Comparison of two synthetic progesterones on ventilation in normal males: CMA vs. MPA

We administered chlormadinone acetate (CMA), medroxyprogesterone acetate (MPA), and placebo to 16 normal male subjects using a randomized double-blind crossover study. After CMA administration, minute alveolar ventilation increased by +1.04 +/- 0.22 (SE) 1/min (P less than 0.05) accompanied by decrements of arterial PCO2 (-4.0 +/- 1.0 Torr) (P less than 0.01) and [HCO3-] (-2.1 +/- 0.05 mM/l) (P less than 0.01). On the other hand, in the MPA runs the corresponding changes of the above parameters were +0.71 +/- 0.21 l/min (P less than 0.05), -2.9 +/- 0.6 Torr (P less than 0.01), and -1.3 +/- 0.3 mM/l (P less than 0.01), respectively. The slopes of hypoxic ventilatory and occlusion pressure response lines remained unchanged in hypocapnia after CMA or MPA ingestion, but they increased when entidal PCO2 was adjusted to the predrug level. The hypercapnic ventilatory and occlusion pressure response lines merely shifted to the left without changing their slopes with these agents. No significant differences in all the above parameters were found between CMA and MPA runs. We concluded that in the normal males the effect of CMA on ventilation was similar to that of MPA, despite the fact that the luteinizing activity of CMA was reported to be approximately 10 times higher than the latter.     

Embryotoxicity of a single dose of medroxyprogesterone acetate (MPA) and maternal serum MPA concentrations in cynomolgus monkey (Macaca fascicularis)

A single dose of MPA (Depo-Provera; Upjohn Co., Kalamazoo, Michigan) was administered intramuscularly to 12 time-mated pregnant cynomolgus monkeys on day 27 (+/- 2) of gestation at 25 mg/kg or at 100 mg/kg. Maternal blood samples were collected immediately prior to MPA injection and then at regular intervals until cesarean section at term (day 152 +/- 3). Infants in both dose groups had external genital abnormalities. Female infants in the low-dose groups had partial or complete labial fusion, prominent median raphe, and clitoral hypertrophy; at high doses (100 mg/kg), the female infants had complete labial fusion and a distinct penile urethra. MPA had an opposite effect on external genitalia of male infants. The penis was short and the scrotal swelling was absent or less conspicuous, and two males had hypospadias. The adrenal glands were significantly smaller (P less than 0.05) in infants of both sexes treated with 100 mg/kg. One of the infants treated with 25 mg/kg of MPA had a muscular ventricular septal defect. Serum concentrations of MPA were determined by radioimmunoassay in eight pregnant monkeys. In the 25 mg/kg group the patterns of MPA profiles in the serum were similar in all four animals. An initial peak occurred at 24-48 hr postinjection (2.7-9.6 ng/ml), followed by a slight decrease at 3 days postinjection (gestational day 30), and then a steady increase to maximum levels of 10-14 ng/ml occurring between gestational days 37 and 50. Serum levels gradually declined to concentrations below 5 ng/ml by midgestation in three of four monkeys. By comparison, both the patterns and magnitude of MPA concentration showed great interanimal variation in the 100 mg/kg group. MPA was present in cord blood at measurable concentrations in infants at both dose groups; the levels ranged from 0.6 to 8.3 ng/ml, corresponding to 40-72% of the maternal concentrations. These results demonstrate that a single injection of MPA during early pregnancy causes selective embryotoxicity in both male and female fetuses. Presence of high levels of MPA in maternal sera during the critical period of genital development can cause specific genital defects; however, the exact mechanism by which MPA causes these paradoxical genital abnormalities is unknown.     

