Long-term efficacy and safety of asenapine or olanzapine in patients with schizophrenia or schizoaffective disorder: an extension study.

INTRODUCTION: Safety and efficacy results, collected in schizophrenia and schizoaffective disorder patients treated for up to nearly 3 years, are presented for asenapine and olanzapine. RESULTS: Patients completing a 52-week randomized double-blind core study on flexible-dose asenapine (5 or 10 mg BID) or olanzapine (10 or 20 mg QD) could continue treatment until study blind was broken.290 patients on asenapine and 150 on olanzapine continued treatment for variable lengths of time [mean ± SD (range) 311.0 ± 146.1 (10 - 653) d and 327.4 ± 139.6 (15 - 631) d, respectively]. Adverse event (AE) incidence was lower during the extension (asenapine, 62%; olanzapine, 55%) than during the core study (78%, 80%). In both groups, body weight increase and incidence of extrapyramidal AEs were negligible during the extension. Mean PANSS total score changes during first year of treatment were - 37.0 for asenapine and - 35.3 for olanzapine, with further changes of 1.6 for asenapine and - 0.8 for olanzapine at the extension study endpoint. CONCLUSIONS: Clinical stability on asenapine as well as olanzapine was maintained, with few recurrent or newly emerging AEs beyond 1 year of treatment.

Long-term assessment of Asenapine vs. Olanzapine in patients with schizophrenia or schizoaffective disorder.

INTRODUCTION: We conducted a double-blind 1-year trial of asenapine in patients with schizophrenia or schizoaffective disorder. METHODS: Patients were randomized to asenapine (5 or 10 mg BID; n=913) or olanzapine (10-20 mg QD; n=312), and monitored regularly. RESULTS: Trial completion rates were 38% with asenapine, 57% with olanzapine; main reasons for discontinuation were withdrawal of consent (22%, 16%) and insufficient response (25%, 14%); fewer discontinuations were due to adverse events (6%, 7%). Mean weight gain was 0.9 kg with asenapine, 4.2 kg with olanzapine. Extrapyramidal symptoms reported as adverse events were more common with asenapine. Mean reductions in PANSS total score with asenapine and olanzapine were -21.0 and -27.5 ( P<0.0001); the exclusion of patients who had previous poor experience with olanzapine may have biased the results in favor of olanzapine. Scores on the subjective well-being on neuroleptics scale and functionality measures were similar between groups. CONCLUSION: Asenapine was well tolerated over 1 year of treatment, causing less weight gain than olanzapine but more frequent extrapyramidal symptoms. PANSS total score improved with both agents; the improvement was greater with olanzapine than with asenapine using last observations carried forward but not in an observed-case analysis.

Intercycle variability of ovarian reserve tests: results of a prospective randomized study.

BACKGROUND: This study was designed to assess prospectively the intercycle variability (ICV) of basal FSH (bFSH), clomiphene citrate challenge test (CCCT) (analysis of the CCCT was performed by the parameter: sum bFSH + sFSH) and exogenous FSH ovarian reserve test (EFORT) (analysis of the EFORT included the following parameters: estradiol (E(2)) increment and inhibin B increment 24 h after administration of FSH), and secondarily to assess the influence of the variability of these ovarian reserve tests. METHODS: Eighty-five regularly menstruating patients, aged 18-39 years, participated in this prospective study, randomized, by a computer-designed four-blocks system into two groups. Forty-three patients underwent a CCCT, and 42 patients underwent an EFORT. Each test was performed 1-4 times in subsequent cycles, one test per cycle. During the first three cycles, patients were treated with intrauterine insemination (IUI). Follicle number and oocyte yield during IVF ovarian stimulation in the fourth cycle were taken as measures for ovarian reserve. RESULTS: The per cycle variance of bFSH ranged from 1.8 to 4.4 (maximum to minimum ratio of 2.44, P < 0.0001), while that of CCCT ranged from 21.3 to 70.6 (3.31, P < 0.0001). No significant change in per cycle variance was found for the E(2) increment (1.25, P > 0.2) and inhibin B increment (1.31, P > 0.2), which were the EFORT parameters. A large ICV of CCCT and bFSH test results was strongly associated with lower ovarian reserve. CONCLUSIONS: Our study shows that the ICV of the inhibin B increment and the E(2) increment in the EFORT is stable in consecutive cycles, which indicates that this reproducible test is a more reliable tool for determination of ovarian reserve than bFSH and CCCT. Women with limited ovarian reserve show a strong ICV of bFSH and FSH response to clomiphene citrate.

