Update on 3-iodothyronamine and its neurological and metabolic actions

3-iodothyronamine (T1AM) is an endogenous amine, that has been detected in many rodent tissues, and in human blood. It has been hypothesized to derive from thyroid hormone metabolism, but this hypothesis still requires validation. T1AM is not a ligand for nuclear thyroid hormone receptors, but stimulates with nanomolar affinity trace amine-associated receptor 1 (TAAR1), a G protein-coupled membrane receptor. With a lower affinity it interacts with alpha2A adrenergic receptors. Additional targets are represented by apolipoprotein B100, mitochondrial ATP synthase, and membrane monoamine transporters, but the functional relevance of these interactions is still uncertain. Among the effects reported after administration of exogenous T1AM to experimental animals, metabolic and neurological responses deserve special attention, because they were obtained at low dosages, which increased endogenous tissue concentration by about one order of magnitude. Systemic T1AM administration favored fatty acid over glucose catabolism, increased ketogenesis and increased blood glucose. Similar responses were elicited by intracerebral infusion, which inhibited insulin secretion and stimulated glucagon secretion. However, T1AM administration increased ketogenesis and gluconeogenesis also in hepatic cell lines and in perfused liver preparations, providing evidence for a peripheral action, as well. In the central nervous system, T1AM behaved as a neuromodulator, affecting adrenergic and/or histaminergic neurons. Intracerebral T1AM administration favored learning and memory, modulated sleep and feeding, and decreased the pain threshold. In conclusion T1AM should be considered as a component of thyroid hormone signaling and might play a significant physiological and/or pathophysiological role. T1AM analogs have already been synthetized and their therapeutical potential is currently under investigation. 3-iodothyronamine (T1AM) is a biogenic amine whose structure is closely related to that of thyroid hormone (3,5,3′-triiodothyronine, or T3). The differences with T3 are the absence of the carboxylate group and the substitution of iodine with hydrogen in 5 and 3′ positions (Figure 1). In this paper we will review the evidence supporting the hypothesis that T1AM is a chemical messenger, namely that it is an endogenous substance able to interact with specific receptors producing significant functional effects. Special emphasis will be placed on neurological and metabolic effects, which are likely to have physiological and pathophysiological importance

Mass spectrometry in the diagnosis of thyroid disease and in the study of thyroid hormone metabolism

The importance of thyroid hormones in the regulation of development, growth, and energy metabolism is well known. Over the last decades, mass spectrometry has been extensively used to investigate thyroid hormone metabolism and to discover and characterize new molecules involved in thyroid hormones production, such as thyrotropin-releasing hormone. In the earlier period, the quantification methods, usually based on gas chromatography-mass spectrometry, were complicated and time consuming. They were mainly focused on basic research, and were not suitable for clinical diagnostics on a routine basis. The development of the modern mass spectrometers, mainly coupled to liquid chromatography, enabled simpler sample preparation procedures, and the accurate quantification of thyroid hormones, of their precursors, and of their metabolites in biological fluids, tissues, and cells became feasible. Nowadays, molecules of physiological and pathological interest can be assayed also for diagnostic purposes on a routine basis, and mass spectrometry is slowly entering the clinical laboratory. This review takes stock of the advancements in the field of thyroid metabolism that were carried out with mass spectrometry, with special focus on the use of this technique for the quantification of molecules involved in thyroid diseases

Perineal and robot-assisted vesico-urethral reconstruction for anastomotic strictures after RP

