Marisa Orrù

Reduced serum level of THDOC, an anticonvulsant steroid, in women with perimenstrual catamenial epilepsy

Purpose: Seizure exacerbation in catamenial epilepsy (CE) is associated with the decrease in progesterone secretion and increase in estradiol secretion during the premenstrual period. Moreover, experimental evidence suggests that tetrahydrodeoxycorticosterone (THDOC), a positive modulator of the type A receptor for γ‐aminobutyric acid (GABA), and dehydroepiandrosterone sulfate (DHEAS), a negative modulator of this receptor, might play a crucial role in modulating seizure frequency during the menstrual cycle. Following these studies it seems of interest to investigate possible variations, among other hormonal parameters, of THDOC and DHEAS in CE patients.

Evidence that treatment with monophasic oral contraceptive formulations containing ethinylestradiol plus gestodene reduces bone resorption in young women

The aim of the study was to evaluate if a pill containing the same dose of the same type of progestin compound (gestodene, GES, 75 microg) but different doses of ethinylestradiol (EE2) (20 or 30 microg) differently influences specific markers of bone resorption (urinary levels of pyridinoline (PYR) and dexoxypyridinoline (D-PYR)). During the 12 months of the study a significant decrease of urinary levels of PYR and D-PYR was found in 2 groups of young post-adolescent women taking the pills with 20 and 30 microg of EE2 in comparison with control women (subjects of the same age group with normal menstrual cycle who did not use contraception). In women taking pills with 20 or 30 microg EE2, the levels of sex hormone-binding globulin (SHBG) significantly increased during treatment in comparison with baseline, whereas in the same time period no changes occurred in control women. These findings suggest that similar to the pill containing 30 microg EE2, the lower dosage of the EE2 pill (20 microg) is also capable of reducing bone resorption. Twenty and 30 microg EE2 pills exert the same biological estrogenic effect. In fact, SHBG levels significantly increased with both pills. However, an additional effect of the progestin compound that could act directly on progestin or estrogen receptors of bone cannot be excluded. Since contraception with a pill containing the lowest estrogen dose is associated with the lowest incidence of side effects, these findings further suggest a pill containing 20 microg EE2 for young post-adolescent women would be the best choice.

Treatment with flutamide improves hyperinsulinemia in women with idiopathic hirsutism

OBJECTIVE To investigate insulin metabolism and its modifications induced by the administration of flutamide, a specific antiandrogen compound, in women with idiopathic hirsutism (IH) and in nonobese women with polycystic ovary syndrome (PCOS). DESIGN Prospective, randomized trial. SETTING Endocrinological Centre of the Department of Obstetrics and Gynecology, University of Caligari, Caligari, Italy. PATIENT(S) Thirty-two women with normal body mass index participated in the study: 11 with clinical and hormonal features of PCOS and 21 age- and weight-matched normally cycling women with IH (n = 11) and without IH (n = 10, controls). INTERVENTION(S) Each subject with PCOS or IH was assigned randomly to receive either flutamide tablets (250 mg twice a day) or placebo for > or =5 months. Twelve subjects (6 with PCOS, 6 with IH) received flutamide and 10 (5 with PCOS, 5 with IH) received placebo. All subjects ingested 75 g of glucose and then underwent an oral glucose tolerance test (OGTT), 3-7 days after spontaneous or medroxyprogesterone acetate (5 mg daily for 5 days)-induced menses. In women with PCOS or IH, the OGTT was repeated at the fourth month of treatment. MAIN OUTCOME MEASURE(S) Fasting and OGTT-stimulated levels of glucose, insulin, and C peptide. RESULT(S) Both fasting and OGTT-stimulated levels of insulin and C peptide were significantly higher in women with PCOS and in those with IH than in controls. Placebo did not modify parameters of glucose metabolism. Flutamide was capable of significantly blunting fasting and OGTT-stimulated secretion of insulin only in women with IH. CONCLUSION(S) Hyperinsulinemia exists in women with IH as well as in nonobese women with PCOS. Treatment with flutamide can completely reverse hyperinsulinemia only in women with IH, which suggests that the efficacy of the drug is dependent on peripheral androgen hyperactivity.

Observational study on the stability of the psychological status during normal pregnancy and increased blood levels of neuroactive steroids with GABA-A receptor agonist activity

We investigated whether pregnancy could modify psychological symptoms and whether neuroactive steroids which exert an anti-anxiety effect by acting on the gamma-aminobutyric acid (GABA)-A receptors, are modified during pregnancy in young healthy women. Healthy volunteer women in the Department of Obstetrics and Gynecology at Cagliari University participated in the study. They were divided into women with low (group 1, seven subjects) and high (group 2, seven subjects) psychological score by SCL-90 psychometric scale. Age, body mass index and physiological status of pregnancy did not differ between the groups. The subjects were studied before pregnancy during the follicular phase (FP), and the luteal phase (LP) of the menstrual cycle (MC) and four times during pregnancy (at 14th, 22nd, 30th, and 38th week). SCL-90 psychometric scale, circulating levels of progesterone (P4), 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone, AP), 3alpha,21-dihydroxy-5alpha-pregnan-20-one (allotetrahydrodeoxy-corticosterone, THDOC), cortisol and DHEAS were assayed at each visit. The SCL-90 global score and the intensity of psychological symptoms differ between the groups, but within each group they did not change both during MC and during pregnancy. The DHEAS and cortisol levels did not differ between the groups. DHEAS did not change during the study, whereas cortisol levels increased during pregnancy in both groups. Progesterone, AP, and THDOC levels were higher during LP than during FP and further increased during pregnancy, without any difference between the groups. In conclusion, pregnancy does not seem to interfere with the psychological status of healthy women independently of the psychological basal score. Some neuroactive steroids with anxiolytic activity seem to increase during pregnancy depending on placental function. Their increase could represent some kind of protection against maternal anxiety and stress due to concerns about the pregnancy outcome.

