Cost-effectiveness analysis in the treatment of heavy menstrual bleeding in Spain.

OBJECTIVE: To compare the effectiveness and costs associated with first-line medical treatments for chronic heavy menstrual bleeding (HMB) in Spain. STUDY DESIGN: A cost-effectiveness analysis was conducted comparing the levonorgestrel-releasing intrauterine system (LNG-IUS) with the estradiol valerate/dienogest multiphase oral contraceptive (E2V/DNG), combined oral contraceptives (COC) and progestins (PROG). Study patients were fertile women diagnosed with HMB who initially wished to remain fertile. A Markov model based on reported clinical data and the opinion of a panel of experts was used. The time horizon of the analysis was 5 years. The analysis was conducted from the perspective of the Spanish National Health System (NHS), discounting both costs (€ 2013) and future effects at an annual rate of 3%. One-way sensitivity analyses and probabilistic sensitivity analysis were performed to test the robustness of the results. RESULTS: In the analysis at 5 years, the LNG-IUS was associated with a gain of 0.67, 2.22, and 3.53 symptoms free months (SFM) compared with E2V/DNG, COC and PROG, respectively. LNG-IUS contributed more quality-adjusted life months (QALM) than the other treatment alternatives (+1.74 vs. E2V/DNG, +3.33 vs. COC +3.53 vs. PROG). First-line LNG-IUS treatment resulted in savings of € 583, € 988, and € 1891 vs. E2V/DNG, COC and PROG, respectively. These cost benefits, coupled with the greater clinical benefits in terms of SFM and QALM, show that LNG-IUS is the dominant option (less costly and more effective). CONCLUSION: LNG-IUS is the medical treatment of choice and cost-saving option for the control of HMB in Spain.

Management of obstetric perineal tears: do obstetrics and gynaecology residents receive adequate training? Results of an anonymous survey.

Background/Aim. To evaluate the obstetrics and gynaecology residents' perspective of their training and experience in the management of perineal tears that occur during assisted vaginal delivery. We hypothesised that residents would perceive room for improvement in their knowledge of pelvic floor anatomy and the training received in tears repair. Design. Descriptive cross-sectional study. Population/Setting. Seventy-two major residents from all teaching hospitals in Catalonia. Methods. A questionnaire was designed to evaluate experience, perception of the training and supervision provided. Results. The questionnaire was sent to all residents (n = 72), receiving 46 responses (64%). The participants represented 15 out of the 16 teaching hospitals included in the study (94% of the hospitals represented). Approximately, 52% of residents were in their third year while 48% were in their fourth. The majority of them thought that their knowledge of pelvic floor anatomy was poor (62%), although 98% felt confident that they would know when an episiotomy was correctly indicated. The survey found that they lacked experience in the repair of major degree tears (70% had repaired fewer than ten), and most did not carry out followup procedures. Conclusion. The majority of them indicated that more training in this specific area is necessary (98%).

Novel (60%) and recurrent (40%) androgen receptor gene mutations in a series of 59 patients with a 46,XY disorder of sex development.

BACKGROUND: Androgen receptor (AR) gene mutations are the most frequent cause of 46,XY disorders of sex development (DSD) and are associated with a variety of phenotypes, ranging from phenotypic women [complete androgen insensitivity syndrome (CAIS)] to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS). OBJECTIVE: The aim of the study was to characterize the contribution of the AR gene to the molecular cause of 46,XY DSD in a series of Spanish patients. SETTING: We studied a series of 133 index patients with 46,XY DSD in whom gonads were differentiated as testes, with phenotypes including varying degrees of undervirilization, and in whom the AR gene was the first candidate for a molecular analysis. METHODS: The AR gene was sequenced (exons 1 to 8 with intronic flanking regions) in all patients and in family members of 61% of AR-mutated gene patients. RESULTS: AR gene mutations were found in 59 individuals (44.4% of index patients), of whom 46 (78%) were CAIS and 13 (22%) PAIS. Fifty-seven different mutations were found: 21.0% located in exon 1, 15.8% in exons 2 and 3, 57.9% in exons 4-8, and 5.3% intronic. Twenty-three mutations (40.4%) had been previously described and 34 (59.6%) were novel. CONCLUSIONS: AR gene mutation is the most frequent cause of 46,XY DSD, with a clearly higher frequency in the complete phenotype. Mutations spread along the whole coding sequence, including exon 1. This series shows that 60% of mutations detected during the period 2002-2009 were novel.

