Pregnancy and Obstetrical Outcomes in Women Over 40 Years of Age.

Introduction: Delayed childbearing is increasing, and advanced maternal age has been associated with an increased risk of obstetrical complications. The purpose of this study was to evaluate pregnancy outcomes in women with advanced maternal age (≥ 40 years). Methods: Maternal and obstetrical data were collected from the Department of Obstetrics and Gynecology of the University of Wuerzburg for the period from 2006 to 2011. In this retrospective analysis we compared the outcomes for women aged ≥ 40 years (n = 405) with those of three younger subgroups (I: < 30 y; II: 30-34 y; III: 35-39 y). Results: Pregnant women older than 40 years had more chronic diseases such as hypertension, needed medical treatment more frequently and had a higher thrombosis risk. Pregnancy-induced diseases such as gestational diabetes, preeclampsia and pregnancy-associated hypertension occurred more often in women ≥ 40 years of age. Compared to mothers who were younger than 30 years, primiparous women ≥ 40 years had a more than four times higher overall cesarean section rate and four times higher elective cesarean section rate. Furthermore, they required longer hospital stays, both after cesarean section and after vaginal delivery. The preterm birth rate (≤ 32 weeks of gestation) was similar across the different age groups. Conclusions: The outcomes of pregnancy and childbirth and for newborns born to women ≥ 40 years did not vary significantly from those of younger women if the following conditions were met: a) pre-existing chronic diseases were treated medically and dietetically; b) pregnancy-induced morbidity was monitored regularly and controlled medically; c) women attended regular prenatal check-ups; d) a healthy lifestyle was adhered to during pregnancy, and e) delivery occurred in a perinatal center.

Culture of Individually Required Number of 2-Pronuclei-Stage Oocytes - Patient Participation in Decision-Making is in Accordance with the Aim of Avoiding Surplus Embryo Freezing.

Background: The aim of this study was to evaluate how many embryos will develop if more than 3 2-pronuclei-stage oocytes (2-PNOs) are cultured at the patient's request and in accordance with the Germany Embryo Protection Law. Methods: A total of 106 cycles of patients undergoing their 1st, 2nd or 3rd cycle of IVF or ICSI treatment in 2010 were prospectively included in the study. In each individual case, a decision was taken prior to treatment about the number of 2-PNOs to be cultured after each cycle. Results: Ninety female patients were treated for a total of 106 cycles. A mean of two to six 2-PNOs were cultivated for a period of between 3 and 6 days for each patient. After culture, no viable embryo was identified for 5 patients (4.7 %), a single viable embryo was identified for 37 cycles (34.7 %), and 2 viable embryos were identified for 52 cycles (48.8 %). Eleven patients (10.3 %) had 3 viable embryos after a further 11 cycles and 1 patient had 4 viable embryos in a single cycle. Ten of the patients with 3 embryos each opted to have all 3 embryos transferred in the same cycle. This meant that a single embryo from one patient with 3 viable embryos and a single embryo of the patient with 4 viable embryos were cryopreserved after culture. The pregnancy rate was 19 % per embryo transfer and 25 % per blastocyst transfer (20 pregnancies in total). All cryopreserved embryos were transferred in a subsequent cycle. Discussion: Based on this study it is possible to make a statement about the number of viable embryos which should be cultivated to obtain, at best, two embryos for transfer without running an unacceptably high risk of producing too many embryos which would then need to be cryopreserved. Only 12 patients (13.3 %) had more than 2 viable embryos. The number of supernumerary pre-implantation-stage embryos was acceptably low (only 2 patients had additional viable embryos, 2.2 %). This means that it is possible to fulfil the wishes of individual patients while complying with the German Embryo Protection Law.

Mild hydronephrosis after uncomplicated hysterectomy.