Vesico-urethral anastomotic stricture (VUAS) following radical prostatectomy is a rare clinical condition in the robot-assisted procedure era, due to the improved magnification of the surgical field and the perfect knowledge of the anatomic structures deputed to maintaining the mechanisms for urinary continence. Improvements in surgical technique such as muco-mucosal apposition, tension-free anastomosis, water-tight vesico-urethral suture, have been recognized as significant contributors to precise vesico-urethral reconstruction. Conversely, excessive intraoperative blood loss, urinary extravasation and previous history of trans-urethral prostatectomy have been commonly cited as predisposing factors for the development of postoperative scars. Terminology used in the definition of VUAS distinguishes the condition from bladder neck contracture (BNC) and identifies the exact site of the contracture/stenosis/stricture. The majority of cases involves the bladder neck and bulbo-membranous urethra mainly in patients who received radical prostatectomy plus adjuvant radiotherapy. Diagnosis of VUAS is mainly based on symptoms and retrograde urethro-cystogram imaging to identify whether or not the sphincter mechanism is involved and the length of the strictured segment, although delineation of the precise anatomy is often complex. Stricture length is a significant factor for prognosis and correlates with probability of recurrence after reparative surgeries such as urethral dilation, trans-urethral scar incision or resection and perineal urethral buccal mucosa repair. Results obtained via different surgical techniques are amply described, with the hindrance of VUAS and BNC often not being properly distinguished in the reported series of patients treated. Notwithstanding, a 0 to 69% success rate has been reported for patients with bladder neck stricture after urethral dilation and/or cold-knife incision and/or holmium laser incision and/or trans urethral resection, while a 60 to 93% success rate was obtained for patients treated via an abdominal and/or perineal approach. Repair of a long-length urethral stricture often implies the complete loss of urinary continence, whilst it does not appear to have significant impact on sexual potency if previously preserved. The risk of developing VUAS/BNC as a complication after radical prostatectomy falls from 30% of patients treated by Retropubic Radical Prostatectomy (RRP) to less than 5% of patients who received Robotic Assisted Radical Prostatectomy (RARP). Subjects with a histological diagnosis of T3 cancer, positive surgical margins and/or Gleason score >7 and treated by RARP who required early adjuvant radiotherapy, reported an overall 8.4% rate of VUAS. Lavollè et al. treated six patients with anastomotic stricture who had previously undergone radical prostatectomy by extraperitoneal robot-assisted vesico-urethral reconstruction obtaining a 50% success rate. Dinerman et al. presented a case report on a patient with long-length post prostatectomy vesico-urethral stricture by combining robotic-abdominal and open-perineal surgical procedure. The combined abdomino-perineal approach allows to provide “complete” scar removal and a new vesico-urethral anastomosis at a lower risk of developing subsequent recurrences of the stricture also in patients with long-length strictures. An extensive dissection of the bladder neck and bulbo-membranous urethra does imply the complete loss of urinary continence, that can however be recovered through subsequent or concomitant artificial sphincter implant. This novel combined technique was adopted on a series of three patients of whom two previously treated by RARP and one by RRP

The Role of a Multidisciplinary Approach in Gender Affirmation Surgery: What to Expect and Where Are We Currently?

Gender Affirmation Surgeries (GASs), erstwhile called Sex Reassignment Surgeries (SRSs), may be necessary for transgender individuals to change their bodily sexual characteristics and thereby affirm their gender identity. GASs encompass all medically necessary interventions to relieve gender dysphoria and should be available to patients who wish to, and who meet the surgical criteria of the World Professional Association for Transgender Health (WPATH) and Standards of Care (SOC). The comprehensive clinical assessment involves many health specialists, including general practitioners, psychologists, psychiatrists, speech therapists, endocrinologists, surgeons, anesthesiologists, nurses, and other healthcare professionals. To define the patients’ complex care needs and their objectives, high-volume specialized centers, accredited training programs, skilled surgeons and health professionals specializing in transgender care within a multidisciplinary team are essential. Currently, the most prominent challenges are related to ethical issues such as the treatment of underage individuals, fertility, parenting and the potential for regret after GAS. Finally, although GAS has been practiced for more than half a century, data on long-term follow-up represents a further topic for investigation

16 years follow-up evaluation of immediate vs delayed vs. combined hormonal therapy on fertility of patients with cryptorchidism: results of a longitudinal cohort study

