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Biomedical subjects

M Bygdeman

Publications and source records attributed to M Bygdeman.

At least 37 records · Page 2Linked to original sources
PubMed1998

Contraceptive efficacy of low doses of mifepristone.

OBJECTIVE: To determine whether a 5-mg dose of mifepristone is sufficient to prevent pregnancy. DESIGN: Clinical study. SETTING: Academic research center. SUBJECT(S): Healthy, fertile, sexually active female volunteers. INTERVENTION: Volunteers received a 5-mg dose of mifepristone once weekly, starting on cycle day 2, for up to 6 months. This was their only contraceptive method. MAIN OUTCOME MEASURE(S): Number of pregnancies. RESULT(S): The treatment resulted in a significant decrease in pregnancy rate without affecting the menstrual cycle or causing disturbing side effects. CONCLUSION(S): A low dose of mifepristone, which does not inhibit ovulation, reduces fertility significantly by affecting the endometrium. However, the contraceptive effect needs to be improved for the drug to compete with other contraceptive methods.

Adult↗
PubMed1998

The effect of antiprogestin on integrin expression in human endometrium: an immunohistochemical study.

Integrins are cell surface receptors for the extracellular matrix and connect extracellular cell adhesion proteins to cytoskeletal components. Several investigators have recently described the expression of different integrins in the human endometrium as markers of receptivity. In the present study we investigated the effect of various doses of the antiprogestin mifepristone on the endometrial expression of integrins during the implantation phase. Endometrial biopsies from healthy fertile women were obtained in the midluteal phase. The study included one control and one, two or three treatment cycles. In treatment cycles either 2.5 (n = 9) or 5 mg (n = 5) of mifepristone was administered once weekly, 0.5 mg daily (n = 5), or 200 mg as a single dose administered on day 2 after the luteinizing hormone surge (day LH + 2; n = 8). By using polyclonal antibodies against integrin alpha(v)beta3, subunit beta3 and subunit alpha4 we found reduced immunostaining for alpha4 and beta3 subunit in glandular epithelium after treatment with mifepristone while alpha(v)beta3, expression appeared to be unaffected. No differences between treatment groups were noted. This study demonstrates that treatment with mifepristone interferes with integrin distribution during the implantation window. This may imply that the contraceptive effect of mifepristone is primarily due to impaired endometrial receptivity. However, since no effect was shown on the distribution of the vitronectin receptor, this integrin might be regulated differently by other factors such as cytokines.

Adult↗
PubMed1997

Effect of low daily doses of mifepristone on ovarian function and endometrial development.

The effects of low daily doses of the antiprogestin mifepristone (RU 486) on ovarian and endometrial function were studied. The study included one control cycle, three treatment cycles and one follow-up cycle. During the treatment cycles, either 0.1 (n = 5) or 0.5 (n = 5) mg of mifepristone was administered once daily. Urine samples were collected three times weekly during the control and treatment cycles and pregnanediol glucuronide and oestrone glucuronide and luteinizing hormone (LH) were quantified by radioimmunoassay. Blood samples for cortisol measurement were collected once weekly and for serum glycodelin at the onset of menstruation. An endometrial biopsy was obtained in the mid-luteal phase in the control cycle and in the first and third treatment cycles and analysed by morphometric and histochemical methods. Binding of Dolichus biflorus agglutinin (DBA) lectin was measured and expression of progesterone and oestrogen receptors and glycodelin were analysed immunohistochemically. All cycles studied were ovulatory with an LH peak and elevated pregnanediol glucuronide concentrations. Follicular development seemed normal as judged by ultrasound examination. The length of the menstrual cycle and the menstrual bleeding were not significantly altered. Following administration of 0.5 mg mifepristone/day, endometrial development appeared to be slightly retarded and glandular diameter was significantly reduced. Furthermore, significant decreases in DBA lectin binding and endometrial expression of glycodelin were observed. Daily doses of 0.1 mg did not have any significant effect on the endometrium. No differences in oestrogen or progesterone receptor immunoactivity between control and treatment cycles were seen. This study provides further evidence that endometrial function is sensitive even to doses of antiprogestin that are low enough not to disturb ovulation. It remains to be established whether these effects are sufficient to prevent implantation.

Adult↗
PubMed1997

The effect of various doses of mifepristone on endometrial leukaemia inhibitory factor expression in the midluteal phase--an immunohistochemical study.

