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Biomedical subjects

B A Lieberman

Publications and source records attributed to B A Lieberman.

At least 19 recordsLinked to original sources
PubMed2004

Identification of viable embryos in IVF by non-invasive measurement of amino acid turnover.

BACKGROUND: IVF is limited by low success rates and an unacceptably high multiple pregnancy rate. These outcomes would be improved significantly if a single embryo of high viability could be replaced in each treatment cycle, but widespread acceptance of such a policy is hindered by the lack of predictive factors for embryo selection. We have conducted a retrospective clinical study of a novel non-invasive method of embryo selection based on the depletion/appearance of amino acids in the culture medium. METHODS: Fifty-three cycles of IVF treatment using ICSI were studied. Embryos were cultured for 24 h in 4 microl drops of medium containing a physiological mixture of 18 amino acids. The spent medium was analysed for amino acid content by high performance liquid chromatography. RESULTS: The turnover of three amino acids, Asn, Gly and Leu, was significantly correlated with a clinical pregnancy and live birth. These correlations were independent of known predictors, such as female age, basal levels of FSH, embryo cell number and embryo morphological grade. CONCLUSIONS: Non-invasive assay of amino acid turnover has the potential to improve significantly the prospective selection of the most viable embryos, or single embryo, for replacement in an IVF cycle.

Adult↗
PubMed2004

Live birth with sperm cryopreserved for 21 years prior to cancer treatment: case report.

Advances in cancer treatment have led to significant improvements in the likelihood of reaching remission and long-term survival for men. Chemo- and radiotherapy-induced infertility are significant treatment side effects. Cryopreservation before the start of treatment enables sperm to be stored, thereby preserving the man's potential fertility. Here, we describe the successful use (with ICSI) of sperm cryopreserved prior to cancer treatment, for a total of 21 years. We believe this to be the longest period of sperm cryopreservation, resulting in a live birth, so far reported in the literature.

Adolescent↗
PubMed2002

Semen cryopreservation, utilisation and reproductive outcome in men treated for Hodgkin's disease.

Between 1978 and 1990, 122 men underwent semen analysis before starting sterilising chemotherapy for Hodgkin's disease. Eighty-one (66%) had semen quality within the normal range, 25 were oligospermic (<20 x 10(6) sperm per ml) and five were azoospermic (no sperm in the ejaculate). Semen from 115 men was cryopreserved and after a median follow-up time of 10.1 years, 33 men have utilised stored semen (actuarial rate 27%) and nine partners have become pregnant resulting in 11 live births and one termination for foetal malformation. Actuarial 10 year rates of destruction of semen before death or utilisation and death before utilisation are 19% and 13% respectively. This retrospective cohort study demonstrates that approximately one-quarter of men utilising cryopreserved semen after treatment for Hodgkin's disease obtain a live birth. The high non-utilisation rate is intriguing and warrants further investigation.

Antineoplastic Agents↗
PubMed2001

Outcome in the second year of life after in-vitro fertilisation by intracytoplasmic sperm injection: a UK case-control study.

BACKGROUND: There have been reports suggesting that children born after in-vitro fertilisation by intracytoplasmic sperm injection (ICSI) are at increased risk of neurodevelopmental delay. We have undertaken a case-control study of this issue. METHODS: We studied 208 singleton children conceived by ICSI and a control group of 221 normally conceived singleton children. Children were recruited from 22 fertility centres and local nurseries throughout the UK. Controls were selected to match cases as closely as possible for social class, maternal educational attainment, region, sex, and race. The primary outcome measure was neurodevelopmental scoring; secondary measures were perinatal outcomes, postnatal health, and congenital abnormalities. A single examiner assessed all the children. FINDINGS: A follow-up rate of 90% for the ICSI group was achieved at a mean age of 17 months. No difference between the study children and controls was found in mean neurodevelopmental scores (98.08 [SD 10.93] vs 98.69 [9.99]) or any subscales on the Griffiths' scales of mental development. Perinatal outcome was similar apart from a higher rate of caesarean section (73 [35.1%] vs 53 [24.0%], p=0.015) and a lower mean birthweight (3163 [SD 642] vs 3341 [606] g, p=0.013) in the study group. Rates of major congenital abnormality were also similar overall (ten [4.8%] study vs ten [4.5%] control), although there were significantly more congenital anomalies among children born to fathers with oligozoospermia than in other children. INTERPRETATION: This population study did not show any significant difference between children conceived after ICSI and their naturally conceived peers in terms of physical health and development.

Analysis of Variance↗
PubMed2001

Orthotopic reimplantation of cryopreserved ovarian cortical strips after high-dose chemotherapy for Hodgkin's lymphoma.

