A multi-centre phase 3 study comparing efficacy and safety of Bemfola(®) versus Gonal-f(®) in women undergoing ovarian stimulation for IVF.

Bemfola (follitropin alfa) (Finox AG, Switzerland), a new recombinant FSH, has a comparable pharmacological profile to that of Gonal-f (Merck Serono, Germany), the current standard for ovarian stimulation. A randomized, multi-centre, Phase 3 study in women undergoing IVF or intracytoplasmic sperm injection (n = 372) showed Bemfola yielding similar efficacy and safety profiles to Gonal-f. Women aged 20-38 years of age were randomized 2:1 to receive a single, daily, subcutaneous 150 IU dose of either Bemfola or Gonal-f. This study tested equivalence in the number of retrieved oocytes using a pre-determined clinical equivalence margin of ±2.9 oocytes. Compared with Gonal-f, Bemfola treatment resulted in a statistically equivalent number of retrieved oocytes (Bemfola 10.8 ± 5.11 versus Gonal-f 10.6 ± 6.06, mean difference: 0.27 oocytes, 95% confidence interval: -1.34, 1.32) as well as a similar clinical pregnancy rate per embryo transfer in first and second cycles (Bemfola: 40.2% and 38.5%, respectively; Gonal-f: 48.2% and 27.8%, respectively). No difference in severe ovarian hyperstimulation syndrome was observed between treatment groups (Bemfola: 0.8%; Gonal-f: 0.8%). This study demonstrates similar clinical efficacy and safety profiles between Bemfola and Gonal-f, and suggests that Bemfola can be an appropriate alternative in ovarian stimulation protocols.

A 10-year follow up of reproductive function in women treated for childhood cancer.

Previously, this study group found that female childhood cancer survivors could be at risk of early cessation of fertility. The aim of the present study was to evaluate reproductive function in the same group of survivors 10 years after the initial study. Of the original cohort of 100, 71 were re-examined. Thirty-six survivors reported regular menstrual cycles. When they were compared with 210 controls, they differed significantly in antral follicle count (AFC) (median 15 versus 18, P=0.047) but not in anti-Müllerian hormone (AMH) (median 13.0 versus 17.8 pmol/l). Survivors cured with minimal gonadotoxic treatment had significantly higher AMH and AFC compared with survivors cured with either potentially gonadotoxic treatment or treatment including alkylating chemotherapy and ovarian irradiation (20.0, 5.8 and <3 pmol/l, P<0.001; and 15, 9 and 2, P=0.03, respectively). Thirty-eight survivors had achieved at least one live birth. Complicated second-trimester abortions (n=4) were observed primarily in survivors cured with radiotherapy affecting pelvic organs. In conclusion, childhood cancer survivors have signs of diminished ovarian reserve. However, if the ovarian function is preserved in the early to mid-twenties, it is likely to persist until the mid-thirties, giving a good chance of childbearing.

Expression of the vitamin D metabolizing enzyme CYP24A1 at the annulus of human spermatozoa may serve as a novel marker of semen quality.

Vitamin D (VD) is important for male reproduction in mammals and the VD receptor (VDR) and VD-metabolizing enzymes are expressed in human spermatozoa. The VD-inactivating enzyme CYP24A1 titrates the cellular responsiveness to VD, is transcriptionally regulated by VD, and has a distinct expression at the sperm annulus. Here, we investigated if CYP24A1 expression serves as a marker for VD metabolism in spermatozoa, and whether CYP24A1 expression was associated with semen quality. We included 130 men (53 healthy young volunteers and 77 subfertile men) for semen analysis and immunocytochemical (ICC) detection of CYP24A1. Another 40 men (22 young, 18 subfertile) were tested for in vitro effects of 1,25(OH)(2)D(3) on intracellular calcium concentration ([Ca(2+)](i)) and sperm motility. Double ICC staining showed that CYP24A1 and VDR were either concomitantly expressed or absent in 80% of the spermatozoa from young men. The median number of CYP24A1-expressing spermatozoa was 1% in subfertile men and thus significantly (p < 0.0005) lower than 25% in spermatozoa from young men. Moreover, CYP24A1 expression correlated positively with total sperm count, -concentration, -motility and -morphology (all p < 0.004), and the percentage of CYP24A1-positive spermatozoa increased (15 vs. 41%, p < 0.0005) after percoll-gradient-centrifugation. We noticed that the presence of >3% CYP24A1-positive spermatozoa distinguished young men from subfertile men with a sensitivity of 66.0%, a specificity of 77.9% and a positive predictive value of 98.3%. Functional studies revealed that 1,25(OH)(2)D(3) increased [Ca(2+)](i) and sperm motility in young healthy men, while 1,25(OH)(2)D(3) was unable to increase motility in subfertile patients. In conclusion, we suggest that CYP24A1 expression at the annulus may serve as a novel marker of semen quality and an objective proxy for sperm function.