The antiandrogenic effect of flutamide improves uterine perfusion in women with polycystic ovary syndrome

OBJECTIVE To evaluate whether, by blocking androgen action, flutamide can decrease and normalize vascular resistance in the uterine artery in patients with polycystic ovary syndrome (PCOS). DESIGN Prospective and controlled study. SETTING Endocrinological Centre of the Department of Obstetrics and Gynecology of the University of Cagliari, Italy. PATIENT(S) Twenty-two patients with PCOS were enrolled in the study and randomly assigned to one of the following two treatments for 3 months: oral administration of flutamide (250 mg twice daily) or placebo. INTERVENTION(S) Doppler flow measurement of the uterine artery and serum hormone concentration determination during the early follicular phase of the menstrual cycle before treatment and during the third month of treatment. MAIN OUTCOME MEASURE(S) Pulsatility index (PI) of the uterine artery before and during treatment. RESULT(S) The PI of the uterine artery decreased significantly during treatment. No difference was found in patients treated with placebo. Correlation was found only between the PI values of the uterine artery and DHEAS. CONCLUSION(S) The low uterine perfusion that characterizes patients with PCOS can be improved by the antiandrogenic effect of flutamide.

Endocrinological, metabolic and clinical features of treatment with oral contraceptive formulation containing ethinylestradiol plus chlormadinone acetate in nonobese women with polycystic ovary syndrome

BACKGROUND Chlormadinone acetate (CMA) is a progestin compound similar to progesterone, with antiandrogenic properties. In healthy eumenorrheic women, it was demonstrated that the monophasic estroprogestin formulation containing CMA (2 mg) plus ethinyl estradiol (EE) (30 mcg) (EE30+CMA) is efficacious both in reducing hyperandrogenic symptoms, fat mass and in improving lipoprotein panel, without changes in insulin-glucose metabolism. These metabolic properties are important for women affected by polycystic ovary syndrome (PCOS) in whom there is a predisposition to insulin resistance. STUDY DESIGN We studied whether in young nonobese women with PCOS (15 subjects, EE30+CMA-PCOS group) a six-cycle treatment with EE30+CMA can reduce androgen levels, androgen bioavailability and the score of hirsutism and acne, and modify glucose-insulin metabolism evaluated by the oral glucose tolerance test and the body composition evaluated by bio-impedenziometry. These parameters were evaluated before (first visit) and during the sixth cycle of EE30+CMA (second visit). All the results were compared with those of a matched-age-group of nonobese PCOS women (15 subjects, no OC-PCOS group) evaluated before (first visit) and after six menstrual cycles in which they did not use any drug or oral contraceptive (second visit). RESULTS In the EE30+CMA-PCOS group women, androgen levels and bioavailability, hirsutism and acne score were significantly lower at the second than at the first visit, whereas they did not change in no OC-PCOS group. At the second visit, in both groups, glucose-insulin metabolism and body composition parameters were not affected. CONCLUSIONS A six-cycle treatment with EE30+CMA is efficacious in nonobese PCOS women to improve hyperandrogenic symptoms, without negative interferences both on body composition and on insulin-glucose metabolism.

Pattern of Bone Markers during Pregnancy and Their Changes after Delivery

Objective: To investigate whether bone resorption markers change during pregnancy and lactation, and how they are correlated with human placental lactogen (hPL) and PRL. Subjects: Young women before pregnancy, during pregnancy and during a 12-month post-delivery period (study group; n = 22); and age- and weight-matched normal cycling women (control group; n = 22) for a 20-month-period participated in the study. Results: In the study group, women both during pregnancy (from the 8th up to the 38th week) and during a 6-month period of lactation, pyridinoline and deoxypyridinoline urinary levels were significantly higher than those of pre-pregnancy and control women. They returned to basal values at the 12th post-delivery month. During pregnancy there were early and late peak increases, at the 8th and 32nd week, respectively. At the 32nd, 34th, 36th and 38th week of pregnancy, pyridinoline and deoxypyridinoline urinary values were significantly correlated with hPL serum levels. Conclusions: During pregnancy the maternal bone resorption seems to vary critically at early and late stages. A complete reversal of these variations seems to occur after lactation. Further studies could evaluate if changes in placental function are capable of differently interfering with maternal bone resorption.