BACKGROUND: Infertility is a common late effect of chemotherapy and radiotherapy, and has a substantial effect on the quality of life for young survivors of cancer. For men, semen cryopreservation is a simple way of preserving reproductive potential but for women, storage of mature eggs rarely proves successful, and the alternative-immediate in vitro fertilisation with cryopreservation of embryos-is not always appropriate. Reimplantation of cryopreserved ovarian tissue has been shown to restore natural fertility in animals. We applied this technique in a woman who had received sterilising chemotherapy for lymphoma. METHODS: A 36-year-old woman underwent a right oophorectomy with cryopreservation of ovarian cortical strips before receiving high-dose CBV chemotherapy for a third recurrence of Hodgkin's lymphoma. 19 months later, when serum sex steroid analysis confimed a postmenopausal state, two ovarian cortical strips were thawed and reimplanted-one onto the left ovary and another at the site of the right ovary. FINDINGS: 7 months after reimplantation of ovarian cortical strips, the patient reported resolution of hot flashes and, for the first time, oestradiol was detected in the serum. This finding was associated with a decrease in the concentrations of follicle-stimulating hormone and luteinising hormone, and ultrasonography revealed a 10 mm thick endometrium, a poorly visualised left ovary, and a 2 cm diameter follicular structure to the right of the midline. The patient had one menstrual period, but by 9 months after the implantation, her sex steroid concentrations had returned to those seen with ovarian failure. INTERPRETATION: Orthotopic reimplantation of frozen/thawed ovarian cortical strips is a well tolerated technique for restoring ovarian function in women treated with sterilising chemotherapy for cancer.

Adult↗
PubMed2001

Achieving pregnancy against the odds: successful implantation of frozen-thawed embryos generated by ICSI using spermatozoa banked prior to chemo/radiotherapy for Hodgkin's disease and acute leukaemia.

Two cases are reported of successful pregnancies following long-term semen banking prior to chemotherapy and radiotherapy for malignancy. With the first case, the patient banked semen at the age of 20 years prior to chemotherapy for Hodgkin's disease; 11 years later the thawed semen was used for IVF with intracytoplasmic sperm injection (ICSI), resulting in twins being born following the transfer of frozen-thawed embryos. In the second case, the patient banked semen at the age of 17 years prior to chemotherapy and radiotherapy for acute myeloid leukaemia; 8 years later it was used for ICSI, resulting in triplets being born following the transfer of frozen-thawed embryos. These cases support long-term semen banking for men whose future fertility may be compromised by suppression of spermatogenesis secondary to administration of chemo/radiotherapy treatment. The advent of successful ICSI combined with embryo cryopreservation has increased the chance of thawed cryopreserved semen achieving fertilization. Banking of a single ejaculate prior to commencement of chemotherapy/radiotherapy treatment may preserve potential fertility without compromising the oncology treatment.

Adolescent↗
PubMed2000

Use of in-vitro fertilisation embryos cryopreserved for 5 years or more.

Human embryos cryopreserved after in-vitro fertilisation can be stored initially for 5 years, and the storage period may be extended to a maximum of 10 years. Of 1344 embryos cryopreserved between 1988 and 1994 at two centres in Manchester, 67% (904 embryos) have had to be destroyed at the end of the first 5-year interval, even if the couples involved remain childless.

Cryopreservation↗
PubMed1999

A computerised study on the results of in-vitro-fertilisation.

This project has been concerned with the comparison of children born as a result of fresh embryo transfer (IVF) with children conceived and born via the natural process. The former included children who were the single outcome of the birth (singletons) and children who were the result of a multiple birth (e.g. twins, triplets). A computer database was established into which was put 23 items of data on each child, making a total of 12,788 items overall. There were 278 "normally conceived" children (controls), 150 IVF Singletons, and 128 children from multiple births. The results show interesting differences in the gestational age at birth, the birth weight, the mode of delivery and the degrees of birth abnormalities and malformations.

Birth Weight↗
PubMed1998

Differential gene induction by glucocorticoid and progesterone receptors.

The question of how glucocorticoid, progesterone, androgen, and mineralocorticoid receptors can generate distinct patterns of gene expression despite similar, if not identical, DNA sequence recognition properties is a central question in steroid biology. This study addresses the hypothesis that glucocorticoid and progesterone receptors can differentially utilize the promoter context created by a series of receptor recognition sites. This hypothesis predicts that for different receptors an individual (often suboptimal) binding site contributes to the overall response element activity to a different degree. Therefore, mutations to an individual binding site of a multipartite hormone response element may differentially affect the response to different steroids. This study tests this hypothesis by introducing mutations into a receptor recognition site that is part of a hormone responsive promoter derived from the mouse mammary tumor virus. We find that weakening one site of a multipartite element differentially affects glucocorticoid and progestin signaling both in fibroblasts and in mammary carcinoma cells. A similar test was done in a simplified promoter context comprised only of a TATA box and a pair of receptor recognition sites. Mutations introduced into one of these sites impaired glucocorticoid response more than the progestin response. However, high receptor expression can partially overcome the effect of some target site mutations. Thus both receptor expression levels and the inherent ability to utilize the context created by a multipartite response element contribute to quantitative differences in the response to receptors that share DNA sequence recognition properties.

