[Treatment in miscarriage and abortion. Widened use of drugs has many advantages].
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Abortion, Missed↗
Biomedical subjects
M Bygdeman
Publications and source records attributed to M Bygdeman.
Human fetal neocortical tissue grafted to rat brain cavities survives, leads to reciprocal nerve fiber growth, and accumulates host IgG.
The human-to-rat xenograft approach offers possibilities to study aspects of primate cortex development and function without monkeys. Human fetal cortical tissue was grafted to prepared cortical cavities of immunosuppressed host rats. Fetal tissue fragments were collected after routine low-pressure vacuum aspiration abortions performed in the first trimester of gestation. Human derived neurons and human nerve fiber outgrowth were visualized by immunohistochemistry with antibodies against human neurofilament protein 70 kD (hNFP70). Ingrowth from rat host striatum or cortex into the grafts was analyzed by immunohistochemistry with antibodies against tyrosine hydroxylase. Astrocytes were evaluated by immunohistochemistry with antibodies against glial fibrillary acidic protein. The grafts grew into different sizes (1-10 mm in diameter) and contained large numbers of hNFP70-positive nerve fibers. All grafts gave rise to outgrowth of hNFP70-positive fibers into the host with partly a cortical layering; layers III and IV received a majority of the human fibers. In several cases, the graft-derived nerve fibers entered the host brain at restricted areas, while there was no crossing over of nerve fibers at the rest of the graft-host interface. Tyrosine hydroxylase-positive fibers were usually not abundant in the grafts. Interestingly, cases of massive ingrowth occurred from host striatum into the graft in a pattern suggesting "permissive sites" at the graft-host interface in the same way as outgrowth from graft to host was found. Additionally, tyrosine hydroxylase-immunoreactive fibers from host cortex were found to grow into the transplant. Glial fibrillary acidic protein immunoreactivity was increased at the interfaces between graft and host cortex or host striatum. Immunohistochemistry using antibodies against rat IgG indicated the presence of rat IgG within the grafts, and in bordering areas of host brain, possibly indicating a defective graft-host barrier. Taken together, these results show that human cortical tissue pieces grafted to cortical cavities of immunosuppressed rats survive grafting and develop, and that reciprocal nerve fiber growth between grafts and hosts occur. Human cortical neurons can grow into the rat host brain in a pattern which is partly determined by host cortical architecture.
Animals↗
Human angiotensinogen is highly expressed in astrocytes in human cortical grafts.
Human fetal parietal cortical tissue was transplanted to cortical cavities in immunosuppressed rats. Protoplasmic astrocytes in the human cortical grafts highly expressed human angiotensinogen mRNA as identified with 35S-labeled and digoxigenin-labeled riboprobes combined with immunohistochemistry for glial fibrillary acidic protein. Antibodies to human specific neurofilament protein 70 KD were used to characterize neurons in the graft and fiber outgrowth into the host brain. Immunohistochemistry revealed human angiotensinogen-like immunoreactivity in many small protoplasmic astrocytes and very few large neurons. These results demonstrate that human angiotensinogen mRNA and protein is synthesized in immature human glia. We assume that angiotensinogen is transformed into angiotensin peptides, which may participate in the regulation of growth processes. The results suggest that human angiotensinogen may play a role during human embryogenesis.
Angiotensinogen↗
Neuronal development in embryonic brain tissue derived from schizophrenic women and grafted to animal hosts.
The distribution of schizophrenia in families supports the hypothesis of heritable risk factors in schizophrenia, but there is as yet no identification of an inherited neurobiological defect. Human embryonic brain tissue fragments, derived from first trimester abortions, can be transplanted into rat hosts, where they continue neuronal development and are accessible for neurobiological investigation. Hippocampal transplants derived from three schizophrenic women and a larger series of normal women have been studied. If there are heritable neuronal defects associated with schizophrenia, a proportion of the transplants from schizophrenic women would be expected to carry these defects. The transplants from the first two schizophrenic women showed profound abnormalities in survival and growth, compared to the series of transplants from normal women. The transplants from the third schizophrenic woman showed normal growth and development, as well as typical histological and electrophysiological features. The data must be regarded as preliminary, because of the small number of subjects that have been studied. However, they are consistent with the transmission of a defect in neuronal development to some of the offspring of schizophrenic women, a possibility consistent with other studies of the pathogenesis of schizophrenia. The mechanism of the defect in development remains to be identified.
Adult↗
The use of progesterone antagonists in combination with prostaglandin for termination of pregnancy.
