Intra-uterine insemination versus cyclic, low-dose prednisolone in couples with male antisperm antibodies

A total of 46 couples with male immunological infertility enteredthe trial at the infertility clinic of the Family Federationof Finland. The men all showed a positive mixed antiglobulinreaction to immunoglobulin G in their semen; 31 men were alsotested for sperm-bound IgA immunoglobulins by flow cytometry.Serum antisperm antibodies were checked in a tray agglutinationtest. The women showed normal reproductive endocrinology andat least one patent Fallopian tube. The couples were randomizedto undergo either up to three intra-uterine inseminations (IUI),or timed intercourse with cyclic, low-dose (20 mg) prednisolonetherapy of the men. Cross-over was carried out if no pregnancyoccurred in the first stage. Timing of ovulation was based onurinary luteinizing hormone assay and transvaginal ultrasonographicmeasurements. In all, 40 couples either completed the studyor the female partner conceived. IUI was significantly better(P = 0.04) with nine pregnancies than timed intercourse withprednisolone (one pregnancy). There were no significant associationsbetween antibody levels, sperm count or motility versus theincidence of pregnancy. In male immunological infertility, well-timedIUI is an effective treatment method: results are obtained rapidlyand steroidal side-effects can be avoided.     

Effects of the antiprogesterone RU 486 in normal women. I. Single-dose administration in the midluteal phase

The response to a single oral dose of the antiprogesterone RU 486 was studied in the midluteal phase in 26 normal women. Each subject received a dose between 50 and 800 mg RU 486 on days 6 to 8 after the luteinizing hormone surge and blood samples were taken over the following 48 hours. Another group of five patients received a single oral dose of 200 mg RU 486 and blood sampling was extended for 14 days. Menses were induced in all women but one within 3 days after RU 486 administration. Two distinct patient populations emerged. In nine of the subjects, there was a single bleeding episode and the treatment cycle was significantly shorter (p less than 0.05) than the following cycle. In 16 of these 25 patients a second bleeding episode occurred 19.0 +/- 0.8 days after the luteinizing hormone surge. The total treatment cycle was significantly prolonged (p less than 0.05) when compared with the following cycle. In the group with a single bleeding episode, there was a significant decline in follicle-stimulating hormone, estradiol, and progesterone over the 48-hour sampling period, but there was no change in these values in the group with two bleeding episodes. These two groups could not be separated on the basis of RU 486 dose or serum levels. After the four higher doses, there was a dose-dependent rise in serum prolactin. There were no alterations in mean cortisol values with the three lower doses, but there was a significant increase at 24 and 48 hours after the higher doses. Serum levels of RU 486 were maximal between 1 and 4 hours and the half-life of serum RU 486 was determined to be 24 hours.     

Andrology: Epididymal sperm aspiration and use of donor spermatozoa when necessary for in-vitro fertilization, and vasoepididymostomy: an acceptable combination in the treatment of obstructive azoospermia

Infertility due to obstructive azoospermia in 24 men was treatedwith a combination of scrotal exploration, microsurgical spermaspiration and vasoepididymostomy, at the same operation. In-vitrofertilization (IVF) and embryo transfer were performed usingepididymal spermatozoa. Donor spermatozoa were used if no motileepididymal spermatozoa were obtained. With this combination,emotionally and economically acceptable pregnancy rates wereachieved: 24% per aspiration, 43% per embryo transfer, and 25%per couple. One twin pregnancy resulting in the birth of twohealthy female infants and one ongoing twin pregnancy were achievedwith epididymal spermatozoa; four pregnancies (one twin, twosingletons, one abortion) were achieved with donor spermatozoa.     

