María J. Martínez de Osaba

Comparative effects of estrogens plus androgens and tibolone on bone, lipid pattern and sexuality in postmenopausal women.

BACKGROUND The main goals of estrogen replacement therapy (ERT) are the prevention of osteoporosis and cardioprotection and the improvement of quality of life (QL). Androgens and tibolone therapy may increase bone mineral density (BMD) to a greater extent than ERT and offer an increase in QL. Lipid and cardiovascular effects, however, are still a major concern. AIM To evaluate whether the addition of a weak androgen to ERT may improve postmenopausal bone loss and sexual activity without adverse effects on lipid pattern and to compare these effects with those observed after tibolone therapy. SUBJECTS AND METHODS This prospective study enrolled 120 surgical postmenopausal women; of these, 96 completed the 1-year follow-up. Patients were allocated to one of four groups. The first group (A; n = 23) received 4 mg of estradiol valerate plus 200 mg of enanthate of dihydroandrosterone im monthly. The second group (E; n = 26) received 50 microg/day of transdermal 17-b-estradiol continuously; the third (T; n = 23) received 2.5 mg of tibolone every day; and finally, the fourth group (C; n = 24) constituted a treatment-free control group. Bone mass (dual X-ray absorptiometry), serum total cholesterol, HDL, LDL, triglycerides, apolipoproteins A1 and B and sexual activity were evaluated before starting therapy and at the end of follow-up. RESULTS All active treatment groups showed an increase in BMD. This increase was higher in the A treatment group (4.08% P < 0.01). Sexuality improved significantly with therapy; however, tibolone and androgens increased scores to a greater extent than ERT. Androgen therapy was associated with significant increases in total cholesterol, LDL and triglycerides. Cholesterol and LDL fall into groups E and T, HDL into groups A and T and triglycerides in group T only. CONCLUSION The combined regimen of androgens and ERT increased vertebral bone mass and enhance sexual activity in postmenopausal women equal to that of tibolone and to a greater extent than ERT alone; its effects on lipids, however, are clearly adverse.

Facial wrinkling in postmenopausal women. Effects of smoking status and hormone replacement therapy

BACKGROUND There is some evidence that hormone replacement therapy may produce significant improvements in fine wrinkling, while aging skin is more frequently found in smokers. However, studies of the combined effect of a protective factor, such as HRT, and a damaging factor, such as smoking, are rare. OBJECTIVES To determine in postmenopausal women the relationship between smoking status and the average number of packets of cigarettes since the subject took up smoking (packs-years) on the one hand, and facial wrinkling on the other, and to evaluate the role of hormone replacement therapy in the prevention of wrinkles in smokers and non-smokers. METHODS All subjects were recruited from our menopause clinic at Hospital Clínic i Provincial in Barcelona and were placed into one of three groups according to their smoking status: 215 life-long non-smokers, 306 former smokers and 209 current smokers. Smoking status, pack-years and hormone replacement were assessed by direct questioning. Facial wrinkle scores were estimated by standardized visual assessment. RESULTS The relative risk of moderate-severe wrinkling for current smokers compared to that for life-long non-smokers was 2.57 (confidence interval: 1.83-3.06; P < 0.0005). Pack-years was positively related to facial wrinkles. Life-long non-smokers receiving HRT had lower facial wrinkle scores than Life-long non-smokers who had never received HRT. HRT did not, in general, modify the facial wrinkle score in current smokers. CONCLUSION Our results suggest that the risk of facial wrinkles is greater in smokers and that HRT does not diminish this risk.

