Trisomy occurring in at least 4% of pregnancies is the most common chromosome abnormality in humans. The majority of trisomies are associated with single additional chromosome. The presence of an additional sex chromosome is often associated with physical behavioral and intellectual impairment. The presence of an additional autosome is even more serious being associated with severe mental and physical retardation and frequently with death in infancy. This review discusses the incidence parental origin and etiology of human trisomy. The incidence of trisomy varies widely among different chromosomes. This variation appears to reflect a real difference in the frequency of the primary event leading to trisomy as well as in differential selection. Studies of parental origin have shown a 1st maternal meiotic division error to be the most frequent source of the additional chromosome regardless of the chromosome involved or the maternal age. Although the magnitude of risk varies among chromosomes increased maternal age is an important risk factor in trisomy. The incidence of trisomy 21 increases from .05% of livebirths at maternal age 20 years to over 3% of all livebirths at age 45 years. The effect of maternal age is most pronounced in double trisomies. It has been hypothesized that the relationship between increasing maternal age and trisomy is due to a gradient in the fetal ovary that affects chiasma freequency. While the basis for the maternal age effect remains unknown it is almost certainly due to factors acting at or before conception. Epidemiologic studies suggest that maternal irradiation exposure may also lead to trisomy; however the effective dosage level and the relationship to maternal age remain unknown. No effect of oral contraceptives spermicides or fertility drugs on the incidence of trisomy has been documented to date. Understanding of the mechanisms by which trisomies are produced represents a major challenge for human cytogenetics.

Trisomy in man

Preimplantation genetic diagnosis

The program for in vitro fertilization at Bourn Hall began in October 1980. Various types of infertility have been treated during this time using the natural menstrual cycle or stimulation of follicular growth with antiestrogens and gonadotrophins. Follicular growth and maturation are assayed by urinary estrogens and LH, monitored regularly during the later follicular stage. Many patients had an endogenous LH surge; others needed an injection of HCG to induce ovulation. All oocytes were recovered by laparoscopy. Wide variations occurred in the time interval between the start of the LH surge and oocyte recovery and between oocyte recovery and insemination. Embryos taken between the one- and the eight-cell stage were replaced into their mother, no standard procedure being adopted for all patients. The results of all treatments including patient's responses during the follicular and luteal phases, oocyte recovery, fertilization, cleavage, replacement, implantation, abortion, and birth and the effect of factors such as replacing two or more embryos, maternal age, and previous obstetric history are described in detail. The incidence of implantation after embryo replacement improved from 16.5% initially to 30% currently. More than 118 babies have been born, and many pregnancies are continuing.

Factors influencing the success of in vitro fertilization for alleviating human infertility

https://www.cell.com/trends/genetics/pdf/S0168-9525(00)89008-3.pdf

Death before birth: Clues from gene knockouts and mutations

https://www.fertstert.org/article/S0015-0282(10)00600-X/pdf

The relationship between blastocyst morphology, chromosomal abnormality, and embryo gender

In vitro fertilization and embryo transfer is now an established treatment for certain forms of human infertility. High success rates have been reported following oocyte recovery and fertilization in vitro, the only major remaining difficulty being the high failure rate (80%) of implantation after replacement of the embryo into the mother. One possible reason for this failure of implantation is that some embryos may carry a lethal chromosome abnormality which does not allow development beyond the preimplantation stage. The need for information on the chromosomal status of early embryos fertilized and developed in vitro is recognized but two reported attempts to examine them have met with technical problems. Here we describe a method for examining chromosomes in 8-cell human embryos. Although we have made complete chromosome analyses for only three oocytes, our findings are surprising in that two of the three embryos were chromosomally abnormal. Data on the DNA content of the nuclei in a further eight cases showed that approximately 20% overall may be haploid.

