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Physiological Reviews Apr 2024Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine... (Review)
Review
Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both cyclic nucleotides are critical secondary messengers in the neurohormonal regulation in the cardiovascular system. PDEs precisely control spatiotemporal subcellular distribution of cyclic nucleotides in a cell- and tissue-specific manner, playing critical roles in physiological responses to hormone stimulation in the heart and vessels. Dysregulation of PDEs has been linked to the development of several cardiovascular diseases, such as hypertension, aneurysm, atherosclerosis, arrhythmia, and heart failure. Targeting these enzymes has been proven effective in treating cardiovascular diseases and is an attractive and promising strategy for the development of new drugs. In this review, we discuss the current understanding of the complex regulation of PDE isoforms in cardiovascular function, highlighting the divergent and even opposing roles of PDE isoforms in different pathogenesis.
Topics: Humans; Phosphoric Diester Hydrolases; Cardiovascular Diseases; Phosphodiesterase Inhibitors; Cyclic AMP; Cyclic GMP; Protein Isoforms; Diethylstilbestrol
PubMed: 37971403
DOI: 10.1152/physrev.00015.2023 -
American Family Physician May 2004Diethylstilbestrol is a synthetic nonsteroidal estrogen that was used to prevent miscarriage and other pregnancy complications between 1938 and 1971 in the United... (Review)
Review
Diethylstilbestrol is a synthetic nonsteroidal estrogen that was used to prevent miscarriage and other pregnancy complications between 1938 and 1971 in the United States. In 1971, the U.S. Food and Drug Administration issued a warning about the use of diethylstilbestrol during pregnancy after a relationship between exposure to this synthetic estrogen and the development of clear cell adenocarcinoma of the vagina and cervix was found in young women whose mothers had taken diethylstilbestrol while they were pregnant. Although diethylstilbestrol has not been given to pregnant women in the United States for more than 30 years, its effects continue to be seen. Women who took diethylstilbestrol during pregnancy have a slightly higher risk of breast cancer than the general population and therefore should be encouraged to have regular mammography. Women who were exposed to diethylstilbestrol in utero may have structural reproductive tract anomalies, an increased infertility rate, and poor pregnancy outcomes. However, the majority of these women have been able to deliver successfully. Recommendations for gynecologic examinations include vaginal and cervical digital palpation, which may provide the only evidence of clear cell adenocarcinoma. Initial colposcopic examination should be considered; if the findings are abnormal, colposcopy should be repeated annually. If the initial colposcopic examination is normal, annual cervical and vaginal cytology is recommended. Because of the higher risk of spontaneous abortion, ectopic pregnancy, and preterm delivery, obstetric consultation may be required for pregnant women who had in utero diethylstilbestrol exposure. The male offspring of women who took diethylstilbestrol during pregnancy have an increased incidence of genital abnormalities and a possibly increased risk of prostate and testicular cancer. Routine prostate cancer screening and testicular self-examination should be encouraged.
Topics: Breast Neoplasms; Diethylstilbestrol; Estrogens, Non-Steroidal; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Male; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 15168959
DOI: No ID Found -
International Journal of Environmental... Mar 2018Natural steroidal and synthetic non-steroidal estrogens such as 17β-estradiol (E2) and diethylstilbestrol (DES) have been found in natural water, which can potentially...
Natural steroidal and synthetic non-steroidal estrogens such as 17β-estradiol (E2) and diethylstilbestrol (DES) have been found in natural water, which can potentially endanger public health and aquatic ecosystems. The removal and biodegradation of E2 and DES by were studied in bacteria-free cultures exposed to single and mixture treatments at different concentrations for 96 h. The results showed that exhibited a rapid and strong ability to remove E2 and DES in both single and mixture treatments by biodegradation. At the end of 96 h, the removal percentage of single E2 and DES achieved 82.0%, 80.4%, 74.6% and 89.9%, 73.4%, 54.1% in 0.1, 0.5, and 1.5 mg·L, respectively. With the exception of the 0.1 mg·L treatment at 96 h, the removal capacity of E2 was more efficient than that of DES by . Furthermore, the removal percentage of mixture E2 and DES achieved 88.5%, 82.9%, 84.3% and 87.2%, 71.8%, 51.1% in 0.1, 0.5, and 1.5 mg·L, respectively. The removal percentage of mixed E2 was significantly higher than that of the single E2. The presence of DES could accelerate the removal of E2 from the mixture treatments in equal concentrations. In addition, the removal was mainly attributed to the biodegradation or biotransformation process by the microalgae cells rather than simple sorption and accumulation in the cells. The microalgae demonstrated a high capability for the removal of the E2 and DES indicating future prospects for its application.