Leukaemia inhibitory factor (LIF) is a cytokine which plays an obligatory role in mouse blastocyst implantation. In human endometrium, LIF expression is significantly increased in the mid-luteal phase indicating that LIF may also play an important role in the human. We have previously shown that a single dose of 200 mg of mifepristone immediately post-ovulation is an effective contraceptive method, probably due to inhibition of endometrial development and function. The purpose of this study was to investigate the effect of various doses of mifepristone on endometrial LIF expression. A total of 22 fertile, regularly-menstruating women were studied during control and treatment cycles. The subjects were divided into four groups: group I received a single dose of 200 mg of mifepristone on cycle day LH + 2 (n = 7). The subjects in groups II and III were treated with either 5 mg (n = 5) or 2.5 mg (n = 5) once a week for 2 months. Group IV subjects received 0.5 mg per day (n = 5) of mifepristone for 3 months. LIF was measured immunohistochemically in endometrial tissue specimens taken on the corresponding day (cycle day LH + 6 to LH + 8) in hormonally-characterized control and treatment cycles. LIF immunostaining was observed in all controls and located to the cytoplasm of the luminal and glandular epithelial cells and stromal cells. In the treatment cycles the staining of luminal epithelium and stroma was similar to controls, while the glandular staining was reduced in all treatment groups. This study reveals that early luteal phase treatment as well as intermittent or daily low dose treatment with mifepristone reduces endometrial glandular LIF expression at the expected time of implantation. The results further support the contraceptive potential of mifepristone in low doses.

Adult↗
PubMed1997

The possible use of antiprogestins for contraception.

BACKGROUND: A number of compounds, antiprogestins, e.g. mifepristone, onapristone and lilopristone, have been developed which compete with progesterone at the receptor level. One of these, mifepristone, is in combination with a prostaglandin analogue currently in use for termination of early pregnancy. The possibility to use these compounds for contraceptive purposes is presently under evaluation. METHODS: The possible contraceptive effect of antiprogestins has been evaluated in both clinical and experimental studies. RESULTS: Administration of antiprogestin during the follicular phase has an inhibitory effect on follicular development and ovulation, and on endometrial development and function if administered during the secretory phase of the menstrual cycle. A high dose of mifepristone, 200 mg, administered immediately following ovulation is highly effective in preventing implantation, most likely due to an effect on endometrial receptivity. It seems that the endometrium is more sensitive to antiprogestin than is the ovulatory process. Low weekly, 2.5 mg to 5 mg, and daily doses, 0.5 mg, of mifepristone did not inhibit ovulation, but a significant effect on endometrial development and especially endometrial function judged from measurement of the expression of a number of markers for endometrial receptivity could be demonstrated. CONCLUSION: The effect of mifepristone on the endometrium may be sufficient to prevent implantation, and if so, an oral contraceptive method could be developed which has no effect on ovarian function.

Contraceptives, Oral, Synthetic↗
PubMed1996

Replens versus dienoestrol cream in the symptomatic treatment of vaginal atrophy in postmenopausal women.

OBJECTIVES: This study was designed to evaluate the efficacy of Replens, a non-hormonal moisturizing vaginal gel, on symptoms of vaginal atrophy in postmenopausal women, in comparison with Dienoestrol (Cilag), an oestrogenic vaginal cream. METHODS: Thirty-nine patients were randomly allocated to either of the two treatments. Replens was given three times a week during the 12 weeks of the study, while Dienoestrol was administered daily during the first 2 weeks and thereafter three times a week. Vaginal dryness index, itching, irritation, dyspareunia, pH and safety were evaluated every week the first month and every month thereafter. RESULTS: Both treatments had a significant increase on vaginal dryness index as soon as the first week of treatment, and the hormonal compound was significantly better than the non-hormonal one. All symptoms such as itching, irritation and dyspareunia significantly decreased or disappeared without any difference between the two treatments. For pH, no significant difference was seen either in each group or between the two groups. No adverse events related with the two drugs were found. CONCLUSION: This study shows that Replens applied vaginally three times a week, is a full therapy for all symptoms of vaginal atrophy as well as local estrogen. No serious adverse event was related. Replens is an alternative treatment to local estrogen and perhaps a good complement of systemic HRT in patient suffering from vaginal dryness.

Administration, Intravaginal↗
PubMed1996

Contraception with anti-progesterone.

Anti-progesterones have potential as contraceptives, acting either by the inhibition of ovulation or the inhibition of endometrial development. Clinical studies have shown that once-a-month treatment with Mifepristone in the early luteal phase is an effective contraceptive method, and that emergency post-coital contraception with Mifepristone is at least as effective as other methods currently used. Recent studies indicate that the endometrium is more susceptible to Mifepristone than are the hypothalamic and pituitary regions, and it may therefore be possible to develop a new contraceptive method based on low daily or once-weekly doses of Mifepristone that does not influence ovarian function.