OBJECTIVE: To explore differences in the incidence of hydronephrosis following different hysterectomy methods for benign gynecological disease. STUDY DESIGN: Retrospective chart review of ultrasound findings on all patients undergoing simple hysterectomy for benign gynecological pathology between July 2004 and September 2008. Elective renal ultrasonography was performed pre-operatively and within 3 days after hysterectomy as part of the routine follow-up in our hospital. RESULTS: Of 385 eligible patients, six were excluded because of pre-existing hydronephrosis or suspected intra-operative ureteral injury. In the resulting group of 379 patients, abdominal (33.3%), vaginal (11.8%) or laparoscopic hysterectomy (54.9%) was performed. The last group included total laparoscopic hysterectomy (TLH, 20.3%), laparoscopic supracervical hysterectomy (LASH, 19.3%), and laparoscopically assisted vaginal hysterectomy (LAVH, 15.3%). Overall, 56.7% of patients showed mild hydronephrosis (5-15 mm pelvicalyceal dilatation) after surgery. Mostly, it occurred unilaterally. The incidence varied according to the type of procedure, the highest being documented following vaginal hysterectomy (64.4%) and the lowest after LASH (46.6%), but this did not reach statistical significance. CONCLUSION: Mild hydronephrosis is a frequent finding after uncomplicated hysterectomy for benign pathology in otherwise asymptomatic patients. Although not statistically significant, there may be variability of mild hydronephrosis depending on the hysterectomy method.

Extracorporeal perfusion of the swine uterus: effect of human seminal plasma.

The active transport of sperm through the female genital tract is a very important factor in the fertilisation process. There is conflicting evidence as to whether seminal plasma has a positive or a negative effect on reproductive performance regarding the sperm transport in the female genital tract. In this study, we investigated if the perfused swine uterus is an appropriate model to study the effect of human seminal plasma on uterine contractility. It was found that repeated application of human seminal plasma caused a significantly higher rise in pressure and frequency of contractions in perfused swine uteri compared to buffer [a 1.8-fold and 1.5-fold pressure rise (Δt1SP, P = 0.025; Δt2SP, P = 0.004)] after the first and second application of seminal plasma respectively, and even a 2-fold pressure rise after the third application with a statistical significance of P = 0.007. The pressure rise caused by the seminal plasma over the entire period of application was calculated using a mathematical programme and was represented by the integral of the pressure curve over time. This perfusion model as well as the use of pressure-time integrals is suitable for patho-physiological studies of the uterus.

The different phenotypes of polycystic ovary syndrome: no advantages for identifying women with aggravated insulin resistance or impaired lipids.

BACKGROUND: According to the classification of polycystic ovary syndrome (PCOS) published by the Androgen Excess Society (AES), 10 different phenotypes of the condition are possible. The question remains of whether using these phenotypes might enable us to identify women with impaired insulin resistance or an impaired lipid profile among patients with PCOS. MATERIALS AND METHODS: A prospective cohort analysis was performed of 313 women with diagnosed PCOS and 80 control individuals. The screening panel included a physical examination, weight and height measurement, ultrasonography of the ovaries, and hormone, glucose, lipid, and insulin resistance measurements. RESULTS: There were no statistically significant differences in insulin resistance parameters between the different phenotypes. There were no statistically significant differences in body mass index (BMI) in any of the groups, but BMI showed the best correlation with insulin resistance in all women with PCOS and controls. Sex hormone-binding globulin (SHBG) was inversely correlated with insulin resistance in women with PCOS and controls. High-density lipoprotein (HDL) was negatively correlated with insulin resistance, and free testosterone was positively correlated with it, only in women with PCOS. CONCLUSIONS: Using the different phenotypes described in the AES classification shows no advantages for identifying women with aggravated insulin resistance or impaired lipid profile among patients with PCOS.

The effect of metformin treatment for 2 years without caloric restriction on endocrine and metabolic parameters in women with polycystic ovary syndrome.

