Juan J. Espinós

Use of letrozole in assisted reproduction: a systematic review and meta-analysis

BACKGROUND Letrozole is the third-generation aromatase inhibitor (AI) most widely used in assisted reproduction. AIs induce ovulation by inhibiting estrogen production; the consequent hypoestrogenic state increases GnRH release and pituitary follicle-stimulating hormone (FSH) synthesis. METHODS A systematic search of the literature was performed for both prospective and retrospective studies. Meta-analyses of randomized clinical trials (RCTs) were performed for three comparisons: letrozole versus clomiphene citrate (CC), letrozole + FSH versus FSH in intrauterine insemination (IUI) and letrozole + FSH versus FSH in IVF. In the absence of RCTs, non-randomized studies were pooled. RESULTS Nine studies were included in the meta-analysis. Four RCTs compared the overall effect of letrozole with CC in patients with polycystic ovary syndrome. The pooled result was not significant for ovulatory cycles (OR = 1.17; 95% CI 0.66–2.09), or for pregnancy rate per cycle (OR = 1.47; 95% CI 0.73–2.96) or for pregnancy rate per patient (OR = 1.37; 95% CI 0.70–2.71). In three retrospective studies which compared L + FSH with FSH in ovarian stimulation for IUI, the pooled OR was 1.15 (95% CI 0.78−1.71). A final meta-analysis included one RCT and one cohort study that compared letrozole + gonadotrophin versus gonadotrophin alone: the pooled pregnancy rate per patient was not significantly different (OR = 1.40; 95% CI 0.67–2.91). CONCLUSIONS Letrozole is as effective as other methods of ovulation induction. Further randomized-controlled studies are warranted to define more clearly the efficacy and safety of letrozole in human reproduction.

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 Wilcoxs and Trussells 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 Trussells 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.

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 Dixons 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.

Random-start GnRH antagonist for emergency fertility preservation: a self-controlled trial.

The aim of this study is to evaluate the feasibility and safety of random-start controlled ovarian hyperstimulation (COH) for emergency fertility preservation, regardless of the phase of the menstrual cycle. A self-controlled pilot clinical trial (NCT01385332) was performed in an acute-care teaching hospital and in two private reproductive centers in Barcelona, Spain. Eleven egg donors participated in the study. Two random-start gonadotropin-releasing hormone (GnRH) antagonist protocols were assessed in which ganirelix was initiated on either day 10 (protocol B) or on day 20 (protocol C) of the menstrual cycle and was continued until estradiol levels were below 60 pg/dL. These protocols were compared with a standard protocol (protocol A). The main outcome of interest was the number of metaphase 2 oocytes retrieved. Results from this study show that the number of mature oocytes retrieved was comparable across the different protocols (14.3±4.6 in the standard protocol versus 13.0±9.1 and 13.2±5.2 in protocols B and C, respectively; values expressed as mean ± standard deviation). The mean number of days needed for a GnRH antagonist to lower estradiol levels, as well as the ongoing pregnancy rates, were also similar when protocols B (stimulation in follicular phase) and C (stimulation on luteal phase) were compared with protocol A (standard stimulation). GnRH antagonists can be effectively used for random-start controlled ovarian hyperstimulation with an ovarian response similar to that of standard protocols, and the antagonists appear suitable for emergency fertility preservation in cancer patients.

Efficacy and safety of human chorionic gonadotropin for follicular phase stimulation in assisted reproduction: a systematic review and meta-analysis

OBJECTIVE To assess the efficacy and safety of hCG to induce follicular stimulation. DESIGN Systematic literature searches of PubMed, EMBASE, CENTRAL, and SciSearch databases. Randomized controlled trials (RCTs) using hCG in early or late follicular phases were included. SETTING Three reproductive medicine services of gynecology in Spain and two universities. PATIENT(S) A total of 1,068 women treated in 11 RCTs were included. INTERVENTION(S) Use of hCG versus other hormone treatments, no administration, or placebo during the period of follicular stimulation. MAIN OUTCOME MEASURE(S) Live birth, clinical pregnancy, mature oocytes, miscarriage, ovarian hyperstimulation syndrome (OHSS), and FSH doses. RESULT(S) No differences in live birth, miscarriage, and OHSS rates between hCG (given at either the early or late follicular phases) and different control regimens were found. Pooled analysis for clinical pregnancy showed significant differences in favor of hCG at the late follicular phase. The doses of FSH were lower in women treated with hCG at either the early or late follicular phase than in those treated with FSH alone. CONCLUSION(S) The use of hCG in the early and late follicular phase in controlled ovarian stimulation has the advantage of decreasing the doses of FSH.

Weight decrease improves live birth rates in obese women undergoing IVF: a pilot study

Obese women have lower pregnancy rates than normal-weight women undergoing assisted reproductive treatment. We conducted a pilot study to evaluate whether a 12-week diet and exercise intervention before an IVF cycle would influence pregnancy rates in obese women. Forty-one patients were enrolled in this study. They were randomly allocated to two groups: an intervention group (n = 21), who underwent an individualized diet and physical exercise programme supervised by a dietician, and a control group (n = 20), who started IVF with no previous intervention. The primary outcome was clinical pregnancy rate after a single treatment cycle. Mean weight loss in the study group after the intervention was 5.4 kg (range 1.1-14.6 kg). The study and control groups had similar total FSH consumption, number of oocytes and embryos obtained, and number and quality of embryos transferred. There was a non-significant trend towards a higher clinical pregnancy rate after fresh embryo transfer (66.7% versus 41.2%). The intervention group had a significantly higher cumulative live birth rate (61.9% versus 30%, P = 0.045) (odds ratio for intervention group, 3.8; 95% confidence interval, 1.03 to 13.9) The data suggest that weight loss resulted in a significantly increased cumulative live birth rate.