Contraceptive Agents, Female↗
PubMed1996

Effect of low weekly doses of mifepristone on ovarian function and endometrial development.

The effect of a low dose of mifepristone (RU486) on ovarian and endometrial function was studied in 14 healthy women. The study included one control and two treatment cycles. During the treatment cycles, either 2.5 mg (n = 9) or 5 mg (n = 5) of mifepristone was administered once weekly. The concentration of ovarian steroids and luteinizing hormone (LH) in urine was measured daily, cortisol in blood once weekly and glycodelin (placental protein 14; PP14) at the time of menstruation. Ovarian function was monitored by vaginal ultrasound. An endometrial biopsy was taken in each cycle in the mid-luteal phase, based on self-measurement of the LH peak, or on cycle day 22 if no LH peak could be detected. In the evaluation of the results, the outcome of the enzyme immunoassay of LH was used to date the biopsy. Endometrial progesterone and oestrogen receptors and Dolichus biflorus agglutinin (DBA) lectin binding were measured. Ovulation was not inhibited by treatment with mifepristone, and an LH peak could be determined in all control and treatment cycles. However, in four subjects (one with the higher and three with the lower dose) the follicular phase was prolonged by 6-13 days. The duration of the luteal phase and the concentrations of pregnanediol and oestrone glucuronide were not affected by treatment. A dose of 5 mg, and to a lesser extent 2.5 mg, mifepristone once weekly caused desynchronization of endometrial development. Endometrial progesterone receptor, but not oestrogen receptor, concentration was significantly increased by the higher dose. A significant reduction in DBA-lectin binding and in serum glycodelin concentrations was also found. Thus, low doses of mifepristone do not inhibit ovulation but delay endometrial development and impair secretory activity. Whether these effects are sufficient to prevent implantation remains to be established.

Adult↗
PubMed1996

Effect of post-coital contraceptive methods on the endometrium and the menstrual cycle.

STUDY OBJECTIVE: To evaluate the effect of treatment with ethinylesteradiol-levonorgestrel or danazol on ovarian function, gonadotrophin release and endometrial development during the time when a pregnancy may occur following unprotected intercourse. METHODS: Women with regular menstrual cycles were followed during one control, one treatment and one follow-up month. The women obtained either a combination of 0.5 mg levonorgestrel and 0.1 mg ethinylestradiol (Yuzpe regimen: n = 16) or 600 mg danazol orally and repeated after 12 hours (n = 16). The treatment was administered on either cycle day (cd) 12 or day LH +2. An endometrial biopsy was obtained once on cd LH +6 to +8 in the subjects treated on cd LH +2 both in control and treatment cycles, and morphometric analysis was performed. The concentrations of LH, pregnandiol (P2G), and estrone (EIG) glucuronide were followed daily in morning urine during control and treatment cycles. RESULTS: Following treatment with the Yuzpe regimen on cd 12 the LH surge was either undetectable (three subjects), postponed to cd 16 to 22 (three subjects) or cd 38 to 39 (two subjects) with lower P2G and LH levels than in the control cycle. Following preovulatory treatment with danazol, no LH peak could be detected in four subjects and in the remaining four subjects the LH peak varied between cd 13 and cd 24. The mean area under the curve for LH was significantly lower, the levels of EIG were slightly higher and the P2G levels were unaffected in comparison with the control cycle. Neither of the two treatments administered on cd LH +2 affected the hormonal pattern and only a discreet effect on the development of the endometrium was seen after the EE/LNG treatment. CONCLUSION: The findings indicate that the contraceptive effect of postcoital treatment with EE/LNG and danazol is mainly due to an inhibition or delay of ovulation and insufficient corpus luteum function. The direct effect on the endometrium is limited, if any.

Administration, Oral↗
PubMed1995

Peripherally grafted human foetal dorsal root ganglion cells extend axons into the spinal cord of adult host rats by circumventing dorsal root entry zone astrocytes.

Human foetal dorsal root ganglia were grafted in place of native lumbar dorsal root ganglia in adult rat hosts. Between 4 weeks and 4 months later, the dorsal root entry zone (DREZ) in the grafted roots showed extensive peripheral outgrowth of astrocytic processes, in contrast to the normal 'smooth' interface between the peripheral and central nervous system compartments of the DREZ. Fibres originating from the grafted neurones and approaching the DREZ changed their direction of growth and entered the spinal cord through the pia by following blood vessels, grew into the grey matter and ramified there. These findings suggest that the DREZ astrocytes in vivo are non-permissive not only to mature peripheral regenerating axons, but also to growing axons from immature neurones.