MPA and postmenopausal coronary artery atherosclerosis revisited

Whether progestins, particularly medroxyprogesterone acetate (MPA), attenuate the cardiovascular benefits of postmenopausal estrogen replacement therapy (ERT) has been controversial for over a decade. Concerns related first to findings that MPA attenuated increases of high density lipoprotein cholesterol (HDLC) concentrations of postmenopausal women compared to conjugated equine estrogen (CEE) alone. That observation was followed by early cynomolgus monkey studies that suggested MPA decreased estrogen's cardiovascular benefits (vascular reactivity and coronary artery atherosclerosis inhibition). In a more recent and larger trial with cynomolgus monkeys, no differences were seen in the coronary artery atherosclerosis protective effect of CEE when MPA was co-administered (HRT). The lack of attenuation of ERTs benefits by progestins has also been seen in at least three studies of carotid artery intima-media thickness (IMT) of postmenopausal women. Additionally, the majority of studies of vascular reactivity of postmenopausal women have not found differences when CEE is given alone or with MPA. Seven observational studies of cardiovascular outcomes of postmenopausal women permit separate consideration of ERT versus HRT use; there is no evidence of attenuation of ERTs benefits by progestin use. In conclusion, it is evident that the current experimental, clinical, and observational data do not provide evidence that progestins attenuate estrogen's cardiovascular benefits.     

Excretion of MPA in the milk of lactating ewes treated for synchronization of estrus

Ten mature lactating ewes of the Chios island breed 3.5 +/- 0.5 (Mean +/- SEM) yr of age and weighing 51.9 +/- 1.6 kg (Mean +/- SEM) were synchronized for estrus with intravaginal sponges impregnated with 60 mg 6a-methyl-17-acetoxyprogesterone (MPA). The sponges remained in place for 14 d and 500 IU im PMSG were injected at their withdrawal. Daily milk samples (3 d pretreatment, 14 d on treatment, and 5 d posttreatment) were collected and analyzed by a double antibody RIA procedure for MPA. The concentration of MPA (Mean +/- SEM) in the milk increased to 5.05 +/- 0.11 ng/ml within the first day of sponge insertion, then declined and remained at a constant level (3.08 +/- 0.26 ng/ml) while the sponge was in place, eventually dropping to the background level (0.65 +/- 0.05 ng/ml) 24 h following sponge withdrawal. The curve for the quantity of MPA excreted in the milk was identical to that of MPA concentrations, showing significant differences among experimental days and among ewes. Finally, there was a significant relationship between milk production and MPA excretion into the milk (r = +0.581( * *)). It is concluded that only a very small percentage (0.08 +/- 0.01) of MPA contained in each sponge is excreted into the milk from the moment of sponge insertion until 5 d after its removal.     

安宫黄体酮在药物流产后治疗阴道流血的效果观察

目的：探讨药物流产术后阴道流血时间延长患者的最佳治疗方式。方法：2005．1～2006．12我院门诊就诊孕32～49天,自愿要求药物终止妊娠的健康妇女,口服药物流产,孕囊排出后仍有少量阴道流血达到或超过半月者,彩超证实宫腔内有少量蜕膜残留（残留面积〈1cm^2）,给予安宫黄体酮保守治疗者75例为观察组,同期同等条件行清宫术者50例为对照组。结果：两组年龄、孕周、阴道流血时间及宫腔残留物比较,无统计学差异。结论：安宫黄体酮,通过子宫内膜撤退性出血,起到了药物性刮宫的作用。     

Metabolism of medroxyprogesterone acetate (MPA) via CYP enzymes in vitro and effect of MPA on bleeding time in female rats in dependence on CYP activity in vivo

