Male contraception: hormonal, mechanical and other

Methods of male contraception that have been developed so farhave mainly focused on the inhibition of spermatogenesis throughsuppression of the hypothalamo- pituitary secretion of gonodotrophins,and simultaneous supplementation with androgens. These methodsinclude the use of combinations of progestogens or luteinizinghormone-releasing hormone antagonists and testosterone derivatives,or high dose testosterone. Though effective contraception canbe obtained, side-effects and/or the high cost of treatmentlimit the widespread use of these approaches. Inhibition ofsperm maturation in the epididymis, or direct interference withspermatogenic cells or the cells of Sertoli by e.g. gossypolhave been abandoned because of toxic side-effects. Voluntarysterilization by vasectomy is the most commonly used methodof male contraception, but its surgical nature, problematicreversibility and suspected link with subsequent prostate cancerrender the method far from ideal. Non-surgical vas occlusionmay overcome some of these problems, but data on long-term side-effectsand reversibility are lacking. New contraceptive developmentsshould focus on interfering with highly specific aspects ofspermatogenesis such as unique enzymatic processes and intercellularcommunication through cytokines, or application of antibodiesagainst antigens of the epididymis or the spermatozoa. Onlythrough better understanding of normal and pathological spermatogenesiswill it be possible to develop an acceptable male contraceptive.     

Routes of delivery for progesterone and progestins

The trends in postmenopausal hormonal therapy (HT) seem to favor the non-oral delivery routes for both the estrogen and the progestin for women with an intact uterus. Targeting the lowest possible dose of the progestin or of the natural hormone progesterone to be delivered directly to the uterus, the target organ for which it is designed, would avoid the possible drawbacks of systemic effects of progestins on other targets. Several delivery systems are either available or in development including vaginal gels and vaginal rings delivering the physiological hormone progesterone or intrauterine systems delivering very low doses of levonorgestrel. In addition, transdermal gels and spray are under development and can deliver very low doses of Nestorone a 19-norprogesterone derivative, not active orally but with high progestational activity when given via non-oral routes. The assumption that these new delivery systems should lead to an improved risk/benefit ratio in HT will need to be demonstrated in larger randomized controlled studies.     

Early onset vulvar Lichen Sclerosus in premenopausal women and oral contraceptives

OBJECTIVE: For vulvar Lichen sclerosus (LS) immunological factors, genetic predisposition, and decreased 5 alpha-reductase activity have been discussed as aetiological factors. During the last decade an increase of LS in young women has been suspected. Aim of this study was to evaluate data of premenopausal women with early onset LS to find potential risk factors focussing on the use of oral contraceptives. STUDY DESIGN: We retrospectively analyzed the data of 40 premenopausal patients with early onset LS regarding use of oral contraceptives (OCPs), and first occurrence of LS. To compare these data in a case-control study we analyzed a matched control group of 110 healthy women. RESULTS: All our LS patients were using OCPs compared to 73 women (66.4%) in the control group. OCPs with anti-androgenic activity (chlormadinone acetate, cyproterone acetate, dienogest, and drospirenone) were used by 28 (70%) of the LS patients and by 35 (47.9%) of the 73 women using OCPs in the control group. Thus, the odds ratio for early onset LS for women using anti-androgenic OCPs was 2.53 (95% CI: 1.12-5.75). CONCLUSION: Our data suggest that disturbance of the androgen dependent growth of the vulvar skin by OCPs and especially by OCPs with anti-androgenic properties might trigger the early onset of LS in a subgroup of susceptible young women.     

性激素及其受体与食管鳞癌及患者性别年龄的关系

目的探讨性激素及其受体与食管鳞癌(ESCC)及患者性别、年龄的关系。方法选择44例ESCC高发区原发性ESCC患者、60例高发区健康者、60例低发区健康者,采用RIA法检测3组受检者血清雌二醇(E2)、睾酮(T)水平。采用免疫组化法检测≤40岁和>40岁的ESCC手术切除标本中雌激素受体(ER)和孕激素受体(PR)表达;对其中9例标本取4.0～5.0mg癌新鲜组织进行ER蛋白Western印迹分析。结果无论男女,低发区健康组血清T、E2水平与高发区健康者、高发区ESCC组比较,差别均有统计学意义(P<0.05)。男、女ESCC患者中,不同TNM分期、分化程度及淋巴结有无转移者血清T、E2水平间差别无统计学意义(P>0.05)。≤40岁组与>40岁组的PR阳性率间差别有统计学意义(P<0.05)。≤40岁患者ER主要定位于细胞质,>40岁患者主要定位于细胞核。Western印迹分析显示,ESCC组织ER表达位于66kD和67kD条带,但以67kD条带表达更为显著。结论性激素及其受体的变化可能是食管癌变的重要机制,并与患者年龄有关。     

Risks and benefits of hormone replacement therapy

Menopause, the permanent cessation of menstruation, is due to ovarian failure, which may lead to oestrogen deficiency diseases, particularly osteoporosis, cardiovascular disease and cerebrovascular disease. Mortality and morbidity caused by these conditions can be modified by using hormone replacement therapy, but the benefits of this therapy must be weighed against the increased risk of breast cancer and the symptomatic side-effects the treatment may cause. The combination of transdermal oestrogen and natural progesterone offers the most favourable risk-to-benefit profile.     

