Stefano Lello

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.

Tibolone in postmenopausal women: a review based on recent randomised controlled clinical trials

Aim. To critically discuss the use of tibolone (T), in light of a series of very recent double-blind placebo (PL) controlled trials (LISA, LIFT, OPAL, THEBES, LIBERATE) conducted worldwide in a large number of postmenopausal women (PMW). Methods. The most relevant publications on T therapy in PMW were considered with emphasis on menopausal symptoms, quality of life, sexuality, bone, cardiovascular system (CVS) and oncologic risk. Results. T significantly relieves climacteric symptoms and improves mood and sexual well-being (LISA). T is as effective as estrogen–progestin therapy in preventing bone loss and reducing the relative risk of vertebral and non-vertebral fractures (LIFT). By using surrogate endpoints of the individual risks for the CVS, studies show mixed results, but a favourable effect on acute miocardial infarction and thromboembolism has been documented (THEBES, LIFT, OPAL). Although findings about endometrial and colon cancer are reassuring, conclusive data on breast cancer risk with T are not available and an increased risk of recurrence in women with previous breast cancer emerged (LIBERATE). Conclusions. T is effective in treating menopausal syndrome with a good tolerability profile. In spite of some unsolved issues in term of safety, T is still a good treatment option for early PMW.

Monitoring of hormone replacement therapy in postmenopausal women by transvaginal sonography and color flow doppler: study in different phases of sequential therapy

OBJECTIVE To assess uterine artery blood flow and endometrial thickness in postmenopausal patients receiving sequential hormone replacement therapy (HRT) at different phases of the treatment. DESIGN Prospective controlled study. SETTING Ultrasound and menopause units of the obstetrics and gynecology department of the University of Tor Vergata, Rome, Italy. PATIENT(S) Forty postmenopausal women were treated with cyclic sequential HRT (transdermal E2, 50 microg/d, days 1-21; and dydrogesterone, 10 mg/d, days 12-24). INTERVENTION(S) All patients underwent transvaginal color Doppler sonography in the estrogen (phase E) and progestogen (phase E/P) phases and after uterine bleeding when no hormone was administered (phase 0). MAIN OUTCOME MEASURE(S) Endometrial thickness; systolic, diastolic, and mean velocities; and pulsatility and resistance indices of the uterine arteries. RESULT(S) No statistically significant difference in endometrial thickness between phase E (6.5+/-1.6 mm) and phase E/P (6.0+/-1.7 mm) was observed. In phase 0, compared with phases E and E/P, a statistically significant decrease in endometrial thickness was found (4.1+/-1.2 mm). Doppler flow impedance parameters of uterine arteries during the different phases of the HRT cycle showed no differences between the phases considered. CONCLUSION(S) The decrease in endometrial thickness in phase 0 suggests a protective effect of our cyclic sequential regimen on the endometrium. Dydrogesterone does not interfere markedly with the vasodilatory effect of estrogen on uterine arteries.

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.

Effects of two estroprogestins containing ethynilestradiol 30 mug and drospirenone 3 mg and ethynilestradiol 30 mug and chlormadinone 2 mg on skin and hormonal hyperandrogenic manifestations

Hyperandrogenic manifestation in women, such as seborrhea, acne and increased hair growth are common reasons of psychological distress. Skin appearance is very important for young women. This study evaluated the hormonal and skin effects of two estroprogestins (EPs) containing ethinyl-estradiol (EE) 30 μg associated with drospirenone (DRSP) 3 mg or chlormadinone acetate (CMA) 2 mg, respectively. Fifty-five women with signs and symptoms of hyperandrogenism (seborrhea, acne and increased hair growth) were enrolled in the study; randomly, 30 women were treated with EE 30 μg + DRSP 3 mg and 25 with EE 30 μg + CMA 2 mg. Follicle-stimulating hormone (FSH), luteinising hormone (LH), 17-hydroxyprogesterone (17OHP), androstenedione (A), testosterone (T), dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG) and free androgen index (T × 100/SHBG, FAI) were assessed at baseline, and after 3 and 6 months of treatment with EPs. Effects on seborrhea, acne and increased hair growth (as Ferriman-Gallwey score) were also evaluated at the same time points. Finally, skin hydration, transepidermal water loss (TEWL) and skin homogeneity were studied with non-invasive technique during the study. Treatment for 6 months with both EPs decreased significantly the circulating androgen levels (A, T, DHEAS) and FAI, and increased SHBG levels; also skin pattern was improved. EP containing EE and DRSP was better than EP containing EE and CMA as for skin changes, as seborrhea, acne, increased hair, hydration, homogeneity and overall quality of the skin; moreover, hormonal changes (as FAI) under therapy were more pronounced with EE/DRSP than EE/CMA. These effects may be considered in EP choice and could be important in improving patients compliance and quality of life in hyperandrogenic women.