Effect of changes to cost and availability of emergency contraception on users’ profiles in an emergency department in Catalunya

Abstract Objective Emergency contraception (EC) accessibility has evolved differently in Catalunya as compared with other autonomous communities in Spain. Free-of-charge access within the Public Health System was authorised in 2004, and over-the-counter (OTC) access was implemented in 2009. The aim of the study is to assess the impact of these measures on demand and users’ profiles at our institution. Methods A retrospective study, in our Emergency Department, was conducted to evaluate EC requests in relationship to accessibility modifications. The age of women and which days of the week they attended were analysed. Results The number of EC requests, the distribution by age and the demand over the week remained stable after access to EC became free of charge. However, requests sharply decreased following OTC access implementation. Distribution by age also changed, with a significant increase in requests from women under 25 years (72% vs 56%, p < 0.001). Demand was greatest on Sunday and Monday, and this distribution persisted over the study period. Conclusion EC requests remained unchanged following free-of-charge access to EC, but decreased after OTC implementation. Women currently seeking EC at no cost at our institution are more likely to be younger and to request it on a Monday. Chinese Abstract 摘 要 目的 与西班牙其他自治区相比，在加泰罗尼亚，紧急避孕药（emergency contraception，EC）获取途径的演变有所不同。2004年公共卫生系统批准其免费发放，2009年后将其列为非处方类药物（over-the-counter，OTC）。本研究目的在于评价不同措施对于公众需求的影响。 方法 运用回顾性研究评价紧急避孕药的需求与药物获取途径间的关系。并分析女性的年龄及一周中有需求的天数。 结果 EC免费发放，EC的需求量、使用者年龄分布及一周中有需求的天数均保持稳定。然而，将EC列为OTC后，其需求量显著减少，在小于25岁的女性中分布上升（72% VS 56%，p＜0.001）。整个研究期间还发现周日与周一的需求量始终保持最高。 结论 免费发放EC并不影响其需求量，但转变为非处方药时，其使用量明显减少。本研究中免费获取EC的女性年龄偏小且倾向于在周一使用。

Pituitary response profile following metoclopramide administration in women with different forms of hyperprolactinemia

Abstract Aims: To test the hypothesis that macroprolactinemia is an extra-pituitary phenomenon by showing that the pituitary production of prolactin in patients with hyperprolactinemia due to macroprolactin is comparable to that in normoprolactinemic women and different from that in women with monomeric hyperprolactinemia. Methods: Twenty-five women were studied: eight with macroprolactin hyperprolactinemia, eight with monomeric hyperprolactinemia, and nine controls. Prolactin levels were measured before and after precipitation with polyethylene glycol at baseline and at 5, 10,15, 30, and 60 min after metoclopramide administration (10 mg i.v.) in the three groups. Results: The response profile of total and monomeric prolactin following the administration of metoclopramide was similar in women with monomeric hyperprolactinemia and normoprolactinemia but different in women with macroprolactinemia. The areas under the curve for total and monomeric prolactin were higher in patients with macroprolactinemia than in the other two groups (p < 0·0001). The maximal concentration of monomeric prolactin was reached before that of total prolactin in macroprolactinemic patients but the differences were not significant. Discussion: Our findings support the hypothesis that prolactin secretion is comparable in women with macroprolactinemia and in normoprolactinemic women. The dynamics of the secretion suggest that the formation of prolactin complexes is an extra-pituitary process.

Genetic analysis does not confirm non-classical congenital adrenal hyperplasia in more than a third of the women followed with this diagnosis

Non-classical congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency is one of the most frequent autosomal recessive diseases, with an estimated prevalence of 1 in 1000. It may manifest at different stages in life. In late childhood, it may present with advanced skeletal maturation, accelerated growth or premature pubarche. In adult women, the disease usually presents with a hyperandrogenic syndrome including hirsutism, acne, androgenic alopecia, anovulation, menstrual dysfunction, and infertility. However, not all individuals with NCCAH are symptomatic and affected males are not usually detected until a female family member is diagnosed.

Long-acting repeatable bromocriptine in the treatment of patients with microprolactinoma intolerant or resistant to oral dopaminergics**Supported in part by Sandoz Pharma Ltd., CH-4002, Basle, Switzerland.

OBJECTIVE To study the efficacy of long-acting repeatable bromocriptine in suppressing abnormal PRL secretion in microprolactinoma patients. To assess the incidence and nature of side effects induced by the product. DESIGN Longitudinal, open label, noncontrolled. SETTING Human hyperprolactinemic volunteers in an academic clinical research environment. PATIENTS Ten patients with radiologically proven microademonas resistant or intolerant to oral bromocriptine were included. INTERVENTIONS The patients were treated with 50 to 150 mg of long-acting bromocriptine monthly during 6 months. MAIN OUTCOME MEASURE The serum PRL concentrations and the side-effects were assessed before and after each new injection. RESULTS Serum PRL levels decreased during the first cycle to normal values in four patients. At the end of the study the PRL levels were normalized in five cases and were only slightly increased in three. One patient was resistant to the treatment. Two among four infertile women became pregnant. In nine patients the accompanying symptoms disappeared after the 2nd month. Adverse events were mild or moderate and circumscribed to the 1st month of treatment. CONCLUSION The long-acting bromocriptine is both effective and well tolerated and is a good alternative to the oral approach in the management of microprolactinoma patients.