Predictive value of menstrual cycle pattern, body mass index, hormone levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years.

BACKGROUND: On the question of how to counsel adolescents with irregular menstrual cycles or oligomenorrhoea, no clear answer has been given. Adolescents with oligomenorrhoea especially show endocrine abnormalities and may be at risk for ovulatory dysfunction and the polycystic ovary syndrome in adulthood. METHODS: We followed a cohort of adolescents to document changes in menstrual cycle pattern between ages 15 and 18 years in the general population. RESULTS: Two per cent (2/128) of adolescents with regular menstrual cycles developed oligomenorrhoea, and 12% (17/148) of those with irregular menstrual cycles did so. Fifty-one per cent (34/67) of the oligomenorrhoeic adolescents remained oligomenorrhoeic. Increase in body mass index (BMI), concentration of LH, androstenedione or testosterone, and polycystic ovaries (PCO) were associated with persistence of oligomenorrhoea. In multivariate analysis only a normal to high BMI (>19.6 kg/m(2)) consistently contributed significantly to predict persistent oligomenorrhoea. Glucose:insulin ratio as a marker for insulin resistance was not associated with an increased risk for oligomenorrhoea. CONCLUSIONS: Oligomenorrhoea at age 18 years is better predicted by menstrual cycle pattern at age 15 years than by LH or androgen concentrations or PCO at this age. Not only obese, but also normal weight oligomenorrhoeic, adolescents have a high risk of remaining oligomenorrhoeic.

Comparison of endocrine tests with respect to their predictive value on the outcome of ovarian hyperstimulation in IVF treatment: results of a prospective randomized study.

BACKGROUND: This study was designed to compare endocrine tests [clomiphene citrate challenge test (CCT), exogenous FSH ovarian reserve test (EFORT) and basal FSH, basal estradiol (E(2)) and basal inhibin B as an integral part of all CCT and EFORT], with respect to their ability to estimate the stimulable cohort of follicles in the ovaries (ovarian capacity) and to analyse which test or combination of tests would give the best prediction of ovarian capacity. METHODS: A total of 110 regularly menstruating patients, aged 18-39 years, participated in this prospective study, randomized by a computer-designed 4-block system study into two groups. Fifty-six patients underwent a CCT, and 54 patients underwent an EFORT. In all patients, the test was followed by an IVF treatment. The result of ovarian hyperstimulation during IVF treatment, expressed by the total number of follicles, was used as gold standard. RESULTS: Univariate linear regression analysis showed that the best correlation with the number of follicles after ovarian hyperstimulation (Y) is found by the inhibin B increment (InhB incr.) in the EFORT (Y = 3.957 + 0.081 x InhB incr. (95% CI 0.061-0.101); r = 0.751; P < 0.001). Multiple linear regression analysis showed a significant contributing value of the variables basal FSH, E(2) increment of the EFORT and inhibin B increment to the basic model with the variable age. The best prediction of ovarian capacity (Y) was seen when E(2) increment and inhibin B increment were used simultaneously in a stepforward multiple regression prediction model [Y = 2.659 + 0.052 x InhB incr. (0.026-0.078) + 0.027 x E(2) incr. (95% CI 0.012-0.054); r = 0.796; P < 0.001]. The CCT could not be used in a prediction model. CONCLUSIONS: The EFORT is the endocrine test which gives the best prediction of ovarian capacity.

The postwash total progressively motile sperm cell count is a reliable predictor of total fertilization failure during in vitro fertilization treatment.