The effect of hormone replacement therapy on postmenopausal bone loss

Eighty-four postmenopausal women who were randomly allocated to one of four groups, completed a 1 year follow-up. The first group (n = 20) received 0.625 mg/day conjugated estrogens cyclically (CE; 25 days/month). The second (n = 23) received 0.625 mg/day of CE continuously, and the third (n = 17) received 50 micrograms/day of transdermal 17 beta-estradiol cyclically (24 days/month). All these groups also received 2.5 mg of medroxiprogesterone acetate sequentially for the last 12 days of hormone replacement therapy, while the fourth group (n = 24) constituted a treatment-free control group. Dual photon absorptiometry was carried out before therapy and was repeated after 1 year. Serum calcium, phosphate and osteocalcine levels, and the urinary calcium/creatinine and hydroxyproline/creatinine ratios, were measured prior to treatment and 6 and 12 months thereafter. All treatment groups showed an increase in bone mineral content. This increase was higher in the continuous CE treatment group (4.4%, P less than 0.05) and in transdermal group (7.1%, P less than 0.01). Concomitant biochemical effects at 6 and 12 months, reduction in urine calcium and hydroxyproline, reduction in blood calcium, phosphate and osteocalcine, were compatible with the observed effects on bone mineral.

Cushing's disease and pregnancy: Report of six cases

We describe six pregnancies in five patients with Cushings disease --four had undergone transsphenoidal surgery, with improvement but no cure of their hypercortisolism; the other woman became pregnant during initial work up. At conception, none of the patients were receiving specific treatment for hypercortisolism. Mean free urinary cortisol (FUC) prior to pregnancy was 430 nmol/24 h (normal range: 51-280). In two patients, FUC throughout pregnancy increased significantly, but no clinical progression was observed. FUC measured in 20 healthy pregnant women was found to rise above the normal non-pregnant range ( < 280 nmol/24 h) in the second (mean +/- 2 S.D. = 463 +/- 256 nmol/24 h; P < 0.01) and third trimester (424 +/- 210 nmol/24 h; P < 0.05). However, in the Cushing patients values were higher. Two pregnancies ended in spontaneous abortions, one resulted in an ectopic pregnancy, and the remaining three were followed to term of which one developed third trimester gestational diabetes, and her baby developed neonatal sepsis which resolved uneventfully. We conclude that despite high abortion and ectopic pregnancy rates, a remarkably uneventful and uncomplicated outcome with no clinical progression of cushingoid symptoms, was observed in two of the three pregnancies followed to term, despite significant increases in FUC.

Effects of bilirubin and sera from jaundiced patients on osteoblasts: Contribution to the development of osteoporosis in liver diseases†

Low bone formation is considered to be the main feature in osteoporosis associated with cholestatic and end‐stage liver diseases, although the consequences of retained substances in chronic cholestasis on bone cells have scarcely been studied. Therefore, we analyzed the effects of bilirubin and serum from jaundiced patients on viability, differentiation, mineralization, and gene expression in the cells involved in bone formation. The experiments were performed in human primary osteoblasts and SAOS‐2 human osteosarcoma cells. Unconjugated bilirubin or serum from jaundiced patients resulted in a dose‐dependent decrease in osteoblast viability. Concentrations of bilirubin or jaundiced serum without effects on cell survival significantly diminished osteoblast differentiation. Mineralization was significantly reduced by exposure to 50 μM bilirubin at all time points (from −32% to −55%) and jaundiced sera resulted in a significant decrease on cell mineralization as well. Furthermore, bilirubin down‐regulated RUNX2 (runt‐related transcription factor 2) gene expression, a basic osteogenic factor involved in osteoblast differentiation, and serum from jaundiced patients significantly up‐regulated the RANKL/OPG (receptor activator of nuclear factor‐κB ligand/osteoprotegerin) gene expression ratio, a system closely involved in osteoblast‐induced osteoclastogenesis. Conclusion: Besides decreased cell viability, unconjugated bilirubin and serum from jaundiced patients led to defective consequences on osteoblasts. Moreover, jaundiced serum up‐regulates the system involved in osteoblast‐induced osteoclastogenesis. These results support the deleterious consequences of increased bilirubin in advanced chronic cholestasis and in end‐stage liver diseases, resulting in disturbed bone formation related to osteoblast dysfunction. (HEPATOLOGY 2011)