INTRODUCTION: The aim of this study was to evaluate long-term changes in endocrine and metabolic parameters and body mass index in women with polycystic ovary syndrome (PCOS) who were treated with metformin over 2 years without caloric restriction. MATERIAL AND METHODS: Twenty-six obese women with PCOS were treated with metformin over 2 years without caloric restriction. Clinical, metabolic and endocrine parameters and the body mass index were measured and an oral glucose tolerance test was carried out to calculate insulin resistance indices at the beginning and at the follow-up after 2 years. The Homeostatic Model for Assessment of Insulin Resistance (HOMA-IR) was calculated. RESULTS: No significant changes in body mass index or HOMA-IR were observed. However, a significant decrease in fasting and 2-h insulin levels was observed. Women showed a significant increase in sex hormone-binding globulin (SHBG) levels, while total testosterone (TT) levels and the free androgen index decreased significantly. Furthermore a significant decrease in hirsutism was observed. There was a decrease in cholesterol and an increase in high-density lipoprotein. CONCLUSIONS: Long-term treatment with metformin in women with PCOS appears to reduce androgen excess due to increased SHBG and decreased TT levels resulting in improvement of hirsutism as a clinical sign of androgen excess. Furthermore a significant decrease in fasting and 2-h insulin levels and slightly improved insulin resistance indices were observed.

Thyroid-stimulating hormone is associated with insulin resistance independently of body mass index and age in women with polycystic ovary syndrome.

BACKGROUND: The aim of this study was to evaluate the association between thyroid function, reflected by thyroid-stimulating hormone (TSH) levels, and insulin resistance (IR) in 337 women suffering from polycystic ovary syndrome (PCOS). METHODS: Clinical, metabolic and endocrine parameters were obtained and an oral glucose tolerance test was performed, with calculation of IR indices. The association between thyroid function and IR was evaluated with classification analysis using logistic regression and 10-fold cross-validation to identify a possible TSH threshold for IR. Parameters were then compared between women above and below the TSH threshold using two-sample tests. One-way analyses of covariance were performed to explore whether the impact of TSH on IR is independent of other variables. RESULTS: A TSH cut-off value around 2 mIU/l had the best sensitivity and specificity for identifying women with IR. Women with TSH >or= 2 mIU/l were younger, had a higher body mass index (BMI) and were more insulin-resistant compared with women with TSH < 2 mIU/l. This effect of TSH on IR was independent of age and BMI. CONCLUSIONS: In women with PCOS, a significant association between thyroid function, as reflected by TSH >or= 2 mIU/l, and IR was found and the association appeared to be independent of age and BMI.

Polymorphisms in estrogen metabolism and estrogen pathway genes and the risk of miscarriage.

PURPOSE: This study investigated genetic variations in the estrogen pathway and their association with miscarriages. METHODS: A total of 483 patients were recruited from a comprehensive control group for case-control studies. Three variants of the CYP19A1 gene (rs10046, rs4646 and rs700519) and one variant each of the estrogen (ESR1) and progesterone (PGR) receptor genes (rs3020314 and rs1042838) were investigated using polymorphism genotyping. The chi-squared test and one-way analysis of variation (ANOVA) were used for statistical analysis. RESULTS: For rs10046 (CYP19A1), the C/C genotype was associated with a greater frequency of miscarriages (P = 0.017). The other genotypes were not found to be associated with recurrent miscarriage. CONCLUSIONS: This is the first study that has identified a single-nucleotide polymorphism in the aromatase gene that suggests a significant association between genotypes and miscarriage. As aromatase is an essential enzyme in the estrogen pathway, it may be speculated that variations in the aromatase gene in some way give rise to different conditions in the endocrine environment that can lead to impaired fertility.

Assessment of pituitary and steroid hormones and members of the TGF-beta superfamily for ovarian function in patients with congenital uterus and vaginal aplasia (MRKH syndrome).