Topics: Adsorption; Biodegradation, Environmental; Chlorophyta; Diethylstilbestrol; Estradiol; Estrogens, Non-Steroidal; Fresh Water; Microalgae; Water Pollutants, Chemical
PubMed: 29510598
DOI: 10.3390/ijerph15030452 -
Cancer Epidemiology, Biomarkers &... Oct 2021The influence of prenatal diethylstilbestrol (DES) exposure on cancer incidence among middle-aged men has not been well-characterized. We investigated whether exposure...
BACKGROUND
The influence of prenatal diethylstilbestrol (DES) exposure on cancer incidence among middle-aged men has not been well-characterized. We investigated whether exposure to DES before birth impacts overall cancer risk, and risk of site-specific cancers.
METHODS
Men (mean age in 2016 = 62.0 years) who were or were not prenatally DES exposed were identified between 1953 and 1994 and followed for cancer primarily via questionnaire approximately every 5 years between 1994 and 2016. The overall and site-specific cancer rates of the two groups were compared using Poisson regression and proportional hazards modeling with adjustment for age.
RESULTS
DES exposure was not associated with either overall cancer [hazard ratio (HR), 0.94; 95% confidence interval (CI), 0.77-1.15] or total prostate cancer rates (HR, 0.95; 95% CI, 0.68-1.33), but was inversely associated with urinary tract cancer incidence (HR, 0.48; 95% CI, 0.23-1.00).
CONCLUSIONS
There was no increase in either overall or prostate cancer rates among men prenatally DES exposed relative to those unexposed. An unexpected risk reduction was observed for urinary system cancers among the exposed relative to those unexposed. These findings suggest that prenatal DES exposure is unlikely to be an important contributor to cancer development in middle-aged men.
IMPACT
The results of this study could lend reassurance to middle-aged men who were prenatally DES exposed that their exposure does not adversely influence their overall cancer risk.
Topics: Diethylstilbestrol; Female; Humans; Incidence; Male; Middle Aged; Neoplasms; Pregnancy; Prenatal Exposure Delayed Effects; Risk
PubMed: 34272263
DOI: 10.1158/1055-9965.EPI-21-0234 -
British Medical Journal (Clinical... Mar 1985
Topics: Adenocarcinoma; Aged; Bone Neoplasms; Castration; Diethylstilbestrol; Humans; Male; Middle Aged; Prostatectomy; Prostatic Neoplasms
PubMed: 3919825
DOI: 10.1136/bmj.290.6472.875 -
Toxicological Sciences : An Official... Aug 2023Significant decreases in fertility have been observed over the past 50 years, with female conception rates dropping by 44% and male sperm counts decreasing by over...
Significant decreases in fertility have been observed over the past 50 years, with female conception rates dropping by 44% and male sperm counts decreasing by over 50%. This dramatic decrease in fertility can be attributed in part to our increasing exposure to endocrine disrupting chemicals (EDCs). Diethylstilbestrol (DES) is an estrogenic EDC that was prescribed to millions of pregnant women between 1940 and 1970 and resulted in detrimental reproductive effects in the offspring that were exposed in utero. Women who were exposed to DES in utero experienced higher rates of infertility, pregnancy complications, and reproductive cancers. Alarmingly, there is evidence to suggest that these effects may persist in the grandchildren and great grandchildren of exposed women. To define the transgenerational reproductive impacts in females following exposure to DES, gestating mice were exposed to DES and the effects monitored in the female descendants across 3 generations. There was a trend for reduced pregnancy rate and fertility index seen across the generations and moreover, the anogenital distance (AGD) was significantly reduced up until the third, unexposed generation. The onset of puberty was also significantly affected, with the timing of vaginal opening occurring significantly earlier in DES descendants. These results indicate a transgenerational effect of DES on multiple reproductive parameters including fertility, timing of puberty, and AGD. These data have significant implications for more than 50 million DES descendants worldwide as well as raising concerns for the ongoing health impacts caused by exposures to other estrogenic EDCs which are pervasive in our environment.