OBJECTIVE: To predict the chance of total fertilization failure (TFF) before the day of ovum pickup with known semen and female variables. DESIGN: A statistical model was constructed to predict TFF by retrospective analysis (2,366 couples) and subsequently tested on a new IVF population (917 couples). SETTING: Academic tertiary referral center. PATIENT(S): Three thousand three hundred eighty-three couples who underwent an IVF-ET treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The ability to predict the probability of TFF in IVF. RESULT(S): Two variables-postwash total progressively motile sperm cell count (postwash TPMC) and number of follicles-were found to be significant. Taking a probability of 25% as an acceptable risk of TFF, we calculated that a postwash TPMC of <1.1 x 10(6) cells results in a risk of TFF of >25%. Low responders (<4 follicles) needed a postwash TPMC of >2.2 x 10(6) cells to reduce the risk of TFF to <25%. High responders (>15 follicles) needed only 0.35 x 10(6) postwash progressively motile spermatozoa. CONCLUSION(S): When postwash TPMC and number of follicles are known and an unacceptable TFF outcome is expected, one can propose an ICSI procedure a few days before the day of ovum pickup.

Determination of endometrial prolactin in vivo as a marker for endometrial development in spontaneous ovulatory cycles and in vitro fertilization cycles.

Decidual prolactin was directly determined in endometrial tissue in order to assess its potential role in improving the accuracy of the diagnosis of luteal-phase defect (LPD). Endometrial biopsies of 124 women with regular cycles (group 1) and 13 women with controlled ovarian hyperstimulation and progesterone-supported cycles (group 2) were evaluated in the secretory phase. In addition, decidual prolactin was measured in the luteal phase of the in vitro fertilization (IVF) cycles. The biopsies dated on or after day 25 showed a significant increase in the slope of the regression line of the cycle day versus decidual prolactin content (p < 0.05). Delayed endometrium was not characterized by a lower amount of decidual prolactin compared with biopsies with the same histological dating. On day 27 of the cycle, less prolactin was measured in the out-of-phase biopsies (p < 0.05). A large inter-individual variation in endometrial prolactin tissue content was noticed. In group 2 all biopsies but one were in phase. Compared to the in-phase biopsies of group 1, a significantly higher amount of prolactin was found in group 2. Production of endometrial prolactin in vivo is associated with decidualization of the stromal cells. However, because of the large inter-individual variation, determination of prolactin is not of adjuvant diagnostic value for clinical assessment of LPD. Three factors might explain the higher amount of decidual prolactin in group 2 compared to group 1: (1) a higher serum progesterone concentration owing to an increased production by multiple corpora lutea, or because of the administered progesterone; (2) increased estradiol levels and thus progesterone receptors; and (3) direct stimulation of decidualization by gonadotropins.

The rise of estradiol and inhibin B after acute stimulation with follicle-stimulating hormone predict the follicle cohort size in women with polycystic ovary syndrome, regularly menstruating women with polycystic ovaries, and regularly menstruating women with normal ovaries.

Polycystic ovaries contain a larger number of antral follicles than control ovaries. The aim of this study was to test whether the increase in estradiol (E(2)) and inhibin B after stimulation with 300 IU recombinant FSH in the early follicular phase and the ovarian volume can predict the size of the follicle cohort in polycystic ovary syndrome (PCOS) patients (n = 10), patients with polycystic ovaries detected by ultrasound but with regular menstrual cycles (PCO; n = 10), and regularly menstruating patients with normal ovaries (n = 10). The follicle cohort size was measured as the FSH-sensitive follicles growing during a standardized in vitro fertilization stimulation. Linear regression analysis showed that the slopes of the regression lines of the E(2) increment and the inhibin B increment in relation to the number of follicles were not significantly different among the three groups, meaning that an increased sensitivity for FSH of the granulosa cells of polycystic ovaries was not found. For the total group (n = 30) we calculated that an E(2) increment of 100 pmol/L predicts 5.5 follicles (95% confidence interval, 2.8--8.2; r = 0.617; P < 0.001), and an inhibin B increment of 100 ng/L predicts 6.2 follicles (95% confidence interval, 3.5--9.0; r = 0.665; P < 0.001). The ovarian volume could not be used in a prediction model because the association with the number of follicles was different in the PCO group compared with the PCOS and the control group. Women with PCO and women with PCOS both had a follicle cohort twice as big as the cohort in control women (P < 0.01). The differences in menstrual cycle pattern between the PCO and PCOS groups cannot be explained by differences in cohort size.

Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population.