Risk of ovarian failure and fertility preserving methods in girls and adolescents with a malignant disease.

Girls and young women suffering from a malignant disease that requires treatment with chemo- and/or radiotherapy are at risk of losing fertility. The most significant risk factors are age and type of treatment given. Preserving fertility is of high priority to both the young patient and her parents. This article reviews the effect of chemo- and radiotherapy on gonadal function, and thus fertility, and offers different fertility preserving methods based on the literature. Cryopreservation of ovarian tissue is a possible way of preserving fertility in this group of patients in the future.

Increased dopaminergic activity inhibits basal and metoclopramide-stimulated prolactin and thyrotropin secretion.

The influence of physiological to pharmacological doses of dopamine (DA) on basal and metoclopramide (MTC)-stimulated PRL and TSH secretion was studied in 11 regularly menstruating women between days 3 and 8 of the cycle. In groups of 6, the women received 5-h infusions of either 5% glucose or DA in a solution of 5% glucose at a rate of 12-16 ml/h, adjusted according to weight. Infusion rates of DA were 0.04 microgram/kg . min (low), 0.4 microgram/kg . min (medium), and 4.0 micrograms/kg . min (high). After 3 h of infusion, 10 mg MTC were given iv. Blood samples were collected every 15 min from 1 h before to 2 h after the infusion, for a total of 8 h, for measurements of PRL and TSH. The mean serum PRL concentrations declined significantly (P less than 0.05) during DA infusions to nadir values of 62 +/- 5% (+/- SEM; low), 43 +/- 3% (medium), and 43 +/- 6% (high) of the basal levels, whereas basal TSH levels declined significantly, to 64 +/- 5% of basal levels (P less than 0.05), during both the medium and high dose DA infusions. On paired comparisons, the hormone responses to MTC were lower (P less than 0.05) during the infusion of high dose DA (PRL, 2286 +/- 495% vs. 891 +/- 328%; TSH, 100 +/- 43% vs. 60 +/- 15%), but were not changed when MTC was given during the low and medium doses of DA. A rebound phenomenon was found for PRL (P less than 0.05) after the medium and high doses of DA and for TSH (P less than 0.05) after the high dose. These results indicate that doses of DA considered physiological inhibit PRL and TSH secretion and larger doses inhibit their responses to the DA antagonist MTC.

Gonadotropin responses to gonadotropin-releasing hormone and prolactin responses to thyrotropin-releasing hormone and metoclopramide in women with amenorrhea and insulin-treated diabetes mellitus.

