Investigation of hormonal male contraception in African men: suppression of spermatogenesis by oral desogestrel with depot testosterone.
(33/142)
BACKGROUND: Suppression of spermatogenesis to azoospermia is required for effective hormonal male contraception, but the degree of suppression varies between ethnic groups. We here report the first study of hormonal suppression of spermatogenesis in two African centres using a regimen of oral progestogen with depot testosterone. METHODS A total of 31 healthy men (21 black) were recruited in Cape Town and 21 men in Sagamu, Nigeria. Subjects were randomized to take either 150 or 300 micro g desogestrel daily p.o. with testosterone pellets. In Cape Town, desogestrel was administered for 24 weeks with 400 mg testosterone re-administered 12 weekly. In Sagamu, desogestrel was administered for 52 weeks with 200 mg testosterone (later increased to 400 mg) re-administered 12-weekly. RESULTS: In Cape Town, 22 men completed at least 20 weeks treatment. Azoospermia was achieved in 8/10 and 8/12 men in the 150 micro g and 300 micro g desogestrel groups. Four men in Sagamu withdrew. Azoospermia was achieved in all 17 men in the two groups. There were no significant changes in lipoprotein or haemoglobin concentrations in any group. CONCLUSION: These data demonstrate that the combination of oral desogestrel with depot testosterone is an effective regimen for suppression of spermatogenesis in African as in Caucasian and Chinese men, with azoospermia achieved in a total of 83/98 (85%) men. (+info)
Effect of long-term treatment with low-dose mifepristone on the endometrium.
(34/142)
BACKGROUND: Mifepristone in low daily doses has contraceptive potential by inhibiting ovulation and menstruation. Because follicular development is maintained, the endometrium is exposed to estrogen for prolonged periods unopposed by progesterone. METHODS: Endometrial biopsies were collected from 90 women in Edinburgh and Shanghai before (late proliferative) and 60 and 120 days after taking 2 or 5 mg mifepristone per day for 120 days. RESULTS: Ovulation and menstruation were inhibited in >90% of cycles and estrogen production was similar to that observed during the follicular phase of the control cycle. By 120 days, endometrial thickness increased significantly in women in Edinburgh but decreased in Shanghai. Endometrial histology showed inactive proliferative or cystic changes with dense stroma. There was a significant decrease in markers of proliferation, i.e. mitotic index and Ki67 staining. There were no pregnancies in a total of 200 women-months in 50 sexually active women who used no other method of contraception. CONCLUSIONS: We confirm that ovulation and menstruation were suppressed in the majority of cycles and there was asynchrony between ovarian activity and endometrial histology, which showed no signs of hyperplasia or atypia. These preliminary data suggest that daily low-dose mifepristone is potentially a safe estrogen-free contraceptive pill which has the added health benefit of amenorrhoea. (+info)
Auditory brainstem response in premenopausal women taking oral contraceptives.
(35/142)
BACKGROUND: The aim of this prospective study was to evaluate the effects of the new monophasic oral contraceptives on the audiological system in premenopausal women. METHODS: The auditory brainstem response (ABR) was measured in 94 women during the follicular, periovular and luteal phases of one menstrual cycle in which ovulation was confirmed using sonography and serum progesterone concentration. The latencies for waves I, III and V were determined, and the inter-peak intervals were calculated for waves I-III, I-V and III-V. All 94 women began taking oral contraceptives: 23 women used 20 microg ethinyl estradiol (EE) plus 150 microg desogestrel, 24 women used 30 microg EE plus 75 microg gestodene, and 47 women used 15 microg EE plus 60 microg gestodene. During the third month of contraceptive intake, each subject was again tested for ABR, as above. RESULTS: The wave latencies and inter-peak intervals showed shorter values during the periovular phase with respect to the luteal phase (P < 0.05), the follicular phase for wave I and for inter-peak interval I-V (P < 0.05) of the menstrual cycle. All of the ABR results in pill users were statistically different from those of the periovular phase (P < 0.05), though similar to those of both the luteal and follicular phases (P = NS). CONCLUSIONS: ABR seems to depend on the variations of ovarian steroids during the menstrual cycle and during oral contraceptive intake. (+info)
Lack of difference among progestins on the anti-atherogenic effect of ethinyl estradiol: a rabbit study.