The aim of this study was to investigate the prevalence of diabetes mellitus, hypertension and cardiac complaints in a Dutch population with polycystic ovarian syndrome (PCOS) and to compare the results with the prevalence of these conditions in the Dutch female population, as retrieved from the Netherlands Health Interview Survey of Statistics Netherlands. A total of 346 PCOS patients were interviewed by telephone, with a mean age of 38.7 years (range 30.3--55.7) and a mean body mass index of 24.4 (range 17.5--55.8). Diabetes occurred in eight (2.3%), hypertension in 31 (9%) and cardiac complaints in three (0.9%) of the women. The prevalence of diabetes and hypertension differed significantly from the prevalence of these conditions in the Dutch female population (both P < 0.05). In PCOS women aged 45--54 years (n = 32) the prevalence of diabetes was four times higher (P < 0.05) and of hypertension 2.5 times higher (P < 0.01) than the prevalence of these conditions in the corresponding age group of the Dutch female population. Hypertension also occurred significantly (P < 0.05) more in the younger (35--44 years) PCOS group (n = 233), but this age group was significantly more obese (P < 0.01) when compared with figures of obesity of the Dutch female population. In conclusion, our data show that in a follow-up study of a relatively lean PCOS population, the prevalence of diabetes mellitus and hypertension was increased when compared with the Dutch female population, especially in women aged 45--54 years.

Obesity, rather than menstrual cycle pattern or follicle cohort size, determines hyperinsulinaemia, dyslipidaemia and hypertension in ageing women with polycystic ovary syndrome.

OBJECTIVE: The aim of this study was to investigate if ageing women with polycystic ovary syndrome (PCOS) who gained regular menstrual cycles differed from women who continued to menstruate irregularly with regard to risk factors for developing diabetes mellitus and atherosclerosis. DESIGN AND PATIENTS: In the original study of a population of 346 PCOS patients, defined in the past as having oligo- or amenorrhoea and elevated LH concentrations, we had sent out a questionnaire to investigate changes in the pattern of their menstrual cycles while ageing. From this cohort of patients, a significantly older group of 53 women (mean age: 41.3 years, range: 33.3-49.4) who were not using oral contraceptives or other hormones visited the outpatient clinic. These women did not differ from the non-participating group in BMI, ethnic origin, the proportion with regular menstrual cycles by age group, parity or the use of clomiphene citrate or gonadotrophins in the past. MEASUREMENTS: A physical examination and a transvaginal ultrasound were performed. The size of the follicle cohort was determined by counting the number of small follicles in the ovaries. Thirty-four women were also willing to give two fasting blood samples for measuring their glucose, insulin and lipid status. RESULTS: Forty-one of the 53 (77.4%) women had a regular menstrual cycle (shorter than 6 weeks) and 12 (22.6%) had an irregular cycle (longer than 6 weeks). The body mass index (BMI), waist: hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and prevalence of diabetes (1-9%) and hypertension (11.3%) did not differ between the two menstrual cycle groups. Also, the fasting glucose, insulin, glucose/insulin ratio, total cholesterol, HDL-c, and LDL-c concentrations did not show any significant difference between the two groups. Instead, these parameters all were significantly higher in women with a BMI > 27 kg/M2 compared to women with a BMI < or = 27 kg/m2. Regularly menstruating PCOS women were older (P < 0.01), showed less follicles in their ovaries (n = 48, P < 0.01) and had lower androgens (n = 34, P < 0.05) than the irregularly menstruating women. Logistic regression analysis showed a second significant influence, after age, of the BMI on the menstrual cycle pattern (age, P < 0.01; BMI, P < 0.05). If age was excluded from the analysis, only the follicle count significantly predicted the menstrual cycle pattern (P < 0.02). CONCLUSIONS: We conclude that hyperinsulinaemia, dyslipidaemia and hypertension in our population of ageing women with polycystic ovary syndrome are not related to the menstrual cycle pattern but rather to obesity. Age and the size of the follicle cohort are the main factors determining the menstrual cycle pattern in ageing women with polycystic ovary syndrome, although an association with the BMI was also found.

Dose-finding study of triptorelin acetate for prevention of a premature LH surge in IVF: a prospective, randomized, double-blind, placebo-controlled study.