Gonadotropin responses to GnRH and PRL responses to TRH and metoclopramide (MTC) were investigated in nine consecutive women with amenorrhea and insulin-treated diabetes mellitus. Nine normal menstruating diabetic women, 12 normal women in the early follicular phase, and nine consecutive nondiabetic women with functional amenorrhea served as controls. No significant differences were found in relation to diabetes regulation within the two diabetic groups. Amenorrheic patients with diabetes mellitus had significantly lower basal PRL levels than normal women and estradiol levels compared to the other groups. Basal plasma LH concentrations were significantly lower in women with amenorrhea and diabetes mellitus than in nondiabetics with amenorrhea, whereas plasma FSH levels were similar in all groups. The LH response to GnRH was significantly lower in amenorrheic patients with diabetes mellitus than in normal women, and a significant correlation (r = 0.81, P less than 0.01) was found between the LH response to GnRH and the basal estradiol level in these women. The FSH response to GnRH and the PRL response to TRH were similar in all groups. Amenorrheic diabetics had significantly lower PRL responses to MTC compared to other groups, and nondiabetics with amenorrhea had significantly lower PRL response than normal women. It is concluded that diabetic patients with functional amenorrhea have low basal and MTC-stimulated PRL levels, low basal LH levels, and decreased LH response to GnRH despite low estrogen levels. These hormonal changes may in part be caused by a raised central dopaminergic activity leading to a depression of pituitary ovulatory mechanisms.

Prolactin and glucose tolerance in normal and gestational diabetic pregnancy.

The relationship between the deterioration of glucose tolerance and plasma prolactin (PRL) levels was investigated in 15 normal pregnant women and in 15 women with gestational diabetes mellitus. Oral glucose tolerance tests were performed in late pregnancy and postpartum, and the insulin, glucagon, and PRL responses were measured. In late pregnancy the gestational diabetics revealed significantly elevated fasting glucose levels compared with the normal pregnant women and after the glucose challenge their insulin responses were significantly diminished and the suppression of glucagon less pronounced. These differences in glucose metabolism were markedly reduced early postpartum. There was no difference in basal PRL concentrations between the two groups neither in pregnancy nor postpartum. The PRL levels were not altered during the oral glucose tolerance tests and no correlation between the deterioration of glucose tolerance and the PRL concentrations could be demonstrated in either group. These results indicate that abnormal PRL levels are not of pathophysiologic importance for the development of gestational diabetes mellitus.

Abnormal prolactin levels and pituitary-gonadal axis in the puerperium.

To investigate the influence of breast-feeding and prolactin secretion on the pituitary-gonadal function, 3 different groups of patients were studied during the first 8 weeks of the puerperium. Group A comprised patients with hyperprolactinemia and secondary amenorrhea who conceived while on a regimen of bromocriptine. Group B was composed of normal lactating women. Group C comprised nonlactating women treated with bromocriptine. Group A patients had a normal decline in serum prolactin levels during the early postpartum period, but serum prolactin remained completely unaltered after clearance of placental estradiol. In group B suckling increased serum prolactin and suppressed luteinizing hormone. This pattern was not seen in group A. Group C patients had a rapid postpartum normalization of the pituitary-gonadal axis. The results indicate that in relation to lactation the pituitary function is rather autonomous in hyperprolactinemic patients.

Pulsatile gonadotropin secretion and basal prolactin levels during dopamine D-1 receptor stimulation in normal women.

The effect of the specific dopamine D-1 receptor agonist Fenoldopam on pulsatile gonadotropin secretion and prolactin (PRL) secretion was investigated in normal women. The gonadotropin response to subsequent gonadotropin-releasing-hormone (GnRH) administration was also studied. Eight women received 8-hour infusions of either Fenoldopam (0.5 microgram/kg per minute) (Smith Kline and French, Harrow, United Kingdom) or placebo. After 7 hours of infusion, GnRH was given intravenously. The luteinizing hormone (LH) response to GnRH was significantly higher during Fenoldopam compared with placebo (LH; 13.1 +/- 9.0 versus 9.4 +/- 4.3 IU/L). Basal LH levels, pulse amplitude, and pulse frequency during Fenoldopam infusion were not different from placebo. Prolactin levels increased significantly during Fenoldopam (24 +/- 2 micrograms/L) compared with placebo (16 +/- 2). The results suggest that D-1 receptor stimulation does not affect pulsatile gonadotropin secretion but increases the pituitary responsiveness to GnRH. Additionally, dopamine and Fenoldopam have opposite effects on PRL secretion, the latter increasing PRL levels.