The GnRH analogue triptorelin confers ovarian radio-protection to adult female rats.

There is a controversy regarding the effects of the analogues of the gonadotrophin-releasing hormone (GnRH) in radiotherapy. This has led us to study the possible radio-protection of the ovarian function of a GnRH agonist analogue (GnRHa), triptorelin, in adult, female rats (Rattus norvegicus sp.). The effects of the X-irradiation on the oocytes of ovarian primordial follicles, with and without GnRHa treatment, were compared, directly in the female rats (F(0)) with reproductive parameters, and in the somatic cells of the resulting foetuses (F(1)) with cytogenetical parameters. In order to do this, the ovaries and uteri from 82 females were extracted for the reproductive analysis and 236 foetuses were obtained for cytogenetical analysis. The cytogenetical study was based on the data from 22,151 metaphases analysed. The cytogenetical parameters analysed to assess the existence of chromosomal instability were the number of aberrant metaphases (2234) and the number (2854) and type of structural chromosomal aberrations, including gaps and breaks. Concerning the reproductive analysis of the ovaries and the uteri, the parameters analysed were the number of corpora lutea, implantations, implantation losses and foetuses. Triptorelin confers radio-protection of the ovaries in front of chromosomal instability, which is different, with respect to the single and fractioned dose. The cytogenetical analysis shows a general decrease in most of the parameters of the triptorelin-treated groups, with respect to their controls, and some of these differences were considered to be statistically significant. The reproductive analysis indicates that there is also radio-protection by the agonist, although minor to the cytogenetical one. Only some of the analysed parameters show a statistically significant decrease in the triptorelin-treated groups.

Long-term efficacy and tolerability of flutamide combined with oral contraception in moderate to severe hirsutism: a 12-month, double-blind, parallel clinical trial.

OBJECTIVE: Our objective was to test the efficacy and tolerability of three doses of flutamide (125, 250, and 375 mg) combined with a triphasic oral contraceptive (ethynylestradiol/levonorgestrel) during 12 months to treat moderate to severe hirsutism in patients with polycystic ovary syndrome or idiopathic hirsutism. DESIGN: We conducted a randomized, double-blind, placebo-controlled, parallel clinical trial. PATIENTS: A total of 131 premenopausal women, suffering from moderate to severe hirsutism, were randomized to placebo or 125, 250, or 375 mg flutamide daily associated with a triphasic oral contraceptive pill. Hirsutism (Ferriman-Gallwey), acne and seborrhea (Cremoncini), and hormone serum levels were monitored at baseline and at 3 (except hormone serum levels), 6, and 12 months. Side effects and biochemical, hematological, and hepatic parameters were assessed. METHODS: We used three-way ANOVA (subject, dose, and visit) with Scheffé adjustment for multiple comparisons or nonparametrical Friedman test and least-squares mean (paired data) and Kruskall-Wallis test for unpaired data analyses. We used chi(2) or Fisher's test for categorical data. RESULTS: A total of 119 patients were included in the intention-to-treat analysis. All flutamide doses induced a significant decrease in hirsutism, acne, and seborrhea scores after 12 months compared with placebo without differences among dose levels. Similar related side effects were observed with placebo and 125 mg flutamide (12.5%), and slightly higher with 250 mg (17.3%) and 375 mg (21.2%). No statistically significant differences were observed either among doses or compared with placebo. CONCLUSIONS: Flutamide at 125 mg daily during 12 months was the minimum effective dose to diminish hirsutism in patients with polycystic ovary syndrome or with idiopathic hirsutism.

What is the seminal exposition among women requiring emergency contraception? A prospective, observational comparative study.