Gonadotrophin-releasing hormone agonists (GnRHa) are routinely used in IVF programmes to prevent an unwanted LH surge and consequent ovulation. Despite its widespread use in IVF, a convincing dose recommendation for GnRHa in IVF does not exist. In our opinion, the lowest possible dose of GnRHa should be used. Thus, we performed a prospective, randomized, double-blind, placebo-controlled study to determine the minimal daily dose of triptorelin acetate needed to suppress a premature LH surge during IVF treatment in a long protocol. A total of 240 women (60 in each group) was randomized to either placebo or to one of three doses of triptorelin, i.e. 15, 50 or 100 microg daily. Ovarian stimulation was performed with two or three ampoules of FSH daily. A premature LH surge occurred in 23% of placebo-treated patients, but in none of the triptorelin acetate-treated patients. There were significantly more oocytes and embryos in the 50 and 100 microg triptorelin groups. There was no dose relationship in rates of either implantation, pregnancy, ongoing pregnancy, live birth or baby take-home. In this study we showed that daily administration of 15 microg triptorelin is sufficient to prevent a premature LH surge, and that 50 microg is equivalent to 100 microg in terms of IVF results.

Direct ovarian effects and safety aspects of GnRH agonists and antagonists.

In in-vitro fertilization programmes, gonadotrophin releasing hormone (GnRH) agonists are now routinely used in order to prevent the undesired pre-ovulatory spontaneous luteinizing hormone surge. The first publications are now appearing in which GnRH antagonists are used with the same purpose. More attention should be addressed to the safety aspects of these drugs. This review aims to summarize studies on direct ovarian effects of GnRH agonists and GnRH antagonists in non-primates and primates with respect to the functional and morphological aspects in-vitro as well as in-vivo. We conclude that there is a wide variety of functional and morphological effects of GnRH analogues on the ovary. The sometimes paradoxical effects indicate that a variety of factors may be involved in the various processes. Those factors are: (i) the type and dose of the analogue, (ii) the different regimens of administration, (iii) ovarian status at the time of exposure, (iv) ovarian cell types in in-vitro systems, (v) hormonal pre-treatment of these cultures, (vi) the type of hormonal stimulation added to the in-vitro culture, (vii) further methodological differences in the experiments and finally (viii) physiological variations in GnRH receptor abundance which depends on species and/or timing in the cycle. With the increasing number of patients using GnRH analogues in assisted reproduction treatments, there will be an increasing number of pregnancies exposed to these drugs. So far, there does not appear to be an increased risk of birth defects or pregnancy wastage in human pregnancies exposed to daily low-dose GnRH agonist therapy in the first weeks of gestation.

Measuring apoptosis in human spermatozoa: a biological assay for semen quality?

OBJECTIVE: [1] To determine whether apoptosis can be measured in ejaculated spermatozoa by flow cytometry using the Annexin V assay, which measures expression of phosphatidylserine on the outer leaflet of the cell membrane, or the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP [deoxy-uridine triphosphate] nick end labeling) assay, which measures occurrence of DNA strand breaks and [2] to correlate the outcome with routine semen variables and the hypoosmotic swelling (HOS) test. DESIGN: Pilot study and clinical trial. SETTING: Large teaching hospital and fertility center. PATIENT(S): Men whose semen was studied for various reasons. MAIN OUTCOME MEASURE(S): Percentage of apoptotic spermatozoa by two different assays, percentage of necrotic spermatozoa, concentration and motility of spermatozoa, and outcome of the HOS test. RESULT(S): Apoptosis can be measured in spermatozoa by flow cytometry using the Annexin V assay and the TUNEL assay. Twenty percent of spermatozoa were apoptotic according to both assays. A significant inverse correlation was seen between phosphatidylserine expression (Annexin V assay) and sperm concentration (r = -0.389; P<.05) and motility (r = -0.289; P<.05). A highly significant inverse correlation was seen between DNA double-strand breaks (TUNEL assay) and sperm concentration (r = -0.629; P<.0001). CONCLUSION(S): Flow cytometry can easily and reliably detect phosphatidylserine expression on the outer leaflet of the cell membrane and DNA strand breaks, both of which are hallmarks of apoptosis. About 20% of ejaculated spermatozoa are apoptotic, and the concentration of spermatozoa is lower in men with more apoptotic spermatozoa.