Antiprogestin alone is not sufficiently effective in terminating early pregnancy to be clinically useful. The only exception seems to be immediate post-ovulatory administration which inhibits endometrial development to an extent that prevents implantation of the fertilized ovum. During early pregnancy the uterus is inactive. Treatment with antiprogestin with result in an increased uterine contractility and a significant increase of myometrial sensitivity to prostaglandin. The effect is probably mainly due to the release of the inhibitory effect of progesterone. Antiprogestin not only activates the uterus, it also causes a ripening of the cervix. The combination of RU486 and either vaginal administration of gemeprost or i.m. injections of nalador provide a safe and effective medical abortion in the first 8 weeks of pregnancy. Recent clinical studies indicate that it may be possible to replace the prostaglandin analogues in current use by the orally active analogue misoprostol. Misoprostol is inexpensive and stable at room temperature and would facilitate the provision of medical abortion with mifepristone. Experimental data also indicate that a combination of RU486 and misoprostol may be developed into an effective once-a-month late luteal method to regulate fertility. Pre-treatment with RU486 is also useful in later stages of gestation. A combination of RU486 and the vaginal administration of gemeprost is a highly effective, safe and simple non-invasive method for terminating both early and late second trimester pregnancy.
Abortifacient Agents, Steroidal↗
Effects of a single post-ovulatory dose of RU486 on endometrial maturation in the implantation phase.
The effect of a single post-ovulatory dose of RU486 on endometrial maturation was studied in the implantation phase. A total of 11 healthy women were followed for one control and one or two treatment cycles. In treatment cycles, a dose of 200 or 400 mg RU486 was administered on day luteinizing hormone (LH)+2. In both control and treatment cycles, an endometrial biopsy was obtained on LH+6 to LH+8. These biopsies were assessed by morphometric and immunohistochemical analyses. The treatment with RU486 did not disturb the normal menstrual rhythm but caused a significant inhibition in the endometrial development. Glandular progesterone receptor staining was significantly more pronounced after RU486 treatment, while there was a reduction in the Dolichos biflorus agglutinin lectin binding, indicating inhibition of the normal secretory transformation of the endometrium. It is likely that these effects on endometrial development and secretory activity represent the basis of the contraceptive effect of post-ovulatory RU486 treatment.
Adult↗
[Egg donation. A desirable therapeutic method?].
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Adult↗
Effect of antiprogestin, hCG and a prostaglandin analogue on human uterine contractility.
In the present study, the effect of hCG and RU 486 on non-pregnant uterine contractility and the sensitivity of the myometrium to the prostaglandin analogue misoprostol (GD Searle, Chicago, IL, USA) was evaluated. Seven healthy female volunteers participated in the study. Uterine contractility was recorded on cycle day LH+13 in two cycles. After recording the spontaneous contractility, 200 micrograms and 400 micrograms of misoprostol were administered orally at an interval of 45-60 minutes. In the second month, 5,000 IU hCG was administered on cycle day LH+8 and 10,000 hCG on cycle days LH+10 and LH+12, and 200 mg RU 486 on cycle day LH+11, 48 hours prior to the recording. In three women, a third month was included in which the same treatment, except for RU 486, was given. Treatment with hCG delayed menstrual bleeding and resulted in a significant increase in the concentration of plasma progesterone. Following hCG, the degree of uterine contractility was reduced, while after hCG and RU 486 the uterus was significantly more active. In the control cycle and following hCG alone, misoprostol had a slight stimulatory effect. When RU 486 was added, the degree of contractility following misoprostol was 4 to 9 times greater than that found if RU 486 was not given. Late luteal administration of RU 486 is not an effective method of fertility regulation. The results of the present study indicate that a combination of RU 486 and misoprostol will be more suitable for this purpose.
Administration, Oral↗
Effect of antihormones on endometrial receptors and protein secretion.
The antiestrogen tamoxifen and the antiprogestin RU 486 both interact with respective hormones at the receptor level, RU 486 as a pure antagonist which inhibits endometrial development, the downregulation of estrogen and progesterone receptors and the production of endometrial protein, such as PP14, during the secretory phase of the menstrual cycle. Tamoxifen, on the other hand, has both agonistic and antagonistic action.
Endometrium↗
Effect of tamoxifen alone and in combination with RU 486 on the endometrium in the mid-luteal phase.