Uterus and endometrium: The effect of local intrauterine levonorgestrel administration on endometrial thickness and uterine blood circulation

To evaluate non-invasively the role of levonorgestrel releasingdevices in direct contact with the endometrium on menstrualspotting and endometrium inactivation, we inserted levonorgestrelreleasing devices (20 µg/24 h) either into the cervicalcanal or the uterine cavity of 30 fertile women. Both beforeinsertion and over the following 3 months, we used transvaginalsonography to measure the endometrial thickness in 20 of thewomen and Doppler flow to measure the uterine blood flow inthe remaining 10 women. The women were asked to keep recordsof menstrual bleeding and they gave blood samples for the measurementof serum oestradiol, progesterone and levonorgestrel. By 10weeks after insertion there was a significant decrease in endometrialthickness in both groups. Intracervical levonorgestrel releaseallowed the endometrium to maintain cyclic changes, whereasdirect intrauterine levonorgestrel release eliminated the cyclicalchanges. The total number of spotting days was significantlyless (P = 0.0249) in the intracervical release group at 3 months;1.2 ± 0.6 versus 8.1 ± 1.8 (mean ± SE).There were no significant differences in hormone concentrationsbetween the groups. The pulsatility index did not change significantlyduring the study. We concluded that the inactivation processof the endometrium can be monitored by transvaginal sonographyand that locally administered levonorgestrel does not changecirculatory conditions detectable by Doppler flow. Our resultsalso suggest that the inactivation process of the endometriumis different between intracervical and intrauterine levonorgestreladministration and may explain the difference in the numberof spotting days.     

International variation in childhood cancer mortality rates from 2001 to 2015: Comparison of trends in the International Cancer Benchmarking Partnership countries

Despite improved survival rates, cancer remains one of the most common causes of childhood death. The International Cancer Benchmarking Partnership (ICBP) showed variation in cancer survival for adults. We aimed to assess and compare trends over time in cancer mortality between children, adolescents and young adults (AYAs) and adults in the six countries involved in the ICBP: United Kingdom, Denmark, Australia, Canada, Norway and Sweden. Trends in mortality between 2001 and 2015 in the six original ICBP countries were examined. Age standardised mortality rates (ASR per million) were calculated for all cancers, leukaemia, malignant and benign central nervous system (CNS) tumours, and non-CNS solid tumours. ASRs were reported for children (age 0-14 years), AYAs aged 15 to 39 years and adults aged 40 years and above. Average annual percentage change (AAPC) in mortality rates per country were estimated using Joinpoint regression. For all cancers combined, significant temporal reductions were observed in all countries and all age groups. However, the overall AAPC was greater for children (?2.9; 95% confidence interval = ?4.0 to ?1.7) compared to AYAs (?1.8; ?2.1 to ?1.5) and adults aged >40 years (?1.5; ?1.6 to ?1.4). This pattern was mirrored for leukaemia, CNS tumours and non-CNS solid tumours, with the difference being most pronounced for leukaemia: AAPC for children ?4.6 (?6.1 to ?3.1) vs AYAs ?3.2 (?4.2 to ?2.1) and over 40s ?1.1 (?1.3 to ?0.8). AAPCs varied between countries in children for all cancers except leukaemia, and in adults over 40 for all cancers combined, but not in subgroups. Improvements in cancer mortality rates in ICBP countries have been most marked among children aged 0 to 14 in comparison to 15 to 39 and over 40 year olds. This may reflect better care, including centralised service provision, treatment protocols and higher trial recruitment rates in children compared to older patients.     

Low-dose prednisolone does not improve the outcome of in-vitro fertilization in male immunological infertility

Early reports of male immunological infertility suggested adecline in antisperm antibody concentrations in some patientsafter even short-term (10 day) therapy with lowdose prednisolone.In the present study, 53 men with positive results in spermatozoalmixed antiglobulin reaction (MAR) and serum tray agglutinationtests (TAT), were randomized to receive either 20 mg of prednisoloneor placebo daily for 2 weeks prior to in-vitro fertilization(IVF) treatment. The antibody levels were also monitored byflow cytometry (FCM). There were no significant differencesbetween these groups as regards fertilization rates (35% withprednisolone; 39% with placebo) and pregnancy rates (29%; 32%).No significant changes occurred in either MAR or FCM resultsin relation to therapy. Patients with fertilization rates of<10% had significantly higher immunoglobulin G (IgG) MARvalues compared with those with better fertilization, whereasthere was no relationship between IgA levels and fertilizationresults. As regards FCM, the results were similar, but withoutstatistical significance. In conclusion, IVF is a good courseof action in severe male immune infertility, but low-dose prednisolonetherapy does not lower the sperm-bound antibody numbers anddoes not improve the IVF outcome.     