(36/142)
BACKGROUND: Progestins in combination with estrogen are believed to have different effects on the cardiovascular system. The aim of this study was to investigate the influence of different oral contraceptive formulations on the development of experimental atherosclerosis and vascular reactivity. METHODS: A total of 160 sexually mature rabbits were ovariectomized and randomly assigned to equally large groups: (i) a cholesterol-rich diet (320 mg/day), either given alone (placebo), or together with (ii) ethinyl estradiol (EE 70 micro g/day, oral), (iii) desogestrel (DSG 525 micro g/day, oral), (iv) gestodene (GSD 262.5 micro g/day, oral), (v) levonorgestrel (LNG 525 micro g/day, oral), (vi) EE + DSG, (vii) EE + LNG, or (viii) EE + GSD. After 31 weeks of treatment, aortic accumulation of cholesterol and vascular vasoreactivity (in vitro) were determined. RESULTS: Progestins alone did not reduce the accumulation of cholesterol. EE alone or in combination with a progestin reduced the accumulation of cholesterol relative to placebo (P < 0.0001). Isolated vessels from EE-treated animals relaxed significantly more to physiological concentrations of acetylcholine than did placebo (P < 0.001), whereas vessels treated with EE plus a progestin showed an intermediate response. CONCLUSION: The progestins investigated can be combined with EE without attenuating the anti-atherogenic effect of EE. (+info)
The effect of ethinyloestradiol and levonorgestrel on the CYP2C19-mediated metabolism of omeprazole in healthy female subjects.
(37/142)
AIMS: To study the effect of an oral contraceptive (OC) formulation containing ethinyloestradiol and levonorgestrel (LNG) (combination OC) or LNG alone on the CYP2C19-mediated hydroxylation of omeprazole in healthy females. METHODS: This was an open crossover study with three phases. In phase one, 10 healthy females received a single 40-mg dose of omeprazole. Thereafter the subjects received in a random order either 40 micro g ethinyloestradiol and 75 micro g LNG or 60 micro g LNG alone once daily for 10 days. On day 10, 1 h after the last OC dose, subjects received a single 40-mg oral dose of omeprazole. The plasma concentrations of omeprazole, 5'-hydroxyomeprazole and omeprazole sulphone were determined for up to 8 h. RESULTS: The use of combination OC increased the area under the curve (AUC) of omeprazole by 38% [95% confidence interval (CI) - 3.8, 80; P = 0.040] and caused a 48% increase (95% CI 28, 68) in the AUC ratio of omeprazole/5-hydroxyomeprazole. LNG alone did not effect the 5'-hydroxylation of omeprazole. Neither of the OC preparations seemed to have an inhibitory effect on the formation of omeprazole sulphone by CYP3A4. CONCLUSIONS: Oral contraceptives containing ethinyloestradiol but not those containing only LNG decrease CYP2C19 activity. (+info)
Dexamethasone and medroxyprogesterone acetate elevate Nm23-H1 metastasis suppressor gene expression in metastatic human breast carcinoma cells: new uses for old compounds.
(38/142)
PURPOSE: Long-term elevation of metastasis suppressor gene expression in micrometastases represents a novel therapeutic strategy for breast and other cancers. We searched for well-tolerated compounds that could elevate Nm23 metastasis suppressor expression in metastatic human breast cancer cell lines. EXPERIMENTAL DESIGN: MDA-MB-435 and MDA-MB-231 human breast carcinoma cells were treated with dexamethasone or medroxyprogesterone acetate (MPA) in cultures containing either charcoal-stripped serum or FCS. Aspects of nm23 expression and function were determined. RESULTS: Previous investigation of the nm23-H1 promoter suggested that glucocorticoids may contribute to the elevation of Nm23-H1 expression. Dexamethasone elevated Nm23-H1 and Nm23-H2 protein levels in two metastatic human breast carcinoma cell lines 2-3-fold over a 4-day time course when cultured in steroid-free culture medium, with high-dose inhibition, via a traditional transcriptional mechanism. Elevation of Nm23-H1 expression was not observed using FCS-containing culture medium, which contains endogenous levels of corticosteroids, limiting the potential in vivo use of dexamethasone. MPA was investigated as a glucocorticoid receptor agonist. MPA elevated breast carcinoma Nm23-H1 protein expression 3-fold over a 10 nM to 1 micro M dose range when cultured in steroid-free or FCS-containing medium, with a shorter time course. Elevation of Nm23-H1 expression in the presence of endogenous corticosteroids found in FCS involved a distinct, glucocorticoid receptor-dependent, posttranscriptional mechanism of action. MPA had no effect on proliferation in vitro but reduced the soft agar colonization of metastatic breast cancer cell lines by approximately 50%. CONCLUSIONS: MPA represents a first generation lead agent for the elevation of Nm23-H1 metastasis suppressor expression and the inhibition of metastatic colonization. (+info)
Interaction of St John's wort with low-dose oral contraceptive therapy: a randomized controlled trial.