Animals↗
PubMed1998

A 3 year retrospective review of intrauterine insemination, using cryopreserved donor spermatozoa and cycle monitoring by urinary or serum luteinizing hormone measurements.

Insemination with donor spermatozoa is an integral part of infertility treatment. For the last 3 years in our unit, intrauterine insemination with donor spermatozoa (IUID) has been used in preference to vaginal insemination. In this retrospective study, patients were offered an initial course of five single intrauterine inseminations with cryopreserved donor spermatozoa and treatment was then reviewed. A total of 389 patients received 1465 inseminations. In all, 1119 cycles were monitored using luteinizing hormone serum analyses and 346 cycles using the urine home test kits. The clinical pregnancy rate per insemination for the cycles monitored by the serum assay was 18.0% (202/1119) compared with the urine cycles (13.7%, 46/346) (P <05). The pregnancy loss rate was not significantly different (14.4%, 29/202 and 21.7%, 10/46) (serum and urine cycles respectively). The viable clinical pregnancy rate was significantly higher (P <03) for the serum cycles than for the cycles using the urinary monitoring (15.5%, 173/1119 and 10.4%, 36/346 respectively). The cycles monitored by serum assay had a significantly higher cumulative viable clinical pregnancy rate (P <0001) of 70.2% after nine inseminations compared with the urine monitored cycles of 54.8%. The majority of patients opted for the serum cycles, with a minority self-selecting the urine cycles mainly for travelling convenience. The explanation for the significant differences between the viable clinical pregnancy rates per insemination and the cumulative viable clinical pregnancy rates may be due to the sensitivity of the urine home test kit or the patients' interpretation of the result.

Cryopreservation↗
PubMed1998

Extreme position dependence of a canonical hormone response element.

Hormone response elements (HREs) are considered enhancers, activating transcription in a relatively position- and orientation-independent fashion. Upon binding to an HRE, steroid receptors presumably contact coactivators and/or proteins associated with the transcription initiation complex. As a receptor target site is moved further from a fixed position such as the TATA box, not only will the spatial separation of the receptor with respect to its interaction partners change, so will the orientation due to the rotation of the DNA helix. Additional constraints may be imposed by the assembly of DNA into chromatin. Therefore, we have endeavored to test rigorously the assertion that HRE action is position independent. We have constructed a series of 42 chloramphenicol acetyltransferase expression vectors that contain a single progesterone/glucocorticoid receptor-binding site separated from a TATA box by 4 to 286 bp. The enhancer activity of the HRE was assessed after transient transfection of progesterone receptor-expressing fibroblasts. We find that the position of the HRE has a dramatic influence on induction by progestins. When closely juxtaposed to the TATA box, the HRE was unable to support a hormone response, perhaps due to direct steric hindrance with the transcription initiation complex. Full activity was gained by moving the HRE 10 bp further from the TATA sequence. As the HRE was moved incrementally further, activity remained near maximal over the next 26 bp. HRE activity then declined over the subsequent 26 bp and remained low for another 2.5 helical turns. Surprisingly, a narrow window of HRE activity occurred at an HRE-TATA box separation of 90-100 bp. Little or no hormone-induced transcriptional activity was observed when the HRE was positioned further from the TATA box. The addition of a second HRE or a basal (nuclear factor-1) element failed to relieve this constraint. A similar series of experiments was carried out in a mammary carcinoma cell line that expressed high levels of both glucocorticoid and progestin receptors. Data in these cells indicate that glucocorticoids and progestins supported a similar HRE position-activity profile, but this pattern of HRE activity was quite distinct from that seen in fibroblasts. This may be indicative of cell type-specific interactions between steroid receptors and adapter/coactivator proteins or cell type-specific activities such as acetylases or deacetylases participating in the steroid response.

Base Sequence↗
PubMed1997

DNA intersegment transfer, how steroid receptors search for a target site.