Ovarian function during use of vaginal rings delivering three different doses of Nestorone.

Contraceptive vaginal rings delivering various progestins alone or in combination with estrogen have been previously studied, showing adequate steroid vaginal absorption and acceptability by the users. Nestorone progestin (NES) is a potent 19-nor-progesterone derivative, inactive by the oral route, but an excellent option for vaginal delivery. The purpose of this study was to evaluate ovarian function during 6 months of continuous use of progestin-only vaginal rings delivering 3 different doses of NES: 50, 75, and 100 microg per day. Blood samples were taken twice a week for 5 consecutive weeks during a control cycle and on months 1, 3 and 6 of use, for the measurement of estradiol (E2), progesterone (P), and NES. A total of 87 volunteers randomly received each of the 3 doses. After an initial peak, NES serum levels remained fairly constant throughout the duration of the study at about 125, 200 and 250 pmol/L, respectively, decreasing slightly with time. Luteal activity occurred very rarely (1.2-2.6% of sampling periods) with no apparent difference between doses. Low E2 levels (< or =100 pmol/L) in all samples of a run were rare (5%) and only with the high dose ring (100 microg/day). E2 remained within normal levels (101-1500 pmol/L) in most of the segments studied. We conclude that the 50 and 75 microg/day NES rings provide adequate ovulation inhibition without hypoestrogenism, while the 100 microg/day ring may deliver an unnecessarily high dose.     

Pharmacokinetics and pharmacodynamics of 7alpha-methyl-19- nortestosterone after intramuscular administration in healthy men

7alpha-Methyl-19-nortestosterone (MENT) is a potent synthetic androgen that is resistant to 5alpha-reductases and therefore less prone to over- stimulate the prostate. It is a good candidate for implant administration in long-term androgen replacement therapy for hypogonadal men or as part of a male contraceptive system. To investigate the pharmacokinetics of MENT after i.m. administration, single i.m. injections of 2, 4 or 8 mg of micronized MENT were given in aqueous suspension to 18 healthy men in two clinics. Blood was sampled frequently for 8 h and 1, 2, 3, 4 and 9 days after the injections. Serum MENT concentrations were determined by radioimmunoassay. Peak MENT concentrations were dose-dependent and were reached about 1-2 h after the injections. Doubling the dose of MENT resulted in an increase of 60% in peak serum MENT concentrations. The mean +/- SE clearance rate was 1790 +/- 140 l/day. The antigonadotrophic activity of MENT was investigated by giving six consecutive daily i.m. injections of 1, 2 or 4 mg of MENT to 24 healthy men in two clinics. Blood was sampled before each injection and up to 24 days after the last injection. Serum testosterone and gonadotrophin concentrations (determined by radioimmunoassay and fluoroimmunoassay respectively) decreased in a dose-dependent and statistically significant manner. The highest dose caused a 74% fall in testosterone, a 70% fall in luteinizing hormone, and a 57% fall in follicle stimulating hormone concentrations. MENT injections did not cause any side-effects. The results show that MENT is a potent antigonadotrophic agent in men.      

Intravaginal administration of RU 486 in humans and rats: inadequate absorption in humans

Vaginal absorption of the antiprogesterone steroid RU 486 wasstudied in humans and rat. In rats, RU 486 was sufficientlyabsorbed to terminate early pregnancy following vaginal, oralor intramuscular administration. The quantitation of RU 486in serum showed that the ratios of the areas under the coocentrationcurves per mg administered were 1:2.8:3.4 for the vaginal, intramuscularand oral routes, respectively. Female voluteers received RU486 vaginally in polyethylene glycol (PEG) suppositories, Intampons and in oil solution. Following vaginal (PEG-suppository)and oral a administration of 100 mg of RU 486, the ratio ofthe areas under the serum concentration curves was 1:56, respectively.From tampons and oil, RU 486 was absorbed in a similar mannerto that of the PEG-suppositories, resulting in nanomolar serumconcentrations. In humans no biological effects were noted followingvaginal administration of RU 486. These data suggest that vaginalrelease of RU 486 is not a successful route of administrationin humans.