Gonadotropin-releasing hormone analog plus an oral contraceptive containing desogestrel in women with severe hirsutism: Effects on hair, bone, and hormone profile after 1-year use

To evaluate the usefulness of D-Trp-6-luteinizing hormone-releasing hormone (LHRH) (triptorelin), a gonadotropin-releasing hormone (GnRH) analog (GnRHa), plus an oral contraceptive (OC) in the treatment of severe hirsutism, a total of 48 women between 19 and 35 years of age suffering from polycystic ovary syndrome (PCOS) with severe hirsutism were studied. Hyperandrogenism of adrenal origin was excluded in all subjects. Twenty-three patients received 3.75 mg D-Trp-6-LHRH intramuscularly monthly for 1 year plus an OC containing 30 micrograms ethinyl-estradiol and 150 micrograms desogestrel. A second group of 25 subjects received an OC containing 35 micrograms ethinyl-estradiol and 2 mg cyproterone acetate (CPA). Immediately before and after months 6 and 12 of therapy, bone mineral density (BMD) and Ferriman-Gallwey scores were evaluated and follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), prolactin (PRL), testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), 17-OH-progesterone (17-OHP), and sex hormone-binding globulin (SHBG) were determined. After 1 year of follow-up study, the combination of a GnRHa plus OC resulted in a decrease of hirsutism similar to that observed in the CPA group (41.9% v 40.5%) and in a suppression of gonadotropins and ovarian steroids in all treated women, without significant changes in bone density. The GnRHa-OC combination can potentially be used in the treatment of hirsutism and hyperandrogenism.

Effects of citalopram treatment on hypothermic and hormonal responses to the 5-HT1A receptor agonist buspirone in patients with major depression and therapeutic response

Serotonin (5-HT) 5-HT1A receptor seems to play an important role in the pathophysiology of major depression and in the mechanism of action of antidepressants. In vivo function of 5-HT1A receptors can be monitored using specific pharmacological challenge tests. The present study aimed at exploring the adaptative 5-HT1A receptor changes in depressed patients before and after 8 week treatment with citalopram. The study population consisted of 30 consecutive outpatients of both sexes aged 18-45 years with major depressive disorders (DSM-IV). Basal score in the Hamilton Rating Scale for Depression (HRSD) was higher than 17. Therapeutic response was defined as a 50% decrease in the HRSD score. The hypothermic and endocrine responses (ACTH, cortisol, and prolactin) induced by the 5-HT1A receptor agonist, buspirone (30 mg p.o.) were measured. After 8 weeks on citalopram, the delta max of hypothermic response elicited by buspirone was markedly decreased (p<0.001). Patients showed a decrease in responses to ACTH (delta max p=0.005; AUC p=0.028) and cortisol (delta max p=0.05). However, the prolactin response increased (delta max p=0.02; AUC p=0.005). There was a significant correlation between the therapeutic effect and reductions of ACTH (r=0.883; p<0.001) and cortisol (r=0.610; p=0.001) responses. Changes induced by citalopram support an alteration of 5-HT1A receptors in major depression. A decrease in the overactivity of the HPA axis may be one factor associated with the response to citalopram.

Effects of a long-acting gonadotropin-releasing hormone analog on the pituitary-ovarian-adrenal axis in women with severe hirsutism