Medroxyprogesterone acetate (MPA) is a drug commonly used in endocrine therapy for advanced breast cancer, although it is known to cause thrombosis as a serious side effect. Recently, we found that cytochrome P450 3A4 (CYP3A4) mainly catalyzed the metabolism of MPA via CYP in human liver microsomes. However, the metabolic products of MPA in humans and rats have not been elucidated. In addition, it is not clear whether thrombosis could be induced by MPA itself or by its metabolites. In this study, we determined the overall metabolism of MPA as the disappearance of the parent drug from an incubation mixture, and identified the enzymes catalyzing the metabolism of MPA via CYP in rats. Moreover, the effects of CYP-modulators on MPA-induced hypercoagulation in vivo were examined. Intrinsic clearance of MPA in rat liver microsomes was increased by treatment with CYP3A-inducers. The intrinsic clearance of MPA in liver microsomes of rats treated with various CYP-inducers showed a significant correlation with CYP3A activity, but not CYP1A activity, CYP2B activity or CYP2C contents. Among the eight recombinant rat CYPs studied, CYP3A1, CYP3A2 and CYP2A2 catalyzed the metabolism of MPA. However, since CYP3A2 and CYP2A2 are male-specific isoforms, CYP3A1 appears to be mainly involved in the metabolism of MPA in liver microsomes of female rats. In an in vivo study, pretreatment of female rats with SKF525A, an inhibitor of CYPs including CYP3A1, significantly (p < 0.05) enhanced MPA-induced hypercoagulation, whereas pretreatment with phenobarbital, an inducer of CYPs including CYP3A1, reduced it. These findings suggest that CYP-catalyzed metabolism of MPA is mainly catalyzed by CYP3A1 and that MPA-induced hypercoagulation is predominantly caused by MPA itself in female rats.     

High conservation of the differentially amplified MPA2 satellite DNA family in parthenogenetic root-knot nematodes

Sequence variability and distribution of a newly characterized MPA2 satellite DNA family are described in five root-knot nematode species of the genus Meloidogyne, the mitotic parthenogens M. paranaensis, M. incognita, M. arenaria and M. javanica, and the meiotic/mitotic M. hapla (isolates A and B, respectively). The lack of distinctive mutations and the considerable contribution (40.8%) of ancestral changes disclose an ancient satellite DNA which existed in the common ancestor of extant parthenogenetic species in the same or similar form and remained preserved for a period of at least 43 My. Nonuniformly distributed polymorphic sites along the satellite monomer suggest differences in constraints acting on particular sequence segments. Sequence diversity is clearly unaffected by significant differences in genomic abundance of the MPA2 satellite DNA in the examined species. Observed results suggest that the dynamics of this satellite DNA family might be in the first instance a consequence of characteristics of its nucleotide sequence and possible constraints imposed on it. Under conditions of mitotic and meiotic parthenogenesis, slow accumulation of mutations and slow replacement of old MPA2 sequence variants with new ones may be equivalent to the dynamics of some satellite DNA sequences conserved for extremely long evolutionary periods in sexual species.     

Evolving MPA Management in New Zealand: Between Principle and Pragmatism

In January 2016 New Zealand released a consultation document proposing a new act on marine protected areas designed to significantly reform current and now dated policy. This article explores those reform proposals in the context of the current regulatory regime, international obligations, and the best practice of selected other states. While the proposed act provides for a much firmer legislative base from which to develop an MPA network to conserve biodiversity and ecosystem function, nevertheless it is limited in geographic and functional scope. As such, it represents a missed opportunity and undermines New Zealand's claims to be an international leader in ocean management.     

南麂列岛海洋保护区浮游动物调查

主要研究南麂列岛海洋保护区浮游动物种类组成、数量分布、多样性指数、浮游动物与浮游植物动态变化及浮游动物数量变化与营养盐的关系。经鉴定共发现,浮游动物98种,主要有2个生态类群:(1)暖温带近海类群,优势种有中华哲水蚤(Calanus sinicus)、中华假磷虾(Pseudeuphausia sinicas)、五角水母(Muggiaea atlantica)、百陶箭虫(Sagitta bedoti)、拿卡箭虫(S.nagae)等;(2)暖水性外海类群,代表性种类有肥胖箭虫(S.enflata)、精致真刺水蚤(Euchaeta concinna)等。结果表明,8月份南麂列岛浮游动物生物量和丰度出现最高值,9、10月份逐渐减少,多样性指数变化范围1.78~4.38,平均3.99;保护区内浮游动物数量与浮游植物细胞密度呈良好的正相关关系,与氮含量呈负相关关系。     