OBJECTIVES: The aim of this study is to determine the number of sperm present in the vagina of women presenting for EC after unprotected intercourse or a condom accident. STUDY DESIGN: A total of 69 women requesting EC were included in a prospective, observational and comparative study. The absence or presence and number of spermatozoa present were examined under light microscopy in endocervical and vaginal smears. An ethinylestradiol-levonorgestrel combination (100 mcg/500 mg for two doses, 12 h apart) was then prescribed. Twenty couples were taken as controls. RESULTS: In 25 (36.2%) of the 69 women, spermatozoa were not observed. In the women in whom sperm could be identified, there were no significant differences in the mean (range) sperm count in relation to the reason for requesting EC, i.e., 11.0 (0.03-149.8) for condom slippage or breakage, and 8.1 (3.9-55) for unprotected intercourse. In the group of controls the median (range) number of spermatozoa (32.5 (2.5-304) was significantly higher (p=0.04) than the observed in the study group. CONCLUSIONS: In one-third of the women presenting for EC, no sperm were identified in the vagina. When sperm were present, the number was much lower than that after intercourse among women wishing to conceive. The risk of an unwanted pregnancy is probably, therefore, lower for women who present for EC compared with that for women who truly have unprotected intercourse.

Guía de práctica clínica sobre menopausia y posmenopausia: riesgos y beneficios del tratamiento hormonal (parte 3) / No disponible

No disponible

Tratamiento farmacológico de la menopausia en España en 2002 / Pharmacological treatment of menopause in Spain in 2002

Fundamentos y objetivo: La administración de estrógenos como tratamiento de los síntomas de la menopausia es motivo de controversia. Dada la gran cantidad de alternativas terapéuticas y de información de calidad aparecida recientemente, nos ha parecido interesante analizar la evolución de su uso como reflejo de la forma en que los clínicos enfocan el problema. Métodos: Se ha investigado la venta en España de los productos de prescripción médica dedicados al tratamiento del síndrome climatérico y de la osteoporosis a partir de los archivos de International Marketing Services (IMS). Se han recopilado los datos anuales correspondientes al período 1990-2002, considerando como segmento básico las mujeres comprendidas entre los 45 y los 64 años de edad. Las unidades vendidas se han pasado a ETY (estimated treatments per year) y con ellas se han calculado las líneas de tendencia de uso por edades. Resultados: Se constata que la utilización de estrógenos aumentó de forma progresiva desde 1990 (1,3 por ciento) hasta un máximo en 2000 (7,8 por ciento), descendiendo luego ligeramente (7,4 por ciento). Observando la distribución geográfica, se ha comprobado un gradiente de uso norte-sur y este-oeste, con unos índices de uso superiores hacia el nordeste y menores hacia el suroeste. La tasa de utilización de la terapia hormonal sustitutiva (THS) en España está muy por debajo de las cifras que presentan países de nuestro entorno socioeconómico y nivel de renta similar. No disponemos de datos objetivos que expliquen estas diferencias. Los estrógenos y similares son la familia terapéutica más utilizada en el período peri y posmenopáusico calculado en ETY por año etario. El raloxifeno y los bisfosfonatos tienen períodos posteriores de implantación mayoritaria. Las curvas de utilización de THS, raloxifeno y bisfosfonatos tienden a coincidir con una estrategia racional basada en estudios de calidad. Conclusiones: Aparentemente, las conductas de prescripción siguen criterios de racionalidad y, por tanto, los clínicos tienen presentes sus objetivos en el momento de plantear la intervención (AU)

Randomized comparison of intranasal and transdermal estradiol.