We evaluated modifications in the pituitary-ovarian-adrenal axis in severely hirsute women after administration of the gonadotropin-releasing hormone analog (GnRHa), D-Trp-6-luteinizing hormone-releasing hormone (LHRH) (Triptorelin) in a prospective study at a tertiary hospital. A total of 20 hirsute women aged 19 to 38 years were included. Hyperandrogenism of adrenal origin was excluded in all subjects. Patients received 3.75 mg D-Trp-6-LHRH intramuscularly (Decapeptyl 3.75; Lasa-Ipsen, Barcelona, Spain). Serum levels of follicle-stimulating hormone (FSH), LH, estradiol (E2), prolactin (PRL), testosterone (T), androstenedione (delta 4 An), dehydroepiandrosterone sulfate (DHEAS), 17-OH-progesterone (17-OHP), and sex hormone-binding globulin (SHBG) were determined before GnRHa administration, 24 and 48 hours after, and on days 7, 15, 30, and 45. GnRHa suppresses FSH, LH, and E2 in all women. Unexpectedly, adrenal steroids showed a flare-up phenomenon in the first days and subsequent decrease to lower values than before GnRHa administration. SHBG showed slight changes. After GnRHa, patients showed a significant decrease in T and delta 4 An: these hormones were reduced to half the basal levels. We conclude that GnRHa can potentially be used in the treatment of hyperandrogenism to reduce androgen levels in hirsute women.

Menstrual history as a determinant of current bone density in young hirsute women

There is evidence that bone mass is influenced by estrogen, declining in situations characterized by a decrease in the production of this hormone. Usually, amenorrhea and oligomenorrhea are associated with a state of hypoestrogenism, and both situations are frequent in hirsute patients. The aim of the present study was to analyze the relationship between bone mass and menstrual cyclicity in hirsute women. A total of 52 nulliparous women complaining of hirsutism in various degrees with associated oligomenorrhea/amenorrhea (OA) in 27 cases and eumenorrhea in 25 were included in this study. Basal serum levels of follicle-stimulating hormone (FSH), luteinzing hormone (LH), estradiol-17beta (E2), prolactin (PRL), testosterone (T), androstenedione (A4) dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone (OHP), and SHBG were determined, and the area under the curve (AUC) for E2 was plotted. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry (DEXA). The mean age for eumenorrheic patients was 26 years (range, 17 to 31), and for OA patients, 24 (range, 16 to 29). Both groups had similar Ferriman-Gallwey scores. Basal levels of PRL, LH, FSH, E2, T, A4, OHP, and DHEAS were similar for eumenorrheic and OA patients. The AUC for E2 was significantly higher for eumenorrheic patients, and DEXA at the lumbar spine demonstrated a significant difference between eumenorrheic (1.222 +/- 0.240 g/cm2) and OA (1.016 +/- 0.108 g/cm2) hirsute women (P < .01). In conclusion, OA, due to a relative hypoestrogenism, may be correlated with osteopenia in young hirsute women.

Interaction between serotonin 5-HT1A receptors and β-endorphins modulates antidepressant response

UNLABELLED Interactions between serotonergic and the endogenous opioid systems have been suggested to be involved in the etiopathogenesis of depression and in the mechanism of action of antidepressants. Activation of serotonin 5-HT1A receptors has been shown to increase plasma beta-endorphin (beta-END) levels in animal studies and in healthy humans. OBJECTIVES To assess interaction abnormalities between 5-HT1A receptors and the endogenous opioid system in patients with major depression and the possible modulating effect of citalopram. METHODS The beta-END response to the 5-HT1A receptor agonist, buspirone (30 mg), was measured in 30 patients with major depression and in 30 age- and sex-matched healthy controls before and after an 8-week treatment with citalopram. Pre-treatment score of the Hamilton Rating Scale for Depression (HRSD) was >or=17. Antidepressant response was defined by a 50% decrease in the HRSD. Pre- and post-treatment maximum peak response (Deltamax) and the area under the curve (AUC) of beta-END response were compared. Three time points were measured (60, 90 and 120 min). We also examined the correlations between the beta-END response and the antidepressant response. Buspirone plasma levels were not measured. RESULTS At baseline, beta-END response was similar in patients and controls. After 8 weeks of citalopram treatment depressed patients showed a significant decrease in the beta-END response (Deltamax: p<.001; AUC: p<.001). A significant correlation between the beta-END reduction in the response and the reduction in the HRSD score (r=.656; p<.001) was observed. CONCLUSIONS Changes in interaction between 5-HT1A receptor system and the endogenous opioid system may play a role both in the mechanism of action and response to antidepressant drugs.