To investigate in a longitudinal cohort study, the best treatment to preserve fertility in cryptorchid subjects. Patients treated with immediate hormonal vs. delayed vs. combined (hormone plus surgery) therapy consecutively enrolled during the period 1987-1997, were evaluated

Clinical use of hyaluronic acid in andrology: A review

Hyaluronic acid is a glycosaminoglycan widely used in the fields of orthopedics, ophthalmology, and aesthetic medicine due to its significant ability to reduce the synthesis of pro-inflammatory proteins and its activity against oxidative stress, a feature of many degenerative illnesses

The effect of high glucose on the inhibitory action of C21, a selective AT2R agonist, of LPS-stimulated tissue factor expression in human mononuclear cells

Background: Intimate links connect tissue factor (TF), the principal initiator of the clotting cascade, to inflammation, a cross-talk amplified by locally generated Angiotensin (AT) II, the effector arm of the Renin Angiotensin System (RAS). C21, a selective AT2R agonist, downregulates the transcriptional expression of TF in LPS-activated peripheral blood mononuclear cell(PBMC)s implying the existence of ATII type 2 receptor (AT2R)s whose stimulation attenuates inflammation-mediated procoagulant responses. High glucose, by activating key signalling pathways and increasing the cellular content of RAS components, augments TF expression and potentiates the inhibitory effect of AT1R antagonists. It is unknown, however, the impact of that stimulus on AT2R-mediated TF inhibition, an information useful to understand more precisely the role of that signal transduction pathway in the inflammation-mediated coagulation process. TF antigen (ELISA), procoagulant activity (PCA, 1-stage clotting assay) and TF-mRNA (real-time polymerase chain reaction) were assessed in PBMCs activated by LPS, a pro-inflammatory and procoagulant stimulus, exposed to either normal (N) or HG concentrations (5.5 and 50 mM respectively). Results: HG upregulated TF expression, an effect abolished by BAY 11-7082, a NFκB inhibitor. C21 inhibited LPS-stimulated PCA, TFAg and mRNA to an extent independent of glucose concentration but the response to Olmesartan, an AT1R antagonist, was quite evidently potentiated by HG. Conclusions: HG stimulates LPS-induced TF expression through mechanisms completely dependent upon NFkB activation. Both AT2R-stimulation and AT1R-blockade downregulate inflammation-mediated procoagulant response in PBMCs but HG impacts differently on the two different signal transduction pathway

Metabolic profiling reveals reprogramming of lipid metabolic pathways in treatment of polycystic ovary syndrome with 3-iodothyronamine

Complex diseases such as polycystic ovary syndrome (PCOS) are associated with intricate pathophysiological, hormonal, and metabolic feedbacks that make their early diagnosis challenging, thus increasing the prevalence risks for obesity, cardiovascular, and fatty liver diseases. To explore the crosstalk between endocrine and lipid metabolic pathways, we administered 3-iodothyronamine (T1AM), a natural analog of thyroid hormone, in a mouse model of PCOS and analyzed plasma and tissue extracts using multidisciplinary omics and biochemical approaches. T1AM administration induces a profound tissue-specific antilipogenic effect in liver and muscle by lowering gene expression of key regulators of lipid metabolism, PTP1B and PLIN2, significantly increasing metabolites (glucogenic, amino acids, carnitine, and citrate) levels, while enhancing protection against oxidative stress. In contrast, T1AM has an opposing effect on the regulation of estrogenic pathways in the ovary by upregulating STAR, CYP11A1, and CYP17A1. Biochemical measurements provide further evidence of significant reduction in liver cholesterol and triglycerides in post-T1AM treatment. Our results shed light onto tissue-specific metabolic vs. hormonal pathway interactions, thus illuminating the intricacies within the pathophysiology of PCOS. This study opens up new avenues to design drugs for targeted therapeutics to improve quality of life in complex metabolic diseases