The effects of RU 486 combined with tamoxifen and tamoxifen alone on hormonal parameters and endometrial development at the time of implantation were studied. Measurements of cytosolic oestrogen and progesterone receptors in endometrium and placental protein 14 (PP14) in plasma were also included. Three dosage schedules were used: single oral dose of 40 mg tamoxifen alone and in combination with 200 mg RU 486, and 40 mg tamoxifen for three consecutive days starting on the first day after the luteinizing hormone (LH) surge. The combined treatment prolonged the luteal phase (P < 0.05) and increased the plasma levels of progesterone. A single dose of tamoxifen did not affect the bleeding pattern and plasma hormone levels, but raised plasma oestradiol and LH with the 3-day treatment. The endometrium was retarded after the combined and the 3-day treatment with tamoxifen. Concentrations of cytosolic progesterone receptors were higher after the combined therapy, but were unaffected after tamoxifen only. PP14 levels were higher (P < 0.05) after repeated tamoxifen doses than in controls, but were lower with combined treatment. Progesterone and oestrogen are evidently necessary for endometrial maturation during the secretory phase of the menstrual cycle. PP14 levels in plasma cannot be used for clinical assessments of endometrial function because high levels coincide with disturbed endometrial development.
Embryo Implantation↗
Early luteal phase treatment with mifepristone (RU 486) for fertility regulation.
Mifepristone (RU 486) is an antiprogestin which interacts with progesterone at the receptor level. Administration of mifepristone immediately after ovulation does not upset the menstrual cycle. However, the maturation and function of the endometrium is inhibited and uterine contractility is changed. To test if these effects are sufficient to prevent implantation, 21 women agreed to use one single treatment with 200 mg mifepristone on day luteinizing hormone (LH) + 2 monthly as their only contraceptive method. The women were treated for 1-12 months. The time of the LH peak was determined in the urine by the women themselves using a rapid LH test (Ovu-quick, Organon). The overall number of cycles studied was 169. In 12 cycles the women were unable to detect the LH peak. In these cycles no treatment was given and the women advised to use barrier methods during the time to menstruation. The remaining 157 cycles with a detectable LH peak were all ovulatory based on plasma progesterone measurement. One pregnancy occurred. On the basis of the time of the LH peak, it was retrospectively calculated that in 124 cycles at least one act of intercourse occurred during the period 3 days before to 1 day after ovulation. The probability of pregnancy in this period of the menstrual cycle is thus 0.008. The women did not complain of any treatment-related side-effects apart from slight bleeding for 2-3 days starting a few days after the day of treatment in 35% of the cycles.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
The effects of an antiprogestin, mifepristone, and an antiestrogen, tamoxifen, on endometrial 17 beta-hydroxysteroid dehydrogenase and progestin and estrogen receptors during the luteal phase of the menstrual cycle: an immunohistochemical study.
The effects of a progesterone antagonist, mifepristone (RU486), and an estrogen antagonist, tamoxifen, given during the early luteal phase on endometrial 17 beta-hydroxysteroid dehydrogenase (17HSD) and estrogen (ER) and progesterone (PR) receptors were studied. Eleven regularly menstruating women were studied during control and treatment cycles. In the treatment cycle on day LH + 2 (2 days after the peak serum LH concentration), 10 subjects received a single dose of 200 mg mifepristone, and 9 received 2 doses of 40 mg tamoxifen on days LH + 2 and LH + 3. In addition, 4 subjects received 400 mg mifepristone in a separate treatment cycle. 17HSD, ER, and PR were measured immunohistochemically in endometrial tissue specimens taken on days LH + 6 to LH + 8. Blood samples were conducted during control and treatment cycles, and serum estradiol, progesterone, and LH concentrations were quantified by RIA. Administration of mifepristone blocked the induction of 17HSD by progesterone and prevented the expression of 17HSD in gland and surface epithelial cells in 8 patients. In 2 patients, staining of 17HSD was seen during both the control and mifepristone treatment cycles. The higher dose of mifepristone additionally given to four subjects did not block the expression of 17HSD in 2 cases where blocking was observed with the lower dose of mifepristone, and in 1 of these patients, very strong staining of 17HSD was observed in basal cells beneath the epithelial cells. ER and PR showed intense staining in the nuclei of both gland and stromal cells in mifepristone treatment cycles, whereas receptor staining was faint or absent in the respective control cycles. Tamoxifen did not have any significant effect on staining of 17HSD or the abundance of receptors. Serum concentrations of estradiol, progesterone, and LH were not significantly affected by the administration of mifepristone or tamoxifen. This study reveals that mifepristone, administered in the early luteal phase, usually blocks the expression of 17HSD and the down-regulation of PR and ER. However, the expression of 17HSD in some patients may reflect the ineffectiveness of the mifepristone treatment used to prevent implantation in certain subjects.