LEI (Lack of tEstosterone Impact) survey in a clinical sample with surgical menopause.

Objectives To assess perception of sexuality and awareness of the impact of testosterone on sexual desire in a clinical sample of Italian women with surgical menopause. Methods In the present cross-sectional study, a structured interview on sexuality-related menopausal symptoms, attitudes towards sexuality and menopausal profile was administered to 568 women (age range 35–69 years) with bilateral oophorectomy with and without hysterectomy for benign conditions. Results The majority of women (58% yes; 36% most of the time) reported they were satisfied with their sexual life before surgical menopause. After oophorectomy, 79.3% noted the appearance/worsening of vaginal dryness, whereas the reduction of sexual desire was reported by 78.7%. Women with low sexual desire (n = 436) were significantly distressed (59.7%) and reported an impairment (24.8% yes/yes, very much) in the relationship with their partner. Sexual reactions of the partner reported by women included reduced sexual desire (17.8%), sexual dysfunction (5.1%) and fears of giving pain/lack of pleasure (28.3%). A high number of women (88.2%) would be willing to discuss sexual matters with their doctors and would consider therapeutic options. Only 36.8% were aware that a lack of testosterone might impact on sexual desire but 71% would like to know more about the role of testosterone. Hormone replacement therapy was used by 38.4% of the women. Conclusions These data suggest that women experience significant vaginal dryness and low sexual desire and report a significant distress in the relationship with their partner after surgical menopause. Sexual counseling is mandatory in order to discuss potential therapeutic strategies, including testosterone use.

Effects of menopause and tibolone on different cardiovascular biomarkers in healthy women

Background and aim. The effects of tibolone on cardiovascular risk is not yet fully understood today. We designed this study to assess the effect of the menopausal status and tibolone treatment (2.5 mg/day for 3 months) on different biomarkers of cardiovascular risk in healthy women. Methods. Blood arterial pressure were measured, and blood samples collected for glucose, lipid profile (total cholesterol, high density lipoproteins, HDL, low density lipoproteins, and triglycerides), inflammatory (C-reactive protein, Interleukin-6, IL-6, tumor necrosis factor α, TNFα) and oxidative stress (hydroperoxides and antioxidant capacity) evaluation in 15 premenopausal (mean age: 30 ± 4 years) and 15 postmenopausal (mean age: 52 ± 3, mean time from menopause 1.4 ± 0.4 years) women before and after tibolone treatment. Results. The menopausal status is associated with increased systolic and diastolic pressure (p < 0.05), higher IL-6 (p < 0.05) and TNFα (p < 0.01), and lower antioxidants (p < 0.01). However, blood pressure (p < 0.05), glucose (p < 0.05), TNFα (p < 0.05) and HDL (p < 0.05) fell after tibolone, which did not significantly affect levels of the other biochemical parameters. Conclusions. As menopause is associated with increased blood pressure, inflammation and oxidative stress, tibolone restores blood pressure and has beneficial effect on inflammation and glycemia without worsening oxidative stress, although it also reduces HDL levels. Such modifications should be taken into account when tailoring menopausal therapies to specific requirements of each woman.

Profile of bazedoxifene/conjugated estrogens for the treatment of estrogen deficiency symptoms and osteoporosis in women at risk of fracture.

