Phosphodiesterase inhibitors in psychiatric disorders

INTRODUCTION
There are different types of female sexual dysfunctions (FSDs), and FSD in general has a high prevalence worldwide. Studies of FSD should consider it as a multifactorial disorder that has biological, psychological, environmental, and relational aspects. In this review we discuss the available therapeutic interventions for FSD.


EVIDENCE ACQUISITION
For the current narrative review the PUBMED database was searched to identify all publications up to 30 March 2021 that were systematic reviews and meta-analyses which examined therapeutic interventions for FSDs based on the diagnostic classifications of ICD-10 and ICD-11.


EVIDENCE SYNTHESIS
Thirty systematic reviews and meta-analyses were included in this review. Hormone therapy (HT) and testosterone are effective to improve sexual desire in menopausal women. In these women HT and ospemiphene may improve pain during intercourse. Flibanserin may improve sexual desire and may reduce desire-related distress in premenopausal women. Bremelanotide is effective to improve desire, arousal, and orgasm scores. Evidence are still limited on the efficacy of psychoactive drugs, phosphodiesterase type 5 (PDE5), oxytocin, herbal drugs, and tibolone to treat FSDs. Psychological interventions such as cognitive-behavior therapy, mindfulness training, sensate focus, bibliotherapy are effective for the management of several different FSDs.


CONCLUSIONS
The management of FSDs may require multidisciplinary and interdisciplinary approaches. Pharmocological and nonpharmacological interventions appears to have potential as a treatment for FSDs, but there are currently no gold standards regarding recommended treatment modalities, and the duration, frequency, and intensity of therapy sessions.

Female Sexual Dysfunctions: an overview on the available therapeutic interventions.

Objective: Thin endometrium (TE) represents a huge challenge in assisted reproduction, since it is related to decreased endometrial receptivity and consequent implantation failure, negatively affecting reproductive outcomes. The application of mesenchymal stem cells (MSE) has shown promising results, as its regenerative properties improves thickness and expression of receptivity biomarkers in the endometrium. However, the costs and complex processes involved in these treatments prevent its routine aplication. In this context, there is a need to create strategies to stimulate specific stem cell recruitment and migration to tissue injury sites. AMD3100 is a CXCR4 antagonist receptor that disrupts the CXCL12-CXCR4 axis which is directly related to stem cell migration and has been used in tissue regeneration studies to increase the influx of stem cells to the site of injury. In addition, its combined use with β3 adrenergic agonists receptors leads to selective recruitment of MSC with better regenerative results proved in a recent paper on bone fracture healing. Thus, the objective of this study is to evaluate the regenerative potential of AMD3100 alone or in association with a β3 adrenergic agonist receptor in a murine animal model of TE and its impact on the reproductive outcomes. Methods: Experiments were carried out on female C57Bl/6 mice (age 9 weeks; 20 g). TE was induced by direct application of 50 μl of 95% ethanol in the exposed uterus through an abdominal incision, while Phosphate-buffered saline(PBS) was used in the sham procedure (SH). Mice in each group were randomly divided into 3 treatment subgroups (n = 8 for each): (1)PBS(PL); (2)AMD 3100(5 mg/kg sc) single dose after surgery (AMD); (3)BRL37344(rodent-selective β3 adrenergic receptor agonist)(10 mg/kg sc) for 4 consecutive days previous to surgery plus AMD 3100(5 mg/kg sc) single dose (AMD/B3). Two estrous cycles after modeling and treatment, all the groups were mated with proven male C57BL/6 mice. The pregnancy rate and litter size were evaluated in order to establish the impact on the reproductive outcomes. In addition, a macroscopic anatomic analysis was performed on the offspring to evaluate possible teratogenic effects. Results: In relation to pregnancy rate, 23 out of 24 sham mice got pregnant (despite the treatment group). The TE model reproduced the literature results, with under 30% of failure in inducing endometrial damage, represented by a pregnancy rate of 25%(2/8) in the TE+PL group in comparison to all sham groups(p<0.05). The AMD/B3 treatment completely restored the endometrial function, promoting pregnancy rates similar to all sham groups(p>0.05). There was no difference between the TE+AMD treatment group and all the other groups(p>0.05) in terms of pregnancy, although a clinically relevant difference between TE+PL and TE+AMD groups was found(25% versus 62.5%, respectively). The litter size was similar between the treatment groups, except for the TE+AMD group with a smaller number of newborns. Regarding the JBRA Assisted Reproduction 2022;26(1):162-164 doi: 10.5935/1518-0557.20210106

Maternal and neonatal outcomes after frozen , fresh and ovulation induction cycles : are there any differences ?


