Adrenal incidentaloma in neurofibromatosis type 1

INTRODUCTION Neurofibromatosis type 1 is one of the most common genetically transmitted diseases with a high index of spontaneous mutations and extremely varied and unpredictable clinical manifestations. It is diagnosed by the existence of certain clinical criteria. The presence of numerous localised cutaneous neurofibromas or a plexiform neurofibroma is virtually pathognomonic of neurofibromatosis type 1. The incidence of pheochromocytoma in neurofibromatosis type 1 is 0.1-5.7%. CASE OUTLINE A 56-year old female patient was admitted for further evaluation of incidental adrenal tumour previously diagnosed on computerized tomography (CT). She had previously unrecognized neurofibromatosis type 1 and a clinical picture which could remind of pheochromocytoma. None of the catecholamine samples in 24 hr urine indicated functionally active pheochromocytoma. Chromogranin A was moderately increased. Decision for operation was made after performing the image techniques. Adrenal incidentaloma had features of pheochromocytoma on abdominal magnetic resonance imaging (MRI), with positive 131I-MIBG (iodine 131-labelled metaiodobenzylguanidine scintigraphy). After being treated with phenoxybenzamine and propranolol, she was operated on. The pathohistological finding showed the case of left adrenal pheochromocytoma. CONCLUSION Detailed diagnostic procedure for pheochromocytoma should be performed with patients having neurofibromatosis type 1 and adrenal incidentaloma. Pheochromocytomas are rare tumours with fatal outcome if not duly recognized and cured.