Animals↗
PubMed1995

Long-term effects of human-to-rat mesencephalic xenografts on rotational behavior, striatal dopamine receptor binding, and mRNA levels.

Fetal ventral mesencephalic grafts have been used as a tool to counteract the symptoms of Parkinson's disease. In this study human fetal ventral mesencephalic xenografts were implanted into the lateral ventricle of unilaterally dopamine-depleted immunosuppressed rats. Rotational behavior elicited by low doses of apomorphine, host striatal dopamine receptor binding, and mRNA levels were investigated. Rotational behavior was reduced beginning 2 months after grafting. After 4 months only a small number of rotations, lasting approximately 30 min, were recorded. Seven months after transplantation, the rotational behavior was completely eleminated. Dopamine D2 receptor binding revealed significantly increased levels in sham-operated 6-hydroxydopamine- (6-OHDA) lesioned control striata. These increased levels decreased, and although still significantly higher at 4 months, normalized at the survival time of 7 months postgrafting. Regional differences were still obvious at 7 months in the dorsolateral quadrant of dorsal striatum. Dopamine D2 receptor mRNA revealed significantly increased levels in the lateral aspects of 6-OHDA-lesioned control striata, reversing by 4 months postgrafting. The D1 receptor binding revealed a moderately reduced signal in striata of lesioned animals. After grafting, this reduction became significantly lower than that seen in the control side, with a continous decrease over time. The same pattern was detected using in situ hybridization for dopamine D1 receptor mRNA, that is, moderate decreases after dopamine depletion and a significant decrease in the dorsomedial part of dorsal striatum 7 months postgrafting. Dopamine D3 receptor binding was increased after dopamine depletion, but reversed already by 4 months postgrafting. Taken together, human ventral mesencephalic xenografts are able to completely reverse apomorphine-induced rotational behavior, provided the grafts are left in vivo for a sufficient time. The increased striatal D2 receptors are reversed after grafting, but the human xenograft further suppressed the D1 receptor subtype both at binding and at mRNA levels. There was no strict correlation in the time courses of dopamine receptor changes and reduction of rotational behavior.

Animals↗
PubMed1994

Peripherally grafted human foetal dorsal root ganglion cells extend axons into the spinal cord of adult host rats by circumventing dorsal root entry zone astrocytes.

Human foetal dorsal root ganglia were grafted in place of native lumbar dorsal root ganglia in adult rat hosts. Between 4 weeks and 4 months later, the dorsal root entry zone (DREZ) in the grafted roots showed extensive peripheral outgrowth of astrocytic processes, in contrast to the normal 'smooth' interface between the peripheral and central nervous system compartments of the DREZ. Fibres originating from the grafted neurones and approaching the DREZ changed their direction of growth and entered the spinal cord through the pia by following blood vessels, grew into the grey matter and ramified there. These findings suggest that the DREZ astrocytes in vivo are non-permissive not only to mature peripheral regenerating axons, but also to growing axons from immature neurones.

Animals↗
PubMed1994

Hormone regulation and hormone antagonist effects on protein patterns of human endometrial secretion during receptivity.

Endometrial receptivity is a particular stage of maturation during the luteal phase to permit implantation. We have studied endometrial protein secretion and its patterns evaluated by SDS-PAGE, laser densitometry and Western blots. Uterine secretion electrophoresis (USE) permits highly sophisticated analyses of the intrauterine milieu and allows clinical determination of the receptive stage of the endometrium. This technique reveals direct parameters by patterns of numerous individual protein bands, mainly resolved between 68.0 and 6.5 kD. Characteristic bands appear during the typical functional states of the menstrual cycle presenting evidence on the diagnostic capacity of this method to identify stages of adequate (= normal) or inadequate (= defective) luteal phase maturation. Several individual protein bands appear as characteristic markers for the receptive stage of the luteal phase. We have isolated and molecularly identified several of these proteins: histones H2A, H2B, H3 and H4. In order to identify the endocrine dependency of the protein bands, which significantly contribute to the "receptive stage pattern," patients were treated with the progesterone antagonist RU 486 at day LH +2. The assessment 4 days later revealed deficient USE patterns, particularly diminished and missing bands of the H2A-, H2B-, and H3-histones. These results demonstrate progesterone-dependent components of the endometrium at the receptive stage, which can be used as useful markers for an improved precision in luteal phase diagnostics. On the other hand, essential parts of the protein pattern may serve as new targets for successful contraceptive interventions ("endometrial contraception").

Animals↗