Efficacy and safety of oral and transdermal hormonal replacement treatment containing levonorgestrel

OBJECTIVES The oral combined formulation of levonorgestrel with estradiol valerate (LNG+EV) has demonstrated to be effective on some postmenopausal symptoms. The availability of a transdermal HRT in sequential formulation with 17-beta-estradiol plus levonorgestrel (TSE2+TSLNG) induced us to do this control-study with the aim to evaluate the efficacy and safety of both oral and transdermal treatments. METHODS At baseline, the psychological symptoms with the psychometric scale SCL-90, the bone resorption with the measurement of the urinary levels of pyridinoline and dexoxypirydinoline, and the insulin and lipid metabolism were assessed in 30 postmenopausal women (PMW) and in 18 premenopausal women. Then, the PMW women were randomly divided in three groups: group A (N=10) assumed EV+LNG, group B (N=10) did not assume any treatment, group C (N=10) was treated with TSE2+TSLNG. The length of the study was 12 months. The aforementioned assessments were repeated at different time-intervals up to the end of the study. RESULTS The total score of SCL-90, the bone resorption, the levels of LDL-cholesterol, total-cholesterol and the parameters of insulin metabolism were higher in PMW than in premenopausal women. During the study, the SCL-90, the bone resorption, total-cholesterol, and LDL-cholesterol levels significantly decreased only in the groups A and C. By contrast, in the group B bone resorption significantly increased at the 12th month. During the treatments, insulin metabolism did not change in the groups A and B. In the group C the secretion of C-peptide and the C-peptide:insulin ratio after OGTT were significantly higher at the 12th month than before treatment. In all groups the endometrium thickness did not change during the study. CONCLUSION A 12-month of either oral or transdermal HRT containing levonorgestrel seems to exert beneficial effects on the main postmenopausal symptoms without negative interferences on the endometrium.

Evidence that an altered prolactin release is consequent to abnormal ovarian activity in polycystic ovary syndrome

OBJECTIVE To investigate whether endogenous dopaminergic activity is impaired in polycystic ovary syndrome (PCOS)-affected women and is normalized by medical ovariectomy. PATIENTS Women with PCOS untreated (n = 23) and treated for 3 months with GnRH analogue (GnRH-a) administration (n = 10) and normal cycling young women (n = 23) as controls. INTERVENTIONS Acute blockade of dopaminergic receptors by the IV administration of 5 mg of the dopaminergic receptor blocking agent sulpiride (sulpiride test) was performed 3 to 7 days after the initiation of spontaneous menses in cycling women or medroxyprogesterone acetate-induced menses in PCOS women. In PCOS women treated with GnRH-a administration (goserelin depot, 3.6 mg SC every 28 days), the sulpiride test was repeated 10 to 15 days after the third GnRH-a administration. MAIN OUTCOME MEASURE Basal PRL levels and PRL increase induced by sulpiride. RESULTS Basal PRL levels and the PRL response to sulpiride were increased in women with PCOS. In women with PCOS medical ovariectomy induced by GnRH-a administration reversed to normal both basal and sulpiride-stimulated PRL levels. CONCLUSIONS In women with PCOS the abnormal regulation of PRL and presumably of hypothalamic neurotransmitters controlling PRL secretion is not a primary alteration but it is likely dependent on abnormal ovarian functionality.

The chronic administration of cabergoline normalizes androgen secretion and improves menstrual cyclicity in women with polycystic ovary syndrome.

OBJECTIVE To investigate whether the administration of the long-lasting dopaminergic drug, cabergoline, improves endocrine and clinical features of women with polycystic ovary syndrome (PCOS). PATIENTS Twenty-nine women participated in the study: 14 women with clinical and endocrinologic features of PCOS and 15 age- and weight-matched normal cycling women. Each subject was assigned randomly to receive either a tablet of cabergoline at the dose of 0.5 mg/wk or placebo for 4 months. Sixteen subjects (PCOS: n = 8; controls: n = 8) received cabergoline, whereas 13 (PCOS: n = 6; controls: n = 7) received placebo. INTERVENTIONS Both before and during the 4th month of treatment, blood samples were collected every 10 minutes from 9:00 A.M. to 3:00 P.M., 3 to 7 days after spontaneous or medroxy-progesterone acetate (MPA; 5 mg daily for 5 days)-induced menses. Follicle-stimulating hormone and androgen levels were measured in the basal samples, whereas LH levels were measured in all samples. MAIN OUTCOME MEASURES Menstrual cyclicity, LH pulsatility, and circulating levels of FSH, PRL, E2, total T, free T, androstenedione, 17 alpha-hydroxyprogesterone, DHEAS, and sex hormone-binding globulin. RESULTS Both in controls and in PCOS-affected women, cabergoline administration blunted plasma PRL levels without affecting LH pulsatility. Androgen levels were reduced in controls and normalized in PCOS. Cabergoline, but not placebo, induced menses reappearance in amenorrheic and a normalization of menstrual cyclicity in oligoamenorrheic women with PCOS. CONCLUSIONS The administration of cabergoline is capable to normalize androgen levels and to improve menstrual cyclicity in PCOS-affected women. Cabergoline may represent an useful treatment for menstrual irregularities of PCOS patients.