17-Hydroxysteroid Dehydrogenases↗
Mode of action of RU 486.
RU 486 is a 19-norsteroid which has a specific high affinity binding to the progesterone and glucocorticoid receptor. It is generally accepted that RU 486 acts as a pure progesterone antagonist almost without agonistic activity. RU 486 acts mainly directly on the target organ, such as the endometrium, but also to some extent indirectly through an effect on the pituitary gonadotrophin secretion. The effect of RU 486 during the menstrual cycle is dependent on time of treatment. Treatment before ovulation will result in a prolongation of the proliferative phase of the menstrual cycle, while treatment during the mid- and late luteal phase will invariably induce bleeding, often followed by a second bleeding episode at the expected time of menstruation. The only treatment period which does not influence the menstrual cycle is treatment immediately following ovulation. Treatment during the proliferative phase has no effect on endometrial morphology but inhibits follicular development and delays oestrogen and LH surge. Treatment on the first days following ovulation has no effect on ovarian steroid concentration, but will significantly delay endometrial development, cause a change in the concentration of oestrogen and progesterone receptor concentration enzyme activity and production of substances thought to be progesterone dependent. The change in endometrial development is sufficient to prevent implantation. In mid- and late luteal phase, treatment with RU 486 will result in endometrial shedding in spite of normal progesterone levels. Post-ovulatory treatment with RU 486 will also significantly change uterine contractility. In early pregnancy, withdrawal of progesterone inhibition will result in uterine contractility and a significant increase in the sensitivity of the myometrium to prostaglandin.(ABSTRACT TRUNCATED AT 250 WORDS)
Abortion, Induced↗
Initial studies of embryonic transplants of human hippocampus and cerebral cortex derived from schizophrenic women.
Human fetal brain tissue was obtained from first-trimester elective abortions of two women who also had schizophrenia. Portions of the embryonic hippocampus or cerebral cortex were transplanted into the anterior eye chamber of immunologically compromised athymic nude rats. In this environment, embryonic brain tissue derived from normal women generally continues organotypic growth and development for many months. Although initial survival after transplantation was normal, the tissue derived from schizophrenic women manifested less robust growth. However, cells in the transplants showed typical neuronal differentiation, with development of different neuronal types, such as pyramidal cells, granule cells, and gamma-aminobutyric acid (GABA)-containing interneurons. Rhythmic electrical activity was also observed, indicative of some local synaptic organization. The presence of messenger RNA (mRNA) for brain-derived neuronotrophic factor (BDNF) was observed using in situ hybridization. The reason for the decreased rate of growth of these transplants remains unknown and the significance of the finding cannot be assessed from only two fetuses. However, these preliminary findings suggest that fetal transplants may be a useful model system for the detection of developmental pathogenic processes in the expression and transmission of schizophrenia.
Adult↗
Target-specific outgrowth from human mesencephalic tissue grafted to cortex or ventricle of immunosuppressed rats.
Human fetal mesencephalic tissue was grafted to rats with unilateral lesions of the nigrostriatal pathway. The animals were immunosuppressed with cyclosporine A. Grafts were placed either into the lateral ventricle ipsilateral to the lesion or in the cingulate cortex above corpus callosum. The grafts and newly formed fibers were visualized by immunohistochemistry with antibodies against tyrosine hydroxylase (TH) and the human Thy-1 glycoprotein. TH-positive fibers covered the total volume of striatum when the graft was placed either in the ventricle or in the cortex. When the transplant was located in the ventricle, TH-positive cells migrated from the graft into host striatum. No cell migration was seen into any other areas than striatum. Cortex and septum were sparsely reinnervated by the graft, but not to a density higher than that normally seen. Globus pallidus was totally devoid of TH-positive fibers. When the graft was placed in cingulate cortex, fiber bundles penetrated through corpus callosum into either striatum, to arborize in its dorsal parts, or followed the medial side of the lateral ventricle to ventral limbic areas, where a fiber network also was formed. Human specific Thy-1-immunohistochemistry revealed positivity only on the lesioned side. These data suggest that dopamine neurons in human mesencephalic tissue, grafted to the rat brain, can migrate specifically into host striatum. Furthermore, TH-positive fiber outgrowth occurred only into dopamine denervated areas of the host, avoiding areas that are normally not innervated by nigral neurons, but also able to reach distant target cells.