(39/142)
AIMS: Breakthrough bleeding or even unwanted pregnancies have been reported in women during concomitant therapy with oral contraceptives and St John's wort extract. The aim of the present study was to investigate the effects of St John's wort extract on oral contraceptive therapy with respect to ovarian activity, breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel. METHODS: Eighteen healthy females were treated with a low-dose oral contraceptive (0.02 mg ethinyloestradiol, 0.150 mg desogestrel) alone (control cycle) or combined with 300 mg St John's wort extract given twice daily (cycle A) or three times daily (cycle B). Ovarian activity was assessed by measuring follicle maturation and serum oestradiol and progesterone concentrations. The number of breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel were assessed under steady-state conditions. RESULTS: During concomitant administration of low-dose oral contraceptive and St John's wort, there was no significant change in follicle maturation, serum oestradiol or progesterone concentrations when compared with oral contraceptive treatment alone. However, significantly more subjects reported intracyclic bleeding during cycles A (13/17 (77%), P < 0.015) and cycle B (15/17 (88%), P < 0.001) than with oral contraceptives alone (6/17 (35%)). The AUC(0,24 h) and Cmax of ethinyloestradiol remained unchanged during all study cycles, whereas the AUC(0,24 h) and Cmax of 3-ketodesogestrel decreased significantly from 31.2 ng ml-1 h to 17.7 ng x ml-1 h (43.9%; 95% confidence interval (CI) -49.3, -38.5, P = 0.001) and from 3.6 ng x ml -1 to 3.0 ng x ml -1(17.8%; CI -29.9, -5.7, P = 0.005), respectively, during cycle A and by 41.7% (CI -47.9, -35.6; P = 0.001) and by 22.8% (CI -31.2, -13.3; P < 0.001) during cycle B respectively, compared with the control cycle. CONCLUSIONS: There was no evidence of ovulation during low-dose oral contraceptive and St John's wort extract combination therapy, but intracyclic bleeding episodes increased. Bleeding irregularities may adversely effect compliance to oral contraceptives and together with St John's wort-induced decreases in serum 3-ketodesogestrel concentrations, enhance the risk of unintended pregnancies. (+info)
Effect of mifepristone on the expression of cytokines in the human Fallopian tube.
(40/142)
Cytokines are believed to play a critical role as mediators between the oviduct and the developing embryo. A synchronous development of embryo and endometrium is essential to successful implantation. It seems to be beneficial for embryo development to rest for some time in the Fallopian tube. Expression of cytokines in the human Fallopian tube and the effect of mifepristone were investigated. Fourteen women with regular menstrual cycles and proven fertility, admitted to the hospital for tubal ligation, were randomly allocated to control or treatment groups. Mifepristone 200 mg was given on day LH+2. Surgery was performed on day LH+3 to LH+5. Biopsies were obtained from the ampullar and isthmic regions of the tubes. Expression of interleukin 8 (IL-8), tumour necrosis factor alpha (TNFalpha), transforming growth factor beta (TGFbeta) and leukaemia inhibitory factor (LIF) was analysed using immunohistochemistry. All cytokines except IL-8 showed the same staining intensity both in the ampullar and isthmic region, while IL-8 was more pronounced in the ampullar region in both epithelial and stromal cells. Exposure to mifepristone made the spatial difference in IL-8 disappear and increased the expression of TNFalpha in the epithelium of the isthmus, but had no effect on the expression of TGFbeta1 or LIF. Changes in cytokine expression in the Fallopian tube are likely to influence embryo development, which could contribute to the contraceptive effect of mifepristone. (+info)