Topics: Pregnancy; Female; Male; Humans; Mice; Animals; Diethylstilbestrol; Prenatal Exposure Delayed Effects; Semen; Fertility; Reproduction
PubMed: 37471692
DOI: 10.1093/toxsci/kfad066 -
The Cochrane Database of Systematic... Sep 2017Sickle cell disease comprises a group of genetic haemoglobin disorders. The predominant symptom associated with sickle cell disease is pain resulting from the occlusion... (Review)
Review
BACKGROUND
Sickle cell disease comprises a group of genetic haemoglobin disorders. The predominant symptom associated with sickle cell disease is pain resulting from the occlusion of small blood vessels by abnormally 'sickle-shaped' red blood cells. There are other complications, including chronic organ damage and prolonged painful erection of the penis, known as priapism. Severity of sickle cell disease is variable, and treatment is usually symptomatic. Priapism affects up to half of all men with sickle cell disease, however, there is no consistency in treatment. We therefore need to know the best way of treating this complication in order to offer an effective interventional approach to all affected individuals.
OBJECTIVES
To assess the benefits and risks of different treatments for stuttering (repeated short episodes) and fulminant (lasting for six hours or more) priapism in sickle cell disease.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 15 September 2017.Date of most recent search of trial registries and of Embase: 12 December 2016.
SELECTION CRITERIA
All randomised or quasi-randomised controlled trials comparing non-surgical or surgical treatment with placebo or no treatment, or with another intervention for stuttering or fulminant priapism.
DATA COLLECTION AND ANALYSIS
The authors independently extracted data and assessed the risk of bias of the trials.
MAIN RESULTS
Three trials with 102 participants were identified and met the criteria for inclusion in this review. These trials compared stilboestrol to placebo, sildenafil to placebo and ephedrine or etilefrine to placebo and ranged in duration from two weeks to six months. All of the trials were conducted in an outpatient setting in Jamaica, Nigeria and the UK. None of the trials measured our first primary outcome, detumescence but all three trials reported on the reduction in frequency of stuttering priapism, our second primary outcome. No significant effect of any of the treatments was seen compared to placebo. Immediate side effects were not found to be significantly different from placebo in the two trials where this information was reported. We considered the quality of evidence to be low to very low as all of the trials were at risk of bias and all had low participant numbers.
AUTHORS' CONCLUSIONS
There is a lack of evidence for the benefits or risks of the different treatments for both stuttering and fulminant priapism in sickle cell disease. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions for priapism in sickle cell disease.
Topics: Anemia, Sickle Cell; Diethylstilbestrol; Estrogens, Non-Steroidal; Humans; Male; Priapism
PubMed: 28926088
DOI: 10.1002/14651858.CD004198.pub3 -
The Cochrane Database of Systematic... 2003Laboratory evidence in the 1940s demonstrated a positive role of placental hormones in the continuation of pregnancy. It was suggested that diethylstilbestrol was the... (Review)
Review
BACKGROUND
Laboratory evidence in the 1940s demonstrated a positive role of placental hormones in the continuation of pregnancy. It was suggested that diethylstilbestrol was the oestrogen of choice for prevention of miscarriages. Observational studies were carried out with apparently positive results, on which clinical practice was based. This led to a worldwide usage of diethylstilbestrol despite controlled studies with contrary findings.
OBJECTIVES
To determine the effects of antenatal administration of oestrogens, mainly diethylstilbestrol, on high risk and unselected pregnancy as regards miscarriages and other outcomes.
SEARCH STRATEGY
We searched the Pregnancy and Childbirth Group Specialised Register of controlled trials in November 2002.
SELECTION CRITERIA
Randomised and quasi-randomised trials were included.
DATA COLLECTION AND ANALYSIS
Both reviewers extracted data from the studies identified that met the selection criteria, and the data were analysed using the RevMan software.
MAIN RESULTS
Miscarriage, preterm labour, low birthweight and stillbirth or neonatal death were not positively influenced by the intervention (diethylstilbestrol) as compared to the control group. Diethylstilbestrol in utero exposure led to increased rate of miscarriage and preterm birth. There was also an increase in the numbers of babies weighing less than 2500 grams. The maternal outcome in terms of pre-eclampsia was not influenced. Exposed female offsprings have a non-significant trend towards more cancer of the genital tract and cancer other than of the genital tract. Primary infertility, adenosis of the vagina/cervix in female offsprings, and testicular abnormality in male offsprings were significantly higher in those exposed to diethylstilbestrol before birth.
REVIEWER'S CONCLUSIONS
There was no benefit with the use of diethylstilbestrol in preventing miscarriages. Both short and long-term adverse outcomes in exposed offsprings were demonstration of the harm that this intervention caused women and their offspring during its usage.