Incipient ovarian failure and premature ovarian failure show the same immunological profile.

PROBLEM: Incipient ovarian failure (IOF) is characterized by regular menstrual cycles, infertility and a raised early-follicular FSH in women under 40. IOF might be a precursor or a mitigated form of premature ovarian failure (POF). Disturbances in the immune system may play a role in ovarian failure. METHOD OF STUDY: Autoantibodies and lymphocyte subsets were determined in 63 POF patients, 50 IOF patients, and 27 controls. RESULTS: The prevalence of autoantibodies did not differ between the groups. There was a statistically significant difference in lymphocyte subsets between the control group and the POF group, with the IOF group taking an intermediate position. We found a decrease in percentage of T-suppressor cells with a rise in T-helper/T-suppressor cell ratio, a decrease in natural killer cells, and an increase in B lymphocytes and HLA-DR positive T cells. CONCLUSIONS: These data support the concept that IOF is a mitigated form of POF. The question remains whether these changes are the cause or the consequence of the ovarian failure.

Polycystic ovaries in adolescents and the relationship with menstrual cycle patterns, luteinizing hormone, androgens, and insulin.

STUDY OBJECTIVE: To evaluate the possible role of inappropriate LH secretion, hyperandrogenism, and hyperinsulinemia in the development of polycystic ovaries (PCO) and the polycystic ovary syndrome. DESIGN: Observational. SETTING: General population samples. PARTICIPANTS: 58 adolescents with regular menstrual cycles, 50 with irregular menstrual cycles, and 29 with oligomenorrhea (age 16.7+/-0.9 years). INTERVENTIONS: Transabdominal pelvic ultrasonography and vena puncture. MAIN OUTCOME MEASURES: PCO; LH, androstenedione, and testosterone levels; overnight fasting insulin concentrations; and oligomenorrhea. RESULTS: The prevalence of PCO increased significantly with the irregularity of the menstrual cycle pattern, as illustrated by the study, finding PCO in 9% of the girls with regular menstrual cycles, 28% of those with irregular menstrual cycles, and 45% of oligomenorrheic girls. The LH and androgen concentrations were significantly higher in girls with PCO; the insulin levels and the glucose-insulin ratio did not differ when the girls with PCO were compared with girls with normal ovaries. Oligomenorrheic girls with PCO had the highest androgen and LH concentrations; their insulin concentrations and glucose-insulin ratio were in the same range as girls with regular menstrual cycles and normal ovaries; and both their hip and waist girths were wider, although their waist-hip ratio was normal. CONCLUSIONS: PCO in adolescents is associated with irregular menstrual cycles, oligomenorrhea, and/or high androgen and LH levels; but no relationship was found with the insulin level or glucose-insulin ratio. Thus, it is doubtful that hyperinsulinemia is an important factor in the development of PCO or polycystic ovary syndrome.

Elevated FSH concentrations in imminent ovarian failure are associated with higher FSH and LH pulse amplitude and response to GnRH.

Imminent ovarian failure (IOF) in women is characterized by regular menstrual cycles and elevated early follicular phase FSH. This study explored underlying neuroendocrine causes of elevated FSH concentrations on day 3 of the menstrual cycle. The characteristics of episodic secretion of FSH and LH, the pituitary response to gonadotrophin-releasing hormone (GnRH), plasma oestradiol, and dimeric inhibin A and inhibin B on day 3 were compared in 13 women with elevated FSH concentrations (>10 IU/l) and 16 controls. FSH amplitudes were higher in the IOF group than in the controls (P < 0. 0001). The FSH pulse frequency did not differ between groups. The FSH response to GnRH was higher in the IOF patients than in the controls (P < 0.0001). Mean LH, LH amplitude and LH response to GnRH were higher in the IOF group, but LH pulse frequency did not differ between the groups. Concentrations of inhibin A and inhibin B were lower in the IOF group, while oestradiol showed no differences. We concluded that in women with IOF, the pituitary is more sensitive to GnRH. This leads to higher FSH and LH pulse amplitudes which underlie the elevated FSH concentrations in the early follicular phase.

Insulin, androgen, and gonadotropin concentrations, body mass index, and waist to hip ratio in the first years after menarche in girls with regular menstrual cycles, irregular menstrual cycles, or oligomenorrhea.