Gonadotropin secretion before and during acute and chronic dopamine-receptor blockade in insulin-dependent diabetic patients with amenorrhea.

The dopaminergic influence on luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (PRL) was studied in 12 diabetic patients with amenorrhea (DMAM) and in 10 normal menstruating diabetic patients (DM). DMAM patients had a reduction in LH pulsatility (P less than 0.05) and basal LH levels (P less than 0.02), compared with DM patients, whereas they had an LH and FSH response to intravenous metoclopramide (MTC) at 30, 45, and 60 minutes and at 30 minutes, respectively (P less than 0.05). Basal (P less than 0.05) and MTC-stimulated (P less than 0.05) PRL levels were lower in DMAM than in DM patients. Serum PRL and FSH increased significantly (P less than 0.02) in six DMAM patients during 10 weeks of oral MTC administration, whereas no significant (P greater than 0.05) alterations occurred in serum LH and estradiol levels. These data point toward increased dopaminergic activity in DMAM patients.

Infertility, fertility drugs, and invasive ovarian cancer: a case-control study.

OBJECTIVE: To assess the risk of invasive ovarian cancer among infertile women treated with fertility drugs. DESIGN: A case-control study. SETTING: Nationwide data based on public registers. PATIENT(S): All Danish women (below the age of 60 years) with ovarian cancer during the period from 1989 to 1994 and twice the number of age-matched population controls. Included in the analysis were 684 cases and 1,721 controls. MAIN OUTCOME MEASURE(S): Influence of parity, infertility, and fertility drugs on the risk of ovarian cancer after multivariate confounder control. Risk measure(s): odds ratios (OR) with 95% confidence intervals. RESULT(S): Nulliparous women had an increased risk of ovarian cancer compared with parous women: OR 1.5 to 2.0. Infertile, nontreated nulliparous women had an OR of 2.7 (1.3 to 5.5) compared with noninfertile nulliparous women. The OR of ovarian cancer among treated nulliparous women was 0.8 (0.4 to 2.0) and among treated parous 0.6 (0.2 to 1.3), compared with nontreated nulliparous and parous infertile women, respectively. CONCLUSION(S): Nulliparity implies a 1.5- to 2-fold increased risk of ovarian cancer. Infertility without medical treatment among these women increased the risk further. Among parous as well as nulliparous women, treatment with fertility drugs did not increase the ovarian cancer risk compared with nontreated infertile women.

Prolonged dopamine receptor blockade in normoprolactinemic amenorrhea: a double-blind placebo study.

Patients with functional amenorrhea may have a raised central dopaminergic activity, leading to inhibition of pituitary-ovarian function. In a double-blind placebo trial, ten patients with amenorrhea received metoclopramide (MTC) orally in daily doses from 20 to 7.5 mg in a sequential form for 10 weeks. Six patients received placebo. Serum levels for luteinizing hormone (P less than 0.02), follicle-stimulating hormone (P less than 0.05), and prolactin (P less than 0.001) increased significantly during MTC administration, and no (P greater than 0.05) hormonal changes occurred in the placebo group. Six patients observed vaginal bleedings during MTC administration but without postovulatory progesterone levels. Dopamine receptor blockade may activate the hypothalamic-pituitary axis of amenorrheic patients, although an ovulatory response is not achieved.

Ovarian stimulation and borderline ovarian tumors: a case-control study.

OBJECTIVE: To assess the risk of borderline ovarian cancer among infertile women treated with fertility drugs. DESIGN: Case-control study. SETTING: Nationwide data obtained from public registers and postal questionnaires. PATIENT(S): All Danish women <60 years old with borderline ovarian cancer during the period 1989-1994 and randomly selected population controls. The analysis included 231 cases and 1,721 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Influence of parity, infertility, and fertility drugs on the risk of borderline ovarian cancer after multivariate confounder control. RESULT(S): The odds ratio (OR) for borderline ovarian cancer among infertile untreated nulliparous women compared with fertile nulliparous women was 1.9. The OR for borderline ovarian cancer among treated nulliparous women compared with untreated infertile nulliparous women was 1.5, and the OR among treated parous women compared with untreated infertile parous women was 1.5. CONCLUSION(S): Among fertile women, the difference in the risk of borderline ovarian cancer between nulliparous women and parous women was not statistically significant. Nulliparous women who were infertile and who did not receive medical treatment had a twofold higher risk of borderline ovarian cancer than fertile nulliparous women. There was no statistically significant increase in the risk of borderline ovarian cancer among nulliparous women who were treated with fertility drugs compared with nulliparous untreated infertile women or among parous women who were treated with fertility drugs compared with parous untreated infertile women.