OBJECTIVE: To compare the efficacy and patient acceptability of intranasal versus transdermal 17 beta-estradiol (E2) delivery systems for postmenopausal symptoms. METHODS: Postmenopausal women were randomly assigned to intranasal 17 beta-E2, 300 microg daily (n = 176) or transdermal 17 beta-E2 (delivering 50 microg/day), two patches per week (n = 185) for 12 weeks, followed by a 4-week period with the alternate treatment. Efficacy was compared between groups using the Kupperman Index and vasomotor symptoms at week 12. Patient acceptability was compared by patient choice of administration route and by questionnaire at week 16. RESULTS: Intranasal and transdermal therapy produced significant reductions in the Kupperman Index and in the occurrence of hot flushes and night sweats at week 12. Alleviation of climacteric symptoms was statistically equivalent in the two treatment groups (P <.001). The difference between groups in the Kupperman Index score of -0.5 +/- 0.9 (95% confidence interval -2.3, 1.3) was within the predetermined interval of equivalence. Both therapies were well tolerated with similar adverse event rates, except for moderate and severe mastalgia which was significantly less frequent with intranasal E2 (7.2%) than with the patch (15.5%, P =.02). Sixty-six percent of patients chose to continue the intranasal therapy and 34% the transdermal therapy (P <.001). Satisfaction was greater with intranasal therapy at week 16 (P <.001). CONCLUSION: Intranasal and transdermal estrogen delivery systems had equivalent efficacy and similar safety profiles. Intranasal therapy was the patients' choice for long-term treatment.

Nuevos avances en el Síndrome de ovarios poliquísticos / New aspects of polycystic ovarian syndrome

El síndrome de ovarios poliquísticos o anovulación hiperandrogénica continúa siendo una entidad mal definida que abarca un espectro amplio de pacientes. La disrgulación enzimática y el hiperinsulinismo constituyen los mecanismos responsables de la mayor parte de las alteraciones que acompañan a esta enfermedad. En la actualidad ambos trastornos parecen tener un trasfondo genético.Los criterios diagnósticos siguen siendo ambiguos y limitados a la clínica, las determinaciones hormonales y la ecografía transvaginal. A las modalidades terapéuticas clásicas se han añadido nuevos antiandrógenos más potentes como la flutamida, fármacos que mejoran la sensibilidad a la insulina o las gonadotrofinas recombinantes cuando existen deseos gestacionales (AU)

Safety and effectiveness of hormonal postcoital contraception: a prospective study.

OBJECTIVE: The aim of this study was to evaluate the demographic characteristics of the population attending our hospital requesting postcoital contraception and to determine the effectiveness of the method and its side-effects. METHODS: A total of 503 women asking for postcoital contraception were included in a prospective open trial. After filling in a questionnaire dealing with demographic and contraceptive data, we prescribed an ethinylestradiol-levonorgestrel combination (100 micrograms/500 mg for two doses 12 h apart). RESULTS: Only 487 women were available for analysis of demographic data. A further 77 were excluded because they presented irregular menstrual cycles and 55 cases were lost for follow-up. Mean age was 22.6 +/- 5.25 years and 35.9% of cases came to the center within the first 5 h after unprotected intercourse. Only 18.8% had previously asked for postcoital contraception. Breakage of condom was the most common reason for request (81.9%). Two pregnancies occurred in the remaining 355 women. According to Dixon's method 15.5 pregnancies should be expected being the overall efficacy of 87.14%. There were no serious adverse effects. Nausea and vomiting (16.33%) were the most prevalent and 59% of the users menstruated at the expected time whilst menses were delayed in 6% of the cases. CONCLUSION: The combination of ethinylestradiol and levonorgestrel in low doses is an effective and safe method of postcoital contraception.

The role of matching menstrual data with hormonal measurements in evaluating effectiveness of postcoital contraception.

