Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pentoxifylline, an inhibitor of cAMP phosphodiesterase activity, favours intracellular cAMP concentration increase. In-vitro treatment of semen with pentoxifylline leads to marked augmentation of sperm motility, enhancement of acrosome reaction, increase of sperm penetration into zona-free hamster oocytes, and protection of the sperm plasma membrane. Such properties indicate that the drug may be a useful tool for semen preparation in assisted reproduction, but its real effectiveness in improving fertilization rates is still uncertain, mainly in association with intrauterine insemination (IUI). Theoretically sperm motility should play an extremely important role for positive results in IUI. Therefore, a retrospective clinical trial was planned in order to evaluate whether addition of pentoxifylline to the previously standardized in-vitro treatment of semen had improved the percentage of pregnancies after homologous IUI. The study involved 55 sterile couples (33 classified infertile for male factor and 22 for other factors) who underwent a total of 150 cycles of homologous IUI: 101 for male factor infertility and 49 for other factors (anovulation n = 26, endometriosis n = 2, idiopathic n = 21). Out of the 101 cycles performed for male factor infertility, 61 underwent the standard preparation of semen and were followed by seven pregnancies (pregnancy rate = 11.5%) while 40 had a semen preparation with pentoxifylline addition and were followed by 11 pregnancies (pregnancy rate = 27.5%) with a significant difference between the two procedures (P < 0.05). Out of the 49 cycles carried out for factors different from male infertility, 10 underwent the standard preparation of semen and were followed by two pregnancies (pregnancy rate = 20.0%), while 39 had pentoxifylline addition and were followed by nine pregnancies (pregnancy rate = 23.1%). The difference between the two groups was not significant. Abortions and malformations were equally distributed in the standard treatment and in the pentoxifylline group.
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PMID:Effectiveness of pentoxifylline in semen preparation for intrauterine insemination. 867 31

Sperm protein tyrosine phosphorylation has been associated with capacitation, motility changes, zona binding, and fertilizing ability. We previously demonstrated that gradient-isolated human sperm subpopulations differ in their plasma membrane composition, their ability to phosphorylate proteins in tyrosine residues, and their capacity to undergo hyperactivation. In this study, we have characterized capacitation-associated changes in protein tyrosine phosphorylation and membrane fluidity in spermatozoa of asthenozoospermic and normozoospermic patients consulting for infertility. Semen samples were studied at baseline and after a capacitating incubation with or without the addition of a permeable cAMP analog and a phosphodiesterase inhibitor. Basic sperm and computer-assisted motion parameters, hyperactivation, protein tyrosine phosphorylation (immunofluorescence and Western blot), and membrane fluidity (fluorescent Laurdan probe) were the main study parameters. In comparison with normozoospermic and proven-fertile donor semen, asthenozoospermic samples showed lower motility, velocity, and amplitude of lateral head displacement, both originally and after a 6-h capacitating incubation. Unlike those in normal samples, asthenozoospermic spermatozoa were unable to increase protein tyrosine phosphorylation during capacitation. Such impairment, however, was overcome when they were incubated with a membrane-permeable cAMP analog and a phosphodiesterase inhibitor, indicating a possible membrane defect. Confirming this hypothesis, plasma membranes of asthenozoospermic sperm showed decreased fluidity (increased Laurdan polarization), even after a capacitating incubation. In conclusion, spermatozoa from functional asthenozoospermic samples may owe their poor motility, and their inability to properly capacitate and develop hyperactivation, to an impairment in the tyrosine phosphorylation of critical proteins caused by decreased membrane fluidity. These findings suggest a molecular pathogenetic mechanism for a common seminal pathology associated with male infertility.
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PMID:Capacitation-associated protein tyrosine phosphorylation and membrane fluidity changes are impaired in the spermatozoa of asthenozoospermic patients. 1592 85