Chromosome abnormalities in human embryos after in vitro fertilization

ALTHOUGH low rates of ovulation constitute a major limitation to increased productivity of sheep and cattle little is known about the mechanisms that control ovulation either within or among species. Androstenedionem a week androgen secreted by ovaries1 and adrenals1, is quantitatively the major steroid secreted by the ovary before ovulation in several species2 and as such it might have a role in determining ovulation rate; it is also an important precursor for the biosynthesis of oestrogens, by the ovary3. Although androstenedione can act as a prehormone by virtue of its peripheral metabolism to oestrogens4 a direct hormonal action has only been demonstrated in the female rhesus monkeys5 where it seems to be important for sexual behaviour. We report here that by actively immunizing sheep against androstenedione a slight but significant increase in ovulation rate can be induced.

Increasing ovulation rate in sheep by active immunisation against an ovarian steroid androstenedione.

In ewes immunized against androstenedione, ovulation rate was increased (P less than 0.001) although the number of live lambs/nursing ewe (1.37), but not the sex ratio (10 females:1 male), was similar to that of controls (1.33).

/pdf/ovulation-and-lambing-rates-in-ewes-actively-immunized-14cfsrv9fk.pdf

Ovulation and lambing rates in ewes actively immunized against androstenedione.

The secretion rates of testosterone measured during the last half of the oestrous cycle in 2 Merino crossbred ewes with utero-ovarian autotransplants were 1.95 +/- 0.34 ng/min and 2.48 +/- 0.63 ng/min. The secretion rate of testosterone was not correlated with the secretion rate of oestradiol or androstenedione in either ewe. Welsh Mountain ewes were actively immunized against testosterone-3-(O-carboxymethyl)-oxime-bovine serum albumin (testosterone-3-BSA) or BSA alone (controls). Immunization against testosterone-3-BSA (5 ewes) resulted in anovulation (2 ewes) and the disruption of oestrous cycles and irregular ovulations (2 ewes). The ovaries showed morphological and endocrinological evidence of over-stimulation. Numerous large non-atretic follicles were present and in those ewes still ovulating the numbers of corpora lutea (ovulation rate) were increased. The concentrations of androstenedione and of oestradiol in the ovarian venous plasma were also markedly increased when compared to those in control ewes. The plasma binding capacity for steroids and the jugular venous concentrations of steroids were higher in immunized ewes. The binding capacity of follicular fluid for testosterone was similar to that of jugular venous plasma from the same ewe. These results show that immunization against testosterone-3-BSA leads to a disruption of ovarian cycles and ovarian over-stimulation.

/pdf/ovarian-function-in-the-ewe-after-active-immunization-19bk3v7sty.pdf

Ovarian function in the ewe after active immunization against testosterone

Volunteer women requesting laparoscopic sterilization were subjected to a fixed schedule of ovulation induction and oocyte recovery. Follicle aspiration was carried out in four groups: those to whom hCG was not administered and 12, 24 or 36 h respectively after the administration of hCG. For each group oocytes were cultured in vitro for 42 h, 30 h, 18 h and 6 h respectively, before insemination with donor spermatozoa. Oocyte recovery rates improved with longer hCG-to-recovery intervals (36% with no hCG to 81% 36 h after hCG). Although there was a slight reduction in fertilization rates when oocytes were not exposed to hCG in the follicle, normal cleavage was noted in more than 50% of oocytes in all four groups. It therefore appears that the final maturation stages of the human oocyte are not dependent on the midcycle gonadotrophin surge, provided the oocyte is matured in vitro before insemination. However, it was also evident that the fertilization rates were reduced when oocytes were removed from less mature follicles, as reflected by high androstenedione/oestradiol ratios.

/pdf/oocyte-recovery-and-fertilization-rates-in-women-at-various-4szfpxvxol.pdf

P. F. A. Van Look

Papers

Chromosome abnormalities in human embryos after in vitro fertilization

Increasing ovulation rate in sheep by active immunisation against an ovarian steroid androstenedione.

Ovulation and lambing rates in ewes actively immunized against androstenedione.

Ovarian function in the ewe after active immunization against testosterone

Oocyte recovery and fertilization rates in women at various times after the administration of hCG.