Progesterone supplementation during early gestation after in vitro fertilization has no effect on the delivery rate.

OBJECTIVE: To compare the delivery rate with IVF or ICSI in women who did and did not receive progesterone supplementation in the first 3 weeks after a positive hCG test result. DESIGN: Retrospective study. SETTING: Fertility Clinic, Rigshospitalet University Hospital, Copenhagen, Denmark. PATIENT(S): 200 pregnant women who did not receive progesterone (intervention group) and 200 pregnant women who received progesterone for 3 weeks after a positive hCG result. INTERVENTION(S): In the study group, vaginal progesterone therapy was withdrawn on the day of positive hCG result. In the control group, treatment with progesterone, 600 mg/d, was continued for 3 weeks after a positive hCG result. Both groups received 600 mg of progesterone starting on the day of embryo replacement until testing positive for pregnancy 14 days after embryo transfer. MAIN OUTCOME MEASURES: Delivery rate. RESULT(S): The number of deliveries was 126 in the study group and 128 in the control group. CONCLUSION(S): The delivery rate was the same in pregnant women who received and those who did not receive progesterone for 3 weeks after a positive hCG result. Progesterone supplementation for more than 2 weeks after embryo transfer may therefore yield no benefit in terms of pregnancy.

Dopaminergic regulation of gonadotropin levels and pulsatility in normal women.

This study was done to define the concentration of dopamine (DA) that inhibits gonadotropin secretion and to study the effect of DA D-2 receptor blockade during the infusions. Normal women received 5-hour infusions of either glucose (n = 14) or DA at rates of 0.04 (n = 6), 0.4 (n = 6), and 4.0 micrograms/kg X minute (n = 9). After 3 hours, metoclopramide (MTC) was administered. Mean serum luteinizing hormone (LH) concentration declined during 0.4 (P less than 0.01) and 4.0 micrograms/kg X minute (P less than 0.05) infusion doses of DA. This effect of DA was not consistently (P greater than 0.05) antagonized by MTC. Six women received DA (4.0 micrograms/kg X minute) or glucose for 18 hours. After 17 hours, MTC was given. Blood samples were collected every 10 minutes during the last 8 hours. No significant effect on LH pulse frequency and pulse amplitude was observed (P greater than 0.05). A marked (P less than 0.01) rise in LH occurred after MTC administration. The authors conclude that (1) physiologic doses of DA may inhibit LH secretion with only little, if any, effect on the pulsatile release; and (2) low-affinity DA receptors responsive to DA D-2 antagonists may regulate LH secretion.

Dispersal distance as a benefit of myrmecochory.

Nutrient-enrichment and predator avoidance are generally considered the major benefits of myrmecochory, but this is apparently not so in Australia where some of the greatest known concentrations of myrmecochorus plants occur. Here I demonstrate that distance dispersal is a potential benefit of myrmecochory in the Australian environment. Although mean dispersal distance at a site in southeastern Australia was only 2.1 m, the dispersal curve was characterised by a narrow peak and long tail. A dispersal curve of this shape has been shown by Green (1983) to be optimal when safe sites for seedling establishment are rare, as is typically the case for Australian myrmecochores in the absence of fire. Both mean disperal distance and shape of the dispersal curve are influenced strongly by nest density and dispersion, population size, and territoriality of seed-dispersing ants. I argue that distance dispersal is likely to be a benefit of myrmecochory throughout Australia, independent of any targeting of seeds to ant nests.