Patients with Mayer-Rokitanski-Kuster-Hauser (MRKH) syndrome have congenital uterine and vaginal aplasia. The main question of this study was, if the absence of a uterus along with other genital and organ malformations could contribute to hormone or other growth factor protein fluctuations involved in communication between the hypothalamus-pituitary axis, ovaries and uterus. Serum from 56 MRKH patients (mean 27.6 years) and 22 female controls (mean 30.7 years) were analyzed using ELISA to determine levels of pituitary and steroid hormones (LH, FSH, estradiol, progesterone), growth factors of the TGF-beta superfamily like activin A, inhibin B, and anti-Müllerian hormone (AMH). All serum levels were analyzed in relation to other organ malformations. Compared to controls, all 56 patients, including 5% with streak ovaries or unilateral ovarian aplasia, were generally similar in hormone and growth factor levels and could be grouped into hormonal phases. However, compared to controls LH/FSH and FSH/LH ratios of patients had significantly higher and lower mean values, of 2.75-fold (p=0.015) and 1.9-fold (p=0.002), respectively. Undetectable inhibin B levels of<10 pg/ml (p=0.05) were noted in 41.1% of MRKH patients, resulting in significantly higher activin A/inhibin B ratios (p<0.001). MRKH patients have hormonal phases supporting ovarian function, but patients with low FSH/LH ratios and undetectable inhibin B levels (<10 pg/ml) could represent cycle phasing irregularities. A model is discussed regarding our findings and the loss of ovarian-uterine communication.

Body mass index and ovarian function are associated with endocrine and metabolic abnormalities in women with hyperandrogenic syndrome.

BACKGROUND: The aim of this study was to evaluate associations of clinical features, such as hirsutism, polycystic ovaries (PCOs), ovulatory dysfunction, and body mass index (BMI) > or =25 kg/m(2), with metabolic abnormalities in hyperandrogenic women. METHODS: Hirsutism was based on the modified Ferriman-Gallwey score. Ovulatory function was classified as eumenorrhea, oligomenorrhea and amenorrhea, and PCOs were assessed using the ultrasound criteria recommended in the Rotterdam definition. An oral glucose tolerance test was performed. Different insulin resistance (IR) indices were calculated. RESULTS: Hirsute women had significantly higher BMI, DHEA sulfate (DHEAS) and free androgen index (FAI), and significantly lower values for sex hormone-binding globulin (SHBG). Women with amenorrhea were younger in comparison to women with eumenorrhea and had significantly higher values for fasting insulin (FI) and 1- and 2-h insulin levels; lower values for glucose to insulin ratio (GIR), quantitative insulin sensitivity check index (QUICKI), and SHBG. Women with PCO had significantly higher levels of LH and low-density lipoprotein (LDL), whereas high-density lipoprotein (HDL) levels were significantly lower. Women with a BMI > or =25 kg/m(2) had significantly higher values for age, fasting plasma glucose, FI, and 1- and 2-h glucose and insulin levels, homeostatic model for assessment of IR (HOMA-IR), homeostatic model for assessment of B-cell function (HOMA-B), and FAI, whereas their GIR, insulin sensitivity index, QUICKI, SHBG, and HDL were significantly lower. CONCLUSIONS: In women with hyperandrogenic syndrome, BMI> or =25 kg/m(2) and amenorrhea appear to be associated with severe endocrine and metabolic abnormalities.

Correlations between anti-müllerian hormone, inhibin B, and activin A in follicular fluid in IVF/ICSI patients for assessing the maturation and developmental potential of oocytes.