Norethisterone is bioconverted to oestrogenic compounds that activate both the oestrogen receptor alpha and oestrogen receptor beta in vitro

In the present study, we used [3H]norethisterone to explore the bioconversion of this compound to A-ring reduced metabolites in African Green Monkey Kidney CV-1 cells and breast cancer T-47D cells. Additionally, we analyzed the capability of each norethisterone tetrahydro-reduced compound to bind the human oestrogen receptors alpha and beta and transactivate an oestrogen-sensitive reporter gene. The results showed that norethisterone is mainly metabolized to 3 alpha,5 alpha-norethisterone (>85% of total [3H]norethisterone added) by CV-1 and T-47D cells, and that both A-ring tetrahydro-reduced metabolites exhibit different capabilities to displace [3H]17beta-oestradiol from the oestrogen receptor alpha and beta, being 3 alpha,5 alpha-norethisterone the weakest competitor. We also found that 3 alpha,5 alpha-norethisterone and 3beta,5 alpha-norethisterone activate both oestrogen receptors at nanomolar concentrations and that the transactivation induced by the oestrogen receptor alpha was generally higher (1.7- to 4.0-fold) than that provoked by the beta receptor isoform. In oestrogen receptor alpha-transfected CV-1 and T-47 D cells, the oestrogenic-like potency of the 3beta,5 alpha-tetrahydro-reduced form was similar to that exhibited by 17beta-oestradiol and 2.5- to 4.0-fold higher than that shown by the 3 alpha,5 alpha-reduced compound; conversely, in the oestrogen receptor beta system the potency of the natural ligand was higher than that presented by the 3beta,5 alpha-tetrahydro-reduced metabolite. In CV-1 cells expressing the oestrogen receptor beta, the transactivation potency of 3beta,5 alpha-norethisterone was approximately 2-fold higher than that exhibited by its 3 alpha,5 alpha-tetrahydro-reduced isomer, whereas in T-47D cells the potency of the 3 alpha,5 alpha-tetrahydro-reduced compound was slightly higher than that shown by the 3beta,5 alpha A-ring reduced norethisterone metabolite. These results demonstrate that CV-1 and T-47D cells possess the enzymatic machinery to bioconvert norethisterone into the 5 alpha-reduced, 3 alpha-hydroxylated form and that neither 3 alpha,5 alpha- or 3beta,5 alpha-norethisterone exhibit preference or selectivity towards a particular oestrogen receptor isoform to induce a particular oestrogenic effect in these cell lines.     

Transabdominal evaluation of uterine cervical length during pregnancy fails to identify a substantial number of women with a short cervix

Objective: To assess the diagnostic performance of transabdominal sonographic measurement of cervical length in identifying patients with a short cervix. Methods: Cervical length was measured in 220 pregnant women using transabdominal and transvaginal ultrasound (US). Reproducibility and agreement between and within both methods were assessed. The diagnostic accuracy of transabdominal US for identifying cases with a cervical length <25 mm was evaluated. Results: Twenty-one out of 220 cases (9.5%) had a cervical length <25 mm by transvaginal US. Only 43% (n = 9) of patients with a short cervix were correctly identified by transabdominal US. In patients with a cervical length of <25 mm by transvaginal US, transabdominal measurement of the cervix overestimated this parameter by an average of 8 mm (95% LOAs, ?26.4 to 10.5 mm). Among women without a short cervix, transabdominal US underestimated cervical length on average (LOA) by 1.1 mm (95% LOAs, ?11.0 to 13.2 mm). Transvaginal US was also more reproducible (intraclass correlation coefficient: (ICC) (0.96; 95% CI, 0.94 to 0.97) based on comparisons between 2D images and immediately acquired 3D volume datasets relative to transabdominal US (ICC: 0.71; 95% CI, 0.57 to 0.84). Transvaginal US detected 13 cases with funneling and six cases with sludge whereas only three cases of funneling and one of sludge were detected by transabdominal US. Conclusion: Transabdominal measurement overestimated cervical LOA by 8 mm among women with a short cervix and resulted in the underdiagnosis of 57% of cases.     

Kinetic analysis of the binding of nomegestrol acetate to the progesterone receptors in rat uterus by competition studies

The characteristics of binding (Kinetic and equilibrium binding analysis) of nomegestrol acetate (NOM, 17 alpha-acetoxy-6 alpha-methyl-19-nor-pregna-4.6-diene-3.20-dione) to the progesterone receptor (PgR) in rat uterine cytosolic fraction were determined in comparison to progesterone (P), to fully appreciate the amplitude and specificity of the induced biological response. Since an appropriate radio-labelled form of this steroid molecule was not available, competition studies were performed against the synthetic progestin: [3H]-Organon 2058 [( 3H]-ORG). This allowed a direct comparison between the unlabelled forms of NOM and P, the kinetic constants of which were respectively: Inhibition constant (Ki): 22.8 and 34.3 nM; Association rate constant (k1): 0.39 X 10(3) and 0.21 X 10(3) M-1.s-1; Dissociation rate constant (k-1): 1.81 X 10(-5) and 2.16 X 10(-5) s-1. These results are much more informative than the mere determination of relative binding affinities which only reflect the specificity of the PgR. It was concluded that NOM behaves like the natural hormone in the cytosol of rat uterus.