The mammalian nucleus contains 6 billion base pairs of DNA, encoding about 100,000 genes, yet in a given cell steroid hormones induce only a handful of genes. The logistical difficulties faced by steroid receptors or other transcription factors of sorting through this much genetic information is further increased by the density of nuclear DNA (approximately 10-50 mg/ml). Standard models propose that steroid receptors find target elements by repeated cycles of dissociation and reassociation until a high affinity site is found (cycling model) and/or by conducting a one-dimensional search along the DNA (sliding model). A third model proposes that steroid receptors search for target sites in the genome by DNA intersegment transfer. In this model, receptor dimers bind nonspecific DNA sequences and search for a target site by binding a second strand of DNA before dissociating from the first, in effect moving through the genome like Tarzan swinging from vine to vine. This model has the advantage that a high concentration of DNA favors, rather than hinders, the search. The intersegment transfer model predicts, in contrast to the cycling and sliding models, that the dissociation rate of receptor from DNA is highly dependent on DNA concentration. We have employed the purified DNA binding domain fragment from the rat glucocorticoid receptor to perform equilibrium and kinetic studies of the DNA dependence of receptor-DNA dissociation. We find receptor dissociation from DNA to be highly dependent on the concentration of DNA in solution, in agreement with the intersegment transfer model. We also find that this interaction is primarily electrostatic, because DNA-like polyanion chains (e.g. heparin and polyglutamate) can mediate the transfer. These studies provide evidence that direct DNA transfer aids the target site search conducted by steroid receptors in their role as inducible transcription factors.

Animals↗
PubMed1997

Patterns of progression and nonprogression through in vitro fertilization treatment.

PURPOSE: Increasing numbers of couples are consulting for infertility and, after some years of investigation and treatment, will become enrolled in in vitro fertilization (IVF) programs. The media have focused on successful outcomes or difficulties in accessing services because of health authority funding guidelines. Couples are often assumed to be highly motivated because of their long prior involvement in treatment. However, little is known about uptake of and continuation through IVF treatment programs. METHODS: One hundred forty-four couples were followed through the process of IVF in a service that allows three cycles of treatment, with a minimum gap of 3 months between treatment cycles. Patterns of engagement in and delay and withdrawal from treatment were examined. RESULTS: One in five couples withdrew from the program before completion of the available number of treatment cycles. A further one in three significantly delayed their involvement in treatment cycles. Mean deviations of the time between attempts increased as the numbers of treatment cycles progressed. A proportion of couples did not complete a single treatment cycle. CONCLUSIONS: The dramatic proportions of patients withdrawing from or very significantly delaying subsequent involvement are indicative of the often unacknowledged difficulties associated with IVF treatment. Implications for care are discussed.

Behavior↗
PubMed1997

Are follicle stimulating hormone measurements predictive of ovarian response to hyperstimulation with human menopausal gonadotrophin?

Previous studies have suggested that elevated serum follicle stimulating hormone (FSH) concentrations are associated with a poor ovarian response to hyperstimulation with human menopausal gonadotrophin (HMG) in in vitro fertilisation (IVF) programmes. We have used the day 2 serum FSH concentration to determine the dose of HMG administered in women under 40 years. If the FSH concentration was below 9 IU/l, a constant dose of 150 IU HMG were administered; if above 9 IU/l a constant dose of 300 IU HMG was used. Women over the age of 40 years were given 300 IU HMG regardless of their serum FSH concentration. This retrospective study was undertaken to assess whether this approach was beneficial for the younger women and also whether the FSH concentration was predictive of outcome in older women. The study included all women < 40 years (n = 143) and > 40 years (n = 32) having their first IVF treatment cycle during 1994. In the younger women, there was no difference in the number of cancelled treatment cycles (9.7% vs. 7.5%); the number of follicles present (9.6 vs. 8.2); serum oestradiol concentration (6971 pmol/l vs. 6686 pmol/l); number of eggs collected (7.9 vs. 5.7); number of embryos created (3.7 vs. 3.6); and pregnancy rate (13.5% vs. 15%) between women with normal (n = 103) or elevated (n =40) FSH concentrations. By using the serum FSH concentration to select women in whom a poor response was expected, and administering a higher dose of HMG, a similar ovarian response was produced and the pregnancy rate was similar to those in women with normal FSH concentrations. Women over 40 years with elevated serum FSH concentrations (n = 17) had a significantly (P < 0.05) higher cancellation rate (17.6% vs. 0%) and fewer number of eggs collected (6.9 vs. 2.5) than the group with normal FSH concentrations (n = 15). One woman conceived in each group. These findings confirmed previous studies showing that the serum FSH is predictive of ovarian response. This study confirmed the value of measuring the day 2 serum FSH concentration as a predictor of response; and it provides a scientific approach to determine the dose of HMG administered for IVF stimulation. A satisfactory response to induction of ovulation will be achieved using 150 IU HMG in women with FSH < 9 IU/l but if the FSH is raised i.e. above 9 IU/l, 300 IU is required to achieve a similar response.

Journal Article↗