Ricerc@Sapienza

TART cells were historically thought to be derived from adrenocortical cells undergoing migration within the gonads during embryonic development. However, the origin of TARTs has recently been traced to pluripotent cells already present in utero, most likely Leydig cells¿ fetal precursors originating from the urogenital ridge. Early and prolonged exposure to high ACTH levels appears to be necessary for the transformation of such pluripotent cells into TARTs: their prevalence is significantly higher in severe forms of CAH, characterized by higher ACTH levels. Furthermore, inadequate compliance to glucocorticoid (GC) treatment, as well as GC underdosing, have been proven to stimulate TART growth. On the other hand, ACTH suppression following intensified GC treatment has demonstrated to induce TART regression in some, but not all the patients treated. Several case reports have identified TARTs in other conditions characterized by strongly elevated ACTH concentrations from early childhood, such as Addison¿s disease, Cushing's syndrome and Nelson's syndrome. Conversely, TARTs have never been observed in adult male patients with high ACTH concentrations due to bilateral adrenalectomy, further suggesting that early exposure to ACTH is necessary for the proliferation of pluripotent cells into TART. Moreover, increasing evidence seems to indicate that other molecules may be involved in the growth of adrenal rest tumors, as TART cells also express receptors for angiotensin II and LH. Most notably, the physiological rise of LH during puberty may play a significant role in TART growth, thus explaining their higher prevalence during adolescence, whereas the pathogenetic role of angiotensin II has yet to be analysed in detail.
To date, the therapeutic management of TARTs is still the subject of extensive scientific debate, especially since there are no clear guidelines in this regard. According to the most recent recommendations, the first-line treatment of these lesions consists in increasing glucocorticoid dose to suppress ACTH levels. This approach seems to have greater efficacy in the early stages of development of TARTs. Furthermore, it is not clear whether the contribution of corticosteroid therapy to the shrinkage of TARTs is due to the increase in the total dose of glucocorticoids, the anti-circadian administration of the same or the use of long-acting steroid-based formulations (dexamethasone rather than prednisone). However, supraphysiological GC doses not always lead to a significant improvement in seminal parameters and, importantly, increase the risk of undesired GC effects, such as arterial hypertension, striae rubrae, weight gain, reduction of target height in adolescents. The potential advantages of a therapeutic regimen based on standard dose of long-acting steroid formulations are still being debated, although some cases of tumor regression and restoration of fertility are reported. This opens question for patients¿ individualized therapeutic approach, especially since biomarkers for treatment monitoring are currently lacking. In this regard, we will develop low-cost, highly sensitive and selective immunosensors and impedance-based biosensors based on single-wall and multi-wall carbon nanotubes and on chemically derived graphene for the ultrasensitive detection of cortisol levels. A core innovation of this project is the use of electrode modification via metal nanoparticles (NPs), as their electrochemical signal amplifications can greatly increase biosensor sensitivities, as well as lower their detection limits for cortisol levels, leading to highly sensitive ¿in vivo¿ biosensing.
The resulting continuous readout of cortisol levels will provide useful information for the clinician, allowing the optimization of GC treatment on an individualized basis.
In conclusion, this study could provide useful information regarding the optimal glucocorticoid treatment for the management of TARTs, shedding new light on the optimal timing, dosage and formulation to employ in order to achieve tumor shrinkage and, potentially, improvement in seminal parameters. Furthermore, by focusing on young men of reproductive age for our cohort, we aim to ascertain whether several factors ¿ including age of TART onset, disease control, hormonal levels, previous GC treatment during childhood ¿ can be identified as possible predictors for response to medical treatment. In this context, the assessment of serum Angiotensin-II levels might represent a novel promising disease marker to target in the treatment strategies. Our study will give important information about the andrological management of males with classic-CAH during reproductive age, and even more those burdened with TARTs, whose experience reduced fertility and fatherhood rates, all responsible for reduced quality of life.