 
 
 Will the treatment with plerixafor alone or associated with β3 agonist cause endometrial regeneration and consequently improve the reproductive outcome of mice with thin endometrium?
 
 
 
 The combined treatment with plerixafor and β3 agonist improved the reproductive outcomes, indicating a potential therapeutic option for infertility related to thin endometrium.
 
 
 
 Thin endometrium represents a huge challenge in assisted reproduction, since it is related to decreased endometrial receptivity and consequent implantation failure. The treatments with mesenchymal stem cells (MSC) have regenerative properties that improve endometrial thickness and expression of receptivity biomarkers.
 Plerixafor is a CXCR4 antagonist receptor that disrupts the CXCL12-CXCR4 axis, which is directly related to stem cell migration, and has been used in tissue regeneration studies to increase the influx of stem cells to the site of injury. In addition, its combined use with β3 adrenergic agonist receptors leads to selective recruitment of MSC with better regenerative results.
 
 
 
 Experiments were carried out on female C57Bl/6 mice (age 9 weeks; 20g). Forty-eight individuals were assigned for either thin endometrium induction or sham procedure; then, mice in each group were randomly divided into three treatment subgroups (n = 8): (1) Placebo - phosphate-buffered saline, (2) plerixafor, (3) plerixafor and BRL37344 (rodent-selective β3 adrenergic receptor agonist). Two estrous cycles after modelling and treatment, all groups were mated with proven C57Bl/6 male mice for four weeks.
 
 
 
 Thin endometrium was induced by direct injection (50 μl) of 95% ethanol in the surgically exposed uterus, while Phosphate-buffered saline (PBS) was used in the sham procedure. Regarding the treatments, the groups received: (1) PBS (5 mg/kg sc) single-dose after surgery, (2) plerixafor (5 mg/kg sc) single-dose after surgery, (3) BRL37344 (rodent-selective β3 adrenergic receptor agonist) (10 mg/kg sc) for four consecutive days previous to surgery plus plerixafor (5 mg/kg sc) single-dose.
 
 
 
 The pregnancy rate and litter size were analysed in order to establish the impact on the reproductive outcomes. In addition, a macroscopic anatomic analysis was performed on the offspring to evaluate possible teratogenic effects.
 Concerning pregnancy rates, 23 out of 24 sham mice got pregnant (despite the treatment group). The thin endometrium model reproduced the literature results, with under 30% of failure in inducing endometrial damage, represented by a pregnancy rate of 25% (2/8) in the PBS group in comparison to all sham groups (p < 0,05).
 The plerixafor plus β3 agonist treatment completely restored the endometrial function, promoting pregnancy rates similar to all sham groups (p > 0,05). There was no difference between the plerixafor alone group and all the other groups (p > 0.05) in terms of pregnancy, although a clinically relevant difference between placebo and plerixafor alone group was found (25% versus 62,5%, respectively). The litter size was similar between the treatment groups, except for the plerixafor group with a smaller number of newborns. Regarding the teratogenic potential of the tested drugs (plerixafor and β3 agonist), we did not observe any relevant macroscopic malformations (internal and external) in the treated groups.
 
 
 
 There is a need to establish the biological mechanisms responsible for endometrial recovery. Moreover, this study provided treatment for an acute injury; therefore, future work should evaluate the application on long term endometrial damage. The long term effect of the single-dose treatment should also be assessed.
 
 
 
 Our findings indicate a potential therapy for thin endometrium. Plerixafor and β3 agonist treatment resulted in an expressive improvement in reproductive outcomes, without a detrimental impact on offspring. Moreover, this treatment utilises two clinical approved classes of drugs, which could reduce the timeline and cost of translational applications in future.
 
 
 
 not applicable


P-800 Plerixafor for endogenous mobilisation of mesenchymal stem cells to induce endometrial regeneration

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Female Sexual Dysfunctions: an overview on the available therapeutic interventions.

Maternal and neonatal outcomes after frozen , fresh and ovulation induction cycles : are there any differences ?

P-800 Plerixafor for endogenous mobilisation of mesenchymal stem cells to induce endometrial regeneration