The effectiveness of postcoital contraception can only be estimated. The most commonly used method of calculation compares the expected pregnancy rate in the exposed population to the resultant pregnancies after treatment. Estimation of the fertile period and the day of ovulation are critical to calculate the expected pregnancies. The aim of this study was to improve the accuracy of calculations by evaluating the hormonal status on the day of contraceptive treatment. A total of 483 consecutive women requesting postcoital contraception was included in a prospective observational trial. A blood sample was obtained at the moment of consultation to measure serum luteinizing hormone, estradiol, and progesterone concentrations. An ethinylestradiol-levonorgestrel combination (100 micrograms/500 mg for two doses, 12 h apart) was then prescribed. The fertile period was estimated according to previous hormonal studies in the normal cycling population. Of 483 women, 64 (13.25%) women were excluded because they presented irregular menstrual cycles and 37 (7.6%) women were lost to follow-up. Two pregnancies occurred in the remaining 382 women. Following Wilcox's and Trussell's methods, 21.1 and 17.75 pregnancies should be expected, yielding an overall treatment effectiveness of 90.52% (95% confidence interval [CI] 62.58%-97.6%) and 88.73% (95% CI 55.93%-97.12%), respectively. Hormonal data were available in 356 women; 303 of whom presented with regular cycles. Hormonal information in this group restricted the number of exposed cases to 88 women. Of the women included in Trussell's method of analysis, only 51 (51.5%; p < 0.05) were at risk using hormonal data. Fifty-six percent (95% CI 34.9%-75.6%) of women with luteinizing hormone levels > 20 IU/L were not between days-1 and +1 of the cycle. Hormonal studies suggest that methods based on pregnancy risk calculated by cycle day do not faithfully reflect the real exposure.

Analysis of compliance with oral contraception in Spain.

OBJECTIVE: The study was designed to analyze factors related to compliance in oral hormonal contraception in Spain. METHOD: A review study and a multicenter analysis of experience of compliance by 300 doctors, by means of a questionnaire and discussion about the determinants of contraceptive use. RESULTS: Compliance is a major problem in Spain, being influenced mainly by side-effects, the general perception of the method and personal factors. The different factors involved in non-compliance in Spain were analyzed, with regard to the perspective of the professionals. CONCLUSIONS: Strategies to improve compliance in Spain aim mainly at improving the general perception of the method and the accessibility of family planning centers. Factors associated with compliance are still not well known in our country. Better knowledge of the determinants of non-compliance in Spain is needed. For this purpose, another research group was formed to conduct a national study among women.

The safety and effectiveness of stepwise and low-dose administration of follicle stimulating hormone in WHO group II anovulatory infertile women: evidence from a large multicenter study in Spain.

PURPOSE: Our goal was to investigate the safety, effectiveness, and feasibility for the practicing physician of stepwise and low-dose administration of FSH in WHO group II anovulatory infertile women. METHODS: Infertile female patients (n = 234) suffering from WHO group II anovulation, and who failed to became pregnant with clomiphene citrate, were included in a multicenter, prospective, clinical study of treatment with a protocol of chronic low-dose and small incremental rises with urinary purified or highly purified FSH. Follicular development was monitored with ultrasonographic scans. RESULTS: The 234 patients received a total of 534 cycles of treatment, for a mean number of 2.3 treated cycles per patient. hCG was withheld in 65 (12.2%) cyles because of no response and in 28 (5.2%) cycles because of hyperresponse. Of the remaining 441 cycles, 419 (95%) were ovulatory, and in 198 (47.3%) of these cycles a single dominant follicle developed. There were 93 pregnancies (39.7% per patient), for a cycle fecundity rate of 17.4%. Cumulative conception rate after two treated cycles was 33.5%. There were 14 (15%) pairs of twins and 10 (10.8%) spontaneous miscarriages. The prevalence of complications was low with no cases of severe OHSS. Basal LH/FSH ratio was significantly higher in the pregnant group of patients than in nonpregnant women. CONCLUSIONS: Stepwise and chronic low-dose administration of FSH is a safe and effective method for treatment of WHO group II anovulatory infertility, mainly in those patients having high LH/FSH ratios.

A gonadotrophin dependent stromal luteoma: a rare cause of post-menopausal virilization.

A stromal luteoma is an uncommon ovarian tumour in post-menopausal women, which presents rarely with hyperandrogenism and virilization. We present the case of a 64-year-old woman referred for evaluation of virilization which had developed over 5 years. Testosterone, FSH and LH were markedly inhibited following the administration of a GnRH analogue, suggesting a gonadotrophin dependent, testosterone secreting ovarian tumour, which could not be localized with imaging techniques. Surgery revealed normal sized ovaries with no apparent lesions, but microscopic examination showed a small stromal luteoma in the right ovary and severe stromal hyperthecosis in the adjacent and contralateral ovarian stroma. We conclude that stromal luteoma is an uncommon cause of virilization in post-menopausal women. This case illustrates, to our knowledge for the first time, that a stromal luteoma is not autonomous but is gonadotrophin dependent.