OBJECTIVE: The objective of the present study was to evaluate the correlation between anti-müllerian hormone (AMH), inhibin B, and activin A in follicular fluid from patients receiving treatment with in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), to identify a parameter to assess the maturation and developmental potential of oocytes. - MATERIALS AND METHODS: AMH, inhibin B, and activin A were measured in follicular fluid from 27 patients undergoing IVF/ICSI treatment for male-factor infertility, tubal occlusion, endometriosis, or anovulation. The values were correlated with the serum estradiol level, the numbers and maturation of the oocytes, and the outcome of IVF/ICSI. - RESULTS: A positive correlation was found between AMH in follicular fluid and the number of oocytes retrieved. High inhibin B levels in follicular fluid and high serum E subset2 levels indicated a normal ovarian response to stimulation, corresponding to the oocyte numbers, while low inhibin B and 17-beta-estradiol (E subset2) levels indicated poor responders to stimulation. An activin A/inhibin B ratio of less than 1 and very high inhibin B levels correlated with large numbers of oocytes, while a ratio of 1-2 and high inhibin levels correlated with regular numbers of oocytes. An activin/inhibin ratio of more than 3 and low inhibin levels were found in poor responders. Pregnancies occurred predominantly in the group with a normal or high response. Patients with elevated ratios for 17-beta-estradiol/AMH, oocyte numbers/AMH, and metaphase II oocyte numbers/AMH had the best chances of becoming pregnant, indicating an inverse correlation between AMH and the maturation and developmental potential of the oocytes. - CONCLUSIONS: In IVF/ICSI patients, a positive correlation was found between AMH, inhibin B, and the activin A/inhibin B ratio in follicular fluid, on the one hand; and between serum 17-beta-estradiol levels and the numbers of oocytes retrieved, on the other. The activin A/inhibin B ratio correlated with the number of oocytes retrieved. The ratio for 17-beta-estradiol, oocyte numbers, and metaphase II oocytes relative to AMH indicated the best developmental potential, and it can therefore be assumed that there is a negative correlation between AMH levels and the maturation and quality of oocytes.

Progesterone bioavailability with a progesterone-releasing silicone vaginal ring in IVF candidates.

A vaginal ring made of silicone polymers and barium sulfate, and containing 1 g of pure micronized progesterone, was developed for luteal supplementation in women undergoing cycles of in vitro fertilization (IVF). The ring, modeled on the Estring, was designed as a means of providing continuous intravaginal delivery of progesterone. Bioavailability of progesterone in the blood was demonstrated for 24 hours in IVF candidates who had an endogenous progesterone deficiency after treatment with gonadotropin-releasing hormone (GnRH) analogues. After the first 4 h of increasing release of progesterone from the ring (with mean serum levels of 1.39 +/- 0.8 ng/ml after 4 h), only a slight increase in serum progesterone levels (with a mean peak of 1.5 +/- 0.45 ng/ml after 24 h) was observed during the rest of the test period. Gonadotropin levels were not affected after insertion of the ring. The ring was well tolerated by the patients. The maximum serum progesterone level was lower in comparison with other forms of progesterone application, but it should be sufficiently high, due to the uterine first-pass effect. This study demonstrated that progesterone administration through a silicone ring for luteal support is feasible in IVF treatment. As the vaginal ring is very well tolerated by the patients, these findings may encourage the pharmaceutical industry to design an appropriate progesterone ring for luteal support.

Influence of body mass index on measured and calculated androgen parameters in adult women with Hirsutism and PCOS.

There is growing evidence that obesity in women lead to a more severe form of hyperandrogenism and other endocrine abnormalities which may have some health implications later in life. Obese females are at higher risk for metabolic syndrome due to severe hyperandrogenemia. Calculated values for free testosterone are equivalent to those obtained by equilibrium dialysis, which is one of the reference measurement procedures (RMP) for estimation of free testosterone and may be capable of replacing values estimated using RMP's. For adult women correlations of body mass index (BMI) with calculated free (cFT) and bioavailable testosterone (cBT) are still rare, while these data are reported for peripubertal and adolescent girls. In this study we aimed to investigate the association between BMI and different androgen parameters (including calculated free and bioavailable testosterone, free androgen index, and sex hormone-binding globulin [SHBG]) in adult women with Hirsutism and with PCOS. In hirsute women with BMI > or = 25 kg/m2 measured total testosterone (TT) was significantly higher, SHBG was significantly lower and the calculated androgen parameter (FAI, cFT and cBT) were significantly higher compared to women with BMI < 25 kg/m2. In PCOS women with BMI > or = 25 kg/m2 TT was significantly higher, SHBG was significantly lower and the calculated androgen parameter (FAI, cFT and cBT) were also significantly higher compared to women with BMI < 25 kg/m2. In both the Hirsutism and PCOS-group there was a positive correlation between BMI and TT, cFT, and cBT, while BMI was negatively correlated with SHBG. In summary, in adult women with Hirsutism and PCOS obesity is associated with increased levels of TT and decreased levels of SHBG resulting in significant elevated calculated free and bioavailable testosterone levels. Obesity might lead to a more severe form of hyperandrogenism with elevated calculated free and bioavailable testosterone in the study population.