中街山列岛海洋保护区鱼类物种多样性

基于2010-2012年在中街山列岛海洋保护区进行的8个航次底拖网调查数据资料,从鱼类分类学和生态类群等方面,结合多样性、资源密度和相对重要性指数,对该保护区鱼类物种多样性特征进行了分析。调查海域共采集鱼类55种,隶属2纲12目32科44属。其中,鲈形目鱼类26种,占47.3%;趋礁性鱼类41种,占74.5%;暖温性、暖水性和冷温性鱼类分别为30、24和1种,其中暖水种约占所有偶见种的70%;定居种、近海洄游种和季节性种分别为27、24和24种;底层、近底层和中上层鱼类分别占40.0%、36.4%和23.6%,其中矛尾鰕虎鱼(Chaeturichthys stigmatias)、龙头鱼(Harpodon nehereus)和鳀科鱼类分别成为各水层的绝对优势种。所有调查站点鱼类平均生物量指数夏季最高(1043.7 kg/km²),春季最低;尾数密度指数春季最高(122×10³ 尾/km²),冬季最低;生物量与尾数密度指数最高与最低季节之间均存在显著性差异(P<0.05)。对多样性的分析显示,Margalef丰富度(D)冬季最高,秋季最低,Shannon-Wiener多样性(H')与Pielou均匀度(J')均为夏季最高,秋季最低。聚类和NMDS方法分析显示不同季节鱼类群落组成格局差异极显著(P<0.01)。研究结果表明,中街山列岛海洋保护区鱼类资源结构受近海季节性洄游种类影响较大,鱼类分布季节动态多呈现洄游性更替节律,保护区内虽已出现鱼类多样性下降趋势和生态系统功能退化现象,传统经济种类的优越性在逐渐下降或边缘化,但独特的岛礁生境仍能很好地发挥着维持固有种类和提供良好栖息场所的优势,随着海洋牧场建设与一系列资源保护与修复措施,石首鱼科幼体已形成优势群体,而且保护区内出现大量小型饵料鱼类。     

MPA increases idarubicin-induced apoptosis in chronic lymphatic leukaemia cells via caspase-3

The caspase family of protease is speculated to have a crucial role in apoptosis. The effect of treatment with Idarubicin (IDA) and Medroxyprogesterone acetate (MPA), used alone or in combination, on the activation of Caspase-3 in canine Chronic Lymphatic Leukaemia (CLL) cells was investigated, in order to clarify the mechanism of chemo- and hormone-therapy mediated apoptosis. Caspase activity was determined by a quantitative fluorimetric assay. Apoptosis was monitored by propidium iodide (PI) and nucleosomes assay. Treatment of CLL cells for 24 h with MPA 5 microM did not significantly activate caspase-3 but its activity was increased almost 5-fold more with IDA 1 microM (P < 0.05) than control. Treatment of CLL cells with IDA 1 microM in equimolecular association with MPA was able to increase the activation of caspase-3 induced by IDA of the 61.2% (P < 0.05) in comparison with IDA alone. The activation of caspase-3 was confirmed evaluating apoptosis by PI and nucleosomes assay. Furthermore, both caspase-3 activation and apoptosis triggered by IDA alone or in combination with MPA were significantly inhibited by specific caspase-3 inhibitor AC-DEVD-CMK. These findings provide an explanation for IDA and MPA induced-apoptosis mechanism.     

Antitumor effects of combination toremifene and medroxyprogesterone acetate (MPA) in vitro and in vivo

The estrogen (ER) and progesterone (PgR) receptor levels in various gynecological tumors were measured. The same tumors were exposed in vitro to toremifene, MPA or their combination and the growth of the tumors was followed by measuring the adenosine triphosphate (ATP) within the cells by a simple bioluminescence assay. Altogether 34 clinical samples were studied. DMBA-induced mammary tumors bearing rats were treated in vivo with toremifene, MPA and their combination. About half of the ovarian cancers and 6 out of the 7 adenocarcinomas of uteri contained ER. The ovarian tumors were PgR rich in 25% and adenocarcinomas of uteri in 6 out of the 7 cases. When compared to control toremifene (concentration 1 mumol/l) was able to decrease the number of living cells to 50% or less in 9/34 samples, MPA (concentration 10 mumol/l) in 17/34 samples, and the combination in 25/34 samples. In five cases the antitumor effect of the combination was synergistic. In two cases signs of weak antagonism were seen. In vivo the antitumor effect of toremifene and MPA was clearly synergistic against DMBA-induced cancers. The effect was dose-dependent and at sufficiently high doses it was possible to eradicate the tumors and cure the animals.     