The effect of endogenous oestradiol levels on protein S concentration during a menstrual cycle and after GnRH analogues and gonadotropin therapy.

We studied two groups of females to investigate the effect of endogenous oestradiol levels on total and free protein S (tPS, fPS) plasma concentrations. One group (group I) consisted of 12 healthy volunteers who were studied throughout one menstrual cycle; the other group (group II) consisted of 16 young women who were treated with GnRH analogues and gonadotropins before undergoing in vitro fertilization. Neither tPS nor fPS varied significantly with respect to the physiological changes of oestradiol or to the very low and high levels of oestradiol, achieved after GnRH analogues suppression and gonadotropin stimulation. These results indicate that endogenous oestradiol does not affect PS concentration.

Dopaminergic resistance in a case of invasive macroprolactinoma.

Invasive prolactinoma is a relatively infrequent variety of macroprolactinoma characterized by a fast and aggressive growth, with infiltration to adjacent structures, and whose management is frequently difficult. We present the case of a fatal invasive macroprolactinoma in whom resistance to different dopaminergic drugs developed.

[Serum insulin and androgen concentrations in women with histories of gestational diabetes]. / Concentraciones séricas de insulina y andrógenos en mujeres con antecedentes de diabetes gestacional.

BACKGROUND: There is a certain degree of peripheral cell resistance to insulin in the physiopathology of gestational diabetes. These disturbances may persist following pregnancy giving place to secondary hyperinsulinism. Insulin exerts a trophic action on the ovary and favors the production of androgens. The aim of this study was to verify whether the patients diagnosed of gestational diabetes present androgenic alterations following pregnancy. The existence of a correlation between the values of insulin and androgens was analyzed. METHODS: Fifty-one patients were studied. The study group (n = 297) was composed of patients diagnosed of gestational diabetes during their last week of pregnancy. The control group (n = 24) included patients with normal carbohydrate tolerance. The basal values of insulin, glucose, androstenedione, testosterone and SHBG were determined in a postmenstrual phase. RESULTS: Insulin was found to be higher in the study group (78.1 +/- 32.9 pmol/1 vs 63.0 +/- 27.6 pmol/1) although the differences were not significant. The insulin/glucose ratio was significantly higher in the study group (18.1 +/- 8.0 vs 13.9 +/- 7.7; p less than 0.05). Basal insulin and the insulin/glucose ratio were comparable among the obese and non obese patients of both groups. The remaining parameters studied dit not present any significant differences. No significant associations were observed between the values of insulin and insulin/glucose with the androgenic hormonal parameters. CONCLUSIONS: No elevated androgenic profile was observed in the women with previous gestational diabetes. The use of insulin and insulin/glucose values as indicators of insulin resistance did not demonstrate any correlation with the androgenic parameters.

Pulmonary endometriosis: conservative treatment with GnRH agonists.

The lung is an infrequent location of extragenital endometriosis, an exceptional cause of hemoptysis or pneumothorax. Adequate management has not yet been well established. We present two cases of pulmonary endometriosis, parenchymal and pleural. The presenting symptoms were catamenial hemoptysis and pneumothorax, respectively, which were treated with GnRH analogues. The first patient received Buserelin (900 micrograms/day intranasally) for 6 months. After 15 months of normal menstrual activity, the symptoms reappeared. The patient was then treated with Triptorelin (3.75 mg/month intramuscularly) for 6 months and remains asymptomatic and menstruating 14 months after discontinuing treatment. The patient presenting with pneumothorax was treated with leuprolide (1 mg/day subcutaneously) for 6 months and is asymptomatic 1 year after stopping treatment. These results suggest that GnRH analogues may be an acceptable alternative to danazol in the medical management of pulmonary endometriosis.