Data on changes in hormone concentrations during the first years after menarche are scarce. We studied the relation between gynecological age (age minus age at menarche), hormone concentrations, and body measurements from the lst to the 6th yr after menarche in 229 observations of girls with regular menstrual cycles, 157 observations of girls with irregular menstrual cycles, and 104 observations of girls with oligomenorrhea. Body Mass Index, waist circumference, hip circumference, LH, androstenedione, testosterone, and dehydro-epiandrosterone sulphate increased significantly (linear regression, P < 0.05) by gynecological age in all menstrual cycle pattern groups. For PRL and estradiol a significant increase with gynecological age was only documented in the regular menstrual cycle group and for waist to hip ratio only in the irregular menstrual cycle group. No significant correlation could be documented between gynecological age and overnight fasting insulin concentrations or glucose to insulin ratio. We found no significant correlation between insulin concentrations or glucose to insulin ratio and androgen concentrations. Significant positive correlations were found between LH and androgens. LH and androgen levels increase during the first years after menarche, and reference values should be adjusted for gynecological age. In these years, no significant correlation between hyperinsulinemia and hyperandrogenemia could be documented.

In-vitro fertilization in a spontaneous cycle: easy, cheap and realistic.

The results of in-vitro fertilization in natural cycles (NIVF) in women with tubal infertility at our department are presented. The study had a prospective design. We needed 75 cycles in 50 patients to obtain one oocyte from each patient. Successful oocyte recovery rate was 67% per started cycle and 82% per oocyte retrieval. Thirty-five embryos were transferred and resulted in four ongoing pregnancies (5.3% per cycle, 6.5% per oocyte retrieval, 11.4% per embryo transfer and 11.4% per embryo). Six patients who participated in the study made a second attempt at NIVF. Five of them conceived of which four were ongoing. Cumulative ongoing pregnancy rates are 9. 8% per cycle, 11.9% per oocyte retrieval, 19.5% per embryo transfer and 19.5% per embryo. We conclude that NIVF is an easy, cheap and realistic method to obtain a pregnancy for patients with tubal infertility.

Intrauterine insemination or in-vitro fertilisation in idiopathic subfertility and male subfertility: a randomised trial and cost-effectiveness analysis.

BACKGROUND: Couples affected by idiopathic subfertility or male subfertility have an estimated spontaneous conception rate of about 2% per cycle. Although various infertility treatments are available, counselling of a couple in their choice of treatment is difficult because of the lack of consistent data from good-quality comparative studies. We compared the results of treatment with intrauterine insemination (IUI) with those of in-vitro fertilisation (IVF), and did a cost-effectiveness analysis. METHODS: In a prospective, randomised, parallel trial, 258 couples with idiopathic subfertility or male subfertility were treated for a maximum of six cycles of either IUI in the spontaneous cycle (IUI alone), IUI after mild ovarian hyperstimulation, or IVF. The primary endpoint was a pregnancy resulting in at least one livebirth after treatment. Cost-effectiveness based on real costs was studied by Markov chain analysis. FINDINGS: 86 couples were assigned IUI alone, 85 IUI plus ovarian hyperstimulation, and 87 IVF. Ten couples dropped out before treatment began. Although the pregnancy rate per cycle was higher in the IVF group than in the IUI groups (12.2% vs 7.4% and 8.7%, respectively; p=0.09), the cumulative pregnancy rate for IVF was not significantly better than that for IUI. Couples in the IVF group were more likely than those in the IUI groups to give up treatment before their maximum of six attempts (37 [42%] drop-outs vs 13 [15%] and 14 [16%], respectively; p<0.01). The woman's age was the only factor that influenced a couple's chance of success. IUI was a more cost-effective treatment than IVF (costs per pregnancy resulting in at least one livebirth 8423-10661 Dutch guilders [US$4511-5710] for IUI vs 27409 Dutch guilders [US$14679] for IVF). INTERPRETATION: Couples with idiopathic or male subfertility should be counselled that IUI offers the same likelihood of successful pregnancy as IVF, and is a more cost-effective approach. IUI in the spontaneous cycle carries fewer health risks than does IUI after mild hormonal stimulation and is therefore the first-choice treatment.