Meat ants as dominant members of Australian ant communities: an experimental test of their influence on the foraging success and forager abundance of other species.

Meat ants (Iridomyrmex purpureus and allies) are perceived to be dominant members of Australian ant communities because of their great abundance, high rates of activity, and extreme aggressiveness. Here we describe the first experimental test of their influence on other ant species, and one of the first experimental studies of the influence of a dominant species on any diverse ant community. The study was conducted at a 0.4 ha savanna woodland site in the seasonal tropics of northern Australia, where the northern meat ant (I. sanguineus) represented 41% of pitfall catches and 73% of all ants at tuna baits, despite a total of 74 species being recorded. Meat ants were fenced out of experimental plots in order to test their influence on the foraging success of other species, as measured by access to tuna baits. The numbers of all other ants and ant species at baits in exclusion plots were approximately double those in controls (controlling for both the fences and for meat ant abundance), and returned rapidly to control levels when fences were removed after 7 weeks. Individual species differend markedly in their response to the fencing treatment, with species of Camponotus and Monomorium showing the strongest responses. Fencing had no effect on pitfall catches of species other than the meat ant, indicating that the effect of meat ants at baits was directly due to interference with foraging workers, and not regulation of general forager abundance. Such interference by meat ants has important implications for the sizes and densities of colonies of other ant species, and ultimately on overall ant community structure.

[Intrauterine insemination with donor semen. Treatment of involuntary childlessness caused by male infertility]. / Intrauterin insemination med donorsaed. Behandling af ufrivillig barnløshed på grund af mandlig infertilitet.

Intrauterine insemination with cryopreserved donor semen was performed in 114 women in a total of menstrual 381 cycles during the period 1.2.1991 to 15.5.1993. Eighty-one pregnancies were recorded corresponding to a conception rate of 21% per insemination cycle. After ten cycles the probability of conception and expected delivery was respectively 96% and 86%. The results show that intrauterine insemination with donor semen is a good treatment for couples with male infertility. Ultrasonic measurement of the follicles and timing of hCG injection were used for optimal timing of intrauterine donor insemination. The quality of the semen used for insemination is important. It is recommended to inseminate with at least two million of spermatozoa where at least 20% have normal motility.

[Homologous intrauterine insemination as a first choice treatment of infertility]. / Homolog intrauterin insemination som basisbehandling af infertile par.

Intrauterine insemination with husband's Percoll preparated sperm was performed in 179 couples in a total of 440 treatment cycles. A total of 60 pregnancies was obtained. The pregnancy and delivery rate was 13.6% and 9.3% per insemination cycle, respectively. The cumulative probabilities of pregnancy and delivery were respectively 42% and 31% after three cycles. There was a significantly higher pregnancy rate when the number of follicles was more than three and a trend towards more pregnancies when the number of spermatozoa was increased. The study shows that this easy and non-invasive treatment gives acceptable results. We recommend an ideal maximum of three treatment cycles, and at least 1-2 million spermatozoa for each insemination.

[Micro-insemination with intracytoplasmic sperm injection]. / Mikroinsemination med intracytoplasmatisk saedcelleinjektion.

Intracytoplasmic sperm injection (ICSI) is now established in the treatment of infertility. Fertilization is achieved by microinjection of a single spermatozoon into the ooplasma. Oligoasthenoteratozoospermia is the main indication, but ICSI is also used in cases of failed fertilization after standard IVF, retrograde ejaculation and male immunological infertility. In obstructive azoospermia ICSI is performed after aspiration of epididymal or testicular spermatozoa. In some anejaculatoric men spermatozon can be obtained following penile vibration or electro-stimulation, but they often have poor motility and ICSI may be used for fertilization. ICSI may also be used after thawing of semen cryopreserved prior to treatment of a malignant disease. Since 1991 the ICSI technique has been improved, and today the pregnancy rates are at least as good as after standard IVF. So far, studies of the foetuses and children born after ICSI show that the number of malformations and abnormal karyotypes is within the range of the normal population.