The aim of this review study is to elucidate the effects that phosphodiesterase 5 (PDE5) inhibitors exert on spermatozoa motility, capacitation process and on their ability to fertilize the oocyte. Second messenger systems such as the cAMP/adenylate cyclase (AC) system and the cGMP/guanylate cyclase (GC) system appear to regulate sperm functions. Increased levels of intracytosolic cAMP result in an enhancement of sperm motility and viability. The stimulation of GC by low doses of nitric oxide (NO) leads to an improvement or maintenance of sperm motility, whereas higher concentrations have an adverse effect on sperm parameters. Several in vivo and in vitro studies have been carried out in order to examine whether PDE5 inhibitors affect positively or negatively sperm parameters and sperm fertilizing capacity. The results of these studies are controversial. Some of these studies demonstrate no significant effects of PDE5 inhibitors on the motility, viability, and morphology of spermatozoa collected from men that have been treated with PDE5 inhibitors. On the other hand, several studies demonstrate a positive effect of PDE5 inhibitors on sperm motility both in vivo and in vitro. In vitro studies of sildenafil citrate demonstrate a stimulatory effect on sperm motility with an increase in intracellular cAMP suggesting an inhibitory action of sildenafil citrate on a PDE isoform other than the PDE5. On the other hand, tadalafil's actions appear to be associated with the inhibitory effect of this compound on PDE11. In vivo studies in men treated with vardenafil in a daily basis demonstrated a significantly larger total number of spermatozoa per ejaculate, quantitative sperm motility, and qualitative sperm motility; it has been suggested that vardenafil administration enhances the secretory function of the prostate and subsequently increases the qualitative and quantitative motility of spermatozoa. The effect that PDE5 inhibitors exert on sperm parameters may lead to the improvement of the outcome of assisted reproductive technology (ART) programs. In the future PDE5 inhibitors might serve as adjunct therapeutical agents for the alleviation of male infertility.
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PMID:Effects of phosphodiesterase-5 inhibitors on sperm parameters and fertilizing capacity. 1808 51

Obesity is a highly prevalent non-communicable disease worldwide and is commonly associated with male infertility. Several etiopathological theories have been mentioned in the literature by which obesity affects spermatogenesis, thus affecting the male fertility potential. Mechanisms for explaining the effect of obesity on male infertility include endocrinopathy, increased aromatization activity, associated erectile dysfunction, psychological and thermal effects, obstructive sleep apnea, increased leptin and oxygen free radicals, and associated inflammatory and obstructive elements of epididymitis. Treatment of such a complex problem includes weight reduction (by lifestyle modification and increased physical activity), optimization of altered testosterone-to-estradiol ratio using aromatase inhibitors and/or gonadotropins, treatment of associated comorbidities by phosphodiesterase inhibitors for erectile dysfunction, and insulin-sensitizing agents for the management of diabetes. The aim of this mini-review is to highlight the pathological basis of this problem and to focus on obesity as an etiology of male infertility.
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PMID:Obesity, An Enemy of Male Fertility: A Mini Review. 2946 92

Sildenafil has had a dramatic influence on the field of sexual medicine over the past 20 years. Not only have phosphodiesterase-5 (PDE5) inhibitors improved the treatment of erectile dysfunction (ED), they have indirectly contributed to the treatment of male factor infertility. A review of the literature between 1998 - 2018 was performed using PubMed with regards to sildenafil and male infertility. Numerous studies have demonstrated sildenafil's safety and efficacy for treating ED. Sildenafil does not alter semen parameters, and, in fact, may positively affect semen parameters. Sildenafil is helpful for treating ED caused by the psychological stress of infertility treatments. Sildenafil has improved the treatment of ED and may have a benefit on semen parameters. This has aided in the management of male factor infertility, and has contributed to hundreds of thousands of pregnancies that would have been more difficult, as it was before its advent.
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PMID:Sildenafil's impact on male infertility: what has changed in 20 years? 3083 20

Intracytoplasmic sperm injection (ICSI) is frequently used to overcome severe deficits in semen quality. Concerns, however, are arising over its increasing use for non-male factor infertility. Moreover, increased risk of cardiovascular disease, congenital abnormalities, aneuploidies and childhood cancers have all been reported in the literature in relation to ICSI and it is possible that the quality of sperm chosen for injection may be an important factor in these unwanted outcomes. Given the wider adoption of ICSI to treat beyond the requirements of male infertility alone, research focussed on alternative methods to diagnose and treat the infertile couple is gaining increasing attention. This review focuses on the information available to date on the use of non-selective phosphodiesterase inhibitors (PDEI), specifically pentoxifylline (PF), caffeine (CF) and theophylline (TP) to stimulate sperm motility, thereby potentially reducing the need for ICSI in certain patient groups who may benefit from either expectant management or from a less stressful, minimally invasive and inexpensive treatment such as intrauterine insemination (IUI). The review focuses firstly on the mechanism of action of PDEI followed by treatment effects on sperm parameters such as motility and hyperactivated motility and sperm DNA integrity. Specific clinical implications are discussed that outline the potential role of PDEI in clinical practice and highlights areas in need of further research.
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PMID:Is there a role for phosphodiesterase inhibitors in the treatment of male subfertility? 3266 51