Animals↗
Cervical softening with mifepristone (RU 486) after pretreatment with naproxen. A double-blind randomized study.
Pretreatment with the progesterone antagonist mifepristone reduces the stiffness and facilitates mechanical dilatation of the uterine cervix. We studied the influence of the cyclo-oxygenase inhibitor naproxen on the softening effect of mifepristone on the cervix in thirty nulliparae. The patients were randomly allocated to receive 500 mg naproxen (group A) or placebo (group B) orally 60, 48, 36, 24 and 12 hours prior to vacuum aspiration. All patients received 100 mg mifepristone 48 and 36 hours before surgery. We found that the cervical softening effect of mifepristone was not antagonized by naproxen. The study indicates that the effect of mifepristone on the early pregnant cervix is not mediated through an increased production of prostaglandins.
Abortion, Induced↗
Human fetal xenografts of brainstem tissue containing locus coeruleus neurons: functional and structural studies of intraocular grafts in athymic nude rats.
Fetal human brainstem tissue including the nucleus locus coeruleus was transplanted to the anterior eye chamber of athymic nude rats. Most transplants survived and grew in the anterior chamber of the eye. After 9-15 months, the host animals were anesthetized and electrophysiological or in vivo electrochemical recordings were performed. The brainstem transplants contained spontaneously active neurons with regular single-spike firing patterns. The neurons responded to ipsilateral light stimulation with an increase in firing rate and to the alpha 2-receptor agonist clonidine with significantly decreased firing rates. In vivo electrochemical studies demonstrated reproducible noradrenergic overflow after local application of potassium. Immunohistochemical evaluation of the brainstem transplants showed an abundance of tyrosine hydroxylase-positive neurons and neurites in all transplants and a dense network of neurofilament-, synapsin-, and glial fibrillary acidic protein-positive profiles throughout the grafts. Taken together, the present physiological and histochemical data indicate that it is possible to obtain transplants containing a specific monoaminergic population within the brainstem from human fetal fragments and to maintain these transplants in oculo in athymic nude rats for at least 15 months, during which time noradrenergic neurons develop.
Animals↗
Eighteen-month course of two patients with grafts of fetal dopamine neurons for severe Parkinson's disease.
Two patients with advanced Parkinson's disease were followed for 6 months before, and 18 months after, receiving stereotaxic grafts of fetal mesencephalic tissue from aborted human fetuses. Parameters studied included a series of standardized tests of movement, response to levodopa, electrophysiological recording of the motor readiness potential, and positron emission tomography (PET) with ligands based upon levodopa and upon the dopamine reuptake inhibitor nomifensine. The patients each received stereotaxic implantation of ventral mesencephalic tissue containing midbrain dopamine neurons from aborted human fetuses of 8 to 10 weeks gestational age into the caudate and putamen of one hemisphere. Throughout their 18-month course, the patients were treated with cyclosporine, azathioprine, and glucocorticoids to minimize the risk of graft rejection. There were no significant complications from the procedure, but there was also no major change in their assessment of impairment on the Hoehn and Yahr scale. However, significant changes were observed in clinical, electrophysiological, and PET measures. Changes in these parameters, apparent at 6 months postoperatively, were described in detail in a previous report. The purpose of this present report is to provide follow-up data from the subsequent year with an emphasis on longitudinal evaluation methodology. Standardized clinical testing showed a small but long-term improvement in the first of the two patients. Following the operation, she was able to walk in "off" periods, which she had not been able to do preoperatively. This improvement was accompanied by increased walking speed and reduction in the time necessary to perform a series of pronation and supination movements using both hands. Although these improvements have continued throughout the postoperative period, they have not alleviated her basic neurological impairment. The second patient showed similar improvement during the first 6 months; she then reverted to her preoperative status at the end of the 18-month follow-up period. The electrophysiological recordings were consistent with the clinical findings. Both patients had significant changes in the motor readiness (bereitschafts) potential amplitude, which was greatest 5 to 7 months postoperation. The amplitude of the potential declined subsequently for both patients, but remained significantly elevated over the preoperative baseline for patient 1. The analysis of the PET scans was somewhat compromised by technical problems in the preoperative scans. However, they are also consistent with the clinical data. In comparisons of the operated and the unoperated sides, fluoro-dopa showed increased uptake in the caudate nucleus of patient 1 at 6 months and at 13 months.(ABSTRACT TRUNCATED AT 400 WORDS)
Brain Tissue Transplantation↗