Evaluation of biochemical hyperandrogenemia and body mass index in women presenting with amenorrhea.

INTRODUCTION: The aim of this study was to evaluate the correlation between biochemical hyperandrogenemia and body mass index in patients with amenorrhea as the main clinical presenting symptom. METHODS: Among 136 patients presenting with secondary or primary amenorrhea, hyperandrogenemia was found to be the hormonal cause of this specific type of irregular menses in 21 patients. A retrospective study was carried out to investigate the patients' serum androgen findings and body mass index. The ultrasound features of the ovaries were also recorded. RESULTS: Twenty-one of the 136 patients presenting with the most severe form of menstrual irregularity, amenorrhea - defined as an absence of menses for at least 6 months - were found to have elevated serum androgen levels. The androgen profile included elevated levels of total testosterone (TT), or dehydroepiandrosterone sulfate (DHEAS), or calculated free testosterone (cFT), or all three, with or without an elevated luteinizing hormone-follicle-stimulating hormone (LH : FSH) ratio. Six patients with a body mass index > 26 kg/m2 all had elevated cFT, while TT was only increased in three patients. All of the patients had low levels of sex hormone-binding globulin (SHBG). Two patients had abnormal TT, cFT, and DHEAS levels together with polycystic ovaries. Eleven patients with a body mass index (BMI) 26 kg/m2 ( P<0.001), while TT serum levels did not significantly differ between the two groups. CONCLUSIONS: Amenorrhea is by definition the most severe form of menstrual disorder. Biochemical hyperandrogenemia can be found in a subgroup of amenorrheic patients. However, none of the biochemical findings of hyperandrogenemia correlated consistently with this specific type of menstrual disorder. In the women studied, there appears to be a correlation between elevated androgen levels and a BMI > 26 kg/m2. cFT appears to be a more appropriate criterion for identifying hyperandrogenemia than TT in patients presenting with amenorrhea. More information about this condition and studies including larger numbers of patients are needed.

Endocrinological markers for assessing hyperandrogenemia in women classified as having polycystic ovary syndrome (PCOS) according to the revised 2003 diagnostic criteria.

The aim of this study was to investigate whether free testosterone estimated by calculation from total testosterone and sex hormone-binding globulin or free androgen indexes were more appropriate markers for assessing hyperandrogenemia in patients with polycystic ovary syndrome (PCOS). 107 Caucasian women were presented at our Division of Gynecological Endocrinology and Reproductive Medicine because of their infertility and hirsutism. Hirsutism was quantitatively assessed using a modified Ferriman-Gallwey score; oligo-ovulation or/and anovulation were assessed; polycystic ovaries were assessed; afterwards women were classified as having PCOS according to the revised 2003 consensus on diagnostic criteria for PCOS or classified as controls; endocrinological parameters were assessed using commercial immunoassays or were calculated. 50 women were classified as having PCOS; 57 women were classified as controls because they did not fulfill the criteria of PCOS. Calculated free and bioavailable testosterone, FAI, total testosterone, free testosterone assessed by immunoassay and DHEAS were significantly increased in women classified as having PCOS. All endocrinological markers for assessing hyperandrogenemia were elevated in the PCOS group regardless if they were assessed using commercial immunoassays or were calculated. Calculated values showed no diagnostic advantage in this study.

Is it necessary to measure free testosterone to assess hyperandrogenemia in women? The role of calculated free and bioavailable testosterone.