Decreasing levels of estrogens during menopause are associated with reduced bone density and an increased risk of osteoporosis. Many women also experience bothersome vasomotor and vaginal symptoms during the menopausal transition. Results of systematic reviews and meta-analyses of randomized controlled trials have shown that both systemic estrogen therapy or hormone therapy (estrogen combined with a progestin) are useful to prevent bone loss, and they are the most effective treatment for such climacteric symptoms as hot flushes, sweating, vaginal dryness, and dyspareunia. Unfortunately, estrogen therapy and hormone therapy increase the risk of endometrial and breast cancer, respectively. The selective estrogen receptor modulators (SERMs) result in positive estrogenic effects on bone, with no negative effects on the endometrium and breast but do not provide relief from postmenopausal symptoms. The combination of a SERM with estrogen as a tissue selective estrogen complex (TSEC) is a new strategy for the prevention of bone loss and the treatment of climacteric symptoms. This combination is particularly interesting from a clinical point of view, taking into account that estrogen alone did not increase breast cancer risk by the Women’s Health Initiative. TSEC is hypothesized to provide the benefits of estrogen-alone therapy, with an improved tolerability profile because the SERM component can make possible the elimination of progestin. The objective of this review was to critically evaluate the evidence from the reports published to date on the use of bazedoxifene (a third-generation SERM) in combination with conjugated estrogens in postmenopausal women. The conclusion is that effectively, the combination of bazedoxifene and conjugated estrogens may be a promising alternative to hormone therapy for the prevention of osteoporosis and the treatment of postmenopausal symptoms in non-hysterectomized postmenopausal women.

Postmenopausal hormone therapy: lessons from observational and randomized studies.

The effect of estrogen replacement therapy (ERT) and hormone replacement therapy (HRT) for cardioprotection in postmenopausal women remains controversial. Observational studies conducted in the past two decades have suggested an average risk reduction of 50% for the primary prevention of CAD, these findings, however, have not been confirmed by recent randomized clinical trials (RCTs). The discrepancies in results between observational and randomized studies are related to several differences in patient selection, hormone regimen, and biological effect of hormones in different periods of women’s life. In an attempt to justify the use of hormone replacement therapy against the mounting contraindications for any use by several opinion leaders and scientific societies, several authors have criticized the design and the results of the randomized clinical trials as the cause of the unexpected results. The randomized clinical studies were conducted exceptionally well; therefore, methodologic issues are not the problem. The main difference between the observational and randomized studies, which may fully explain the discrepancies between these studies, are the women under study and their reasons for taking hormone therapy. In the observational studies women choose to take ovarian hormones initially for menopausal symptoms and then may have decided to continue for other reasons, while in the randomized studies the absence of menopausal symptoms was a pre-requisite for inclusion in the study. This apparently small difference has important implications because symptomatic women are younger and have clinical symptoms that suggest the lack of estrogen effect on several organs or systems. In conclusion, several biological reasons may have contributed to the divergent findings from observational studies and RCTs. Clearly time elapsed since menopause seems to be an important one for its effect on vascular responsiveness to ovarian hormones and to prothrombotic effects. In the meantime, a role remains for combined estrogen and progestin supplementation in the treatment of menopausal symptoms.

Effects on body weight and body composition of a low-dose oral estroprogestin containing ethinyl estradiol 20 μg plus levonorgestrel 100 μg

Weight gain is a common problem reported by users of estroprogestins (EPs) and is a frequent reason for EP discontinuation, even if this problem is not confirmed in several clinical studies. We studied the impact of a EP containing ethinyl estradiol (EE) 20 μg plus levonorgestrel (LNG) 100 μg on body weight (BW) and body composition in 47 treated women and 31 women as controls. Also, we studied the effect of this association on metabolic parameters (glycemia, lipid profile). EE20/LNG100 had no significant impact on body weight, body composition (fat mass, fat-free mass, total body water, intracellular water, extracellular water) or metabolic profile in comparison with no treatment. Thus, the use of EE20/LNG100 showed no impact on metabolic parameters, body weight and body composition. This could be important not only for the safety profile of this combination, but also in increasing patient compliance.