Topics: Abortion, Spontaneous; Diethylstilbestrol; Estrogens, Non-Steroidal; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Obstetric Labor, Premature; Pregnancy; Pregnancy Outcome
PubMed: 12918007
DOI: 10.1002/14651858.CD004353 -
International Journal of Environmental... Sep 2021Psychiatric disorders in children exposed in utero to diethylstilbestrol (DES) are still debated. We report here the impact of DES prescribed to suppress lactation on...
BACKGROUND
Psychiatric disorders in children exposed in utero to diethylstilbestrol (DES) are still debated. We report here the impact of DES prescribed to suppress lactation on the children born after such treatment and their progeny, focusing particularly on psychiatric disorders.
CASE PRESENTATION
We report here an informative family in which one or more psychiatric problems (e.g., bipolarity, suicide attempts and suicide, eating disorders) were detected in all children of second-generation (DES-exposed children; = 9), but for II-2 who died at the age of 26 years due to rupture of a congenital brain aneurysm, and were associated with non-psychiatric disorders (particularly, endometriosis and hypospadias). In the third generation, 10 out of 19 DES-exposed grandchildren had psychiatric disorders (autism spectrum disorder, bipolar disorder, dyspraxia and learning disabilities, mood and behavioral disorders, and eating disorders), often associated with comorbidities. In the fourth generation (7 DES-exposed great-grandchildren, aged between 0 and 18 years), one child had dyspraxia and autism spectrum disorder. The first daughter of the second generation (not exposed to DES) and her children and grandchildren did not have any psychiatric symptoms or comorbidities.
CONCLUSIONS
To our knowledge, the high prevalence of psychiatric disorders of various severities in two, and likely three generations, including DES-free pregnancies and DES-exposed pregnancies from the same family, has never been reported. This work strengthens the hypothesis that in utero exposure to DES contributes to the pathogenesis of psychiatric disorders. It also highlights a multigenerational, and possibly transgenerational, effect of DES in neurodevelopment and psychiatric disorders.
Topics: Adolescent; Autism Spectrum Disorder; Child; Child, Preschool; Diethylstilbestrol; Female; Humans; Hypospadias; Infant; Infant, Newborn; Male; Mental Disorders; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 34639263
DOI: 10.3390/ijerph18199965 -
The Journal of Biological Chemistry Dec 1985Diethylstilbestrol is carcinogenic in rodents and in humans and its peroxidatic oxidation in utero has been associated with its carcinogenic activity. Horseradish...
Diethylstilbestrol is carcinogenic in rodents and in humans and its peroxidatic oxidation in utero has been associated with its carcinogenic activity. Horseradish peroxidase-catalyzed oxidation of [14C]diethylstilbestrol and [14C]diethylstilbestrol analogs induced binding of radiolabel to DNA only when the compound contained a free hydroxy group (Metzler, M., and Epe, B. (1984) Chem. Biol. Interact. 50, 351-360). We have found that horseradish peroxidase or prostaglandin-H synthase-catalyzed oxidation of diethylstilbestrol in the presence of the spin trap 5,5-dimethyl-1-pyrroline-N-oxide caused the generation of an ESR signal indicative of a free radical intermediate (aN = 14.9 G, aH = 18.3 G). The identity of the trapped radical could not be identified on the basis of published hyperfine coupling constants, but the observation that horseradish peroxidase-catalyzed oxidation of 1-naphthol produced an identical ESR signal suggests that the radical was either a phenoxy or phenoxy-derived radical. During horseradish peroxidase-catalyzed oxidation of diethylstilbestrol in the presence of glutathione the thiol reduced the diethylstilbestrol radical to generate a thiyl radical. This was shown by a thiol-dependent oxygen uptake during horseradish peroxidase-catalyzed oxidation of diethylstilbestrol and the observation of an ESR signal consistent with 5,5-dimethylpyrroline-N-oxide-glutathionyl radical adduct formation. A diethylstilbestrol analog devoid of free hydroxy groups, namely diethylstilbestrol dipropionate, did not produce an ESR signal above control levels during horseradish peroxidase-catalyzed metabolism in the presence of 5,5-dimethylpyrroline-N-oxide. Thus, free radicals are formed during peroxidatic oxidation of diethylstilbestrol and must be considered as possible determinants of the genotoxic activity of this compound.
Topics: Carbon Radioisotopes; Diethylstilbestrol; Electron Spin Resonance Spectroscopy; Free Radicals; Glutathione; Horseradish Peroxidase; Oxygen Consumption; Peroxidases; Prostaglandin-Endoperoxide Synthases
PubMed: 2999150
DOI: No ID Found