Hirsutism in women is defined as excessive facial and/or body terminal hairs showing a masculine distribution; the condition affects approximately 7% of women of reproductive age, and chronic anovulation is a common problem for infertile couples, with a rate of 20-25%. There is a general consensus that these women should be evaluated endocrinologically, as many are found to have an androgen excess (AE) disorder. Free testosterone (FT) is the most prevalent marker in women with androgen excess, but the reference measurement procedures for FT are time-consuming and complex manual procedures that are not routinely practicable in large laboratories. Recently, models have been developed for calculating FT from total testosterone (TT), sex hormone binding globulin (SHBG), and albumin. These calculated values have been found to correlate closely with values estimated using the reference measurement procedures. This study compared measured endocrinological parameters--TT, free testosterone (aFT) by analogue ligand immunoassay method, dihydrotestosterone (DHT), dehydroepiandrosterone sulfate (DHEAS), (SHBG), And calculated parameters--calculated free testosterone (cFT), calculated bioavailable testosterone (cBT), and the free androgen index (FAI) in hirsute women and women with polycystic ovary syndrome (PCOS)--with the values in control individuals. A modified Ferriman-Gallwey score was use to describe the hirsutism pattern. No differences were observed when the measured hormone parameters were compared, while the calculated parameters were significantly increased in women in the hirsutism and PCOS groups in comparison with the values in the control group. Calculate parameters mat be more appropriate markers for assessing hyperandrogenemia in women in comparison with measured values of simple enzyme immuno-assays. These calculated values may be capable of replacing the values estimated using reference measurement procedures, so that time-consuming and complex manual procedures for measuring free testosterone with the reference methods may be dispensable in clinical practice.

Effects on the male endocrine system of long-term treatment with gonadotropin-releasing hormone agonists and estrogens in male-to-female transsexuals.

We studied hormonal changes resulting from long-term treatment with gonadotropin-releasing hormone agonist and 17beta estradiol valerate in 40 healthy middle-aged male-to-female transsexuals over a period of two years. All of the participants received injections of 3.8 mg goserelin acetate every four weeks in combination with 6 mg oral 17beta estradiol valerate per day for cross-sex hormone treatment for male-to-female transsexuals. There was a significant reduction in the levels of serum luteinizing hormone and follicle-stimulating hormone to the hypogonadal stage. Mean testosterone levels decreased by 97% to 0.52 and 0.59 nmol/l after 12 months and 24 months, respectively. There was a significant reduction in dehydroepiandrosterone sulfate by 37% after 12 months and 43% after 24 months, and androstendione by 29% after 12 months and 27% after 24 months, respectively. Cortisol levels were reduced by 43% and 50%, respectively. Estrogen levels were significantly increased from 77.51 to 677 after 12 months and 661 pmol/l after 24 months. Sex hormone-binding globulin and corticoid-binding globulin levels were significantly increased after 12 and 24 months. There was a significant decrease in all measured androgen fractions and cortisol during long-term treatment with gonadotropin-releasing hormone agonist and 17beta estradiol valerate. Apart from suppression of testicular hormone production, one possible interpretation is that treatment with long-term gonadotropin-releasing hormone agonist and 17beta estradiol valerate influences adrenal hormone levels in healthy middle-aged male-to-female transsexuals. Cortisol serum levels may be decreased due to estrogen-induced increase in corticoid-binding globulin.

Endocrine treatment of male-to-female transsexuals using gonadotropin-releasing hormone agonist.

In transsexual people, cross-sex hormone therapy is an important component of medical treatment. In male-to-female transsexuals, feminizing effects should be achieved before irreversible sex reassignment surgery (SRS) is considered. The most common treatment regimen in male-to-female transsexuals is a combination of ethinyl oestradiol and cyproterone acetate, with the exception of transdermal oestradiol-17beta in individuals over the age of 40. The mortality and morbidity rates with this treatment regimen have been reported in more than 800 patients. Typical side effects include venous thrombosis, elevated liver enzymes, symptomatic gallstones, hyperprolactinaemia and depression. Sixty male-to-female transsexuals were treated with monthly injections of gonadotropin-releasing hormone agonist (GnRHa) and oral oestradiol-17beta valerate for 2 years to achieve feminisation until SRS. There was a significant decline in gonadotropins, total testosterone and calculated free testosterone. In general, the treatment regimen was well accepted. An equal increase in breast size was achieved compared to common hormone therapy. Two side effects were documented. One, venous thrombosis, occurred in a patient with a homozygous MTHFR mutation. One patient was found to be suffering from symptomatic preexisting gallstones. No other complications were documented. Liver enzymes, lipids, and prolactin levels were unchanged. Significantly increased oestradiol and SHBG serum levels were detectable. In addition, an increase in bone mass density, in the femoral neck and lumbar spine, was recorded. We conclude that cross-sex hormone treatment of male-to-female transsexuals using GnRHa and oestradiol-17beta valerate is effective, and side effects and complication rates can be reduced using the treatment regimen presented here.