Refuges and risks: Evaluating the benefits of an expanded MPA network for mobile apex predators

Aim

Concurrently, assessing the effectiveness of marine protected areas and evaluating the degree of risk from humans to key species provide valuable information that can be integrated into conservation management planning. Tiger sharks (Galeocerdo cuvier) are a wide‐ranging ecologically important species subject to various threats. The aim of this study was to identify “hotspots” of tiger shark habitat use in relation to protected areas and potential risks from fishing.

Location

Southwest Indian Ocean, east coast of South Africa and Mozambique.

Methods

Satellite tags were fitted to 26 tiger sharks. A subset of 19 sharks with an average period at liberty of 197 (SD = 110) days were analysed using hotspot analysis to identify areas of core habitat use. The spatial and temporal overlap of significant hotspots with current and planned marine protected areas as well as risks from fishing and culling was then calculated.

Results

There was a 5.97% spatial overlap between tiger shark hotspots and marine protected areas, which would increase significantly (p < .05) to 24.36% with the expansion of planned protected areas in South Africa and could be as high as 41.43% if Mozambique similarly expanded neighbouring protected area boundaries. Tiger sharks remained largely coastal, but only showed a spatial overlap of 5.12% with shark culling nets in South Africa. Only three sharks undertook open ocean migrations during which they were more likely to interact with longline fisheries in the region.

Main conclusions

This study demonstrates how spatial information can be used to assess the overlap between marine protected areas and the core habitats of top marine predators and highlights how congruent transnational conservation management can improve the effectiveness of protected areas. Core habitat use of marine apex predators may also be indicative of productive habitats, and therefore, predators such as tiger sharks could act as surrogate species for identifying key habitats to prioritize for conservation planning.

     

In vitro functions of lymphocytes during high-dose medroxyprogesterone acetate (MPA) treatment

Summary The number and function of T and B lymphocytes were studied in endometrial cancer patients during 3 months' treatment with high-dose medroxyprogesterone acetate (MPA). No significant changes were observed in the proportions of T and B cells or in the function of B cells during MPA treatment. At 3 months, lymphocyte blastogenic responsiveness to mitogens was slightly reduced both in patients treated with standard therapy alone (intracavitary radium and surgery) and in patients receiving additional MPA therapy. These results indicate that other factors than progesterone are responsible for the suppression of lymphocyte blastogenesis induced by mitogens during high-dose progestin treatment.     

褪黑素联合MPA抑制子宫内膜异常增生的作用及机制研究

摘要 目的：探索褪黑素联合MPA（醋酸甲羟孕酮）对子宫内膜异常增生细胞增殖活性的抑制作用及其机制。方法：取分化良好的子宫内膜增生细胞株Ishikawa和内膜癌细胞株ECC1于适宜条件培养,加入褪黑素、MPA单独或者联合处理48 h后,检测子宫内膜细胞株的增殖活性。收集褪黑素、MPA单独或者联合处理48 h后的子宫内膜增生细胞株Ishikawa细胞,提取细胞内的蛋白,检测人20α-羟基类固醇脱氢酶（AKR1C1）的表达情况。结果：褪黑素和MPA联合使用后对子宫内膜异常增生细胞的抑制作用明显高于褪黑素或MPA单独使用。褪黑素和MPA可抑制AKR1C1的表达,二者联合使用对AKR1C1的抑制高于两者单独使用。结论：褪黑素可提高子宫内膜异常增生细胞对MPA的敏感性,降低MPA的使用剂量,同时抑制AKR1C1的表达,使孕酮的代谢速率降低。褪黑素与MPA联合使用给子宫内膜增生和内膜癌的治疗策略带来新的思路。