Sequential FISH analysis of oocytes and polar bodies reveals aneuploidy mechanisms.

OBJECTIVES: Constitutional aneuploidy occurs in at least 5% of recognised pregnancies, with apparent preferential involvement of the X chromosome and the smaller autosomes. Molecular cytogenetic investigations of cleavage-stage embryos have revealed anomalies affecting all sizes of chromosomes. The aim was to investigate the variety of anomalies arising during maternal meiosis I by analysis of unfertilised oocytes and polar bodies to gain insight into aneuploidy mechanisms. METHODS: Sequential FISH analysis was carried out with specific probes derived from eight chromosomes, representing all sizes. Only imbalance due to a gain of a whole chromosome or chromatid, represented by extra signals, was counted to avoid artefact. RESULTS: Data were obtained on 236 eggs from 124 patients of average age 32.5 years (range 22-44). Ten patients (average 32.6 years) had abnormal eggs. The abnormality rate for oocytes and for polar bodies was close to 4% for each. Fourteen hyperploidies were found, seven involving additional single chromatids. The abnormalities affected chromosomes 13,16,18, 21 and X but not chromosomes 1, 9 or 12. CONCLUSION: The data provide evidence for several mechanisms leading to aneuploidy, including classical non-disjunction of whole univalents; pre-division of chromatids prior to anaphase I, leading to imbalance detected at metaphase II; gonadal mosaicism for a trisomic cell line and preferential involvement of the smaller chromosomes. Monosomy for the large autosomes is not uncommon in cleavage-stage embryos and may additionally arise from anaphase lag preferentially affecting such chromosomes.

Expression of vascular endothelial growth factor mRNA in human preimplantation embryos derived from tripronuclear zygotes.

OBJECTIVE: To detect the expression of vascular endothelial growth factor (VEGF) mRNA and/or secretion of VEGF protein by human preimplantation embryos. DESIGN: Human preimplantation embryos not suitable for uterine transfer were examined for beta-actin and VEGF mRNA expression. Culture media from normally fertilized and developing preimplantation embryos were assessed for VEGF protein secretion. SETTING: Clinics and academic research laboratories at the Departments of Obstetrics and Gynecology at the Stanford University, Palo Alto, California and the Heinrich-Heine-University, Düsseldorf, Germany. PATIENT(S): Couples undergoing IVF by intracytoplasmic sperm injection for various reasons. INTERVENTION(S): Six unfertilized oocytes and 33 pathologically fertilized (tripronucleic, 3PN) preimplantation embryos were examined for VEGF mRNA expression, and 16 embryos were examined for VEGF protein secretion. MAIN OUTCOME MEASURE(S): Embryonic expression of VEGF mRNA and VEGF protein as determined by reverse transcription (RT)/nested polymerase chain reaction (PCR) and ELISA. RESULT(S): VEGF mRNA and protein could not be detected in unfertilized oocytes. However, 30/33 preimplantation embryos did express VEGF mRNA (11/12 10-to-16-cell embryos, 3/4 morulae, 11/12 early blastocysts, 5/5 hatched blastocysts). The VEGF protein level was below the sensitivity of the ELISA. CONCLUSION(S): Production of VEGF may give the embryo the ability to induce neoangiogenesis at the implantation site, thus creating an environment necessary for its survival.